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501 Manual – Conducting Human Research

501 Manual – Conducting Human Research

This manual is immediately in effect. HRPO will consider all feedback received regarding content and will revise information, as appropriate.

The information in this manual and associated guidance documents reflect HRPO's current thinking on a topic and does not establish legal responsibilities unless specific regulatory or statutory requirements are cited.

IMPORTANT: For studies relying on an external IRB, researchers must comply with the external IRB's requirements.

Please email comments or questions to: HRPO@hhrinstitute.org

Contents

1. Research personnel considerations

2. Requests for IRB review

3. Using Cayuse HE

4. Requests for IRB reliance

5. Recruiting and screening study participants

6. Obtaining informed consent

7. Research with special populations

8. Children in research

9. Privacy and confidentiality

10. HIPAA

11. FDA definitions and regulations

12. Drugs in research

13. Devices in research

14. Humanitarian Use Devices (HUDs)

15. Expanded access

16. Emergency research

17. OEQCR guidance on clinical research evaluations

18. OEQCR guidance on study conduct and management

GLOSSARY

Revision history

Version date Summary of substantive revisions
01 AUG 2022 1.6: Clarifications/updates to CITI and OEQCR education/training requirements

2.2: Updates to ancillary review requirements to match existing IRB process; add column Impact on IRB Review or Approval

3.5: Clarifications to describe continuing review requirements pre-2018 vs. post-2018 common rule

New - 5.7: Can I use Care Everywhere for Research?

New - 5.10: How should I document screening of subjects? (EQ Guidance)

7.10: Addition of reference to requirement for study staff to obtain fluency certification to bulleted list of researcher responsibilities; updates to instructions for how to obtain language certification and mirrors guidance recently shared by EQ

7.11: Clarifications to bulleted list and additional of table Short form consent – Who signs what? Add reference to impact on HIPAA authorization when using short form

New - 7.12: How do researchers obtain HIPAA Authorization for non-English speakers?

New - 9.5: What are some ways to protect the security and confidentiality of research data? (EQ Guidance)

New chapter – 17: OEQCR guidance on clinical research evaluation (EQ guidance)

New chapter – 18: OEQCR guidance on study conduct and management (EQ guidance

25 APR 2022 Origination

1. Research personnel considerations

The Principal Investigator acknowledges these responsibilities:

  • Acknowledge and accept responsibility for protecting the rights and welfare of human research subjects and conduct the research in compliance with the Federalwide Assurance (FWA) and in accordance with the IRB approved protocol, applicable federal regulations and state/local laws.
  • The Principal Investigator (PI) may choose to delegate certain tasks to other IRB-approved study personnel. However, task delegation does not relieve the PI of primary responsibility for overseeing and ensuring compliance with all requirements pertaining to the research.
  • Will not make the final determination of exemption from applicable Federal regulations or provisions of the Hennepin Healthcare FWA. Upon review, the Hennepin Healthcare IRB will determine exemption status.
  • Report any actual or perceived conflict of interest involving human research to the HHRI Conflict of Interest Committee and IRB and will abide by the conflict of interest management mitigation plan as approved by the Conflict of Interest Committee and IRB.
  • Will not start human research activities until final IRB approval is received and until all other required institutional approvals, including department/division approval, are obtained.
  • Ensure adequate resources to carry out the research safely. This includes, but is not limited to, sufficient investigator time, appropriately qualified research team members, equipment, and space.
  • Ensure that research staff are qualified (e.g., including but limited to appropriate training, education, expertise, credentials and, when relevant, privileges) to perform procedures assigned to them during the study.
  • Appropriately manage and maintain all study records and signed consent documents. All study records and signed consent documents must be retained for a minimum of three years beyond the study completion date and as required by applicable regulations and/or award terms and conditions for the approved research.
  • Recruit subjects in a fair and equitable manner.
  • Will not accept or provide payments to professionals in exchange for referrals of potential subjects (finder’s fees).
  • Will not accept payments designed to accelerate recruitment that were tied to the rate or timing of enrollment (bonus payments).
  • Provide a copy of the current IRB-approved, informed consent document to each subject at the time of consent, unless the IRB has specifically waived this requirement.
  • Submit all proposed changes in previously approved research to the IRB. The proposed changes may not be initiated without review and approval. Changes where necessary to eliminate apparent immediate hazards to the subjects that have not been approved prior to initiation must be reported in accordance with IRB requirements.
  • Complete Renewal submissions as required to maintain ongoing IRB approval.
  • Complete Incident submissions in accordance with IRB reporting criteria and timelines.
  • Will allow access to their study records as needed to complete study reviews, audits, or investigations initiated by the OEQCR or IRB, or any other applicable agencies with regulatory or legal purview.
  • Ensure that if subjects enrolled in protocols under their direction are transferred to another institution and continued participation in the research protocol is anticipated, the IRB, office of grants and contracts, and other appropriate officials at both institutions will be notified in a timely manner. If the transfer of research subjects is a planned occurrence in the research protocol, the investigator is responsible for ensuring that the new institution possesses an OHRP-approved FWA.
  • If the study is a clinical trial and supported by a Common Rule agency, an IRB-approved version of a consent form that has been used to enroll research participants must be posted on ClinicalTrials.Gov or a public federal website designated for posting such consent forms by the awardee or the federal department or agency component conducting the trial. The form must be posted after recruitment closes and no later than 60 days after the last study visit.
  • For externally-sponsored research, investigator is responsible for understanding and complying with sponsor requirements in addition to the requirements outlined in this section.
  • No research investigator who is obligated by the provisions of the Hennepin Healthcare FWA, any associated inter-institutional amendment, or IRB authorization agreement will seek to obtain research credit for, or use data from, patient interventions that constitute the provision of emergency medical care without prior IRB approval.  A physician may provide emergency medical care to a patient without prior IRB review and approval, to the extent permitted by law; however, such activities will not be considered research nor will the data be used in support of research.

Every research study requires a Principal Investigator (PI). The PI is ultimately responsible for all aspects of research including the responsibility for the oversight of all staff to whom tasks are delegated and for the fiscal management of the research.  The PI is expected to conduct research in accordance with the IRB approved research plan. In addition to complying with all applicable regulatory policies and standards, PIs must comply with organizational and administrative requirements for conducting research.

To serve as PI on an IRB submission, an individual must be:

  • Affiliated with HHS/HHRI (defined as employed at HHS or HHRI);
  • Qualified by experience, education, and training to conduct research at HHS/HHRI (i.e., a terminal degree such as MD or PhD in a scientific field);
  • A fellow or medical resident who is participating in a program that has a clinical affiliation agreement with HHS (requires a Hennepin Healthcare mentor/advisor) IMPORTANT: A fellow or medical resident cannot serve in a PI role for research involving HHRI as IND/IDE holder

The IRB considers investigator qualifications when reviewing research and may determine that an investigator may not serve as PI or may require the addition of other investigators, for example, to supplement the expertise available on the research team or to conduct or oversee certain research activities.

The following may not serve as PI on an IRB submission:

  • Individuals who are not HHS/HHRI employees or participating in a program with a clinical affiliation agreement with HHS;
  • RNs, therapists, or technicians who do not hold an advanced degree/advanced research training may not serve as sole PI for non-exempt research;
  • Persons who are debarred, disqualified, or otherwise restricted from participation in research or as a recipient of grant funds for research by a federal, state, or other agency may not serve as PI;
  • Persons with a history of compliance issues related to the conduct of research (e.g., recipients of an FDA Warning Letter; investigators whose research approval has been suspended or terminated by an IRB for serious or continuing noncompliance) will be considered on a case-by-case basis. Factors to consider include whether corrective actions have been accepted by the FDA as adequate, whether information from an audit or quality review indicate that the issues have been resolved, and similar considerations.

Under limited circumstances, HRPO in collaboration with HHS/HHRI leadership may approve an exception to PI eligibility criteria.
To request an exception, follow the instructions on the 306 FORM PI eligibility exception request

A change in PI must be approved by the IRB prior to initiating the change. Note that such a change often requires changes to other aspects of the study. Review all consent/assent forms, recruitment materials and other documents to manage updates accordingly. The current PI may transfer responsibility to a new PI by submitting a Modification in Cayuse HE.  The new PI’s role is effective only after the Modification submission has been approved by the IRB.

What happens if the principal investigator abruptly goes on leave or departs the institution without transferring responsibility for his or her studies?

Not all transitions can be anticipated. If a PI goes on an unanticipated leave or there is an abrupt departure from Hennepin Healthcare, follow the steps below to request changing the PI. 

  • The department head/division chief prepares a letter on official letterhead to the IRB explaining the circumstances of the leave, identifying the current PI and study number, and naming the new PI. 
  • The study primary contact (PC) prepares the modification in Cayuse HE to change the PI (and may request other changes, as applicable).
  • When the Modification is complete, email HRPO@hhrinstitute.org to request administrative certification.

OR

  • If there is no appropriate replacement for the PI and the department/division wishes to close the study, the study PC may complete a Closure submission in Cayuse HE or email HRPO@hhrinstitute.org to request administrative closure. Include a letter from the department head/division chief stating that the PI is no longer affiliated with Hennepin Healthcare and that no further study activities will be conducted.

NOTE: If the study does not include a PC other than the PI, please contact HRPO at HRPO@hhrinstitute.org.

In order to ensure adequate oversight, an advisor must be listed in Cayuse HE when a fellow or resident serves in the role of PI. As an advisor, you are ultimately responsible for the conduct of research initiated by your advisee. In serving as an advisor, you assure the IRB of the following:

  • You have thoroughly reviewed the proposed research study;
  • The topic and design of the study are appropriate for a fellow or resident;
  • The fellow or resident has the necessary experience and training to conduct the research;
  • You will meet with the resident or fellow on a regular basis to monitor study progress;
  • If the study procedures are carried out in a location away from HHS or regular channels of communication are not feasible, you will make alternate arrangements to continue communication with the resident or fellow;
  • The resident or fellow will adhere to all requirements for continuing review;
  • If the resident or fellow leaves HHS, you will provide all necessary documents for terminating the study or continuing review; and
  • If you will be unavailable, you will arrange for an alternate advisor to assume the above responsibilities and will advise the IRB of this change.

All personnel involved in human research activities conducted under the auspices of HHS (including ceded studies) must be listed in the Cayuse HE study record, either in the Initial submission or a subsequent Modification submission. Study personnel must be approved by the Hennepin Healthcare IRB prior to their involvement in human research activities.

Human research activities include any of the following:

  • Interacting with human subjects (e.g., conducting informed consent processes, manipulating a subject’s environment for research purposes, conducting invasive or non-invasive research procedures)
  • Collecting, reporting, or analyzing identifiable subject data, or
  • Providing direct oversight of research involving human subjects or human subjects’ private information
  • Being listed on FDA Form 1572 (Statement of Investigator) even if human research activities do not otherwise apply. Note: If you are listing study staff (e.g., Manager, Coordinator, RA, etc.) as Sub-investigators on the FDA Form 1572, it’s important to identify them by their functional study role (i.e., not as a Sub-investigator) on other internal documents (e.g., DOA logs, training logs, etc.) and in the Hennepin Healthcare other personnel section of Study Personnel in Cayuse HE 
  • Functions outside of regular work practice to conduct research (e.g., student administering research testing)*

*Activities in which an individual is functioning within regular work practice and involvement in the research is limited to only those work practices with no other contribution to the research may be considered standard of care activities (i.e., non-engagement in research) and such individuals should not be listed as study personnel.

Examples of activities that may be considered non-engagement in research:

  • a physician providing clinical care and referring potential participants to a research study
  • a phlebotomist collecting blood for research tests following standard practice, when it is not the intervention being evaluated
  • an x-ray technician following standard practice performing an x-ray for research, when it is not the intervention being evaluated

See 107 GUIDANCE or consult with HRPO for assistance in determining engagement.

Only individuals affiliated with Hennepin Healthcare may be added as study personnel. If you’re unable to add an individual in a submission using the Cayuse Person Finder, please email HRPO@hhrinstitute.org to request a Cayuse account for the individual. IMPORTANT: for individuals not listed in the HHRI or HHS company directory, provide documentation of their affiliation with Hennepin Healthcare.  Visit the HRPO website for information regarding the onboarding requirements for non-employees in order to list them as study personnel.

All study personnel are expected to understand and adhere to all applicable laws, regulations, standards, and requirements that pertain to research and clinical trials.

There are training and education requirements for all personnel involved in human research activities. The Hennepin Healthcare IRB may modify minimum training and education requirements when deemed appropriate for approval criteria.

NOTE: Training and education requirements do NOT apply to Humanitarian Use Device (HUD), expanded access, or emergency use submissions.

Personnel roles

Key personnel: Hennepin Healthcare employees who are essential to carrying out the work of a project, typically those responsible for the design, conduct, and/or reporting of the research, e.g., principal investigators/project directors, mentors/advisors, and co-investigators

Other personnel: Hennepin Healthcare employees such as staff, coordinators, assistants, and non-employee research collaborators (NRCs)who are involved in research activities involving human subjects, such as recruitment, ongoing coordination of activities, data management, etc.

 

Requirements based on research role

Role

Online coursework

OEQCR training

CITI Program

HHRI
Human Subjects Protection

HHRI Research

Consent Competency

Bloodborne Pathogens

Hazardous Materials

Shipping

Phlebotomy

Key personnel

R

R

if research is non-exempt

N/A

N/A

N/A

N/A

N/A

Other personnel

R

N/A

R

if research is non-exempt

R

if role involves consenting

R

if role involves biospecimen handling

R

if role involves biospecimen shipping

R

if role involves phlebotomy

R= Required; N/A = Not Applicable

Online coursework

See 401 CHECKLIST Required education for IRB approval for CITI Program requirements for all personnel according to the type of research being conducted and the Hennepin Healthcare Human Subjects Protection online training required for key personnel.

OEQCR consent competency training

Individuals identified as non-key personnel (i.e., other personnel) who have been delegated the task of obtaining informed consent as part of their study role, regardless of level of experience, must complete a one-time, interactive session with the HHRI Office of Education and Quality in Clinical Research (OEQCR) on conducting the informed consent process. This training must be completed before conducting informed consent activities. Contact OEQCR at EQ@hhrinstitute.org to schedule training for new staff and/or to review requirements and practice of the informed consent process for any study personnel.

Consent competency training involves the following:

  • Introduction to the informed consent process
  • Review of mock consent form and demonstration of starting and conducting the informed consent process
  • Small group practice with techniques and documentation of the informed consent process
  • OEQCR feedback

NOTE: Shadowing and mentorship is important for new study personnel to be successful in building confidence in their approach and knowing that they are properly conducting informed consent.

OEQCR phlebotomy competency assessment

Individuals identified as non-key personnel (i.e., other personnel) who have been delegated phlebotomy tasks as part of their study roles, regardless of level of experience, must annually pass a Phlebotomy Safety and Competency Assessment with the HHRI Office of Education and Quality in Clinical Research (OEQCR). This competency assessment must be completed/current prior to performing phlebotomy research activities. Contact OEQCR at EQ@hhrinstitute.org to schedule training for new staff and/or to review requirements and phlebotomy practices for any study personnel.

If a licensed medical professional is an HHS employee and will perform phlebotomy as part of standard of care and also perform phlebotomy for research purposes, they do not need to complete the phlebotomy assessment.

The Phlebotomy Safety and Competency Assessment involves the following:

  • Watching instructional videos
  • Technique instruction by an OEQCR staff member
  • Practice on an artificial arm until comfortable with technique
  • If needed:
    • Further practice on artificial arm, with or without OEQCR staff offering guidance
    • Supervised live venipuncture performance with other employee(s) who are up to date on the Phlebotomy Safety and Competency requirements
    • Supervised live venipuncture performance with OEQCR staff, if available and willing
  • Competency assessment by OEQCR staff of venipuncture performance on live volunteer
  • Successful completion of written Phlebotomy Knowledge Check

OEQCR will notify the supervisor of outcomes of the assessment, e.g., whether an individual is competent to perform phlebotomy on study participants or requires additional training.

Personnel with no previous phlebotomy experience or training will complete the following:

  • Introduction to Phlebotomy with OEQCR staff.
    • Includes surface education on anatomy, technique, approved areas to draw, trouble-shooting, etc.
    • OEQCR reserves the option to utilize other HHRI/HCMC education opportunities when available and appropriate.
  • Observation of phlebotomy by approved personnel
  • Practice on artificial arm
  • Watching instructional videos
  • Technique instruction by OEQCR staff
  • Practice on artificial arm until comfortable with technique
  • If needed:
  • Further practice on artificial arm, with or without OEQCR staff offering guidance
  • Supervised live venipuncture performance with other employee(s) who are up to date on the Phlebotomy Safety and Competency requirements
    • Supervised live venipuncture performance with OEQCR staff, if available and willing
  • Competency assessment by OEQCR staff of venipuncture performance on live volunteer
  • Successful completion of written Phlebotomy Knowledge Check

OEQCR may grant permission to begin performing phlebotomy only under supervision of approved experienced personnel; approval for independent blood draw will be based on five (5) supervised draws within a specified timeframe and continued competency level assessment by OEQCR. Once deemed competent by OEQCR to perform phlebotomy on study participants, the supervisor will be notified.

IMPORTANT: It is the policy of HHRI that blood draws for research can only be performed by venipuncture in the antecubital site. No blood may be drawn from any other sites, or any lines or ports. If a need arises to use other methods, please contact OEQCR at EQ@hhrinstitute.org for assistance on how to connect with HHS medical personnel to provide this type of blood draw.   

Principal Investigator (PI) responsibilities:

  • The PI must ensure that the research personnel have completed all institutional and study site-specific required training.
  • The PI may delegate the responsibility of documenting and tracking site/study-specific training for research personnel but retains primary responsibility for training and research personnel conduct of trial related duties.
  • If training and education requirements are incomplete or not current for any study personnel, the individual may not conduct any human research activities.
  • Training records for all research personnel working on a specific study must be updated and kept in the study’s regulatory binder or a note to file should be placed in the regulatory binder that identifies the training documentation location within the department.

Study team responsibility to verify CITI Program required courses

The PI or designee is responsible for verifying that the CITI information for required modules can be viewed in the Cayuse HE submission and haven’t expired for each individual listed as PIkey personnel, and other personnel by clicking VIEW under Trainings for each person listed. If VIEW shows no information, there may be an email mismatch. Please refer to the HRPO website for additional information under Education & training for research involving human subjects or contact HRPO@hhrinstitute.org for assistance.

If training and education requirements are incomplete or not current for any study personnel, HRPO will indicate this during pre-review and training must be completed prior to final approval. Alternatively, an individual with incomplete or expired training or education may be removed from a submission; however, such an individual may not conduct any human research activities until IRB-approved (e.g., via a subsequent Modification submission for new personnel). For Renewal submissions, personnel whose certification for a required course has expired or will expire as of the IRB renewal or check-in date will be required to update their course certification.

All training and education requirements must be met to obtain IRB approval.

For multisite research when Hennepin Healthcare has agreed to serve as the IRB of record, external researchers must comply with the training and education requirements of their home institution unless the terms and conditions of a reliance agreement specifically state otherwise. If an Individual Investigator Agreement (IIA) is established with an external researcher, it is the responsibility of the Hennepin Healthcare Principal Investigator to ensure that the external researcher complies with the Hennepin Healthcare training and education requirements.

OEQCR clinical research coordinator certification reimbursement

OEQCR will provide reimbursement for Clinical Research Coordinator (CRC) certification when the following qualifications have been met:

  • CRC certification by a nationally recognized organization such as SoCRA or ACRP
  • Employment with HHS/HHRI at the time the exam was passed
  • Documentation of certification

Any active HHRI research employees may seek CRC certification reimbursement if they also meet the certifying institution’s requirements to sit for the exam. At this time, reimbursement is limited to the CRC certification exam and re-certification only. OEQCR will also reimburse for re-certification costs.

To request reimbursement, please contact EQ at EQ@hhrinstitute.org for the CRC Certification Reimbursement form.

The PI is responsible for ensuring compliance with the “Hennepin Healthcare Research Institute Conflict of Interest Policy” (https://www.hhrinstitute.org/wp-content/uploads/HHRI-Conflict-Of-Interest-Policy.pdf), which includes identifying and monitoring whether any Hennepin Healthcare key personnel participating in their research or their spouse/domestic partner, and/or dependent child/children have a potential conflict of interest related to the research. Key personnel are individuals engaged in human research that are in a position to influence the study's design, conduct, and/or reporting (e.g., PI, co-investigators).

Knowledge of potential conflict of interest prior to initiating a study or changes to COI status should be reported to the HHRI Conflict of Interest (COI) Committee in accordance with the HHRI policy. For submission to the IRB, the COI Committee determination and applicable approved management plan must be attached COI attestation section of a Cayuse HE submission for review.

The conflict determination and/or management plan will be reviewed by the convened IRB or assigned designated reviewer, depending upon the level of review required for the study. The convened IRB has final authority to approve a proposed COI management plan after it has been approved by the COI committee to ensure that human research protections are appropriate for the study.

Institutional Conflicts of Interest

The potential for institutional conflict of interest exists where Hennepin Healthcare has a significant financial interest in the research under review.  These situations are generally handled in the same manner as potential individual conflicts of interest. See the “Hennepin Healthcare Research Institute Conflict of Interest Policy” for policy details (https://www.hhrinstitute.org/wp-content/uploads/HHRI-Conflict-Of-Interest-Policy.pdf). The Institutional Conflict Committee determination and management plan must be attached in a Cayuse HE submission for IRB review. The convened IRB has final authority to approve a proposed institutional COI management plan after it has been approved by the Committee to ensure that human research protections are appropriate for the study; the IRB may determine that the conflict requires independent IRB (e.g., Advarra) review.

For multisite research, external researchers are responsible for understanding and obtaining appropriate approval(s) at their institution. Each institution is responsible for determining whether it is engaged in research. Every institution engaged in multisite human research must obtain IRB approval. Unless the Hennepin Healthcare IRB has agreed to serve as the IRB of record for multiple sites, IRB approval for each site must be obtained from their institution’s IRB or the IRB that the institution has agreed to rely on for IRB review. Multisite research is often approved by a single IRB (sIRB) and for federally funded research, an sIRB may be required.

  • If an external site (e.g., university, hospital) is engaged in human research: The protocol should include information regarding external sites/collaborators. Do not list external researchers as study personnel in Cayuse HE. External collaborator(s) at an external institution must obtain approval from their IRB. The Hennepin Healthcare IRB may request verification of external site IRB approval during review of the protocol.
  • If the external site (e.g., university, hospital) is not engaged in human research: The study submission only needs to include a description of that site's involvement. Do not list external researchers as study personnel in Cayuse HE.

NOTE: Providing feedback on the design of a project or feedback on interview/survey questions does not constitute engagement in human research.

In general, an external researcher that will be involved in research activities involving human subjects at a Hennepin Healthcare location must be onboarded via Human Resources and listed as Hennepin Healthcare Study personnel in the Cayuse HE study record. Please contact HRPO@hhrinstitute.org for additional information.

Hennepin Healthcare as the IRB of record for a non-onboarded external researcher

On a case-by-case basis, the Hennepin Healthcare IRB will consider serving as the IRB of record for an external researcher engaged in non-exempt Hennepin Healthcare research when onboarding through HHS/HHRI is not applicable and the external researcher is NOT affiliated with an institution that:

  • Has its own IRB or designated IRB (e.g., a hospital or academic institution); and
  • Has its own federalwide assurance (“FWA”); and
  • Is routinely engaged in human research.

Requests must be submitted to IRBReliance@hhrinstitute.org and should include a detailed description of the individual’s study activities, their institutional affiliation, and a completed 331 FORM External Personnel IIA (email IRBReliance@hhrinstitute.org to request the 331 FORM).

If Hennepin Healthcare agrees to enter into an agreement, HRPO will notify the requesting study team. The study team will be required to upload a completed 331 FORM External Personnel IIA and the partially executed IIA (will be provided by HRPO) in Cayuse HE Study Details section under “Other attachments” as either part of the initial IRB submission (prior to IRB review) or as a modification submission.

2. Requests for IRB review

All human research conducted under the auspices of Hennepin Healthcare are subject to oversight by the Hennepin Healthcare IRB.  If you are unsure whether a project meets the definition of research or research involving human subjects, refer to the following:

Step 1. Is your project research?

  • If your activity doesn’t fit one of the definitions of research (e.g., research as defined by DHHS or FDA regulations, or Minnesota law), you do not need to obtain IRB approval or a determination. Examples of activities that are not considered research: QA/QI projects, case reports, public health surveillance activities, scholarly/journalistic activities

If you need documentation that your activity is QA/QI (e.g., to obtain or access data from a source; to publish results; to confirm a complicated project), you may complete a submission in Cayuse HE to request a not research determination. Please contact HRPO@hhrinstitute.org to obtain a Cayuse user account.

Step 2. If your project is research, is it human research?

  • If your research does not involve human subjects (e.g., human subject as defined by DHHS or FDA regulations), the research is not subject to IRB oversight and you do not need to obtain IRB approval or a determination.
  • If you need a determination letter from the IRB that the research is not human research (e.g., to obtain or access data from a source; to publish results; to confirm a complicated project), you may complete an Initial submission in Cayuse HE to request: Not human research determination

Step 3. If your project is human research, is it exempt human research?

Minimal risk human research that is not subject to FDA oversight may qualify as exempt from IRB oversight.

  • Review the 160 GUIDANCE Criteria for exemption from IRB oversight to learn more about specific exempt categories.
  • Investigators do not have authority to determine whether human research is exempt from IRB oversight. An Initial submission must be completed in Cayuse HE to request: Exemption from IRB oversight
  • When you receive an IRB determination of Exempt, the research is not subject to IRB oversight

Step 4. If your project is non-exempt human research, is Hennepin Healthcare engaged?

The Hennepin Healthcare Human Research Protection Program (HRPP) has jurisdiction over all human research, as defined by federal regulation (DHHS, FDA) and Minnesota law, that is conducted under the auspices of Hennepin Healthcare and for which the institution is engaged in the research.

  • Engagement is a federal regulatory concept that defines whether an institution is engaged in conducting research. It has nothing to do with the physical location of the research procedures.
  • 107 GUIDANCE Engagement determinations provides criteria to evaluate whether an institution is considered engaged in research.
  • If Hennepin Healthcare is not engaged, the research is not subject to Hennepin Healthcare IRB oversight and you do not need to obtain IRB approval or a determination.
  • If you need a determination letter from the IRB that Hennepin Healthcare is not engaged, you may complete an Initial submission in Cayuse HE to request: Non-engagement in human subject research determination

NOTE: Federal regulations require that the prime awardee of federal funding have IRB approval even if no human subject activities are taking place at the prime awardee institution.

If there is a question regarding engagement of the institution for a particular research project, contact  HRPO@hhrinstitute.org.

In addition to IRB approval of research involving human subjects, you may need to contact other components of the Hennepin Healthcare HRPP to review and approve their respective aspects of human research oversight.  Some approvals are required prior to IRB pre-review; others are required prior to final IRB review.

All study personnel are responsible for understanding and complying with the requirements of all applicable reviews and approvals. The Principal Investigator is ultimately responsible for ensuring that all applicable approvals have been obtained and are appropriately maintained.

Hennepin Healthcare component Type of oversight Impact on IRB Review or Approval

Office of Education and Quality in Clinical Research (OEQCR)

EQ@hhrinstitute.org

EQ study start-up program/assessment – Hennepin Healthcare investigator-initiated research requiring convened IRB must be reviewed by the Office of Education and Quality in Clinical Research (OEQCR). Examples of studies that require this review include:

  • Research requiring convened IRB review that has no external sponsor
  • NIH-funded research for which Hennepin Healthcare is the prime awardee
  • Research for which Hennepin Healthcare holds/will hold the IND or IDE
Program completion is require prior to IRB pre-review.

Office of Grants and Contracts

GC@hhrinstitute.org

  • Study budget assessment – required for research with no external sponsor
  • Sponsored research agreements – required for externally funded research
  • Data transfer agreements – required for research that involves any transfer of human research data to and/or from any third party
  • Material transfer agreements – required for research that involves any transfer of human specimens or materials to and/or from any third party
  • International research agreements – required if you are conducting research outside of the United States. Research must adhere to regulations governing human research for the host country in addition to Hennepin Healthcare requirements. HRPO may request evidence of local review by an official review body. Consult The International Compilation of Human Research Standards

Agreements are generally executed after research receives IRB approval.

Description of necessary agreements is confirmed in the IRB submission.

Department/Physician Chief Department/Physician Chief Acknowledgment – required for all research submissions to ensure departmental approval. Signed 322 FORM is  required prior to final IRB review.

Investigational pharmacy

contact Tzivia Leviton:  or (612) 873 3103

Investigational pharmacy registration – generally required for research that will dispense medication. Use of the Investigational pharmacy is confirmed in the IRB submission.
Institutional BioSafety Committee Research involving biohazardous materials (human biological specimens, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or gene therapy) must receive approval from the Institutional Biosafety Committee. Documentation of IBC approval is required prior to final IRB review.
Radiation Safety Committee (RSC) Required for research involving the use of radiation procedures for research purposes. Documentation of RSC approval is required prior to final IRB review.
Conflict of Interest Committee
Policy

(Individual) Research in which financial conflict of interest may exist as defined by the Hennepin Healthcare conflict of interest policy must be reviewed by the Conflict of Interest Committee

(Institutional) Research in which an institutional conflict may exist as defined by Hennepin Healthcare conflict of interest policy must be reviewed by the Institutional Conflict Committee

Committee-approved management plan is required prior to final IRB review.
Administrative advisory review Research at Hennepin Healthcare that will enroll using Exception from Informed Consent (EFIC) or other types of research that may elicit significant community concerns may require review HHS/HHRI leadership to consider potential community impact. HRPO will facilitate this process as part of the IRB submission. Advisory review is required prior to obtaining IRB approval.
International Ethics Review May be required for research which will take place or engage sites outside the United States. Documentation of local ethics review is required prior to final IRB review.
Other HRPP personnel, in consultation with IRB members, may assess the need for involvement of other review committees or components of the HRPP on a case-by-case basis  

Under the revised Common Rule (2018 Rule), continuing review is not required for:

  • Research that is eligible for expedited review
  • Exempt research conditioned on limited IRB review
  • Research that has completed all interventions and now only includes analyzing data, even if the information or biospecimens are identifiable
  • Research that has completed all interventions and now only includes accessing follow-up clinical data from clinical care procedures.

The elimination of the continuing review requirement applies only to studies subject to the 2018 Rule that meet at least one of the above criteria. For studies subject to the pre-2018 Rule, continuing review is required. For studies that do not require continuing review, HRPO requires an administrative check-in.

IMPORTANT: Non-exempt studies that are subject to FDA oversight (regardless of the level of risk), conducted or supported by the Department of Justice (DOJ), or the Consumer Product Safety Commission (CPSC), require continuing review even if the study is eligible for expedited review. All research initially approved by the convened IRB require continuing review.

In addition, the IRB can require continuing review for minimal risk research, as long as the IRB documents the decision and the rationale for this decision. The IRB will make these determinations on a case by case basis, and may consider:

  • Previous determinations of serious or continuing non-compliance
  • Studies with additional regulatory oversight (e.g. conflicts of interest, international research in some cases)
  • Studies with new findings that require additional oversight (e.g., UPIRTSO)

The study’s IRB approval letter will provide the renewal or administrative check-in date, as applicable.

No, the IRB cannot provide retrospective approvals for human research that has already been conducted. The foundation of IRB oversight is to provide prospective and ongoing assurance to the public that ethical considerations and risks related to the research have been considered, mitigated when possible, and determined to be appropriate.

The consequences of conducting human research without prior IRB approval are significant and may include, but are not limited to, some or all of the following:

  • Required destruction of any data collected without IRB approval
  • Prohibition against publication and presentation of research findings
  • Retraction of any published research findings
  • Loss or clawback of funding
  • Other disciplinary actions initiated by the IRB, institution, and/or department

If you are concerned that research you conducted may have required IRB review, email HRPO@hhrinstitute.org

A protocol serves many purposes, one of which is to provide the IRB with all of the necessary information to ensure that the study will follow principles of sound scientific design and that the research will be conducted in accordance with federal regulations, state law and IRB and institutional policies.

It is the responsibility of the PI to ensure that the protocol serves as a robust, stand-alone document that fully describes the conduct of the study.  A poorly written protocol can contribute to substantial delays in IRB approval, especially for investigator-initiated studies. The protocol provides the scientific basis for the proposed research: it defines the study objectives, the population to be studied, the procedures to be followed, the evaluations to be performed, and the plan for analysis. It also describes the administrative aspects of the study such as safety management and regulatory issues.

The HRPO website provides protocol templates:

TIPS when using a 6xx TEMPLATE:

  • If a section of the template is not applicable to your research, mark it “not applicable”; do not delete sections
  • Remember to delete the template instructions/example language in the final version of your protocol

NOTE: The IRB does not require the use of a template; they are meant to serve as an outline for required elements that must be included in a protocol submitted for review

Here are some general key points to remember when developing a protocol:

  • If a protocol is from a sponsor or other external source that does not fully or accurately describe Hennepin Healthcare activities, you will need to provide supplemental information to complete your submission in Cayuse HE (e.g., local recruitment strategy, process for consent etc.)
  • Include a version number and/or version date in the body of the protocol (e.g., title page, header, and/or footer) and in the protocol file name. These should be updated each time the document is revised.
  • If you plan to recruit individuals of the following populations as participants in your research, the inclusion criteria must specifically describe these populations as there are additional regulatory implications for the IRB to consider:
    • Children
    • Pregnant women
    • Prisoners
    • Adults lacking capacity to consent and/or adults with diminished capacity to consent
    • Non-English speakers
    • Other vulnerable populations, as indicated (e.g., economically disadvantaged, etc.)

All human research should establish procedures for reviewing study data and monitoring subject safety (i.e., data and safety monitoring plan (DSMP)). A DSMP is needed to ensure and enhance protections for subjects and their data and protect the scientific validity and integrity of the study.

As part of the Initial submission, the IRB will evaluate a DSMP and consider whether it is appropriate, given the risk level, number of subjects, and scope of the research. Because the risks inherent to research vary greatly from study to study, data and safety monitoring is reviewed within the context of the study. Consult 150 GUIDANCE Data and Safety Monitoring in Research for more information on DSMP requirements.

In general, there are 2 types of JIT notifications:

  1. NIH generic notification
  2. IC-specific notification (JIT due within 2 weeks except for IRB/IACUC approvals)

Unless there's a specific request from an IC Program Officer or other unusual circumstances, submission for IRB approval in response to JIT requests will follow the standard IRB review/approval process. Under normal circumstances, JIT information may be submitted within the 2-week timeframe without an IRB approval date. Once IRB approval is obtained, the JIT submission can be updated. Please contact your HHRI sponsored research administrator for questions regarding JIT submissions.

HHS utilizes the IRB to review and approve the use of a HUD before it can be used for clinical care. You can refer to 719 HUD criteria for approval  for additional information regarding the criteria that the IRB uses to review and approve HUD uses. The clinical use of a HUD is not considered human research but must still be submitted for review and approval by the IRB prior to clinical use (with the exception of emergency use).

To submit a HUD request, follow the How do I submit new human research? under the Using Cayuse HE section. In the Submission intro section, answer NO to the question “Does the study meet the FDA definition of a clinical investigation?” and YES to the HUD question.

Typically, the IRB does not require the use of a consent form to obtain written informed consent for a HUD submission; however, an information sheet must be provided. You can find a template on the HRPO website.

See also: Section 14. Humanitarian Use Devices

Research regulations require investigators to retain research data after the research is completed. Retention requirements vary depending on whether federal funding was provided for the project, whether there is funding from industry with contractual provisions governing data retention, whether the study was conducted under FDA regulations, and/or subject to HIPAA. It is the responsibility of the Principal Investigator to identify and comply with the retention requirements specific to the research; compliance with the longest applicable standard is recommended.

The following are examples of potential record retention requirements that may apply:

  • NIH-sponsored studies must be maintained for at least three (3) years after the study ends per NIH policy and for a longer time if required by regulations or local institutional policies.
  • Maintain signed and dated HIPAA authorizations and consent documents that include HIPAA authorizations for at least six (6) years after completion of the research.
  • For drug studies conducted under an IND, keep records for two (2) years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, for two (2) years after the investigation is discontinued and FDA is notified.

For device studies conducted under an IDE or abbreviated IDE, keep records for two (2) years after the latter of the following two dates: the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol.

3. Using Cayuse HE

To access Cayuse Human Ethics (HE): hhrin.app.cayuse.com

To request access to Cayuse HE, email HRPO@hhrinstitute.org. Only individuals affiliated with Hennepin Healthcare will be set up with a user account. If you are not listed in either the HHRI or HHS company directory, please provide other documentation of your affiliation. You may request access for both the Investigator(s) and Primary Contact(s) for an initial submission.

HRPO will initiate the Cayuse activation request. If you do not receive a Cayuse mail within one business day regarding your user account, please contact HRPO@hhrinstitute.org

NOTES:

  • When your user account is activated, you'll receive an email from Cayuse: New Cayuse Account Created.
  • The temporary password to log in will expire after 30 days.
  • If you're experiencing technical difficulties logging in, please review the Configuring your browser section or contact HRPO@hhrinstitute.org
  • There is currently an intermittent issue with the Cayuse Forgot your password? reset. Please securely store your password for future reference.

Cayuse HE is a web-based submission system. You will need internet access to login to the system.   

Cayuse recommends using Chrome and opening a New incognito window. The URL to access Cayuse is hhrin.app.cayuse.com. If saving as a bookmark, make sure that the URL is hhrin.app.cayuse.com (e.g., vs a signin page).

If you're able to log into Cayuse but are having issues accessing the Cayuse HE module, you may need to clear your browser cache. See the Cayuse Support Center for guidance on clearing your browser cache.

If using Firefox, you may need to configure your Firefox browser as follows:

  1. Cookies Enabled

    Under Options, Privacy & Security, Cookies and Site Data, click Manage Exceptions and enter Address of website: hhrin.app.cayuse.com - click Allow - Save Changes to accept cookies for only Cayuse while blocking cookies on other websites

  2. Pop-ups Allowed

    Under Options, Privacy & Security, Permissions, when Block pop-up windows is checked, click Exceptions... and enter Address of website: hhrin.app.cayuse.com - click Allow - Save Changes to allow pop-up windows only for Cayuse while blocking pop-ups on other websites.

For additional information on updating Firefox, see: https://support.mozilla.org/en-US/kb/update-firefox-latest-release or for additional information about your current Firefox version, see: https://support.mozilla.org/en-US/kb/find-what-version-firefox-you-are-using.

Once you've activated your Cayuse HE account, you can create a submission.

Note that when you initially login, you'll see the Cayuse platform Home page. This screen will show ad-hoc tasks only. To see your tasks in Cayuse HE, you must choose Human Ethics from the Products switcher:

Choosing Human Ethics will bring you to your HE dashboard:

To complete an Initial submission, follow the Logging into Cayuse HE instructions in this section to navigate to Cayuse HE.

From your HE dashboard, click +New Study to create a new submission:

On the next screen, enter the study title and click the checkmark:

On the Study Details tab, click +New Submission and choose Initial:

Complete the required elements of the submission, as applicable.

Once all sections of the submission are complete, click COMPLETE SUBMISSION to route it to the PI for certification.

IMPORTANT: All first-time submissions of any type (Initial, Renewal, Modification, Incident, and Closure) require PI certification. The PI will receive an email notification to log into Cayuse HE to certify the submission. If a submission is sent back for changes, the PC may re-certify, as designated by the PI.

Co-investigators (i.e., individuals listed in the Study personnel section as “key personnel”) cannot certify a submission unless they are also listed as a PC.

The IRB must conduct continuing review of research that is reviewed by the convened IRB, subject to the pre-2018 rule, or regulated by the FDA, DOJ, or Consumer Product Safety Commission. When continuing review is required, your approval letter will include a renewal date. Cayuse HE sends auto-generated email courtesy reminders to the PI and PC beginning 90 days prior to the renewal date. To request continuing review, you must complete a Renewal submission in Cayuse HE.

Submit for renewal no later than 45 days prior to the renewal date to prevent approval from expiring.   

IMPORTANT:

  • It is the responsibility of the PI (not HRPO) to monitor IRB review status and ongoing approval requirements for their research.
  • If IRB approval expires, all research activities involving human subjects, including recruitment, advertisement, screening, enrollment, consent, interventions, interactions, and collection or analysis of private identifiable information should stop. Conducting such activities when IRB approval has expired is a violation of Hennepin Healthcare If current subjects may be harmed by stopping one or more research activities, immediately contact HRPO and provide a written list of the currently enrolled subjects, the activities that must continue and an explanation as to the harm that could otherwise occur.
  • If the IRB reviewed your Renewal submission and requires modifications to secure re-approval, complete a Modification submission in a timely fashion to prevent the study’s approval from expiring in Cayuse HE. The PI is responsible for responding to any stipulations for approval as soon as possible for the study to maintain approval.
  • The IRB will not approve new human research for an investigator who has expired IRB approval(s).

Renewal submissions:

To complete a Renewal submission, follow the Logging into Cayuse HE instructions in this section to navigate to Cayuse HE. From your HE dashboard, navigate to the applicable study, click +New Submission and choose Renewal.

Complete the required elements of the submission, as applicable.

Once all sections of the submission are complete, click COMPLETE SUBMISSION to route it to the PI for certification.

For legacy studies, see also Completing follow-on submissions for legacy studies in this section.

NOTE: All first-time submissions of any type (Initial, Renewal, Modification, Incident, and Closure) require PI certification. The PI will receive an email notification to log into Cayuse HE to certify the submission. If a submission is sent back for changes, the PC may re-certify, as designated by the PI.

Researchers must submit planned changes to previously approved research and receive IRB approval prior to implementing the changes, except where necessary to eliminate apparent immediate hazards to participants. In the case of changes implemented to eliminate immediate hazards to participants, the emergency protocol changes must be reported to the IRB via an Incident submission in Cayuse HE.

Modification submissions:

To complete a Modification submission, follow the Logging into Cayuse HE instructions in this section to navigate to Cayuse HE.  From your HE dashboard, navigate to the applicable study, click +New Submission and choose Modification.

Complete the required elements of the submission, as applicable.

IMPORTANT: When submitting changes to previously approved documents, such as protocols, consent forms, recruitment materials, etc., ensure the following:

  • You are making changes to the most recently approved document
  • You have appropriately updated version date in the document
  • You have appropriately updated the file name for the modified document being uploaded
  • If you are submitting a revision to a previously approved document, you have deleted the existing document in the Modification submission and replaced it with the CLEAN version (i.e., without tracked changes)
  • If you are submitting a new document, you have uploaded the new document in the applicable location

Once all sections of the submission are complete, click COMPLETE SUBMISSION to route it to the PI for certification.

For legacy studies, see also Completing follow-on submissions for legacy studies in this section.

NOTE: All first-time submissions of any type (Initial, Renewal, Modification, Incident, and Closure) require PI certification. The PI will receive an email notification to log into Cayuse HE to certify the submission. If a submission is sent back for changes, the PC may re-certify, as designated by the PI.

It is the responsibility of the Principal Investigator to determine whether submission to the IRB is required. Information that is not listed in the guidance documents below do not require reporting to the Hennepin Healthcare IRB:

Reports submitted by study sponsors directly to the IRB will be returned with a request to the sponsor to ensure forwarding to the local study investigator.

Incident submissions:

  • To complete an Incident submission, follow the Logging into Cayuse HE instructions in this section to navigate to Cayuse HE. From your HE dashboard, navigate to the applicable study, click +New Submission and choose Incident.
  • Complete the required elements of the submission, as applicable
  • Once all sections of the submission are complete, click COMPLETE SUBMISSION to route it to the PI for certification.

NOTE: All first-time submissions of any type (Initial, Renewal, Modification, Incident, and Closure) require PI certification. The PI will receive an email notification to log into Cayuse HE to certify the submission. If a submission is sent back for changes, the PC may re-certify, as designated by the PI.

Researchers are required to close their study in Cayuse HE upon completion. A study may be closed when:

  • Study is permanently closed to subject enrollment OR not applicable (e.g., secondary research that does not enroll subjects)
  • All subjects have completed all study-related interactions/interventions OR not applicable (e.g. secondary research that has no subject interaction/intervention)
  • Collection/use of private identifiable information is complete OR not applicable
  • Analysis of private identifiable information is complete OR not applicable
  • The study is not subject to FDA oversight OR the study sponsor has confirmed that all FDA requirements for closure for the Hennepin Healthcare site have been met

Maintaining individually identifiable private information collected under an IRB approved protocol without using, studying, or analyzing such information is not considered human research and does not require ongoing IRB oversight. 

Closure submissions:

  • To complete a Closure submission, follow the Logging into Cayuse HE instructions in this section to navigate to Cayuse HE. From your HE dashboard, navigate to the applicable study, click +New Submission and select Closure.
  • Complete the required elements of the submission, as applicable
  • Once all sections of the submission are complete, click COMPLETE SUBMISSION to route it to the PI for certification.

NOTE: All first-time submissions of any type (Initial, Renewal, Modification, Incident, and Closure) require PI certification. The PI will receive an email notification to log into Cayuse HE to certify the submission. If a submission is sent back for changes, the PC may re-certify, as designated by the PI.

Virtual office support for Cayuse HE

Please contact HRPO@hhrinstitute.org to request a Zoom meeting invitation for HRPO staff assistance to navigate Cayuse HE

Cayuse Help Center

Visit the Cayuse Help Center for online guidance and tutorials on the Human Ethics module

4. Requests for IRB reliance

External IRB: An external IRB refers to an IRB that is not affiliated with Hennepin Healthcare. In a reliance arrangement, the external IRB agrees to take on the IRB regulatory review and oversight for a specific study or set of studies.

Local Context: Knowledge of the institution and community environment in which the research will be conducted. In order for the External IRB to review for another institution, it must have adequate knowledge of that institution’s local context (i.e., local research policies, state and local laws, and a community’s attitude toward research).

Reliance Agreement: the formal written agreement that documents respective authorities, roles, responsibilities, and communication between an institution/organization serving as the IRB of record and the institution relying on that IRB. This term includes: IRB Authorization Agreement (IAA), cooperative agreement, master services agreement (“MSA”), master joint agreement (“MJA”), or umbrella agreement.

Relying Institution: The institution that has agreed to rely on the review of another IRB to provide IRB review and oversight for a specific study or set of studies.

Single IRB: The selected IRB of record that conducts the ethical review for participating sites of a multi-site study.

 

Reliance refers to an arrangement (legal arrangement) between two or more institutions to allow for IRB regulatory review and oversight of a study by one institution’s IRB for one or more other institutions when multiple IRBs have jurisdiction for the same research protocol.

This term to refers to the formal written agreement that documents respective authorities, roles, responsibilities, and communication between an institution/organization serving as the IRB of record and the institution relying on that IRB.

Hennepin Healthcare is signed onto the SMART IRB Agreement and frequently uses that agreement for reliance requests.

Every institution is responsible for research conducted by its personnel, regardless of where the research occurs. When Hennepin Healthcare conducts human subjects research, the Hennepin Healthcare IRB must review it unless a reliance arrangement is established and you receive administrative approval to rely on the IRB review of another qualified IRB.

An external IRB refers to an IRB that is not affiliated with Hennepin Healthcare. In a reliance arrangement, the External IRB agrees to take on the IRB regulatory review and oversight for a research protocol. An example of an external IRB is an IRB at another institution (e.g. a university’s IRB) or an independent IRB (e.g. Advarra). Other terms may include IRB of record, reviewing IRB or central IRB (cIRB), or single IRB (sIRB).

Approval to rely on another IRB requires an administrative review by the Hennepin Healthcare IRB office. Requests to rely on an external IRB are reviewed on a case-by-case basis. Various factors are considered in determining eligibility to rely on an external IRB such as whether the study is required to use a single IRB (e.g., a multi-site federally funded study), risk level of study and whether the other institution is accredited. Reliance is generally NOT appropriate if the study is determined to be exempt or if Hennepin Healthcare is not engaged in human subject research.

Refer to the 112 Guidance Relying on an external IRB/single IRB for more information on submitting a request for reliance.

Use of an external IRB will require that you work with and become familiar with another IRB’s submission process and IRB policies and SOPs, if applicable. Depending on the institution and reliance arrangement, you may be working through a designated IRB liaison from the lead study site or coordinating center OR working directly with the external IRB office. Questions on the IRB submission requirements and process for a specific institution should be directed to that institution.

Reliance on an external IRB (i.e. an sIRB) is limited to the IRB regulatory review.

What that means is that you:

  1. still need to work with components of the Hennepin Healthcare HRPP;
  2. remain responsible for completion/compliance with any institutional policies and requirements (including ancillary reviews); and
  3. Hennepin Healthcare retains overall responsibility for conduct of research at Hennepin Healthcare.

No. When the Hennepin Healthcare IRB office approves relying on an external IRB, the study team must still obtain IRB approval from the external IRB before beginning any study activities. The study team remains responsible for ensuring all Hennepin Healthcare institutional requirements are met before beginning the research and over the course of the research study. You must receive Hennepin Healthcare IRB office approval for external IRB review before submitting to the external IRB for local site approval (via Cayuse HE) for external IRB review before submitting to the external IRB for local site approval.

No. Policies regarding acceptance of IRB oversight are specific to each institution. If you wish to request that an institution’s IRB serve in this capacity, you should contact them to confirm their policy before proceeding. At this time the Hennepin Healthcare IRB is not agreeing to serve as the IRB of record on multi-site research.

Questions about how to submit your study to the external IRB should be directed to the external IRB or designated coordinating center. Your reliance arrangement may involve standard operating procedures (SOPs) that describe with whom and how to communicate with the external IRB.

The reliance agreement is negotiated and finalized by HRPO and will also coordinate review by legal counsel, as needed, and signature from the Hennepin Healthcare Institutional Official or designee. The Hennepin Healthcare IRB office will also work on any local context form requested by the external IRB.

SMART IRB is NOT an IRB. SMART IRB is the name of a model reliance agreement designed to streamline the reliance process. SMART IRB was developed under an award from the National Center for Advancing Translational Sciences (“NCATS”) of the National Institutes of Health (“NIH”) to support single IRB review of multi-site human subjects research.

SMART IRB includes:

  • An IRB reliance agreement that permits eligible institutions that join it (“Participating Institutions”) to rely on the IRB review and oversight of human research by another Participating Institutions’ IRBs;
  • A set of standard operating procedures (SOPs) to guide implementation of the reliance relationship among Participating;
  • Resources and tools to support study teams, reviewing IRBs, relying institutions, and IRB/HRPP staff;
  • Centralized online system to support sign-on and reliance determinations (i.e. Participating Institutions agreeing which institution will serve as the reviewing IRB and whether the other Participating Institutions are willing to rely on review by that IRB). Note: Some SMART IRB Participating Institutions use the online platform but others do not. The alternative to the online system is the SMART IRB Agreement Letter of Acknowledgement/Implementation Checklist.

You can find more information about SMART IRB:

Hennepin Healthcare is signed on to the SMART IRB Agreement as a Participating Institution. Using the SMART IRB Agreement means that the institutions collaborating on a project and seeking to utilize single IRB review do not have to establish and execute a reliance agreement. A decision to use the SMART IRB Agreement is made on a study-by-study basis by each Participating Institution. Using SMART IRB does not replace or negate the internal process here at Hennepin Healthcare for requesting reliance on an external IRB. You can refer to the information on the IRB website for more information on that process.

Even when your research relies on an external IRB, there are ongoing reporting obligations to the Hennepin Healthcare IRB office. Refer to:

113 Guidance Notifications to HRPO for ceded studies

Most federally-funded research conducted by more than one U.S. based institution must use a single IRB (sIRB). As of January 20, 2020, the revised Common Rule established that research involving human subjects conducted by more than one U.S. institution must use a single IRB (sIRB) unless the research meets exemption criteria. The National Institutes of Health (NIH) implemented a variation of the sIRB policy that went into effect on January 25, 2018.

IMPORTANT: If you’re unsure whether your project is subject to the single IRB requirement, you may contact your program officer/funding agency for clarification. Any exception to the sIRB requirement must be obtained writing.

For more information or other questions, please contact the IRB office (IRBReliance@hhrinstitute.org) or your Grant Administrator (https://www.hhrinstitute.org/researcher-resources/sponsored-research-administration/grant-administration-portfolio- assignments/)

For more information on the Common Rule sIRB requirement:

OHRP: Revised Common Rule Cooperative Research Provision (45 CFR 46.114): https://www.hhs.gov/ohrp/regulations-and- policy/single-irb-requirement/index.html

 

For more information on the NIH sIRB policy:

Single IRB Policy for Multi-site Research https://grants.nih.gov/policy/clinical-trials/single-irb-policy-multi-site-research.htm

Frequently Asked Questions – Single IRB Policy for Multi-site Research https://grants.nih.gov/grants/policy/faq_single_IRB_policy_research.htm#5182

Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html

Guidance on Exceptions to the NIH Single IRB Policy https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-003.html

Additional Guidance on the NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-058.html

Scenarios to Illustrate the Use of Direct and Indirect Costs for Single IRB Review under the NIH Policy on the Use of a Single IRB for Multi-site Research https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-109.html

The institution submitting the grant application or the federal awarding agency is responsible for selecting the sIRB. The sIRB may be an IRB of an institution that is participating site or an independent/commercial IRB. Hennepin Health Research Institute (HHRI) IRB is not currently agreeing to serve as the sIRB.

HRPO SRA
IRBReliance@hhrinstitute.org You may find your Grant Administrator contact information here: Sponsored Research Administration - Hennepin Healthcare Research Institute (hhrinstitute.org)

Provide the following information, if known:

  • Name of the Hennepin Healthcare PI
  • Name of the lead site (if it is not Hennepin Healthcare)
  • Name of the sIRB, if already selected
  • Title of the grant
  • Grant deadline
  • A link to the NIH Request for Applications (RFA) or contract solicitation
  • Brief description of the project
  • Brief description of Hennepin Healthcare's role on project

Scenario 1: HHRI is NOT the prime institution for the application (i.e., another institution will be submitting the application to the funding agency):

Contact IRBreliance@HHRInstitute.org to obtain an HHRI letter of commitment for the sIRB selected by the prime institution

Contact IRBreliance@HHRInstitute.org for obtaining an institutional letter of support for an sIRB when HHRI is a participating/subcontract site

Unless otherwise required by the funding agency, no IRB/sIRB approval is required at the time of proposal submission

NOTE: Hennepin Healthcare IRB is not currently available to serve as an sIRB for multi- site research

Scenario 2: HHRI is the prime institution for the application (i.e., HHRI will be submitting the application to the funding agency):

Contact IRBreliance@HHRInstitute.org to discuss the process/approval of sIRB selection

Contact IRBreliance@HHRInstitute.org for guidance in identifying an sIRB when HHRI is the prime institution for a proposal

You may select a commercial IRB (HHRI recommends Advarra)

You may select a collaborating academic institution willing to serve as the sIRB for the study (HHRI recommends identifying a participating institution of SMART IRB to facilitate reliance – you may search the SMART IRB website for participating sites: https://smartirb.org/participating-institutions/)

NOTE: Hennepin Healthcare IRB is not currently available to serve as an sIRB for multi- site research

Include the cost of the sIRB services in the budget – this is a direct cost

If using Advarra, complete the Advarra Budget Questionnaire to obtain a cost estimate for IRB fees for your study. You must include a budget for IRB review fees in your grant submission.

If a collaborating institution is serving as the sIRB, the IRB fees for sIRB services (if that IRB is charging) must be included in their subaward budget

IMPORTANT: Also consider other costs such as funds for study monitoring or need for a designated staff position to serve as the IRB liaison for working with the sIRB and all participating sites

If submitting an NIH proposal, include an sIRB plan

For NIH grant applications: You must include an sIRB plan; refer to Section 3.2 of the NIH General Application Guide (G.500) for instructions on what information must be included

You can reach out to IRBReliance@hhrinstitute.org for a template sIRB plan

Obtain documentation of commitment from participating sites to confirm selection of the sIRB Note: You are NOT required to include any letters or other documentation of commitment in the grant application
Complete application for submission to funding agency Unless otherwise required by the funding agency, no IRB/sIRB approval is required at the time of proposal submission
Contact IRBreliance@hhrinstitute.orgto initiate the request to rely on the designated sIRB

Scenario 1: If Hennepin Healthcare is the prime awardee (lead site):

Notify IRBReliance@hhrinstitute.org that the grant was funded

Develop the protocol, consent(s), and other materials required for IRB submission Work with the designated sIRB to submit for overall study approval

IMPORTANT: If your protocol is greater than minimal risk, connect with the Office of Education and Quality in Clinical Research (OEQCR) to initiate the EQ study start-up program/assessment

  • Notify IRBReliance@hhrinstitute.org that the grant was funded
  • Develop the protocol, consent(s), and other materials required for IRB submission
  • Create submission in Cayuse HE for the OVERALL study with the draft protocol/materials PRIOR to submitting to the sIRB for overall study approval. IMPORTANT: This initial submission will serve as notification to HRPO that you’ve developed the overall study protocol and materials and ready to submit to the sIRB. This initial submission is NOT site approval to rely but HRPO will acknowledge submission and return the submission to the study team pending overall study approval Work with the designated sIRB to submit for overall study approval
  • Once you receive overall study approval, follow the steps in the 112 Guidance Relying on an external IRB/single IRB available on the IRB website – REMINDER: You will have already created a submission in Cayuse HE to provide HRPO the initial notification to submit for overall study approval – you will update that submission with the approved protocol, consent etc.

Scenario 2: If Hennepin Healthcare is NOT the prime awardee/lead site:

Follow the steps in the 112 Guidance Relying on an external IRB/single IRB available on the IRB website

This step will usually occur AFTER the lead site obtains initial overall study approval so that you can provide the following materials with your request for reliance:

  • Final IRB approved protocol
  • IRB approval letter (overall study approval)
  • IRB approved consent form localized for Hennepin Healthcare participants

5. Recruiting and screening study participants

Submissions for IRB review must explain how subjects will be identified and recruited for a study. The IRB considers how the researcher proposes to approach the designated pool of potential subjects. Any approach to subjects must be non-coercive and the potential subjects must voluntarily participate in the recruitment process. The IRB and researchers must respect and protect subjects’ privacy, i.e., subjects’ right to control access to themselves. The IRB will review the study recruitment methods and all recruitment materials and will consider the overall nature of the research, the designated population to be studied, and how the materials will be used.

Researchers should consider the following ethical issues when planning their recruitment strategies:

  • Equitable selection of participants: The recruitment plan ensures the selection of research participants is equitable and appropriate for the study.
  • Respect for persons: The recruitment plan ensures appropriate procedures are used for the study population, especially if the population presents any special problems requiring specific safeguards. Such populations may include vulnerable populations such as children, prisoners, pregnant women, economically disadvantaged persons and cognitively impaired persons or those lacking of decision-making capacity. Other populations (e.g., employees, students, etc.) may be considered a vulnerable population depending on their circumstances in relation to the research.
  • Lack of pressure: The study is introduced to potential participants in a way that allows them ample time to consider, with no undue pressure because of the timing of the request, who makes the request, how the request is made, or the offering of excessive inducements.
  • Respect for privacy: Recruitment plans should respect an individual’s reasonable expectations for privacy. Consider whether potential participants be identified using confidential information such patient records. If investigators ask screening questions, will the questions be asked in a private setting where others will not overhear the answers? Prospective participants generally should be contacted by people directly involved in their care, not by unknown researchers.
  • Unbiased presentation: All information used for recruitment should be accurate, balanced, free of misleading emphases, and appropriate for each stage of recruitment.
  • Avoidance of therapeutic misconception: Therapeutic misconception can occur any time participants believe that they will directly benefit from participation in a research study, even if they are told there is no assured benefit. The recruitment plan should work to counteract this misconception (when applicable).

Recruitment activities can be passive (e.g., advertisements such as flyers or ads aimed at recruiting participants into a research study) or active (e.g., research staff approach and interact with specific individuals with an aim of enrolling them in research). All recruitment methods must be adequately described in the IRB submission (e.g., an attached study protocol) and all recruitment materials must be attached in the Cayuse HE submission for IRB review. Advertisements must be submitted to the IRB and approved in their final form prior to their use. Any changes to approved materials must obtain IRB approval prior to implementation.

Recruitment methods/materials can include:

  • Medical record review – See also 5.6 Can I use medical records to identify and screen potential participants?
  • Recruitment letters – See also 5.7 Can I send recruitment letter to potential participants?
  • Written scripts for telephone or in-person discussion
  • Hard-copy flyers, posters, postcards, newspaper ads, press releases
  • TV and/or radio spots
  • Websites/internet ads
  • Electronic mailings (e.g., email, text)
  • Social media pages, ads, blogs, tweets, etc.
  • Referrals
  • Screening/recruitment protocols, recruitment databases
  • Review of publicly available records or other records

Researchers are responsible for complying with any applicable federal, state and/or institutional requirements, e.g., HHRI/HHS policies regarding the use of institutional electronic systems, social media, etc.

IMPORTANT: the IRB prohibits incentives, finder’s fees, or bonuses of any type in exchange for referral of potential participants or tied to the rate or timing of enrollment, which may encourage recruiters to put inappropriate pressure on prospective participants.

Materials to recruit subjects should include information that would help them determine their eligibility and interest.

For example, the following items should be considered for inclusion:

  • The word researchmake it clear that it is a research study and not clinical care
  • Name and contact information of the primary investigator and institution conducting the research (Hennepin Healthcare information must be included even when not the primary investigator/institution)
  • Brief description of the condition or concept being studied and/or the purpose of the research
  • Key criteria that will be applied to determine eligibility for the study
  • Required time commitment (e.g., number of visits, duration of study, etc.)
  • A brief description of potential benefits, if any
  • Location of the research
  • Contact for further information

The IRB will not allow recruitment materials that are misleading, inaccurate, exculpatory, coercive, or unduly influential. For example, the IRB does not allow:

  • Statements or implications of favorable outcomes or other benefits beyond what is outlined in the IRB submission
  • Exculpatory language
  • Emphasis on payment to participants (e.g., larger or bold type). NOTE: The dollar amount to be paid to participants may be included in advertisements; however, the IRB may determine that stating the specific amount is coercive or unduly influential. In these instances, the IRB will only allow the advertisement to state that compensation will be offered without including the dollar amount. See also 5.9 Are payments to participants permitted?
  • Promise free treatment when the intent is only to say participants will not be charged for taking part in the study

The IRB advises all investigators conducting research subject to FDA oversight to review the FDA Information Sheet Recruiting Study Subjects.

For recruitment of FDA-regulated research, the IRB does not allow:

  • Claims, either explicitly or implicitly, about the drug, biologic or device under investigation that are inconsistent with FDA labeling (e.g., stating the test article is known to be equivalent or superior to any other drug, biologic or device)
  • Use of terms such as new treatment, new medication, or new drug without explaining that the test article is investigational
  • Sponsor coupons/discounts to participants on the purchase price of their product once it has been approved for marketing

IRB approval of information posted on a clinical trial website is not required if the information is limited to: study title, purpose of the study, protocol summary, basic eligibility criteria, study site location(s), and how to contact the study site for further information. For example: clinical trial listing services that do not require IRB approval include:

  • National Institutes of Health (NIH) ClinicalTrials.gov website
  • NIH National Cancer Institute’s cancer clinical trials listing

In addition, the following are not considered direct advertising and do not require IRB approval:

  • Communications intended to be seen or heard by health professionals, such as "Dear Doctor" letters and doctor-to-doctor letters (even when soliciting for study participants)
  • News stories, so long as information is not provided regarding recruitment; it is the responsibility of the investigator to understand HHS/HHRI Public Relations requirements
  • Publicity intended for other audiences
  • Public facing materials within the Hennepin Healthcare system not intended for study-specific recruitment; it is the responsibility of the investigator to understand HHS/HHRI Public Relations approval requirements

Use of medical records for the purpose of identifying, contacting, and recruiting participants is subject to HIPAA regulations. The Hennepin Healthcare IRB requires investigators to request a partial waiver of authorization if using medical records for screening or recruitment. See also 8.6.5 What is a waiver or alteration of HIPAA authorization? IMPORTANT: Before using an individual’s information, it must be confirmed in the Epic record that the patient has not opted out of research activities.

When a partial HIPAA waiver of authorization is approved, researchers can access information in the Epic medical record (for patients who have not opted out of research activities) for screening purposes. Researchers may only record the minimal information required to contact potentially eligible participants. Any additional screening activities required to determine eligibility should be performed only after the consent and authorization have been obtained from the participant.

The Epic Care Everywhere user agreement states that Care Everywhere may not be used for research recruitment or to access records for research purposes. Epic designed Care Everywhere to be used for treatment and care coordination purposes, and all Epic organizations that participate in Care Everywhere consent patients to its use as a patient care tool, not a research tool.  Patient information from Care Everywhere that is already in the Hennepin Healthcare Epic system because it was previously requested for treatment or care coordination may be used for research or other lawful purpose; however, accessing Care Everywhere to retrieve/use patient information for research is not permitted.

If an investigator plans to send a recruitment letter to potential participants, the following issues must be considered:

  • If recruitment involves accessing Hennepin Healthcare medical records or other Hennepin Healthcare databases to identify potential participants, the recruitment letter to Hennepin Healthcare patients should come from their clinic/care team. If the study team does not have a patient care relationship with prospective participants, the study team should collaborate with the clinic/provider care team to have recruitment letters signed/sent out by the clinic/provider group.
  • If recruitment involves re-sending recruitment letters to individuals who do not initially respond, the initial letter must describe this possibility so individuals are made aware of potential additional mailings; there should also be easy instructions for individuals to opt out of future contact. For example, return postcards on which individuals may indicate whether they have interest, this model may reduce mailings and allows the investigator to know who is interested and who should not be contacted any further.
  • For research of a sensitive nature, for example, a study regarding sexually transmitted diseases, special efforts must be made to protect the privacy and confidentiality of potential participants and to take appropriate precautions to avoid any real or perceived breach of privacy or confidentiality. An investigator cannot guarantee that a mailing will be opened by the intended recipient and, therefore, must carefully consider what information should be included, and efforts should be made to ensure that the return address or any materials that will be sent back are vague.
  • If the study involves follow-up via telephone, the initial letter must describe the follow-up so individuals are made aware of an unsolicited phone call. Further, a recruitment script must be created for research staff to follow, e.g., whether to leave a message (keeping in mind that privacy and confidentiality must be protected), what information to provide during a conversation, etc., and the script must be reviewed and approved by the IRB.

IMPORTANT: Generally, the Hennepin Healthcare IRB does not approve cold calling recruitment. Cold calling is the process of contacting prospective participants for research via telephone, who were not expecting such an interaction. If a researcher wishes to contact potential participants by telephone, a recruitment letter (as described above) should be sent prior to the telephone call. If individuals have given prior written permission to be contacted by researchers, contacting those individuals by telephone without sending an initial recruitment letter is permitted.

Compensation may be provided to reimburse participants for their time, effort, or other expenses. Compensation includes any monetary compensation, gift certificates or vouchers, mileage reimbursement, movie tickets, promotional items, etc.

The IRB reviews compensation arrangements to research participants to ensure they promote an equitable selection of subjects and do not introduce coercion or undue influence. Additionally, compensation must be adequately and accurately described in the consent document.

When compensation will be offered to participants, IRB approval will be based on the following guidelines:

  • The amount of compensation should be appropriate for the time and effort put forth by study participants.
  • Credit for payment should accrue as the study progresses and not be contingent upon the participant completing the entire study. Investigators should provide a plan for pro-rating compensation should a participant withdraw from a study. Pro-rating compensation may not be feasible in all studies that offer compensation and may be approved on a case-by-case basis.
  • While the total compensation should not be contingent upon completion of the entire study, a small incentive for completion of the study is acceptable, providing that such incentive is not coercive. The IRB considers whether such an incentive is reasonable and would not unduly induce participants to stay in the study when they might otherwise have withdrawn.
  • Unless it creates undue inconvenience or a coercion, compensation to participants who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn. For example, for a study expected to last only a few days, an IRB may find it permissible to allow a single electronic payment date at the end of the study, even to participants who had to withdraw before that date.
  • All information concerning compensation, including the total amount, schedule for compensation, and any apportion plan if a participant does not complete the study should be described in the consent document.

The following are additional considerations for compensation to participants in FDA-regulated clinical trials:

  • The FDA does not consider reimbursement for travel expenses to and from the clinical trial site nor associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.
  • Compensation for participation in a clinical trial offered by a sponsor may not include a coupon/ discount on the purchase price of the product once it has been approved for marketing.
  • See also: 5.4 Are there additional recruitment considerations for FDA-regulated research?

NOTE: The Department of Defense has additional considerations for compensation to participants. Refer to DoD guidelines.

Researchers should use a sponsor-provided screening log (when available) or develop a screening log based on inclusion/exclusion criteria.

Related: 641 TEMPLATE Site screening and enrollment log (OEQCR)

6. Obtaining informed consent

Informed consent is the voluntary agreement from a research subject to participate in research and one of the central protections and ethical principles of the protection of human subjects in research.

Informed consent is founded on the principle of respect for persons described in The Belmont Report. The principle of respect for persons requires that individuals be treated as autonomous agents and that the rights and welfare of persons with diminished autonomy be appropriately protected. The informed consent requirement is one of the central protections defined in regulations:

  • Department of Health & Human Services (HHS) regulations at 45 CFR part 46
  • Food and Drug Administration (FDA) regulations at 21 CFR part 50

Informed consent is a process, not merely a form, by which a research subject gains an understanding of the research and its risks and potential benefits, in order to decide whether to participate; this is an ongoing process throughout the course of study participation. Unless the IRB waives the requirement for informed consent, researchers must first obtain legally effective informed consent from the participant or the participant’s legally authorized representative prior to enrolling the individual in the research.

The IRB will evaluate both the consent process and the procedures for documenting informed consent to ensure that adequate informed consent is obtained from subjects. Researchers must adequately and accurately describe the informed consent process in the IRB submission. The informed consent process will depend on the research setting and subject population. Special consent processes are needed with some subject populations to ensure that information about study participation is communicated effectively and that subjects’ rights and welfare are protected.

 

Assent – Agreement by an individual not competent to give legally valid informed consent (e.g., a child or cognitively impaired adult) to participate in research. If an individual is unable to consent to participate in research, a researcher must obtain that individual’s assent whenever possible.

Consent –Agreement by an individual who is competent to voluntarily give legally valid informed consent, based upon adequate knowledge and understanding of relevant information, to participate in the research.

Information sheet – A document that may be used as part of the consent process in certain circumstances where a signature could compromise the participant or in studies where written documentation of consent is not required.

Legally Authorized Representative (LAR)an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research. [45 CFR 46.102, 21 CFR 50.3(1)]

Parental permission – When children/minors are included in research, the parent/guardian must sign a parental permission consent document. Some situations require permission from at least one parent, while other situations require permission from both parents. The IRB makes the determination on whether signature is required from one or both parents/guardians.

Verbal consent – A process that can only be used when the IRB has approved a waiver of documentation of consent. The prospective subject provides consent verbally and does not sign a consent document. The researcher must provide all of the required elements of consent verbally or via an information sheet. If the subject verbally agrees to participate, the researcher obtaining consent should document the consent process in the subject’s research record.

Short form –may be used when a subject is a non-English speaker and an IRB-approved consent can be verbally translated in the subject’s native language. See 7. Human research with special populations section 7.11 When can I use the short form to consent non-English speakers?

Waiver of documentation of informed consent –When specific regulatory requirements are met and IRB approval of a waiver of documentation of informed consent is granted, a researcher may involve human subjects in the research by obtaining implied or verbal consent.

Waiver of informed consent or alteration of the requirements for informed consent – When specific regulatory requirements are met and IRB approval of a waiver of informed consent is granted, a researcher may involve human subjects in the research without obtaining their consent. If the IRB approves an alteration of the requirements of informed consent, the information provided by a researcher to obtain subjects’ consent can omit the element(s) waived by the IRB.

For studies that are exempt from IRB oversight (as determined by the IRB), the requirements for informed consent are not applicable; however, the HENNEPIN HEALTHCARE IRB recommends a consent process for exempt studies that involve interaction with study subjects, such as for research exempt under Category 1 (educational practices), Category 2 (interviews, surveys, focus groups, observations of public behavior), and Category 3 (benign behavioral interventions). The consent process may be via an information sheet or a verbal consent script rather than a signed consent document. Participants should be provided consent information that includes, at minimum:

  • An explanation that they are being asked to participate in a research study.
  • The identity and affiliation of the researcher.
  • A clear description of the study procedures and how data will be used in the future.
  • A statement that participation in the research is voluntary.
  • Contact information for questions and concerns about the research.

For exempt research that does not involve interaction with subjects (e.g., Category 4 (secondary data research)), consent is not required and researchers do not need to request a waiver of consent; however, if the study involves PHI, a waiver of HIPAA authorization is required. See also section 10. HIPAA

For a detailed description of categories of exempt research, see: 160 GUIDANCE Criteria for exemption from IRB oversight

Under federal regulations, a researcher must obtain legally effective informed consent to enroll a person into a research study. Informed consent is legally effective if:

  • It is obtained from the participant or the participant’s legally authorized representative; and
  • It is documented in a manner that is consistent with the federal (i.e., DHHS, FDA) regulations on protection of human subjects and the applicable laws of the jurisdiction in which the research is conducted, and
  • It is obtained under circumstances that:
    • provide the prospective participant or the legally authorized representative sufficient opportunity to consider whether to participate in the research;
    • minimize the possibility of coercion or undue influence, and
    • provide privacy of the potential participant by taking place in a setting that is not open to the public

Informed consent may NOT include any exculpatory language (language that waives or appears to waive any of the participant’s legal rights or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence).

The person consenting participants for involvement in a study may be the Principal Investigator (PI) or an individual authorized by the PI and approved by the IRB to obtain informed consent for the specific study, such as co-investigators or other study team members.

Regardless of who is obtaining consent, the PI is ultimately responsible for the overall conduct of the study and, therefore, must ensure that informed consent is performed only by IRB-approved personnel and that the correct procedures are carried out (e.g., appropriate documentation and use of current IRB-approved consent materials). The PI is responsible for assuring that all study personnel are knowledgeable about the specific research study and are appropriately trained in the process of obtaining informed consent.

HHRI study staff who may obtain informed consent as part of their study role must complete a one-time, interactive introduction to conducting the informed consent process with the HHRI Office of Education & Quality in Clinical Research. Contact EQ@hhrinstitute.org for more information.

The consent process refers to who will obtain informed consent and from whom, when, where, and how the consent process will take place. The process for obtaining consent includes the steps that will be followed and the resources/information that will be used to allow the person providing consent to make an informed choice regarding participation in a study. It also involves an assessment by the study team to confirm that the person providing informed consent understands what is being asked of them. The process for obtaining consent should be customized to fit the needs of persons providing consent, while considering a study's risks and procedures, as well as the study’s location and the study team's access to potential participants.

Researchers may initially provide information to potential study participants via one or more of the following modes of communication, among others: face-to-face dialogue, mail, electronic interface, telephone, or fax; however, when a researcher seeks to obtain informed consent, it must be in real-time with the person providing consent to give them an opportunity to ask questions and receive responses. Researchers must obtain consent prior to entering a participant into a study, gathering data about a participant, and/or conducting any procedures required by the research plan, unless the IRB has issued a waiver regarding such activities.

When obtaining consent, researchers must ensure the process incorporates the following:

  • Gives the participant/legally authorized representative (LAR) (i.e., person providing consent) with all of the required information about the study.
    See 109 GUIDANCE Informed consent for an outline of requirements
  • Provides information in a language that the person providing consent understands:
    1. Use the language that the participant speaks, reads, and understands; and
    2. Use terms that are appropriate for the participant's understanding. To the extent possible, use language understandable by a person who is educated to an 8th grade level, simplify scientific terms, use short sentences, etc.

      NOTE: If the participant/representative cannot speak English, the IRB must have specifically approved the protocol to allow the enrollment of participants able to speak in language that the participant understands.

  • Gives the person providing consent an opportunity to ask questions before providing consent. It is important that individuals understand the information they receive about the study. If an individual has questions, an appropriate study team member must be available to answer those questions before proceeding with the consent process. Researchers should assess individuals’ understanding by using open-ended questions and nondirective questions. See also 7.6 How do I assess capacity to consent?
  • Gives the person providing consent enough time to consider their options before providing consent. It is important that individuals do not feel undue pressure to be in a study. Giving them enough time to think about their choice helps to reduce this pressure. It is recognized that some studies have urgent timelines for enrolling in a study. In these cases, the study team must consider additional ways to reduce the pressure.
  • Does not use exculpatory language in the consent process. Exculpatory language is:
    1. Any language that waives or appears to waive the rights of study subjects
    2. Any language the waives or appears to waive the liability of those conducting the research (investigators, sponsors, institutions, etc.)
  • Documents that consent was obtained before beginning study procedures. For each person consented, fully document the process in the study record. See also 6.11 How do I record that consent has been obtained?
  • Provides a copy of the signed consent form to the person providing consent. This is required when consent is documented with a signed consent form.

IMPORTANT:

  • All discussions for consent should be conducted in a private and quiet setting.
  • If at any point an individual indicates that he or she does not want to take part in the research study, the researcher must stop the consent process.

The process for obtaining consent may occur with:

- An adult capable of providing consent. In the US, adults (as defined by State law) may provide consent for themselves. In Minnesota, adults are defined as persons aged 18 or older. Investigators who conduct research outside of the State of Minnesota must follow the law that applies in the local jurisdiction to determine who is an adult who may give legal consent and how consent from adults who lack capacity should be obtained.

- The legally authorized representative (LAR) for an adult who is NOT capable of providing consent. The study must be approved by the IRB to allow enrollment of adults unable to consent prior to seeking consent from an LAR for an adult unable to consent.

- One or both biologic or adoptive parents when the participant is a child; or in the absence of a parent, a person other than a parent authorized under applicable law to consent on behalf of the child to participate in the research. If a potential participant is a child, the study must be approved by the IRB to allow enrollment of children. In Minnesota, anyone under 18 years of age, with few exceptions, is considered a child. Federal regulations require that any person, including a child, who participates in research must do so voluntarily. In general, a researcher must obtain permission (informed consent) from a child's parents and seek assent of the child to participate. Permission is obtained from both parents unless: one parent is deceased, unknown, incompetent, not reasonably available; only one parent has legal responsibility for the care and custody of the child; or the IRB has specifically approved the protocol to allow the permission of one parent.

Minnesota does not have separate state law requirements regarding the use of a legally authorized representative (LAR) for consent to participate in research except for individuals under a civil commitment.* Unless the IRB waives the requirement to obtain consent, when research involves adults unable to consent, permission (consent) must be obtained from an LAR. The HENNEPIN HEALTHCARE IRB follows the informed consent laws applicable to clinical care in Minnesota to determine an acceptable LAR for purposes of providing surrogate consent for adults unable to consent.

When research is conducted in Minnesota, if an individual has a court appointed guardian or a health care agent previously appointed by a health care directive, that guardian or agent must consent.

In the absence of a court appointed guardian or health care agent, the closest adult relative would generally be considered the LAR. If there is more than one individual with the same degree of kinship, it is recommended that all such individuals jointly serve the role. While Minnesota law does not have a required hierarchy for determining LAR, Hennepin Healthcare System (HHS) recommends the following order of priority:

  • Spouse
  • Parents
  • Adult children
  • Adult siblings

IMPORTANT: HENNEPIN HEALTHCARE IRB policy on who is an LAR for research may be different than HHS policy on informed consent for clinical care. Individuals other than those described above may not serve as LARs for research participation. For example, an LAR may not be a member of the clinical or research staff or an employee or beneficiary of the sponsor of the research project.

The study Principal Investigator or authorized designee is responsible for identifying appropriate LARs. For study participants who are HHS patients, researchers must check Epic for documentation of LARs.

Researchers may seek guidance from legal counsel if there are questions about legal authorization for surrogate consent in specific situations. If there are any doubts as to who may serve as an LAR for a research subject, HHS legal counsel must be contacted. The IRB may also consult with HHS legal counsel on who may serve as an LAR under the laws of the jurisdiction in which research is conducted.

Researchers who conduct research outside of the State of Minnesota involving recruitment and consent of participants must follow the laws that apply in the local jurisdiction to determine who and how consent from adults who lack capacity to consent should be obtained.

*Under Minn. Stat. 253B.095, persons under a civil commitment order may not give consent to participate in a psychiatric clinical drug trial unless the court approves the specific drug trial.

For most research, informed consent involves a  written document that provides key information regarding the research. The consent form is intended, in part, to help facilitate the consent process, record that consent was obtained (e.g., signatures),  as well as provide written information that the participant may reference over the course of study participation.

Federal regulations set out the information that must be included in an informed consent document (“elements of consent”). The regulations include a list of elements that are required during every consent process as well as a list of elements that are required under certain circumstances. For additional information on the required elements of consent, see 109 GUIDANCE Informed consent

Consent document templates are available on HRPO website. The templates are designed to help researchers include all applicable consent elements. These templates may also be used to design consent letters, emails, and verbal scripts, to ensure to that all consent elements are included. Use of the HRPO templates is not required. For example, researchers may use sponsor-provided consent forms, so long as the required elements are included.

The following are general tips in creating your consent documents:

  • Use simple language, no higher than 8th grade level, or language that is appropriate to the specific subject population. Consider the environment and context in which the consent is presented to a potential research subject.
  • As much as possible, avoid the use of, or replace, complicated or medical/technical language with lay language to ease subject comprehension. For instance, use action instead of intervention and high blood pressure instead of instead of hypertension.
  • Write in second person so as not to be interpreted as suggestive or coercive.
  • Define any abbreviations and acronyms.
  • Use short, simple, and direct sentences.
  • Be sure that formatting and grammar are consistent throughout the document. Font choice and size are up to you and should be chosen based on your specific subject population; however, be sure both are consistent throughout. Do not format specific sections to over or underemphasize the information provided. For example, don’t use bold or larger font in the payment section, or smaller font in the risks section.
  • Signature blocks on the consent document are important for ensuring the appropriate consent is obtained and only those populations approved by the IRB for inclusion are consented. Prior to submitting a consent document for approval, assess whether the blocks intended for participant signatures are consistent with the research being done. For example, if the study will not include participants who lack capacity to consent for themselves, the signature block should not include a line for a legally authorized representative to sign on the participant’s behalf.
  • The consent document must include a version number and date (e.g., in a header or footer).

NOTE: If the study is approved to use an external IRB and a Hennepin Healthcare consent template is not used, see also 117 GUIDANCE External IRB reliance: localized language for consent forms for language that may need to be incorporated into the consent form.

The following resources are publicly available for suggested lay terms and testing the readability of consent forms:

When consenting study participants, the researcher should consider how the identity of the person providing consent will be verified. For example, verifying someone’s identity may be done using information from some form of official identification, such as a birth certificate, government-issued passport, or a driver’s license. For electronic consenting, use of security questions to confirm an individual’s identity may also be considered.

For studies that obtain consent from participants, researchers must ensure that all items in the signature block of the IRB-approved consent document are complete, including dates and applicable check boxes.

For long form consent documents:

  • Verify that the most current IRB-approved version of the study specific consent document.
  • Obtain signature and date on the consent document from the person providing consent (not applicable if the study has an IRB-approved waiver of documentation of informed consent).
  • Obtain signature and date on the consent document from the study team member obtaining consent. (If consent is obtained remotely, obtain signature and date from the study team member who conducted remote consent upon receipt of the signed document from the consenting party.)
  • If the IRB and/or sponsor requires a witness to consent, obtain witness signature and date on the consent document.
  • Retain the original, signed and dated informed consent document in the study records. As applicable for HHS patients, scan and upload the consent document into the patient’s Epic record.
  • Provide a copy of the signed and dated consent document to the consented party. NOTE: If the study has an IRB-approved waiver of documentation of informed consent, it may still be appropriate to provide the consented party with written information about the study, e.g., via a study information sheet, cover letter, or script when feasible.

For consent of non-English speakers using the short-form process, see section 7. Research with special populations  7.11 When can I use the short form to consent non-English speakers?

When an LAR will provide consent, the prospective participant should still be informed about the study in a manner compatible with the participant’s likely understanding and, if possible, be asked to assent to participate. There may be instances when obtaining assent is impossible (e.g., intubation with deep sedation, severe brain injury, etc.).

When research involves assent for some or all participants, researchers must provide an assent plan in the IRB submission, including:

  • a description of when and how assent will be obtained and documented
  • provisions that will be taken to promote understanding and voluntariness,
  • a copy of the assent form (as applicable)

For adults lacking capacity to consent, see section 7. Research with special populations 7.5 Research involving adults with absent, diminished, or fluctuating capacity to consent to participate in research

For children, see section 8. Children in research, section 8.5 When is child assent required?

For studies in which researchers do not meet in-person with the consenting party, a remote consent process may be approved by the IRB. A remote consent process includes interaction with potential subjects by phone, telemedicine, other institutionally approved synchronous communication applications, such as Zoom, or mail/email. A researcher must describe remote consent activities in the IRB submission (e.g., why it is necessary, how it will be operationalized, documented, etc.). If the remote process includes obtaining verbal consent only, the IRB submission must include a request for a waiver of documentation of informed consent; the IRB approves waivers on a study-by-study basis, based on whether the study meets regulatory criteria. If a study does not meet criteria for a waiver of documentation of informed consent and consent must be obtained remotely, consent documents can be sent to prospective participants by USPS or other mail carrier, or electronically for their signature. See also: 6.6 What is the general process for obtaining consent?

Whether part or all of an electronic informed consent (eIC) process is conducted onsite or remotely, the responsibility for obtaining informed consent remains with the principal investigator and designated study personnel and requires synchronous interaction with potential participants. An investigator cannot delegate authority to obtain informed consent to an electronic system. Digital signatures must also meet state law requirements.

The State of Minnesota made provision for electronic signatures in its Uniform Electronic Transactions Act (UETA) first adopted in the 2000 legislative session. The Minnesota UETA defines electronic signatures as:

An electronic sound, symbol, or process attached to or logically associated with a record and executed or adopted by a person with the intent to sign the record.

The definition above is not technology-specific and does not mandate the use of a particular hardware or software application. Any tool that can authenticate the signer and the signed document can be considered an acceptable electronic signature, as long as the parties can demonstrate the veracity of the process that created and preserved the records in question.

Electronic informed consent may be used to either supplement or replace paper-based informed consent processes to best address participant’s needs throughout the course of the study. For example, some participants may prefer one method over another. Other participants may have difficulty navigating or using electronic systems because of, for example, a lack of familiarity with electronic systems, poor eyesight, or impaired motor skills. For such participants, the eIC process may not be appropriate; therefore, participants should have the option to use paper-based or electronic informed consent methods completely or partially throughout the informed consent process.

In some circumstances, it may be appropriate for researchers to assist participants in using an eIC technology. For example, study personnel may help the participant navigate the consent by clicking on links for the participant.

 

Researchers must describe eIC activities in the IRB submission and attach informed consent documents (e.g., Word or PDF versions). The IRB recommends receiving approval of informed consent documents prior to developing eIC versions. Researchers must submit their finalized eICs (e.g., by providing a link or screenshots) to allow the IRB to confirm the electronic version complies with the IRB approved Word version. In addition, any subject-facing informational materials, such as videos or web-based presentations that will be viewed during the eIC process should be included (e.g., via attachments or links).

IMPORTANT: For FDA regulated research or research data that will be submitted to the FDA in the future as part of a marketing application or other FDA related application, the electronic consent process and platform must meet the requirements of 21 CFR part 11. Failure to comply with 21 CFR part 11 will result in noncompliance and the FDA may determine that the information collected cannot be used. You may contact HHRI IT for details regarding the Hennepin Healthcare REDCap system and e-Consent module Part 11 compliance.

See also: FDA – OHRP Guidance on Electronic Consent

FDA Guidance Document: Use of Electronic Informed Consent Questions and Answers: Guidance for Institutional Review Boards, Investigators, and Sponsors

Digital signatures are acceptable for documentation of informed consent. Electronic, computer, or tablet-based consent documents may facilitate record keeping even when an individual is present and could sign a paper form. There are two forms of digital signatures:

  1. actual signatures on tablets or computers (where an individual uses a stylus or finger to make a representation of their signature) OR
  2. validated electronic signatures on platforms with password entry (such as those used to sign medical notes or electronically write prescriptions). Validated electronic signatures typically require a user to set up an identity and password within an electronic system and may not be easily and rapidly activated.
    NOTE: Scanned signatures that are copied and pasted to a document are not acceptable "digital" signatures for FDA regulated research; for FDA regulated research, the digital signature platform and process must be 21 CFR part 11 compliant.

When using digital signatures to document informed consent, the IRB submission must describe the technologies and processes that will be used. Additionally, if consent is to be conducted entirely remotely with digital signatures, it is important for the researcher to consider how participants’ identity will be validated.

Consent is an ongoing process and researchers should engage participants in consent discussions throughout the lifecycle of the study. While federal human subject research regulations do not reference the term re-consent, the federal regulations at 45 CFR 46.116 (b)(5) and 21 CFR 50.25 (b)(5) do state that, when appropriate, the informed consent document include a statement that significant new findings developed during the course of the research which may relate to the participant’s willingness to continue participation will be provided to the participant.

Examples of when notification or re-consent may be required:

  • Identification of new research-related risks
  • Increase in the frequency or magnitude of previously described risks (e.g., serious cardiac event, severe allergic reaction)
  • Unanticipated problem that exposes subjects to new risks, such as a data breach.
  • Decrease in expected benefits to participation (e.g., limited efficacy of experimental therapy)
  • Change to the research that results in increased burden/discomfort
  • Availability of new alternative therapies (e.g., FDA approval of a new drug or device for the condition under study)
  • Impact of participation on alternative therapies (e.g., investigational agent reduces effectiveness of alternatives or precludes future treatment with standard of care therapy)

The term re-consent means that subjects will go through a complete consent process that supersedes the original consent using a document that contains all required elements of consent and is documented in accordance with the federal regulations. The term notification refers to presentation of new information through other mechanisms, such as a consent addendum or an information sheet.

When circumstances arise necessitating that new information be provided to a research participant, the research team should take into consideration the subject population, the status of the participants, the information to be conveyed, length of the consent document, and the urgency of information.

Methods of providing new information include:

  • Re-consent with a revised full document – Researcher repeats the informed consent process with the revised informed consent document(s) and documents consent following the requirements for documentation of consent.
  • Re-consent with consent form addendum – Researcher presents the new information through the use of an addendum to the original informed consent document and either obtain documentation directly or describe the communication process in the subject’s research records.
  • Letter - The letter should contain the three elements of consent (new information, right to withdraw, and voluntary consent). The nature of the new information would dictate whether participants need to sign and return a copy to the study team. If signature is required, two copies of the letter should be included; one for the participant to keep and one to be returned with signature.
  • Verbal communication - Researchers verbally communicates the new information and document the communication process in each subject’s research records. The documentation should include what information was provided, by whom, and date of the interaction.

Prior IRB approval is required before subjects are informed of new information except when updated safety information requires urgent action. Researchers must promptly notify the IRB of significant new findings and describe plans for notification/re-consent of participants. The IRB determines the method or combination of methods for providing new information to future, current, and/or past participants (i.e., notification, re-consent, both). Regardless of the method used, the researcher must employ an appropriate process for providing subjects with the new information and ascertaining their willingness to continue as well as appropriate documentation, either through documentation of the process in the research record or a signed written document.

The Secretary’s Advisory Committee for Human Research Protections (SACHRP) provides a resource outlining scenarios and notification/consent options based on the significance of the information, whether the information is time-sensitive, and recruitment status of the study.

Low literacy

A person from whom consent is sought who speaks and understands English but cannot read and write is considered to have a low level of literacy. Low literacy individuals can provide consent by making their mark on the consent document instead of providing their signature.

The following steps should be incorporated into the general process for obtaining and documenting consent with a person who has low literacy:

  • Obtain the services of an impartial witness (e.g., not a member of the study team and not a family member) to observe the consent process who can be present during the entire consent discussion to attest to the adequacy of the consent process and to the participant's voluntary consent.
  • Ensure that all written consent materials have been presented orally (and visually, if applicable) during the consent discussion.
  • Consider using a video or audio recording of the consent discussion as part of the documentation of informed consent 

To document consent for a person who has low literacy, IRB requirements are consistent with the March 2018 FDA guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) section 4.8.9:

  • The participant can mark an “X” on the consent signature line or their fingerprint can be captured on the consent signature line
  • The witness must sign and date the consent form. By doing so, the witness attests that the consent information was accurately explained and that the participant apparently understood the information, and informed consent was given freely
  • The study team member obtaining consent must sign and date the consent form 
  • The participant must receive a copy of the consent form. If the study is FDA regulated, the participant must receive a signed copy of the consent form
  • The study team must retain a signed/dated copy of the consent form in the study records
  • The study team should document in the research record the names of all the individuals who were present for the consent process and any procedures the study team used to enhance the participant’s comprehension

Legal blindness

A person from whom consent is sought who speaks and understands English but cannot read consent materials due to blindness is considered legally blind. The following steps should be incorporated into the general process for obtaining and documenting consent with a person who is legally blind:

  • Obtain the services of an impartial witness (e.g., not a member of the study team and not a family member) to observe the consent process who can be present during the entire consent discussion to attest to the adequacy of the consent process and to the participant's voluntary consent.
  • Ensure that all written consent materials have been presented orally during the consent discussion.
  • Consider using a video or audio recording of the consent discussion as part of the documentation of informed consent 
  • If the individual has access to equipment that can read the consent materials for them, provide sufficient time for them to independently review the consent materials

To document consent for a person who is legally blind, IRB requirements are consistent with the March 2018 FDA guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) section 4.8.9:

  • The participant can sign and date the consent form
  • The witness must sign and date the consent form. By doing so, the witness attests that the consent information was accurately explained and that the participant apparently understood the information, and informed consent was given freely
  • The study team member obtaining consent must sign and date the consent form 
  • The participant must receive a copy of the consent form. If the study is FDA regulated, the participant must receive a signed copy of the consent form
  • The study team must retain a signed/dated copy of the consent form in the study records
  • The study team should document in the study record the names of all the individuals who were present for the consent process and any procedures the study team used to enhance the participant’s comprehension

Physical disablement

A person from whom consent is sought who can understand and comprehend spoken English, but is physically disabled, such as unable to talk or write, can provide consent if they are competent and able to indicate approval or disapproval by other means.

The following steps should be incorporated into the general process for obtaining and documenting consent with a person who is physically disabled and cognitively competent:

  • Obtain the services of an impartial witness (e.g., not a member of the study team and not a family member) to observe the consent process who can be present during the entire consent discussion to attest to the adequacy of the consent process and to the participant's voluntary consent.
  • Ensure that all written consent materials have been presented orally (and visually, if applicable) during the consent discussion.
  • Consider using a video recording of the consent discussion as part of the documentation of informed consent 

To document consent for a person who is physically disabled:

  • The participant should indicate their agreement in a predefined manner such as blinking or raising an arm
  • The witness must sign and date the consent form. By doing so, the witness attests that the consent information was accurately explained and that the participant apparently understood the information and informed consent was given freely
  • The study team member obtaining consent must sign and date the consent form
  • The participant must receive a copy of the consent form. If the study is FDA regulated, the participant must receive a signed copy of the consent form
  • The study team must retain a signed/dated copy of the consent form in the study records
  • The study team member obtaining consent must document in the research record the names of all the individuals who were present for the consent process, the method used to communicate with the participant, and the specific means by which the participant communicated agreement to participate

For all such individuals, it is the principal investigator's responsibility to judge their comprehension of the consent information including that participation is voluntary and that a participant has the right to withdraw from the study at any time. If the investigator doubts an individual's ability to provide informed consent, the individual should not be enrolled in the study.

A waiver of informed consent means that the requirement for researchers to obtain prospective consent from subjects is waived; therefore, for research conducted with a waiver of informed consent, individuals are not aware when they become a human subject. For some waiver of consent studies, subjects will be provided information about the study retrospectively and given the opportunity to withdraw. A waiver of informed consent can only be granted approval by the IRB.

A waiver of documentation of informed consent means that researchers must obtain prospective consent form subjects, however, the requirement to obtain a signature from the participant is waived. Researchers who receive IRB approval for a waiver of documentation of informed consent still must perform an appropriate prospective consent process and may be required to provide subjects with written information regarding the research. A waiver of documentation of informed consent can only be granted approval by the IRB.

Depending on the applicable regulatory oversight, a waiver of documentation of consent must meet the regulatory criteria (see below) of DHHS (45 CFR 46.117) and/or FDA (21 CFR 56.109). When the IRB approves a waiver of documentation of consent, it may require the researcher to provide subjects/legally authorized representatives with a written statement describing the research.

A waiver of documentation of consent must be requested via an IRB submission in which the consent process is adequately and accurately described; as applicable, consent-related materials provided to subjects must be attached (e.g., information sheet, cover letter, script).

For research not subject to FDA oversight, a waiver of documentation of informed consent may be approved by the IRB when:

  • The only record linking the participant to the research would be the consent document and, the principal risk to the participant would be potential harm resulting from a breach of confidentiality. In this case, each participant will be asked if they want documentation linking him/her to the research and the participant’s wishes will govern;
  • The research presents no more than minimal risk to the participants and involves no procedures for which written consent is normally required outside of the research context; or
  • If the subjects or legally authorized representatives are members of a distinct cultural group or community in which signing forms is not the norm, that the research presents no more than minimal risk of harm to participants and provided there is an appropriate alternative mechanism for documenting that informed consent was obtained.

For research subject to FDA oversight, a waiver of documentation of informed consent may be approved by the IRB when:

  • The research presents no more than minimal risk to the participants and involves no procedures for which written consent is normally required outside of the research context; or
  • The IRB may, for some or all subjects, find that the requirements in 21 CFR 50.24 for an exception from informed consent for emergency research are met.

An IRB may approve a request for a waiver of informed consent for researcher that meets all of the following criteria:

  • The research involves no more than minimal risk to the subjects;
  • The waiver or alteration will not adversely affect the rights and welfare of the subjects;
  • The research could not practicably be carried out without the waiver or alteration;
  • If the research involves using identifiable private information or identifiable biospecimens, the research could not be practicably carried out without using such information or biospecimens in an identifiable format; and
  • Whenever appropriate, the subjects will be provided with additional pertinent information after participation; see Information sheets below for requirements and standards.

A waiver of consent must be requested via an IRB submission. Researchers must provide sufficient justification that conducting the research with a requirement to obtain consent is not practicable. The justification must provide a thorough rationale for why the research would not be possible without the waiver understanding that practicable does not mean that it is not possible to get consent but rather, it would not be practicable to conduct the research without a waiver. For more information on what not practicable means, see the January 31, 2008 SACHRP letter to HHS Secretary: Recommendations related to waiver of informed consent.

Acceptable reasons for it to be impracticable to conduct research using a consent process include, but are not limited to:

  • Participants are no longer followed or are lost to follow-up (e.g., moved away, deceased, no longer coming to clinic, etc.)
  • There are too many participants to be included in the study to contact them all
  • The scientific validity of the research would be compromised if consent was required (e.g., the research depends on inclusion of all possible participants due to rare condition, limited participant pool, etc.)
  • The sample size required is such that if the researchers only included those for which consent could be obtained, the conclusions could be skewed (e.g., epidemiology studies)
  • Ethical concerns may occur if consent is required (e.g., the only link to participants is the consent, contacting participants could inflict harm on individuals or their families)
  • Considerations of possible inconvenience or burden to the researcher (e.g., convenience, time, costs, etc.), may be part of the overall justification but cannot serve as the sole justification; practicable means possible, not convenient.

IMPORTANT: FDA regulations do not permit waiver of consent for FDA-regulated research with the narrow exception of emergency research; however, in July 2017 the FDA released guidance: IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects, allowing IRBs to waive or alter consent requirements using the Common Rule criteria until the FDA is able to harmonize its regulations with those of the Common Rule for waiver of consent.

NOTE: For Department of Defense (DoD)-funded or supported research, additional considerations for a waiver of informed consent apply—refer to DoD resources.

Information sheets

Human research regulations for IRB approval of a waiver of consent also include a requirement to provide subjects with additional pertinent information after participation, whenever appropriate. Such additional pertinent information is often referred to as an information sheet. Although human research regulations do not address specific requirements, the Hennepin Healthcare IRB considers The Belmont Report's ethical principle, Respect for Persons, to evaluate whether providing additional information to subjects is appropriate and how such information should be provided.

Therefore, when a waiver of consent is requested in an IRB submission, researchers must indicate whether an information sheet will be provided and describe how it will be provided to subjects.

For prospective research that is minimal risk and involves a waiver of consent, Hennepin Healthcare has established the following standards for providing additional pertinent information to subjects post-enrollment:
(NOTE: These standards typically do not apply to retrospective research, e.g., review of existing records)

  • Information must be provided to enrolled subjects to communicate that they may opt out of the study and whether their collected data will be retained if they do so; the IRB generally requires data to be discarded if a subject opts out.
  • Researchers should secure funding for translation costs; depending on the nature of the study and subject population, the IRB may require information to be translated into common non-English languages of HHS patients.
  • A member of the study team must provide information (e.g., IRB-approved study information sheet) directly to subjects or their LAR and document delivery in the study record.
    IMPORTANT: Leaving an information sheet in a patient’s bedside chart or room is NOT an acceptable method of providing information.
  • If the study team is unable to provide information to a subject, this must be explained and documented in the study record.
  • If an enrolled subject/LAR does not speak English and an appropriate translation of an information sheet is not available, the study team should obtain the services of an interpreter to provide the information; the study team must document use of an interpreter in the study record.

The above standards reflect considerations specific to conducting research at Hennepin Healthcare, such as the high likelihood of encountering non-English speaking subjects, in addition to efforts to enhance transparency and trust with Hennepin Healthcare patients and community members.

If a study is a clinical trial and supported by a signatory to the 2018 Common Rule, one IRB-approved version of a consent form that has been used to enroll research participants must be posted on a public federal website designated for posting such consent forms by the awardee or the federal department or agency component conducting the trial. The form must be posted after recruitment closes and no later than 60 days after the last study visit.

At this time, two publicly available federal websites that will satisfy the consent form posting requirement, as required by the revised Common Rule, have been identified: ClinicalTrials.gov and a docket folder on Regulations.gov (Docket ID: HHS-OPHS-2018-0021).

For more information on this posting requirement, visit: https://www.hhs.gov/ohrp/regulations-and-policy/informed-consent-posting/index.html

7. Research with special populations

HENNEPIN HEALTHCARE is designated as one of the essential hospitals in the U.S. due to its function in the community as a safety net. Researchers should evaluate whether additional considerations or safeguards are necessary for vulnerable populations described in this section as well as persons with other types of vulnerability (e.g., economically disadvantaged or disenfranchised, limited English proficiency, etc.). IRB submissions should fully describe considerations regarding vulnerable populations and appropriate additional safeguards.

Vulnerable populations are those research participants who are likely to be vulnerable to coercion or undue influence or lack decision-making capacity, including:

  • Populations that have been designated as vulnerable groups [45 CFR 46.111(b); 21 CFR 56.111(b)], such as children, prisoners, pregnant women, fetuses, neonates, mentally disabled persons, or economically or educationally disadvantaged persons, and
  • Persons who may be vulnerable because of a physical condition, severe illness or pain, psychological or emotional condition, status relationship with a member of the research team, cultural or political factors, or other circumstances

When research intends to involve participants who are likely to be vulnerable to coercion or undue influence or have diminished decision-making capacity, the research must provide additional safeguards to protect the rights and welfare of these participants. The IRB submission must describe the plan for inclusion of vulnerable populations for the IRB to ensure that all of the regulatory requirements for the protection of vulnerable subjects are met and that appropriate additional protections for vulnerable subjects are in place.

The requirements to enroll a vulnerable population vary by the particular population. In all cases, researchers must justify why enrollment of a vulnerable population is important to answer the research question, how it ensures equitable selection of subjects, and generalizability of results. The IRB submission should also describe the additional safeguards in place to protect the rights and welfare of subjects for each vulnerable population that researchers intend to enroll, which will vary based on the nature of the study and the vulnerable population involved. In many cases, special procedures related to recruitment, consent, payments, and ongoing participation may be needed.

Federal regulations [45 CFR 46 Subpart B] require additional safeguards when approving research involving pregnant women and fetuses. The IRB may approve research involving pregnant women or fetuses only if all conditions for research are met provided that the research also meets the general criteria for approval.

If a woman becomes pregnant while participating in a study that has not been approved for inclusion of pregnant women, the IRB must be notified in accordance with reporting guidelines (see 113 GUIDANCE Notifications to HRPO for ceded studies or 133 GUIDANCE New information/Incident reporting for non-ceded studies. The IRB will determine whether the subject may continue in the research, whether additional safeguards are needed, and other determinations, as required by regulation.

NOTE: Hennepin Healthcare currently prohibits this type of research:

  • Transplantation of human fetal tissue into humans
  • Human fetal tissue obtained from elective abortion

Studies in which pregnancy is coincidental to participant selection

A research study in which women of childbearing potential are possible participants or in which pregnant women may inadvertently be enrolled, federal regulations require that, when appropriate, participants be provided a statement as part of the informed consent process that the particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant) which are currently unforeseeable.

In some studies, researchers may need to assure that non-pregnant participants are advised to avoid pregnancy or nursing for a time during or following the research. Furthermore, when appropriate, participants should be advised to notify an Investigator immediately should they become pregnant. In some instances, there may be potential risk sufficient to justify requiring that pregnant women either be specifically excluded from the research or studied separately. When applicable, male participants must also be advised that their partner should avoid pregnancy and informed of potential risks to offspring as a result of participation in research activities.

NOTE: IRB special provisions for research involving prisoners do not apply to:

  • minimal risk research qualifying for expedited review that doesn’t intend to enroll prisoners
  • secondary research that involves no interaction with subjects

The special vulnerability of prisoners makes consideration of involving them as research participants particularly important. Prisoners may be under constraints because of their incarceration that may affect their ability to make a truly voluntary and uncoerced decision whether to participate in research. To safeguard their interests and to protect them from harm, special ethical and regulatory considerations apply for reviewing research involving prisoners. [45CFR46 Subpart C] The IRB may approve research involving prisoners only if these special provisions are met.

DEFINITIONS

Prisoner - any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. [45CFR46.303(c)]

The definition of minimal risk for research involving prisoners differs from the definition of that applies generally to research involving human subjects:

Minimal risk (general) – the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. [45CFR46.102(j)]

Minimal risk (research involving prisoners) – the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. [45CFR46.303(d)]

For research involving prisoners, the definition of minimal risk:

  • refers to physical or psychological harm rather than harm or discomfort
  • compares the probability and magnitude of harm in the research to the probability and magnitude of those harms normally encountered in daily life, or in routine medical, dental, or psychological examinations, rather than in daily life or routine physical or psychological examinations or tests
  • identifies healthy persons as the comparison group against which the risks of the research should be measured, rather than leaving the comparison group unspecified

OHRP certification

For prisoner research supported by the U.S. Department of Health and Human Services (DHHS), the IRB will notify the U.S. Office of Human Research Protections (OHRP) and certify that the requirements for prisoner research have been met. OHRP will review the IRB’s determination. Only if OHRP concurs, may the research proceed. For OHRP guidance, see Prisoner Involvement in Research.

What happens if a participant becomes a prisoner during a study?

If a participant becomes incarcerated while participating in a study that has not been approved for inclusion of prisoners, the IRB must be notified in accordance with reporting guidelines (see 113 GUIDANCE Notifications to HRPO for ceded studies or 133 GUIDANCE New information/Incident reporting for non-ceded studies. The IRB will determine whether the subject may continue in the research, whether additional safeguards are needed, and other determinations, as required by regulation.

See also: section 3.Using Cayuse HE – 3.9 How do I request IRB review of incidents/reportable information?

Adults with impaired, fluctuating, or diminishing decision-making capacity are particularly vulnerable. Researchers must carefully consider whether inclusion of such subjects in a research study is appropriate; and when it is, how best to ensure that these subjects are adequately protected. Research involving adult subjects without the ability to provide consent or with impaired decision-making capacity should only be conducted when the aims of the research cannot reasonably be achieved without their participation.

Researchers planning to enroll adult subjects in a research study who have a condition known to cause diminished functional abilities that affect capacity to consent must provide a detailed plan and justification for including individuals with impaired, fluctuating, or diminishing capacity and use of an LAR in the IRB submission. If persons with questionable, impaired, or fluctuating capacity may be enrolled, researchers must specify procedures for assessing their capacity prior to providing informed consent and, if appropriate, for re-evaluating ongoing capacity to consent.

If a prospective subject’s capacity to consent is expected to diminish over time, the researcher may be required to request designation of a future LAR at the time of initial consent and/or written documentation of the subject’s wishes regarding the study. When the study includes subjects likely to regain capacity to consent, the researcher should include future provisions to inform them of their participation and seek consent for ongoing participation, as applicable. For research involving subjects who may have fluctuating or declining decision-making capacity, the IRB may require periodic re-evaluation of capacity and/or periodic re-consent.

Decision-making capacity

Decision-making capacity refers to a potential subject’s ability to make a rationale and meaningful decision about whether or not to participate in a research study. This ability is generally thought to include at least the following four elements:

  • understanding of the nature of the research and participation in it;
  • appreciation for the consequences of participation;
  • ability to consider alternatives, including the option not to participate; and
  • ability to make a reasoned choice. A reasoned choice should not be equated with the choice that would be considered reasonable by most people; it is simply a choice that has been considered by the individual and is logically consistent with that specific individual’s stated values.

Decision-making capacity should not be confused with the legal concept of competence. While the courts may consider information about a person’s decision-making capacity in making a competency determination, the terms are not synonymous. Incompetence is a legal determination made by a court of law. For example, someone who is judged legally incompetent to manage their financial affairs may retain sufficient decision-making capacity to make meaningful decisions about participating in a particular research study. Persons who have normal cognitive functioning and are considered legally competent may be put into circumstances where their decision-making capacity is temporarily impaired by a physical or mental condition or by alcohol or drugs. It is important to note that capacity to consent does not equate to competency or even cognitive ability of a certain degree. For example, individuals who have a cognitive impairment such as slight dementia may, based on the factors above, have capacity to consent.

Researchers should not to equate physical incapacity with lack of capacity to consent. Potential subjects who retain consent capacity but lack ability to provide written signature should still provide consent and the study team should consider alternate mechanisms for allowing the subject to demonstrate their consent to participation.

Capacity to consent impairment

Capacity to consent impairment may occur with a wide range of conditions and disease states and is not limited to specific medical or psychiatric disorders. The capacity to consent is task-specific and depends on the nature and complexity of the proposed study and study procedures and may even be impacted by the decision-making process itself. It is not a static phenomenon and may improve, deteriorate, or fluctuate over time.

Researchers should present a plan for assessing potential participants’ consent capacity when the target population includes individuals whose consent capacity is likely to be in question for any reason. This includes, but not limited to, individuals with any of the following conditions or disorders:

  • under the influence of drugs or alcohol
  • sedated or unresponsive
  • acute medical conditions
  • neurological disorders
  • psychiatric disorders
  • traumatic brain injury or other acquired brain injury or disorder including potentially temporary conditions affecting brain function, such as delirium
  • dementia or other progressive brain disorder (e.g. Alzheimer’s Disease)
  • intellectual disabilities and/or developmental disorder

For some participants, consent capacity may vary from day-to-day or deteriorate over time. For such participants, consent capacity should be reassessed on a regular basis depending on changes in their underlying condition. If a participant no longer demonstrates consent capacity, and the researchers have not documented at the time of initial consent whether the subject would like ongoing consent to involve their LAR in the event their consent capacity diminishes, steps should be taken to obtain LAR consent. Conversely, if a participant was originally consented via an LAR and later regains consent capacity, consent should be obtained from the participant.

Capacity to consent assessment

When research involves adults who may have an impaired capacity to consent, researchers must submit a detailed plan for assessing capacity that includes information on which individuals will be assessed, timing of assessment, tools that will be used to be assess capacity, and any recruitment presumptions. While many participant populations may be presumed to have capacity until the study team receives information otherwise, circumstances for specific populations must be considered. For example, participants who are sedated or unresponsive should be presumed to lack capacity, unable to complete an assessment, and require an LAR to consent on their behalf.

See also section 7.6 How do I assess capacity to consent?

For adults lacking capacity to consent, the following are considerations for assent:

  •  Assent (affirmative agreement) should be sought unless the capability of the adult is so limited that the adult cannot reasonably be consulted or the IRB determines that assent is not a requirement.
  • A study should be explained to the extent possible using language that is appropriate and/or cognitively consistent with the adult’s ability to understand, including: an explanation of the research procedures, a description of any risks, discomforts, or inconveniences that may be experienced, and assurance that the he/she can withdraw from the study at any time.
  • If an adult lacking capacity to consent indicates that he or she does not want to take part in the research study, the assent process must stop.

The appropriate mechanism for conducting an assessment varies from study to study and should be based on several factors, including level of risk, potential for direct benefit to subjects, and the likelihood that potential subjects will have capacity. Informal approaches such as the teach-back method may be appropriate for studies that are easy to explain or that enroll subjects who are likely to have capacity. In this method, the study team asks potential subjects directed questions about the study to assess the potential subjects’ capacity based on the abilities described above. Questions might include:

  • In your own words, can you tell me why you are doing this study?
  • What will happen if you take part in this study? What will we ask you to do?
  • Do you have a choice about taking part in this study?
  • What are the risks of being in this study? What side effects might you experience?
  • What are the benefits of being in this study?

Complicated clinical trials enrolling subjects whose capacities vary and that present greater than minimal risk to subjects may call for a more formal, intensive assessment mechanism such as the MacArthur Competence Assessment Tool for Clinical Research [MacCAT-CR]. In some cases, assessment by an independent, qualified assessor other than a researcher involved in the study may be appropriate, e.g., when the risks of the research are more than a minor increase over minimal or when the researcher is in a position of authority over a prospective participant. Researchers should identify an appropriate mechanism and describe the assessment plan in their IRB submission. Cognitive assessments such as the mini-mental state examination (MMSE) are designed to assess cognitive function and should not be used as a stand-alone demonstration that consent capacity exists. If the MMSE is used, it should only be as part of a broader effort to determine capacity.  Assessments of capacity must be documented in the study record, and when appropriate, in the patient's medical record.

If it is determined that a potential research participant cannot provide informed consent based on a capacity to consent assessment, consent must be obtained from a legally authorized representative (LAR). The study must be approved by the IRB to include consent by a LAR.

The LAR should be provided with the same information during the informed consent process that would be given to the potential research participant. If the LAR provides consent on the participant's behalf, the researchers should provide updates to the LAR with about the participant’s status and any new information that may affect the LAR’s willingness to permit the participant to continue in the study.

Under Minnesota law, an incapacitated adult who has a court appointed guardian or conservator may not receive experimental treatment of any kind unless:

  • the court first approves the treatment through a court order; or
  • the court’s guardianship order specifically authorizes the guardian to consent for research participation in addition to medical treatment generally.

Experimental treatment is defined under Minnesota Rules as drugs, therapies, or treatments that are unproven, have been confined largely to laboratory use, or have progressed to limited human application and trials and lack wide recognition from the scientific community as a proven and effective measure of treatment.

Minnesota law specifically addresses inclusions of persons under involuntary hold and commitment proceeding in clinical drug trials:

  • All clinical drug trials: Under Minnesota law, researchers are prohibited from enrolling a patient on an involuntary hold (72‐hour emergency admission hold, peace officer transport hold, or court apprehend‐and‐hold order) into any clinical drug trial. This provision does not prohibit a patient from continuing participation in a clinical drug trial if the patient was participating in the drug trial at the time of the emergency admission or peace officer/court hold.
  • Psychiatric clinical drug trials: Under Minnesota law, a person who has had a commitment hearing and is released by the court before a commitment order is issued cannot be enrolled or participate in a psychiatric clinical drug trial during the period of a stay of commitment unless the court specifically authorizes the participation.

The governing principles of human subject research require that subjects are not excluded based solely on their inability to read, speak, or understand English. Federal regulations state that informed consent shall be in language understandable to the subject or the representative.

While persons should not routinely be excluded from participation in research simply because they do not understand English, researchers must carefully consider the ethical ramifications of enrolling or excluding potential participants when a language barrier exists between themselves and some or all of the potential participants. Because non-English speaking individuals may not fully understand what they are consenting to, it may not be appropriate to enroll such individuals in:

  • early phase clinical trials without a prospect of direct benefit and that enroll only a limited number of participants;
  • greater than minimal risk research without the prospect of direct benefit; or
  • when interpreters will not be readily available throughout research

Researchers who intend to enroll individuals with limited English proficiency must provide certified, translated versions of the full study consent form and other key study documents into the language(s) they expect to encounter. Researchers must also obtain the services of a qualified interpreter to facilitate the consent process and ongoing study participation.

Researchers are responsible for ensuring that:

  • Translation of documents is conducted by a reputable translation service
  • All study documents for participants (e.g., study questionnaires, instruments, information sheets, or other materials) have obtained written translation in the language(s) of the non-English speaking populations expected to be enrolled in the study
  • All translated study document(s) and their certifications are submitted to the IRB
  • As applicable, fully translated study documents are provided to individuals who previously consented using a short form for the translated language
  • Interpreters are available for all study visits and other communications with non-English-speaking participants. Any study personnel who serve to interact with non-English speaking participants in their language must be fluent in that language and in English. Such study personnel are required to complete language fluency certification requirements (see below: How to obtain non-English language fluency certification for study personnel) prior to engaging in non-English communication tasks for a study.

During the consent process, the study team member conducting consent is responsible for presenting the information in the English version of the study’s consent document verbally to the potential participant and for ensuring that the potential participant understands the information as the interpreter translates the study team member’s presentation.

Interpreters/certified study personnel may participate by phone or videoconference for research that has fully translated consent documents; in such circumstances, they are not required to sign the consent form; however, interpreter services by phone or videoconference must be documented in the consent document(s) and study records. Also, it is important that technology issues do not interfere with the consent discussion.

Related: 605 TEMPLATE for the interpreter statement used to document how the interpreter was present.

Translation services

  • Contact a translation service – the service used by Hennepin Healthcare System (HHS) is LanguageLine Solutions, languageline.com (800) 878-8523
  • Request a quote from the translation service for the study materials to be translated
  • Ensure the study budget has sufficient funds for all translation costs; researchers should contact their grant administrator to request a contract amendment if translation services exceed the originally budgeted amount

To reduce translation costs, it is recommended that you obtain IRB approval for your English-language consent document before seeking translation of it. After approval of the English consent, have it translated into the desired language(s) and submit the translated document(s) in Cayuse HE as a Modification along with the Certificate of Translation.

NOTE: Exempt research does not require certified translations and the translation can be completed by the researcher if he or she is a native speaker of the language or other appropriate mechanism. However, researchers must provide an attestation that the translation accurately depicts the study information. The attestation should be provided in the IRB submission.

Interpreter services

For non-English speaking participants, researchers may contact HHS Interpreter Services when an interpreter is needed. Alternatively, a certified member of the study team may serve as an interpreter.

How to obtain certification as an interpreter:

  • Call HHS HR (3-2277)
  • Provide account number to charge cost of test
  • Provide contact information for study team member to be tested
  • HHS HR will reach out to the study team member directly to schedule the exam
  • Once complete, the certification documentation must be provided to the EQ office
  • The Study personnel section in the IRB submission must describe the study member's role as a certified interpreter

NOTE:

    • HCMC works with an outside testing company
    • Exam cost: $150 per person
    • Staff member will be sent two days to choose from with 3 hours of availability each
    • Exam time: 30 minutes over-the-phone

How to obtain non-English language fluency certification for study personnel

Process

  • Contact HHS HR via HRsolutioncenter@hcmed.org
    • Provide account number to charge cost of test
    • Provide contact information for study team member to be tested
  • HHS HR will reach out to the study team member directly to schedule the exam
  • Once complete, the certification documentation must be provided to the EQ office (EQ@hhrinstitute.org)
  • The Study personnel section in the IRB submission must describe the study member's role and non-English language fluency certification

Requirement

Non-English spoken language study staff must have passed the ACTFL Oral Proficiency Interview (OPI) with a minimum score of Advanced-mid in the non-English language interpreted.

Additional information:

  • HHS works with an outside testing company
  • Exam cost: $150 per person
  • Staff member will be sent two days to choose from with 3 hours of availability each
  • Exam time: 30 minutes over-the-phone
  • Certification completed by an organization other than HHS’s contracted agency will be evaluated by the EQ office on a case-by-case basis

IMPORTANT: For studies relying on an external IRB, researchers should follow this guidance on use of short forms UNLESS the external IRB’s requirements regarding the use of short forms/full translation is more restrictive, in which case, the external IRB’s requirements must be followed.

A short form may be used when an unexpected need arises to consent non-English speakers. The available short form consent documents are posted on the HRPO website. If the language you need is not available, you must have the English short form translated into the appropriate language and submitted to the IRB for approval prior to use. A short form should not be used for studies that anticipate enrolling non-English speakers, i.e., consent documents should be fully translated into the languages of the anticipated populations.

The short form consent document attests that required elements of informed consent have been presented verbally to the participant or the participant's legally authorized representative.

Use of the short form method also requires:

  • A qualified interpreter to assist in verbally presenting the IRB-approved informed consent information to the subject
  • An impartial witness (e.g., not a member of the study team and not a family member) during the consent process who:
    • reads, speaks, and writes the native language of the participant and English
    • can be physically present for the oral presentation of the study-specific details
    • is willing to sign and date the short form consent
    • is willing to sign and date the IRB-approved English version of the consent form

NOTE: The interpreter may also serve as the witness

Short forms vs fully translated documents

Targeting non-English speakers? Short form method allowed? Fully translated study consent document(s) required?
YES NO YES
NO - 1-3 participants of a particular language

Yes – up to 3 times for a particular language

The study must have current IRB approval for use of the short form method AND
researchers must complete an IRB Incident submission within 7 working days of short form use

NOTE: After the second use of the short form in a particular language, researchers should seek full translation of informed consent document(s) into that language for future use

NO
NO - 3+ participants of a particular language

NO – after it has been used 3 times for a particular language; consent document(s) must be translated for the fourth (and subsequent) use with participants of that language

Certified translated document(s) must be submitted to the IRB via Modification submission to obtain approval prior to use.

YES

For short form consent documents, the study team member conducting consent:

  • Verifies that the most current IRB-approved version of the study specific consent document is being used with the short-form consent document of the appropriate language.
  • Obtains the services of an interpreter fluent in both English and the language understood by the person providing consent who can present the consent materials orally and support the consent discussion.
  • Obtains the services of an impartial witness who is fluent in both English and the language spoken by the person providing consent who can be present (with the participant and study personnel) during the entire consent discussion to attest to the adequacy of the consent process and to the participant’s voluntary consent.
  • Retains the original, signed and dated informed consent documents in the study records. As applicable for HHS patients, scan and upload the consent document into the patient’s Epic record.
  • Provides a copy of the signed and dated short form consent document AND English consent to the consented party.

Short Form Consent – Who signs what?

Participant

The participant must sign the short form consent document and the stand alone HIPAA authorization* if HIPAA oversight applies to the study.

Researcher Obtaining Consent

The study personnel obtaining consent must sign the English consent document.

Interpreter

The interpreter only signs study materials if they will also serve as the impartial witness. See below for what the witness must sign.

Impartial Witness

The witness must sign the short form consent, the English consent document, and the stand alone HIPAA authorization, if HIPAA oversight applies to the study.

Related: 605 TEMPLATE for the witness statement to be used with the short form consent process.

*When research is approved to use the short form consent process and HIPAA oversight applies, a stand-alone HIPAA authorization must be included in the study materials in order to obtain all necessary signatures.

Use of the short form consent process with research which also uses an electronic remote consent may not be feasible, as an impartial witness must be physically present with the participant. In this situation, the IRB may require use of translated materials.

If research plans to enroll non-English speakers, the study team should have the HIPAA authorization (or if using a combined Informed Consent and HIPAA authorization) translated into the appropriate language(s).

If research is approved to use the short form consent process (i.e., unexpected encounters of non-English speakers), a stand-alone HIPAA authorization must be used. An interpreter must verbally translate the stand-alone HIPAA authorization to the potential participant, the participant must sign the English version of the form and be provided a copy. Use of an interpreter to obtain HIPAA authorization must be documented in the research record.

In order to recognize the autonomous authority of sovereign nations and acknowledging the need for community awareness and permission for access, the IRB requires Tribal approval for research that is to be conducted within the jurisdiction(s) of federally-recognized American Indian and Alaska Natives (AIAN) Tribal government(s). You will need to secure approval from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council.

The form of documentation of approval may vary according to tribal requirements. In instances where more than one tribe or band is involved in the research project, separate permission from each entity may be required. Additional IRB or other research committee review or approval may also be required by the Tribe. In those cases, final approval by the Hennepin Healthcare IRB will be contingent upon Tribal approval. The IRB applies this requirement to all research, irrespective of funding source or rank or ethnic/racial identity of the researcher.

8. Children in research

DEFINITION

Children are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. [45CFR46.402](a) In the State of Minnesota, persons who are under the age of eighteen and, unless specified otherwise, are considered children.

The special vulnerability of children makes consideration of involving them as research participants particularly important. To safeguard their interests and to protect them from harm, special ethical and regulatory considerations apply for reviewing research involving children. Federal regulations [45CFR46 Subpart D; 21CFR50 Subpart D] limit research involving children to those activities which meet one of four categories of research, which are based on the level of risk and potential for benefit to the individual participant.

Categories of research that can be approved to involve children

The IRB considers the degree of risk and discomfort involved in the research in relation to the direct benefits it offers to the child in order to determine whether the study is approvable under the federal regulations. The IRB may approve studies involving children only if the research falls into one of the below categories:

  1. Research involving no greater than minimal risk [45 CFR 46.04; 21 CFR 50.51]
    • If the IRB determines the interventions or procedures present no more than minimal risk to children, the research is approvable under this category regardless of whether there is a prospect of direct benefit to the child. Minimal risk is based on the daily lives of healthy children. Procedures that are deemed minimal risk in a healthy population may not be deemed minimal risk when considered in a population suffering from a disease or condition.
    • The IRB will determine if the permission of one parent/legal guardian is sufficient for participation in the research approved under this category.
  2. Research involving interventions or procedures that present greater than minimal risk but offers the prospect of direct benefit or may contribute to the well-being of the individual child [45 CFR 46.405; 21 CFR 50.52]
    • Most therapeutic medical trials that hold out the prospect of direct benefit to the child may be approvable under this category. Phase I trials and placebo-controlled trials often do not hold out the prospect for direct benefit to participants and may not be approvable under this category.
    • This category extends benefit to studies that include a monitoring procedure that is likely to contribute to the child's well-being.  Any benefit of monitoring must be an objective of the study and cannot be incidental.
    • The IRB will determine if the permission of one parent/legal guardian is sufficient for participation in the research approved under this category or if both parents’ permission is necessary.
  3. Research involving interventions or procedures that present a minor increase over minimal risk and no prospect of direct benefit to individual children, but likely to yield generalizable knowledge about the child's disorder or condition [45 CFR 46.406; 21 CFR 50.53]
    • The risk involved with each procedure must represent a minor increase over minimal risk.
    • The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and
    • The intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition.
    • Both parents must provide permission for the child to participate in research approved under this category.
  4. Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children [45 CFR 46.407, 21 CFR 50.54]
    • If a proposal involving children cannot be adequately justified in one of the above three categories, the IRB must either disapprove the research, or:
      • For DHHS-regulated research, the IRB can refer research in this category to the S. Secretary of DHHS, who then consults with a panel of experts and allows for public review and comment to make the determination.
      • For FDA regulated research, the IRB can refer research in this category to the S. Commissioner of Food and Drugs, who then consults with a panel of experts and allows for public review and comment to make the determination.
      • For all other research, the research may proceed only upon written approval from Hennepin Healthcare System Administration.
    • Before the IRB refers a project, it must first find that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.
    • Both parents must provide permission for the child to participate in research approved under this category.

Children may be included in research only if parental permission is obtained in writing from the parents or legal guardian, except where the IRB has explicitly waived such permission or in cases where the child has authority to provide effective legal consent (see Child consents below. Federal regulations have specific requirements for obtaining permission from parents or legal guardians that are based upon the category of approval:

§46.404/§50.51 Minimal Risk One or both parents’ permission, as determined by the IRB
§46.405/§50.52 Greater than minimal risk with prospect of direct benefit One or both parents’ permission, as determined by the IRB
§46.406/§50.53 Greater than minimal risk, without prospect of direct benefit, likely to yield general knowledge about the subject’s disease or condition Both parents’ permission required by regulation, when reasonably available
§46.407/50.54 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children Both parents’ permission required by regulation, when reasonably available

 

Researchers must make adequate provisions for soliciting the permission of each child's parents or legal guardians. Because children are often recruited from clinic visits, both parents may not be with the child when the research consent process takes place.  The principal investigator is responsible for determining whether the absent parent is reasonably available.  For example, a parent that is unknown, incarcerated, uninvolved in the child’s life, deceased, or deployed may be considered not reasonably available; however, context and circumstances need to be very carefully considered.  When attempts are made to contact a parent, the attempts need to be documented in the study record along with the entire consent process.

If a parent has sole legal responsibility for a child, permission from that parent is sufficient for participation; the parent must provide documented proof of the custody arrangements.

Even though an agency may acquire legal authority to place a child through a voluntary placement agreement between the agency and the child’s parent, this does not mean that the agency has the authority to make major life decisions regarding the child, including major medical decisions (https://www.revisor.mn.gov/statutes/2011/cite/260D.02 ​(subd. 11)). As such, a parent retains the authority to provide legal consent for their child in foster care unless the parent has been stripped of parental rights or has agreed to relinquish parental rights​​ through a court proceeding. However, if parental rights have been stripped or voluntarily relinquished and the child has not been adopted or placed in the custody of relatives, the child would be a ward of the state (https://www.revisor.mn.gov/statutes/cite/260C.515).

Researchers must consider how encounters with children in foster care will be conducted and the implications for obtaining parental permission in these situations. Such encounters may require consultation with legal counsel.

IMPORTANT: Under Minnesota law, a minor who has a court appointed guardian may not receive experimental treatment of any kind unless:

  • the court first approves the treatment through a court order; or
  • the court’s guardianship order specifically authorizes the guardian to consent for research participation in addition to medical treatment generally.

Experimental treatment is defined under Minnesota Rules as drugs, therapies, or treatments that are unproven, have been confined largely to laboratory use, or have progressed to limited human application and trials, and lack wide recognition from the scientific community as a proven and effective measure of treatment.

For non-FDA regulated research involving children, a waiver may be granted if the IRB determines that the research is designed for conditions or for a subject population for which parental/guardian permission is not a reasonable requirement to protect the children (e.g., neglected or abused children). For such research, a waiver may be granted only when an appropriate mechanism exists in lieu of parent permission to protect children and the waiver is not inconsistent with federal, state, or local law.

The requirements for informed consent as well as criteria for waiver approvals also apply to parental permissions.
See 6. Obtaining informed consent  6.20 When can the IRB approve a waiver of consent?

Assent is the affirmative agreement of the child to participate in the research.  It is important to note that a child’s mere failure to object does not constitute assent.  The IRB will evaluate the research and determine if assent is required for none, some or all of the child subjects; researchers must provide adequate information in the submission for the IRB to consider age, maturity, and psychological state of the children involved. The IRB’s determination regarding assent may apply to all children or only certain children to be involved in a given research study, as the IRB deems appropriate.

For children, the following are considerations for assent:

  • Federal regulations do not specify any of the elements of informed assent and do not provide an age at which assent ought to be possible. The HENNEPIN HEALTHCARE IRB does not have a specific age for when assent is required and will make the determination as to whether assent is required on a study-by-study basis. In determining whether children are capable of assenting, the IRB takes into account the ages, maturity, and psychological state of the children involved. The IRB determines whether all or some of the children are capable of assenting.
  • Assent (affirmative agreement) should be sought unless the capability of the child is so limited that the child cannot reasonably be consulted or the IRB determines that assent is not a requirement. In general, the IRB recommends, when appropriate, that children under age 7 should be assented verbally and 7+ assented in writing.
  • A study should be explained to the extent possible using language that is age appropriate and/or cognitively consistent with the child’s ability to understand.
  • The researcher should give the child information that includes: an explanation of the research procedures in language appropriate to the child, a description of any risks, discomforts, or inconveniences that the child might experience, and assurance that the child can withdraw from the study at any time.
  • When documentation of assent is required, the researcher must create an assent form that is age-appropriate and study-specific, taking into account the typical child's experience and level of understanding to convey the essential information about the study.
  • If a child indicates that he or she does not want to take part in a study, the assent process must stop.

When assent will be obtained, researchers are responsible to determine the manner in which it is obtained and to describe the assent process in their IRB submission. The assent process may be documented in a number of ways. For instance:

  • When child/adolescent participants provide written signature as part of the assent process: a separate assent form may be used or an assent signature area may be added to the main document used to obtain parental permission
  • When child/adolescent participants provide verbal assent: researchers must document verbal assent in their study records (including date and time verbal assent was obtained, any questions or concerns the child/adolescent expressed during the process, the resolution of those questions and concerns, and the study team member obtained the verbal assent)

 Waiver of assent: The IRB may consider waiver of assent requirements under the following regulatory criteria:

  • The child is incapable of providing or communicating assent;
  • The study intervention offers the prospect of direct benefit to the child that is only available through research;
  • The study is conducted by, or subject to the approval of, public officials and concerns public service programs and could not be carried out without the waiver; or
  • The research involves no more than minimal risk, the waiver will not adversely impact the rights and welfare of the participants, the research would be impracticable without the waiver, and when appropriate additional information will be provided to the children.
  •  

NOTE: In circumstances where the research involves an option for a child whose illness has not responded to other available treatments or for whom standard therapies are not suitable, it is unlikely that a child’s refusal to participate would be honored. In such cases, it is more appropriate to provide children with an information sheet that contains the same information as an assent form would, but without the indication of choice. This respects the child’s right to understand the research and what will happen to him/her, while acknowledging that there are situations in which a parent’s authority must override the wishes of the child.

In Minnesota, minors may provide consent for their own medical treatment in two contexts:

  1. Confidential minor services

Minors may provide consent for their own medical treatment for confidential minor services: services for which a minor can give consent and the consent of a parent or other person is not required, such as:

    • care related to pregnancy (including birth control),
    • care related to STDs,
    • care related to drug or alcohol dependency,
    • hepatitis B vaccination, and
    • admission of a 16 or 17-year-old for treatment of a mental illness.
  1. Emancipated minors

Emancipated minors are allowed to give effective consent for any medical services. An emancipated minor is a person:

    • living separately from parents or guardians (with or without the consent of a parent or guardian) and who is managing their own personal financial affairs, regardless of the source or extent of income; OR
    • who has been married; OR
    • who has given birth; OR
    • declared by a court to be emancipated. Minnesota statute 144.343 addresses requirements for parental notification before a minor may undergo an abortion.

For research in which minors that have authority to consent under these conditions, researchers may seek guidance from HHS legal counsel regarding Minnesota law and/or consider whether the research qualifies for a waiver of parental permission.

NOTE: For research conducted in jurisdictions other than Minnesota, the research must comply with the laws regarding the legal age of consent in the relevant jurisdictions.

Children who turn 18 while they’re actively participating in a study must consent on their own behalf.  Researchers can obtain consent for such a circumstance in two ways:  

  • Have subjects sign the study’s IRB-approved main consent document(s) when they turn 18 years of age
  • Incorporate a section into the consent/assent document that addresses consent for continued participation for a subjects' review and signature in the event they may turn 18 during the course of a study

9. Privacy and confidentiality

Maintaining research data securely with the appropriate level of anonymity, confidentiality, and de-identification is a key factor to ensuring a low risk threshold for the human subjects associated with that data, as well as the researchers and the institution.   

Researchers are expected to include in their IRB submission a data management plan that adequately describes measures to ensure confidentiality and protection of data that could be associated with individuals or groups using mechanisms that are appropriate to the medium in which the data are collected, analyzed, stored, or transmitted. Researchers may also consider whether a waiver of written documentation of consent is appropriate to reduce the collection of personally identifiable, e.g., when the consent form is the only link to the identity of a subject.

In addition, researchers must ensure that the electronic systems, devices, and other resources used to store, transmit, or process research data comply with HHRI and HHS information security processes and standards. If research will involve the use of any non-standard technology for data collection and management, researchers are responsible for appropriate institutional approval of such use, e.g., via the HHRI office of Information Technology & Services.

Refer to HHS and HHRI IT policies for additional information.

Generally, yes; however, if researchers plan to store study related documents, including source documents (such as informed consent documentation) electronically, they must ensure that a standard operating procedure is followed to scan, certify, and store materials electronically. For example, source documents/consent forms should be scanned individually with labeling on each page to appropriately identify the document. The person who certifies the scanned copy as an accurate and complete representation of the original, having all the same attributes and information as the original, should be the same person who actually created the electronic copy from the original.

Researchers must comply with specific sponsor requirements regarding use of electronic records. For FDA-regulated research, systems and processes must be FDA compliant (including 21 CFR Part 11). For questions regarding 21 CFR Part 11 compliance, please contact the HHRI office of Information Technology & Services.

The GDPR may apply if researchers are participating in research that involves the European Union (EU). The GDPR regulates collection, storage, and processing of any personal data collected from individuals present in the EU at the time the information is collected. For example, research or other sponsored activities involving the collection of such regulated personal data, including clinical trials with subjects in the EU, is subject to GDPR requirements. Responsibility for GDPR compliance should be explicitly determined with EU collaborators, EU subrecipients, and any third-party used for processing of data (including storage and analysis). Consent form content, personal data handling, and reporting (e.g., in the event of a breach of confidentiality) are all governed by the GDPR.

A Certificate of Confidentiality (CoC) protects the privacy of research participants by prohibiting forced disclosure of their individually identifiable, sensitive research information to anyone not associated with the research, except when the participant consents to such disclosures or in other limited, specific situations. The intent of a CoC is to prevent forced disclosure of identifiable participant information (e.g., in response to a subpoena or other legal demand); it is not to withhold this information from individuals at the research institution who need access to perform their job duties (e.g., information needed for scheduling a participant for a study visit).

For complete information, visit: Certificates of Confidentiality (CoC) | grants.nih.gov.

CoCs for research funded by NIH

All ongoing or new research as of December 13, 2016 that is:

  • funded wholly or in part by the NIH and
  • collects or uses identifiable, sensitive information

will be automatically issued a Certificate of Confidentiality as a term and condition of the NIH grant award. NIH will no longer issue a separate document. The Notice of Award and the NIH Grants Policy Statement will serve as documentation of the Certificate protection.

CoCs for research not funded by NIH

NIH will consider requests for Certificates of Confidentiality for specific research projects that are not funded by NIH, e.g., research funded by other federal agencies or non-federally funded research. These considerations include if the research project is: 

To request a CoC for research not funded by NIH, access the online system: Certificates of Confidentiality (CoC) | grants.nih.gov

Researcher responsibilities

Researchers must comply with the responsibilities associated with the CoC, as applicable, such as protecting access to subject identifiers and including language about the CoC in the consent document. Sample language is included in HHRI consent templates available on the HRPO website.

In the event that a researcher receives a subpoena or any other legal process request seeking disclosure of research records, the researcher should contact HRPO; no records or information can be released prior to approval from Hennepin Healthcare legal counsel.

Printed data:

  • Keep records in a secure location such as a locked office or file drawer
  • Assure that only appropriate study personnel have access to records
  • Limit public access to areas containing research records
  • Original records should not be removed from the source location or from an approved research site
  • Do not leave records unattended
  • Do not bring records home

Electronic data:

  • Keep computer resources including laptops, flash drives and external hard drives in a secure location such as a locked office or storage area
  • Do not leave resources unattended
  • Do not store data on a personally owned computer
  • Store study data on a designated institutional secure server
  • Position computer monitors or add a privacy screen to minimize viewing by others
  • Do not share passwords with other research personnel

Face-to-face data collection:

  • Conduct interviews/study visits in a private location so that subject information will not be overheard
  • Use video, audio, or supplementary media in a private location when possible so that subject information will not be overheard
  • Store all paper or electronic records from face-to-face data collection as outlined above
  • When using a cloud-based video conferencing platform such as Zoom or Microsoft Teams, ensure the version is not a personal account and is HIPAA compliant. HHRI IT will be able to provide details about specific versions

De-identify subject treatment or diagnostic records before sending to sponsor:

  • Remove or obscure all individual identifiers based on the HIPAA identifier list
  • Remove identifiers within a document body as well as the subject’s name and medical record number
  • Ensure that identifiers cannot be discerned after obscuring
  • Ensure that all identifiers cannot be seen when source record copied or scanned (wax pencil suggested for redaction of paper documents)

10. HIPAA

The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule governs the use and release of a patient's Protected Health Information (PHI), by a covered entity. Research is subject to HIPAA when research personnel: 

  • are part of a covered entity or receive information from a covered entity, and;
  • access, use, collect, or generate protected health information (PHI) for any part of the research, including recruitment.

To use and/or disclose PHI for research purposes generally requires either a signed authorization from the individual or a waiver of authorization. The Hennepin Healthcare IRB can grant a waiver of HIPAA authorization to permit use and/or disclosure of PHI for research purposes. An IRB may also approve an alteration of the requirements of written HIPAA Authorization provided the research meets the criteria for waiver or alteration (see below for more information about waiver or alteration of HIPAA Authorization).

The Privacy Rule also allows, without individual authorization, use/disclosure of PHI under a selected few additional circumstances:

  • Activities involving PHI are solely preparatory to research (such as assessing the feasibility of conducting a study)
  • PHI pertains solely to decedents (deceased individuals)
  • Data is de-identified by a covered entity and researchers never view PHI, such as when researchers receive from ACE/VDW the full research dataset, which contains only de-identified data
  • limited data set is established under the terms of a written data use agreement

For research subject to Hennepin Healthcare IRB oversight, the IRB will provide the applicable determinations regarding HIPAA compliance via expedited or convened IRB review.

NIH resources

Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule

Clinical Research and the HIPAA Privacy Rule

Research Repositories, Databases and the HIPAA Privacy Rule

Except as otherwise permitted, the Privacy Rule requires that research subjects “authorize” the use or disclosure of their PHI to be used in research. This authorization is distinct from a subject’s informed consent to participate in research that is required under federal regulations. Just as valid informed consent under regulations must meet certain requirements, a valid HIPAA authorization must contain certain statements and core elements. [45CFR164.508(c)].

At Hennepin Healthcare, the HIPAA authorization may be a stand-alone document or the HIPAA authorization language may be provided within the consent document. Documents for HIPAA authorization must be submitted in Cayuse HE as part of the study submission for review by the IRB. 

For a stand-alone template, see: 601 TEMPLATE HIPAA authorization for research

Research subjects have the right to revoke their HIPAA authorization at any time. Researchers may continue to use and disclose PHI that was obtained before an individual has revoked authorization to the extent necessary to protect the integrity of the research. Withdrawal of authorization stops the collection and use of information from the date of revocation but does not require destruction of previously collected data. Researchers must describe the revocation process as part of the HIPAA authorization.

IMPORTANT: Refer to section 7 Research with special populations - 7.12 How do researchers obtain HIPAA Authorization for non-English speakers? for HIPAA authorization requirements for research involving non-English speakers.

The Hennepin Healthcare IRB may approve a waiver or alteration of HIPAA authorization provided that the research meets the criteria outlined in 45CFR164.512(i)(2)(ii). Criteria are similar to those for waiver of consent and waiver of documentation of consent; however, HIPAA criteria are more stringent.

HIPAA waiver/alteration criteria

An IRB or privacy board may approve a waiver or alteration of HIPAA authorization if it satisfies the following criteria:

  • The use or disclosure of protected health information involves no more than a minimal risk to the privacy of individuals, based on, at least, the presence of the following elements:
    • an adequate plan to protect the identifiers from improper use and disclosure;
    • an adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the research, unless there is a health or research justification for retaining the identifiers or such retention is otherwise required by law; and
    • adequate written assurances that the protected health information will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research project, or for other research for which the use or disclosure of protected health information would be permitted by this subpart;
  • The research could not practicably be conducted without the waiver or alteration; and
  • The research could not practicably be conducted without access to and use of the protected health information.

For research requesting approval from the Hennepin Healthcare IRB for a waiver or alteration of HIPAA authorization, both the protocol and Cayuse submission should address the above criteria.

Partial waiver of HIPAA authorization

An approved partial waiver allows an investigator to obtain, use, and/or disclose PHI for one specified portion of a study or activity (e.g., recruitment) without first obtaining subjects' authorization. In this case, the partial waiver allows recruitment/screening to be conducted without subjects' authorization; however, HIPAA authorization is required to proceed beyond recruitment/screening.

Full waiver of HIPAA authorization

The IRB may approve a full waiver of HIPAA authorization provided the research meets the HIPAA waiver/alteration criteria. For example, researchers must justify why the research could not be practicably carried out without the waiver. Practicable means possible; it does not mean convenient. For example, if a subject is available to provide authorization, then it is usually practicable to obtain their authorization.

Alteration of HIPAA authorization

The IRB may approve an alteration of the requirements of written HIPAA authorization provided the research meets the HIPAA waiver/alteration criteria.

The most frequent alteration is for verbal HIPAA authorization when the IRB has also waived the requirement for written consent; however, researchers must justify why the research could not practicably be conducted without the waiver or alteration. If the subject is physically present, it is usually practicable to obtain written HIPAA authorization.

Researchers are responsible for establishing and monitoring appropriate data security and confidentiality measures for all research activities involving PHI, including:

  • Collection - e.g., acquiring PHI from clinical or field data collection processes or from health records
  • Transmission - e.g., migrating PHI from one place to another
  • Storage - e.g., keeping PHI in hard-copy and/or electronic format
  • Computation - e.g., performing data analysis/manipulation
  • Archival - e.g., storing data after a study ends for research reproducibility and record retention requirements

.

HIPAA requires that either an IRB or a Privacy Board make determinations about the use of PHI in research. At Hennepin Healthcare, the IRB is responsible for making these determinations (unless the research is overseen by an external IRB that has agreed to oversee compliance with HIPAA). The IRB is well-suited to review protections for PHI since it already has responsibilities under the human research regulations to protect the privacy of subjects and their confidential information, including review of consent documents that describe how individuals' private information will be protected. The IRB's role at Hennepin Healthcare includes:

  • Review and approval of HIPAA authorization language when combined with an informed consent document [45CFR164.508(b)(3) and (c)]
  • Review and approval of requests for a waiver or alteration of the requirements for written HIPAA authorization [45CFR164.512(i)(1)(i)]
  • Review of attestations from investigators who propose to use PHI without a HIPAA authorization or waiver, including:

Yes, if secondary research involves use/disclosure of PHI, the HIPAA Privacy Rule applies. For instance, secondary research that involves PHI data from medical records, HIPAA applies and researchers must either obtain HIPAA authorization from patients or receive approval for a waiver of HIPAA authorization. 

A signed copy of HIPAA authorization must be provided to the individual providing authorization. At minimum, signed authorizations must be retained for 6 years from the date of signature or date it was last in effect, whichever is later. Researchers must retain authorization records for a longer period, if applicable under a sponsor agreement.

11. FDA definitions and regulations

Clinical investigation per 21CFR56.102(c), means any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the Federal Food, Drug, and Cosmetic Act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of nonclinical laboratory studies. The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous.

For research involving a drug, a clinical investigation is described by the FDA as any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of the IND regulations, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. [21CFR312.3(b)]

Drug is defined per the Federal Food Drug and Cosmetic Act (FD&C Act) and FDA regulations, in part, by reference to its intended use, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” Therefore, almost any ingested or topical or injectable product that, through its label or labeling (including internet websites, promotional pamphlets, and other marketing material), is claimed to be beneficial for such uses will be regulated by FDA as a drug. The definition also includes components of drugs, such as active pharmaceutical ingredients. Biological products may also be considered drugs within the meaning of the FD&C Act. Biological products include, among other products, bacterial vaccines, allergenic extracts, gene therapy products, growth factors, cytokines, and monoclonal antibodies. See FDA Guidance on Human Drugs.

Investigational device means a device, including a transitional device (a device subject to the Federal Food, Drug, and Cosmetic Act section 520(l)), that is the object of a clinical investigation (research) involving one or more subjects to determine the safety or effectiveness of a device.

Investigator means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.

Medical device per the statute: Federal Food, Drug, and Cosmetic Act Sec 201.h [21USC321] is defined as a device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article which is recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement, and is:

  • Intended:
    • For use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
    • To affect the structure of any function of the body of man or other animals;
  • And which does not achieve its primary intentional purposes through chemical action and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

Medical devices include, among other things, surgical laser, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy.  Medical devices can also include investigational software, whether it is “standalone” software meant for use on a general-purpose computer/other device, or it is a component of or accessory to another medical device (such as a MRI machine or CT scanner).

Significant risk device means an investigational device that:

  1. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
  2. Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;
  3. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or
  4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

Sponsor means a person who initiates a clinical investigation, but who does not actually conduct the investigation, i.e., the test article is administered or dispensed to or used involving, a subject under the immediate direction of another individual. A corporation or agency that uses one or more of its own employees to conduct a clinical investigation it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators.

Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term applies only to an individual, i.e., it does not apply to a corporation or agency.

Title 21 Food and Drugs (selected parts)

21 CFR 11 Electronic records and electronic signature

21 CFR 50 Protection of human subjects

21 CFR 54 Financial disclosure by clinical investigators

21 CFR 56 Institutional review boards (IRBs)

21 CFR 210 Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; General

21 CFR 211 Current good manufacturing practice for finished pharmaceuticals

21 CFR 312 Investigational new drug (IND) application

21 CFR 314 Drugs for human use

21 CFR 320 Bioavailability and bioequivalence requirements

21 CFR 330 Over-the-counter (OTC) human drugs which are generally recognized as safe and effective and not misbranded

21 CFR 601 Biologics licensing

21 CFR 807 Establishment registration and device Listing for manufacturers and initial importers of devices

21 CFR 812 Investigational device exemptions (IDEs)

21 CFR 814 Premarket approval of medical devices

21 CFR 820 Quality system regulation

21 CFR 860 Medical device classification procedures

Informational FDA links

FDA Guidance Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND

Ask the FDA for advice

Submit an IND application to the FDA for a determination

 

12. Drugs in research

Federal law prohibits the distribution of new drugs or biologics until the Food and Drug Administration (FDA) has reviewed clinical data and determined that a particular product is safe and effective for a specific use in human subjects.

There are specific FDA regulations for clinical investigations of drugs. [21CFR312] For clinical investigations that involve safety/effectiveness testing of drugs or dietary supplements, researchers must submit an Investigational New Drug (IND) application to the FDA, unless the proposed use meets IND exemption criteria [21CFR312.2(b)].

A clinical investigation using a drug product that is lawfully marketed in the United States may be exempt from the requirements for obtaining an IND if ALL of the following apply [21CFR312.2(b)]:

  1. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;
  2. If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;
  3. The investigation does not involve a route of administration or dosage level or use in a subject population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
  4. The investigation is conducted in compliance with the requirements for institutional review and informed consent; and
  5. The investigation is conducted in compliance with the requirements regarding promotion of investigational drugs [21CFR312.7]

For criteria 1, 2, and 3, the protocol should describe how these criteria for IND exemption have been met;  if the proposed use of the drug product is not identical to that described in the FDA approved labeling, the protocol must explain how the research does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the product.

The reviewing IRB will confirm that the clinical investigations meets exemption criteria 4 and 5.

For clinical investigations using a dietary supplement, an IND must be obtained if the clinical investigation is intended to evaluate the dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent a disease unless the FDA provides written documentation that an IND is not required.

IMPORTANT: If an investigation involving a drug is IND exempt, it is not subject to 21CFR312; however, it is subject to FDA regulations at 21CFR50 (informed consent) and 21CFR56 (institutional review).

The clinical investigation’s sponsor/sponsor-investigator is responsible for determining whether an IND is required and should consult with the FDA, as appropriate. The IRB submission requires researchers to provide IND information or adequately address (e.g., in the protocol) why an IND is not required.

In the event that the IRB reviews a submission involving an FDA-regulated product without an IND number and determines that an IND may be required, the sponsor/sponsor-investigator must submit an IND application to the FDA. Documentation of the FDA outcome (e.g., IND number) must be submitted to proceed with IRB approval.

NOTE: When the FDA receives an IND application, the sponsor/sponsor investigator is notified via email and the FDA assigns an IND number; however, this is not FDA approval. In most cases, passive approval is assumed if there has been no formal contact from the FDA within 30 calendar days of the submission of the IND application to the FDA. Studies cannot be initiated until after the 30-day period (and until the IRB has approved the study).

Additional IND resources:

A sponsor-investigator is someone who both initiates and actually conducts a clinical investigation. The sponsor-investigator may conduct the research alone or with other researchers. A sponsor-investigator who conducts a study involving an FDA test article for which they hold the IND is responsible for compliance with the same FDA regulatory requirements as if they were an industry sponsor, regardless of whether the investigator has the same resources, e.g., labeling, annual reporting, record keeping, etc. FDA regulatory requirements for sponsors can be found in the Code of Federal Regulations (see section 11. FDA definitions and regulations).

The Hennepin Healthcare IRB requires that sponsor-investigators submit a monitoring plan describing how they will fulfill all the FDA requirements for sponsors. Additionally, investigators must complete the EQ study start-up program/assessment by the Office of Education and Quality in Clinical Research (OEQCR). This review should be completed PRIOR to submitting an IRB application for review.

13. Devices in research

There are specific FDA regulations and additional requirements for clinical investigations of medical devices: 21 CFR Part 812

All clinical investigations of devices must have an approved Investigational Device Exemption (IDE) from the FDA or be exempt from the IDE regulations before beginning a clinical investigational of a significant risk device. An IDE allows the investigational device to be used in a clinical study to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification 510(k) submission to FDA. 

Researchers are responsible for understanding device classifications and compliance with the applicable FDA regulations and guidance:

Investigational device classification Overview of IDE requirements &
applicable FDA regulations
FDA guidance

Significant risk (SR) device

An SR device is one that:

  • Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
  • Is purported or represented to be for the use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;
  • Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or
  • Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
  • IDE required (issued by FDA)
  • FDA regulations apply:
    1. IDE regulation: 21 CFR 812
    2. Informed consent: 21CFR50
    3. Institutional review: 21CFR56

Significant Risk and Nonsignificant Risk Medical Device Studies

Frequently Asked Questions About Medical Devices

Off-Label and Investigational Use of Marketed Drugs, Biologics, and Medical Devices

FAQ about IDE

Drug-Device Combination Products

Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical studies, Including Certain First in Human (FIH) Studies

IDE Approval Process

FDA Decisions for Investigational Device Exemption Clinical Investigations

Non-significant risk (NSR) device

An NSR device is one that does not meet the definition for a significant risk device.

  • IDE required (issued by FDA)
  • FDA regulations apply:
    1. Abbreviated IDE regulation: 21CFR812.2(b)
    2. Informed consent: 21CFR50
    3. Institutional review: 21CFR56

Exempt devices

Exemption categories are defined in 21CFR812.2(c)

An SR/NSR device determination is not applicable for exempt devices

  • IDE NOT required (exemption issued by IRB)
  • FDA regulations apply:
    1. Informed consent: 21CFR50
    2. Institutional review: 21CFR56

In-Vitro Diagnostic (IVD) Device Studies FAQ

Informed Consent for In-Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable

Significant risk/Non-significant risk (SR/NSR) determinations

The IRB will provide an SR/NSR determination via convened review; this risk determination is specific to the use of the device in the proposed research. For example, an SR device determination applies if potential harm to research subjects could be life-threatening, result in permanent impairment of body function, or permanent damage to body structure. Note that if the research involves a medical procedure (vs standard of care procedures only), the IRB will consider the risks associated with the procedure conducted as part of the research as well as the use of the device when making a risk determination.

If the sponsor/sponsor-investigator has provided an NSR device assessment in the IRB submission and the IRB disagrees and no IDE exempt determination from the FDA has been attached in the IRB submission, the IRB will provide an SR device determination. The sponsor/sponsor investigator is responsible for notifying the FDA of the IRB’s determination. The IRB will not approve the research until the IRB submission is updated to provide written documentation of one of the following:

  • The FDA has granted an IDE to the sponsor, or
  • The FDA has granted an IDE to the sponsor with an NSR determination

With the exception of 21CFR812.119, the IDE regulation, 21 CFR Part 812, does not apply to device studies that meet the criteria for exempted investigations under 21CFR812.2(c).

Examples of devices that are exempt from the IDE regulation include:

  1. a legally marketed device when used in accordance with its labeling
  2. a diagnostic device, if it complies with the labeling requirements in 21CFR809.10(c) and if the testing:
    1. is noninvasive;
    2. does not require an invasive sampling procedure that presents significant risk;
    3. does not by design or intention introduce energy into a subject; and
    4. is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure

The protocol should describe how the device meets IDE exemption criteria and confirm that the device will be used in accordance with its approved labeling.

The clinical investigation’s sponsor/sponsor-investigator is responsible for determining whether an IDE is required and should consult with the FDA, as appropriate.

The IRB submission requires researchers to provide IDE information, including a copy of FDA communications (as applicable) and adequately address (e.g., in the protocol) whether an IDE application to the FDA is required. In addition, the sponsor/sponsor-investigator's SR/NSR assessment and rational must be provided, as applicable.

The IRB submission for device research must include an attached device manual (also called Instructions for Use) and ONE of the following:

  • Unredacted FDA letter granting an Investigational Device Exemption (IDE); OR
  • Unredacted letter from sponsor stating that the investigation involves only a non-significant risk IDE device and the basis for that determination; OR
  • Documentation of why the investigation is exempt from the IDE requirements (e.g., a PMA approval letter/number or 510(k) clearance letter/number) or is otherwise exempt

In the event that the IRB reviews a submission involving an FDA-regulated device without an IDE and determines that an IDE may be required, the sponsor/sponsor-investigator must submit an IDE application to the FDA. Documentation of the FDA outcome must be submitted to proceed with IRB approval.

NOTE: When the FDA receives an IDE application, the sponsor/sponsor investigator is notified via email and the FDA assigns an IDE number; however, this is not FDA approval. An IDE application is considered approved 30 calendar days after IDE assignment, unless the FDA otherwise informs the sponsor/sponsor-investigator that the IDE is approved, approved with modification, or disapproved. [21CFR812.30]

Studies cannot be initiated until after the 30-day period (and until the IRB has approved the study).

Additional IDE resources:

A sponsor-investigator is someone who both initiates and actually conducts a clinical investigation. The sponsor-investigator may conduct the research alone or with other researchers. A sponsor-investigator who conducts a study involving an FDA test article for which they hold the IDE is responsible for compliance with the same FDA regulatory requirements as if they were an industry sponsor, regardless of whether the investigator has the same resources, e.g., labeling, annual reporting, record keeping, etc. FDA regulatory requirements for sponsors can be found in the Code of Federal Regulations (see section 11. FDA definitions and regulations).

The Hennepin Healthcare IRB requires that sponsor-investigators submit a monitoring plan describing how they will fulfill all the FDA requirements for sponsors. Additionally, investigators must complete the EQ study start-up program/assessment by the Office of Education and Quality in Clinical Research (OEQCR). This review should be completed PRIOR to submitting an IRB application for review.

14. Humanitarian Use Devices (HUDs)

A Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease that affects fewer than 8,000 individuals in the United States per year. To be considered for HUD status, a device sponsor must complete a humanitarian device exemption (HDE) application with the FDA. Humanitarian Device Exemption (HDE) is the regulatory pathway for devices that are intended for certain rare conditions where it would not be feasible to develop sufficient evidence of safety and effectiveness to support full FDA approval.

FDA approval of an HDE authorizes an applicant to market the HUD, subject to certain profit and use restrictions. HUDs cannot be sold for profit, except in very limited circumstances. An HUD must be IRB-approved prior to use, except in certain emergencies.

The use of an HUD for its approved indication does not constitute research unless is involves collection of safety or effectiveness data. 

Even when not considered research, clinical use of a HUD requires prospective review and approval by the convened IRB, except for an emergency use situation. The IRB does not make an SR/NSR determination for such use.  

An IRB submission for HUD use must include the following documents:

  • HUD manufacturer's product labeling, clinical brochure, and/or other pertinent manufacturer informational materials
  • HUD manufacturer's patient information packet, if available, which should be provided to patients
  • FDA HDE approval letter

NOTE:

  • For non-research HUD use, the requirements for human subjects in research training, independent scientific assessment, and HIPAA authorization for research do not apply
  • The IRB may approve HUD use of the device in general, for a specific number of patients, or only under specific circumstances
  • FDA regulations require continuing review of a HUD, which may be conducted via convened IRB or expedited review
  • Per the FDA and its HDE regulations, informed consent is not required; however, the Hennepin Healthcare IRB requires an information sheet (604 TEMPLATE Information sheet for use of an FDA-regulated HUD) and some cases, may require full prospective consent

The investigator named in the IRB submission is responsible for:

Modification approval: any proposed changes to information and/or attached materials in the IRB-approved record must be approved prior to implementation, unless the change is necessary to avoid or mediate an apparent immediate risk to a patient.

Renewal approval: HUD use is subject to continuing review and must receive IRB approval prior to expiration. Materials to be submitted include:

  • Any safety reports or summaries provided by the HDE holder that had not previously been submitted
  • The current patient information packet, if applicable
  • The current consent, if applicable
  • Other materials as identified on the Renewal submission
  • Any other new relevant information or materials

Incident reporting: HUD use includes compliance with required reporting to the FDA, IRB, and the device manufacturer/HDE holder, for example, whenever a HUD may have caused or contributed to a serious injury or death. See the Medical Device Reporting (MDR) Regulation [ 21 CFR Part 803] for specific reporting requirements.

Additional information:

FDA guidance: Humanitarian Device Exemption Program (HDE) Program 

An HUD used in a clinical investigation (i.e., to collect safety and effectiveness data) is considered investigational use, whether or not the device is used for the HDE-approved indication. Such use is considered research and is subject to the full requirements for IRB review/approval, (e.g., human subjects in research training, informed consent, HIPAA authorization) as well as applicable FDA regulations.

It is essential to differentiate whether the HUD is being studied for the indication(s) in its approved labeling or for different indication(s). When the HUD is being studied for the indication(s) in its approved labeling, the IDE regulations at 21 CFR 812 do not apply; however, when the HUD is being studied for a different indication(s), 21 CFR 812 does apply, including the requirement for an FDA-approved IDE before starting the clinical investigation of a Significant risk device.

Additional information:

FDA guidance: Humanitarian Device Exemption Program (HDE) Program 

15. Expanded access

Expanded access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. While many of the requirements and approvals necessary for expanded access use of an investigational product are similar or the same as for research, expanded access is considered clinical care and NOT research.

The expanded access mechanisms are somewhat different for devices than for drugs and biologics. The Hennepin Healthcare IRB follows requirements outlined by FDA when evaluating these uses.

FDA expanded access information for patients, physicians, and Industry

https://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm.

FDA guidance on expanded access to drugs

FDA guidance on expanded access to medical devices

https://www.fda.gov/medical-devices/investigational-device-exemption-ide/expanded-access-medical-devices

FDA's expanded access contact information

https://www.fda.gov/news-events/expanded-access/fdas-expanded-access-contact-information

Yes. Prospective IRB approval is required for all expanded access mechanisms except single patient emergency use. 

Expanded access mechanisms involve use of an investigational item in a vulnerable population (i.e., seriously ill patients with no good alternatives), raising concerns that are sufficiently similar to clinical research such that the FDA believes that IRB review and a research-like informed consent process are warranted.

Drug or biologic expanded access refers to the use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition rather than to obtain the kind of safety and effectiveness information about the drug that is generally derived from clinical trials. Expanded access and treatment use may also refer to:

  1. use in situations when a drug has been withdrawn for safety reasons, but there exists a patient population for whom the benefits of the withdrawn drug continue to outweigh the risks;
  2. use of a similar, but unapproved drug (e.g., foreign-approved drug product) to provide treatment during a drug shortage of the approved drug;
  3. use of an approved drug where availability is limited by a risk evaluation and mitigation strategy (REMS) for diagnostic, monitoring, or treatment purposes, by patients who cannot obtain the drug under the REMS; or
  4. use for other reasons.

The expanded access mechanisms are intended for use with patients who have a serious or life-threatening disease or condition.

Under FDA’s current regulations, there are three categories of expanded access:

  • Expanded access for individual patients, including for emergency use [21CFR312.310]
  • Expanded access for intermediate-size patient populations (generally smaller than those typical of a treatment IND or treatment protocol — a treatment protocol is submitted as an amendment to an existing IND by the sponsor of the existing IND) [21CFR312.315]
  • Expanded access for widespread treatment use through a treatment IND or treatment protocol (designed for use in larger patient populations) [21CFR312.320]

For each category of expanded access, there are two types of regulatory submission options:

  1. an expanded access protocol submitted as a protocol amendment to an existing IND (i.e., an expanded access protocol) or
  2. a new IND submission, which is separate and distinct from any existing INDs and is intended only to make a drug available for treatment use (i.e., an expanded access IND).

A sponsor or physician may contact the appropriate FDA review division for consultation about which may be the most appropriate submission.

FDA information about expanded access, including contact information for review divisions:

https://www.fda.gov/news-events/expanded-access/fdas-expanded-access-contact-information

Expanded access is also a potential pathway for patients with a serious or life-threatening disease or condition to access an investigational medical device that has not been approved or cleared by the FDA for treatment outside of clinical trials when no comparable or satisfactory alternative therapy exists.

See the FDA's guidance, Expanded access for Medical Devices for additional information, including:

  • Emergency use
  • Compassionate use (or Individual Patient/Small Group Access) - use of an investigational device to treat or diagnose an individual patient or a small group of patients with a serious disease or condition when there are no available alternative options
  • Treatment Investigational Device Exemption (IDE) - use of an investigational device to treat or diagnose a group of patients with a serious or immediately life-threatening disease or condition when the device is also being studied for the same use under an approved IDE

16. Emergency use

The FDA defines emergency use as the use of a test article (drug/device) on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval [21CFR56.102(d)]. The FDA regulates use of all investigational drugs and devices, including emergency use. A physician who treats a patient under emergency use provisions must justify the treatment according to FDA criteria, complete an IRB submission, and complete follow-up reporting as part of the IRB submission process.

Emergency use is considered clinical care, versus research; therefore, IRB oversight is not applicable. However, physicians are required to complete an IRB submission for the IRB to confirm that all FDA criteria and requirements for emergency use are met.

NOTE: Planned research designed to evaluate emergency care treatments is not emergency use. Prospective IRB approval for such research is required before any activities can begin involving human subjects; this also applies to planned emergency research under a waiver of informed consent (EFIC). [21CFR50.24]

Emergency use of an FDA-regulated investigational product is permitted only if all of the following criteria are met:

  • The patient faces a serious or life-threatening or severely debilitating condition

Life-threatening: Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life threatening do not require the condition to be immediately life threatening or to immediately result in death. Rather, the subjects must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.

Severely debilitating: Diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.

  • The patient is likely to benefit from treatment with the unapproved drug, biologic, or device
  • No generally acceptable alternative for treating the patient is available
  • There is not sufficient time to obtain IRB approval

The emergency use provision in the FDA regulations [21CFR56.104(c)] is an exemption from prospective review and approval by the IRB provided that such emergency use is reported to the IRB within 5 working days. The exemption may not be used unless all of the criteria described in 21CFR56.102(d) are met to allow for one emergency use of a test article without prospective IRB review. Any subsequent use of the test article must have prospective IRB review. FDA acknowledges, however, that it would be inappropriate to deny emergency treatment if the only obstacle is insufficient time for convened IRB review.

The treating physician should notify the IRB before the emergency use of the test article by completing an IRB submission or via email to HRPO@hhrinstitute.org. If immediate use of the test article is required to save the life of the patient and there is not sufficient time to notify the IRB, the treating physician may proceed with the emergency use. An IRB submission must be completed no later than 5 working days from the time of the emergency use.

The IRB does not provide approvals for emergency use submissions; instead, letters will be issued to confirm receipt of notification regarding emergency use and that the emergency use complies with FDA regulatory requirements.

NOTE: If there is sufficient time for an emergency use request to be submitted and reviewed at a scheduled IRB meeting prior to the use of the test article, it is not considered exempt from prospective IRB review.

For emergency use, obtaining informed consent of the patient or the patient’s legally authorized representative is required. The drug/device manufacturer may provide a consent form for emergency use or the 602 TEMPLATE Informed consent for emergency use of a test article may also be used. Language in the consent form must reflect that the intervention is not FDA-approved and is considered experimental.

FDA provides an exception from the requirements of informed consent [21 CFR 50.23] in limited circumstances that meet all of the following criteria:

  • Before the use of the test article, both the treating physician and a physician who is not otherwise participating in the clinical investigation must complete the 323 FORM Independent physician certification to certify all of the following:
    1. The patient is confronted by a life-threatening situation necessitating use of test article.
    2. Consent cannot be obtained because of an inability to communicate with or obtain consent from the patient.
    3. Time is not sufficient to obtain consent from patient's legal representative.
    4. No alternative generally approved or recognized method of treatment is available that provides an equal or greater likelihood of saving the patient’s life.
  • If immediate use of the test article is required to save the life of the patient and time is not sufficient to obtain independent determination by another physician, a determination of the above criteria must be documented in writing by the treating physician. A physician who is not participating in the investigation must review and evaluate the treating physician's determinations and complete the 323 FORM Independent physician certification.

IMPORTANT: The treating physician must complete an IRB submission and provide the applicable documentation within 5 working days after the use of a test article.

.

Emergency use of an unapproved investigational drug or biologic requires an Investigational New Drug (IND) number. For more information, please refer directly to the Emergency Use of an Investigational Drug or Biologic - Information Sheet on the FDA website. 

Obtaining access to an IND number can be accomplished in two ways:

  • Contact the manufacturer (or IND holder) of the product to determine if the drug or biologic can be made available for the emergency use under the existing IND.  There may or may not be an existing, approved study (at any of the manufacturer’s study sites) using the IND. The manufacturer may be required to contact the FDA to obtain permission for the emergency use to occur using the existing IND. 
  • A treating physician may request an emergency use IND (eIND) from the FDA.  An eIND number is not associated with another clinical trial or other emergency use case. If there is not adequate time to complete an eIND submission, the FDA may authorize shipment of the test article in advance of the submission.

A treating physician who is responsible for the emergency use of a drug that is controlled by the Hennepin Healthcare Investigational Pharmacy, must provide the Pharmacy with:

  • written FDA documentation of eIND approval
  • manufacturer approval to ship drug
  • applicable IRB documentation

The drug must be shipped to the Pharmacy to maintain the appropriate chain of custody. The Pharmacy will not accept medications shipped to the investigator without proper shipping and storage information.

NOTE: Refer to HHS Policy “Investigational Medications” (Policy #005361) for additional information on the safe handling of medication used in clinical research, including: ordering, procuring, storing, handling, dispensing and administration.

After emergency use, the physician/investigator must:

  • Report to the IRB via Cayuse HE within five working days after the use of the test article (regardless of whether or not an initial notification was made to the IRB before use)
  • Report the use, including adverse events to the FDA (required reporting information available on the FDA website)
  • Evaluate the likelihood of future use, and if future use is likely, initiate the process to obtain IRB approval and regulatory clearance (IND) for such future use

The FDA provides helpful guidance on the timeline and process for emergency use of a drug, including steps to take before use and reporting requirements:

When there is a need to use a device that has not received the FDA’s approval or clearance in an emergency, it is considered emergency use. Emergency use may apply if the device is being studied in clinical trials under an investigational device exemption (IDE), such as when a physician who is not involved in the clinical trial wants to use the device to treat a patient in an immediately life-threatening situation. Emergency use may also apply if there is no IDE or ongoing clinical studies for the device.

A physician who intends to treat a patient with an unapproved medical device in an emergency situation must: meet the general requirements for emergency use and informed consent noted above but is not required to secure an IDE.

After emergency use, the physician/investigator must:

  • Report to the IRB via Cayuse HE within five working days after the use of the test article (regardless of whether or not an initial notification was made to the IRB before use)
  • Report the use, including adverse events to the FDA
  • Evaluate the likelihood of future use, and if future use is likely, initiate process to obtain IRB approval and regulatory clearance (IDE) for such future use

Emergency use of an investigational device must be reported to the FDA by the IDE sponsor within 5 working days. If no IDE exists, the treating physician must report the emergency use to CDRH or CBER.

Refer to the FDA guidance - Expanded Access for Medical Devices for additional information on emergency use.

17. OEQCR guidance on clinical research evaluations

Evaluating the feasibility of a protocol will enhance the probability of timely and successful completion of the clinical research trial:

  • Notify the sponsor if the protocol cannot be executed as written.
  • Collaborate with the sponsor to institute necessary changes.
  • Collaborate with the appropriate Grant Administrator for budget needs, recommendations, and concerns.
  • Consult the funding source for Investigator-Initiated studies to obtain additional instructions, requirements, and templates for protocol development and evaluation

Related: 640 TEMPLATE Protocol feasibility checklist (OEQCR)

The sample protocol evaluation checklist may be used to evaluate the protocol, Investigator’s Brochure, and Clinical Trial Agreement to ensure that the appropriate information is available (if applicable) to the study. Evaluating the protocol will enhance the probability of timely and successful completion of the clinical research trial.

It’s important to notify the sponsor right away if the protocol does not meet minimum standards and cannot be executed as written. Collaborating and communicating with the sponsor about necessary changes will ensure the study team can successfully conduct the study.

The sample protocol evaluation checklist may also be used as a template for important topics when designing an Investigator Initiated study protocol. Other options include:

Related: 642 TEMPLATE Protocol evaluation checklist (OEQCR)

Define all study-related costs and cost recovery:

  • Grant Administrators are available for advice via ResearchInquiry@hhrinstitute.org
  • The total study budget is the total anticipated study cost across all fiscal years including appropriate indirect costs.

Review the study schedule of activities:

  • Develop a budget worksheet using the schema and protocol.
  • Separate the budget worksheet into two sections for protocol costs and personnel costs.

Budget templates are available through EQ and/or Grants and Contracts: EQ@hhrinstitute.org and ResearchInquiry@hhrinstitute.org

Assess protocol costs:

  • Protocol costs are costs directly linked with the protocol, subject care, or subject related stipends.
  • Protocol costs may be a one-time cost or recurring throughout the life of the subjects’ enrollment
  • Protocol fees may include, but are not be limited to, IRB fees, test fees (laboratory, ECG, radiology, etc.), pro-fees, rental fees, copying costs, investigational pharmacy costs, advertising costs, mailing fees, or subject remunerations.
  • Identify services and tests used in the protocol that are NOT standard care.
  • Ensure that a HCMC Research Utilization Checklist is completed when enrolling HHS patients, even if no HHS resources will be used.
  • Pricing information and contacts of various resources (i.e., Laboratory, Radiology) are available. Ensure that you have the correct research pricing information by contacting Grants and Contracts: researchinquiry@hhrinstitute.org
  • HHS research pricing for patient care procedures provided to HHRI projects is based on reimbursement rates set by CMS/Medicare. For specific pricing rates, either email the Research IT Specialist at jbanchor@hhrinstitute.org or review the CMS pricing tools at https://www.hhrinstitute.org/researcher-resources/clinical-research-resources/#TrialManagement
  • Review the schematic design and add up the fees for all tests and services for one subject. Add any other recurring protocol induced costs for one subject.

Assess personnel (staffing) costs:

  • Evaluate the time required by study personnel to complete study specific tasks for one subject.
  • In addition, do not forget time needed for non-subject duties such as Site Initiation Visit, study-specific training, screening, recruiting, team meetings, completing case report forms, creating documents and processes for SOPs/MOPs, processing and/or shipping samples, managing study supplies and resources, participating in study monitor visits both onsite and remote, answering study queries, corresponding with the sponsor, IRB, laboratory, and maintaining regulatory files.
  • Ensure that all personnel are accounted for including study coordinator, PI, and ancillary staff.

Calculate direct costs:

  • Once you have the per-subject protocol and personnel costs added, multiply it by the number of subjects to be enrolled at the site.
  • Add the one time protocol cost fees.
  • The resulting number will be the total direct costs for the study.

Consider the need to budget time for increased screening:

There are common characteristics that can make it more difficult to recruit and increase screening time. These common characteristics include:

  • The complexity of the protocol
  • The time commitment of the protocol
  • Length of subject follow-up
  • Complicated inclusion and/or exclusion criteria
  • Recruiting vulnerable populations such as children, minorities, women, and the elderly
  • Requiring DNA or genetic sampling as part of the protocol

Epic research billing:

  • Often there are study procedure costs that need to be billed to the study and not the patient, their insurance, or Medicare.
  • If HHS resources are utilized, the study must be set up in Epic.
  • The HHRI study becomes the guarantor.
  • It is important that subjects or insurance NOT BE CHARGED for research activities.
  • Epic research billing training is required. Contact the Research IT Specialist at jbanchor@hhrinstitute.org for more information and to schedule training.
  • Contact the Research IT Specialist at jbanchor@hhrinstitute.org for assistance with the Medicare Analysis Tool and pricing.

Calculate indirect costs:

  • Add the appropriate indirect costs to the direct costs and you will have the total costs for the study.
  • There are different formulas depending on the type of project (Federal vs. Non-Federal).
  • See Sponsored Project Administration Guidance 7th Edition for a full explanation of calculating indirect cost: August 4, 1997 (hhrinstitute.org).
  • Grants and Contracts ResearchInquiry@hhrinstitute.org or EQ: EQ@hhrinstitute.org can also provide guidance.

Ensure that the assigned HHRI Sponsored Project Administrator is aware of budgetary requirements and or budget changes throughout the study so that they may negotiate with sponsor as needed.

Ensure that the sponsor’s confidentiality agreement has been signed and returned (check with the appropriate Grant Administrator).

Review protocol materials to assess study protocol and feasibility of carrying out the protocol.

Identify personnel to be assigned to the study.

Connect with the sponsor/CRO to determine who they will want to meet. Collaborate with the sponsor/CRO to schedule a mutually convenient date and time when all required parties can attend.

Prepare explanatory information for the sponsor/CRO. This may include, but not be limited to:

  • Dates of IRB meetings
  • Dates of other regulatory meetings, e.g., HHS Radiation Safety Committee
  • Overview of the local protocol review process
  • Overview of HHRI, Sponsored Research Administration, and Finance

Collect supporting documentation:

These may include but not be limited to:

  • Organizational Charts of HHRI and HCMC as appropriate
  • Copies of medical licenses of PI and sub-investigator(s)
  • Current signed and dated curriculum vitae (CVs) for PI and sub-investigator(s)
  • Copies of nursing licenses if required
  • Staff CVs if required
  • Copy of institutional laboratory certification(s)

Collaborate with all desired attendees:

Develop a schedule for the sponsor/CRO to meet personnel and tour the facility. Individuals and/or areas the sponsor/CRO may want to visit include:

  • PI
  • Sub-investigator(s)
  • Pertinent research personnel
  • Grant Administrator
  • Research pharmacist
  • Office areas of the research team
  • Secure area for study participant documents/binders
  • Research pharmacy
  • Clinical laboratory
  • Radiology
  • In-patient hospital areas or out-patient clinic areas
  • Storage area and temperature monitoring plan for investigational drug if out-patient study
  • Storage area(s) for investigational devices
  • Storage area for collected specimens

Be prepared to discuss with the sponsor:

  • The protocol
  • Central facilities that will be used
  • Grants Administration
  • IRB process
  • Special needs the sponsor/CRO should be willing to supply (i.e., equipment, training)
  • Anticipated study timeline
  • Investigators’ meeting and/or study initiation meeting
  • Sponsor/CRO chain of command and communication plan

Determine if there is other information required by the sponsor/CRO.

Request that the sponsor/CRO notify the site in writing if selected to participate in the trial.

18. OEQCR guidance on study conduct and management

All research team members must comply with federal, sponsor, and HHRI regulations, policies, and guidance governing human research. The safety and welfare of study participants must be protected by all personnel by being knowledgeable and up to date about pertinent regulations, protocol(s), and investigational articles. Suspected or actual research misconduct may be reported to the IRB, Institutional Official, OEQCR Director, and/or the Office of Grants and Contracts.

Human research must be conducted in accordance with:

  • The ethical principles outlined in the Belmont Report to protect the rights and welfare of research participants – The Belmont Report (hhs.gov);
  • All federal, state, local, and other applicable regulations;
  • Institutional policies and procedures of the HHRI and Hennepin Healthcare;
  • The IRB-approved protocol/submission

Study conduct is ultimately the responsibility of the Principal Investigator (PI). Principal Investigators (PIs) must maintain knowledge of, and overall responsibility for, the conduct of the research.

PI responsibilities:

  • Personally conduct or supervise the research:
  • Evaluate proposed study protocols for completeness, budget adequacy, and feasibility for successfully carrying out the protocol.
  • Participate in the hiring and training of research team members.
  • Ensure that the study team is informed and updated on study related matters with scheduled meetings, memos, emails, or other communication methods pertinent to the research environment.
  • Ensure that resources are adequate to carry out the research safely. These include, but are not limited to, sufficient time, qualified research team members, equipment, and space.
  • Delegate study responsibilities to the appropriate research personnel while maintaining overall responsibility:
  • The PI must assure that all research staff are qualified, including, but not limited to, the appropriate training, education, expertise, credentials, and privileges to perform assigned responsibilities.
  • Develop and/or review study budgets and maintain fiscal authority for the project. Provide a budget to the assigned HHRI Grant Administrator for review and assistance as needed.
  • Submit all contracts, material transfer agreements, and confidentiality agreements to the Office of Grants and Contracts for review.
  • Document all required approvals for charges made to the project.
  • Certify effort in accordance with HHRI policy.
  • Conduct clinical research according to Good Clinical Practices (GCP) and other federal, state, local, and other applicable regulations.
  • Complete and sign the FDA 1572 (IND) or Investigator’s Agreement (IDE) (if applicable).
  • Maintain current Minnesota licensure to practice medicine in accordance with license.
  • Responsible for all study related medical decisions.
  • Dispense study drug, biologic, or device and/or delegate appropriate personnel and oversee dispensing activities.
  • Maintain records to account for all articles and/or delegate appropriate personnel and oversee activities.
  • Be familiar with the investigational product, assume responsibility for the investigational product at the trial site, and confirm that the investigational product is used only for enrolled eligible individuals.
  • Obtain informed consent and/or delegate appropriate personnel and oversee activities.
  • Ensure that research is conducted according to the HRPO approved protocol.
  • Ensure that specific sponsor requirements are fulfilled.
  • Participate in monitoring visits and audits (internals, sponsor, regulatory).
  • Assure protocol compliance.
  • Comply with all HRPO and IRB initial protocol submission and continuing review reporting.
  • Submit protocol changes, adverse events, and protocol deviations according to policy.
  • Respond to all surveillance requests.
  • Maintain appropriate data and records.
  • Ensure the validity and confidentiality of the data reported to the sponsor, HRPO, and regulatory authorities.
  • Maintain records and study files for the regulated period after study discontinuation or completion.
  • Complete appropriate federal, sponsor, and institutional financial disclosure forms.

All members of the study team should have a clear understanding of their individual and team member responsibilities regarding safe and ethical study conduct.

  • Each team member must be kept aware of the study’s progress, protocol changes, IRB standing, and other new or recently received information that is required to conduct the study
  • Ensure that pertinent HHS/HCMC staff remains informed about the research study.
  • Ensure the study is conducted according to the details in the IRB approved protocol.

Research team member responsibilities:

  • Manage delegated areas of the research under the direction of the PI. May include, but not be limited to:
  • screening
  • recruitment
  • obtaining informed consent
  • participant enrollment
  • participant follow-up
  • case report form completion
  • investigational product dispensing and log maintenance
  • reporting of adverse events
  • participating in monitoring visits and audits
  • Maintain accurate documentation including, but not limited to:
  • regulatory documents
  • informed consent forms
  • HRPO approvals and communications
  • CRFs, source documentation
  • investigational drug/device dispensing logs
  • study-related communication
  • Ensure organizational management of all aspects of the investigational trial within delegation of authority.
  • Communicate all protocol-related issues/problems to appropriate staff.
  • Maintain correspondence with sponsors, HRPO, and participants as required by sponsor, federal, state, and local regulations.
  • Fulfill job responsibilities specific to job title and description.
  • Complete appropriate federal, sponsor, and institutional financial disclosure forms.
  • Maintain current Minnesota licensure as applicable.

Perform study related visits/procedures:

  • Review all study requirements with the subject.
  • Ensure that the current IRB approved informed consent has been obtained.
  • Confirm that the subject remains eligible be reviewing inclusion/exclusion criteria and that the PI has reviewed and signed off on the Inclusion/Exclusion case report form (CRF)
  • Perform study examinations, laboratory testing, and study visits.
  • Provide the primary care provider acknowledgement of the subject’s enrollment into the study if the subject is agreeable.
  • An FYI should be added in Epic, if applicable
  • Update subjects on changes or information that may affect a subject’s decision to continue the trial. Re-consent subjects if applicable.
  • Document unscheduled subject encounters, including telephone conversations.

Administer the investigational product as applicable:

  • Confirm that the investigational product is dispensed according to protocol outline.
  • Document who dispensed the investigational product.
  • Document the time, route, dose, and administrator of the investigational product as applicable.
  • Document any untoward effects. Institute appropriate therapy if required as directed by the PI or sub-investigator.

Monitor subject safety:

  • Observe, query for, and document unanticipated problems involving risks to subjects or others, protocol violations, and incidents of unexpected serious harm.
  • Report unanticipated problems involving risks to subjects or others, protocol violations, and incidents of unexpected serious harm to the HRPO and sponsor as applicable.
  • Notify the PI and appropriate non-study healthcare providers of urgent abnormalities disclosed by protocol testing. This may include, but not be limited to, abnormal blood or imaging results, abnormal electrophysiologic test results, or written questionnaires (e.g., endorsement of suicidality).

Implement PI’s plan for treatment of unanticipated problems involving risks to subjects or others and unexpected serious harm which may include, but are not limited to:

  • Notify the subject.
  • Notify relevant healthcare providers.
  • Stop the investigational product.
  • Follow up with additional testing.
  • Initiate specific treatment interventions.
  • Notify sponsor, HRPO, and regulatory authorities.
  • Follow-up to ascertain resolution of adverse events.

Continue the informed consent process:

  • Keep the participant updated on the study process and progress.
  • Assess the participant’s level of comfort with the study, may need to remind him/her that they have the right to withdraw from the study.
  • Inquire if the participant has any questions, answer subject questions.
  • May need to re-consent participants if information becomes known that may alter participants’ desire to participate in the study.

Maintain primary source documents. Primary source documents must include:

  • That a participant was enrolled into the study.
  • Notification of sponsor approved protocol waivers.
  • When study treatment(s) were administered.
  • All incidents of unanticipated problems involving risks to participants or others and unexpected serious harm along with treatment if applicable.
  • Protocol deviations
  • If the participant completed, withdrew, or was discontinued from the study.

Primary source documents are made at the time any assessment is performed and include, but are not limited to:

  • Interviews
  • Baseline physical
  • Diaries or other records maintained by the subject
  • Physician and nursing notes
  • Clinical assessments
  • Vital signs
  • Laboratory, radiology, or results of other testing
  • Phone logs

Maintain regulatory files/binder:

  • Add new sponsor information
  • Add correspondence from/to sponsor and IRB
  • Maintain delegation of authority logs, training logs, and monitoring logs
  • Ensure that all certifications and accreditations are up-to-date

 

Maintain case report forms:

  • Maintain complete and accurate source documentation
  • Collect data from source document(s).
  • Source documents may include, but are not limited to:
  • Site created worksheets
  • Sponsor created worksheets
  • Electronic Health Record reports
  • Follow case report form completion procedures supplied by the sponsor if applicable
  • Protect all study materials and any protected health information.
  • Do not leave materials unattended.
  • Keep all study materials in a locked file drawer or locked office when unattended.
  • Ensure that only appropriate study personnel have access to study material.
  • Do not allow anyone to use a personal EPIC or other computer access code.

Interact with the sponsor:

  • Clarify questions and respond to queries.
  • Schedule and prepare for monitoring visits.
  • Arrange for source document review.
  • Arrange for ancillary visits as needed (i.e., study pharmacist).

Respond to data queries:

  • Receive data clarifications/queries from the sponsor.
  • Review/resolve queries by comparing it to the applicable primary source document(s). Change data on the query form as needed if a discrepancy is noted. If the previously submitted data is accurate, provide an explanation on the query form.
  • Make data changes per the sponsor’s instructions.
  • Sign, date, and return to the sponsor per sponsor instructions.
  • File resolved queries in the appropriate case report forms.

Interact with Clinical Research Associate (monitor) as applicable:

  • Schedule a mutually convenient time for monitor to visit.
  • Confirm which case report forms (CRFs) the monitor wishes to review.
  • Contact the Office for Education & Quality in Clinical Research (OEQCR) to notify of HHRI of monitor and if necessary, obtain monitor Epic access.
  • Ensure that all original source documents are available for the monitor- provide only those records and files applicable to the study under review.
  • Ensure that the regulatory binder is current and available for review.
  • If applicable, notify research pharmacy or other ancillary departments of the monitor’s visit.
  • Provide a suitable work area for monitor.
  • Schedule adequate time to spend with the monitor to discuss protocol related issues, review of the regulatory binder, verification of data in the case report forms, and study drug dispensing and accountability requirements.
  • File monitoring visit and any follow-up communications in the regulatory binder.

Maintain financial study records:

  • Reimburse subject stipends per payment schedule.
  • Reconcile monthly HHRI statements with outstanding study income and outgoing vendor payments.
  • Reconcile HCMC and external billings for research related tests.
  • Compare costs to previously agreed upon costs, mark conventional care costs as not-research.

Maintain documentation of subjects who screen fail, drop out or withdraw from the study:

  • Document the reason(s) the participant screen failed, dropped out or withdrew from the study.
  • Maintain a record of attempted and actual participant contacts, i.e., phone calls or certified letters sent to subject.
  • If the participant agrees, follow all protocol procedures identified to be performed for participants who withdraw from the study.
  • Obtain all unused investigational product if applicable.
  • Document a participant as lost to follow up if participant refuses further contact or participation in the study.

The EQ Study Start-up program has been established to provide guidance and support to Principal Investigators and research staff conducting Investigator-sponsored research.

IRB requirement: all investigator-initiated research reviewed by the Hennepin Healthcare convened IRB must complete the EQ Study Start-up program. This requirement also applies to ceded research for which the Hennepin Healthcare PI is the overall PI of an investigator-initiated study and/or the holder of a test article IND and/or IDE. The IRB has discretion to establish the requirement for other research based on review of an IRB submission and identification of need for additional support from EQ.

EQ may also identify studies to complete their Study start-up program prior an IRB submission.

In addition, study teams may request to complete the EQ program.

Study start up program pathways:

EQ will determine the appropriate start up pathway: Full or expedited. Factors that EQ uses to determine the pathway can include, but aren’t limited to:

  • PI and study team experience conducting clinical research
  • Support from a larger regional or national clinical trial network
  • Type of funding and budget available to conduct the research
  • Infrastructure already in place for the study team

Full start-up

  • Review of all study documents – can include but not limited to:
  • Protocol
  • Informed consent
  • Recruitment materials
  • Investigator brochures
  • Informational sheets
  • Any other relevant material
  • This process may involve several rounds of reviews before all issues/concerns are addressed.
  • Cayuse submissions should be started during this process.
  • Once the full review is complete, EQ will provide the study team with a completed/signed full review checklist that addresses what was reviewed, resolved, and any outstanding issues that will need to be addressed at the IRB level.
  • Study team must submit the completed EQ form in Cayuse as part of the Initial IRB submission.

Expedited start-up:

  • EQ provides a checklist template for the study team to complete.
  • Checklist requests specific details about the study and the study team’s overall infrastructure.
  • Some study materials may be required to be provided, but a full review of these materials is not required.
  • Once the review is complete EQ will provide the study team with a completed/signed full review checklist.
  • Study team must submit the completed EQ form in Cayuse as part of the Initial IRB submission.

While working through the IRB approval process, there is still work to do to get the study ready for enrollment. Common clinical study infrastructure that needs to be completed:

  • PI delegation of authority to research staff – ensure all duties have been delegated appropriately via the Delegation of Authority (DOA) log
  • Ensure all study staff have completed the required human subject training
  • Conduct protocol specific training, sponsor specific training and review study procedures with assigned study staff
  • Develop or use sponsor-generated worksheets, checklists, and flow sheets to assist study staff in conducting the study
  • Ensure space is available and reserved for conducting the study visits, storage of investigational product (if applicable), storage of study equipment (if applicable), and any other study materials
  • Order any required supplies not directly provided by the sponsor. Example: PPE for study staff
  • Ensure that all pre-study activities by other ancillary service providers have been completed. Example: installation and testing of analyzer required to be set up in study space.
  • Confirm that sponsor/funder agreements such as a contract or grant have been awarded and/or fully executed. See Sponsored Research Administration webpage - Sponsored Research Administration - Hennepin Healthcare Research Institute (hhrinstitute.org)
  • Confirm any data and or sub-agreements with external research collaborators have been fully executed. See Sponsored Research Administration webpage - Sponsored Research Administration - Hennepin Healthcare Research Institute (hhrinstitute.org)
  • If conducting research in specific HHS departments, be sure to connect with HHS department Chief and unit manager/supervisor to ensure they have knowledge of the study. Topics include:
  • Name of the study
  • Rationale for the study
  • Name and number of PI
  • Name and number of research coordinator
  • If HHS staff will be conducting research activities involving human subjects, they must be named in study personnel section of the IRB record. Here are some topics to ensure are communicated to all personnel:
  • Research training requirements
  • Responsibilities to be performed by HHS staff
  • Prohibited medications or other interventions outlined by the protocol
  • Potential adverse events to monitor participant for
  • Name and number of PI
  • Name and number of research coordinator
  • Ensure that all regulatory documents are complete, up-to-date, and in the regulatory binder.

Applicable Clinical Trial (ACT):

See the Checklist June Version (v5) (clinicaltrials.gov) (PDF) (June 2018) for complete statutory definitions and more information on the meaning of applicable clinical trial.

Federal agencies including the FDA and NIH require clinical trial registration:

You may contact EQ (EQ@hhrinstitute.org) for assistance if the trial qualifies for registration:

  • To create a ClinicalTrials.gov personal account if needed
  • to walk through clinical trial registration and to familiarize the study team with how to create and manage the clinical trial record in ClinicalTrials.gov

ICMJE requirements:

International Committee of Medical Journal Editors (ICMJE) member journals require, as a condition of consideration for publication, registration in a public trials registry.

The ICMJE defines a clinical trial as: “Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Health-related interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-or-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator will not require registration.

Devise a regulatory binder for each study.

  • Paper, electronic, or a hybrid of both are acceptable.
  • Electronic regulatory files must be organized, accessible and kept current.
  • If FDA regulated, all electronic regulatory files must also be saved and stored in a 21 CFR part 11 compliant electronic system.
  • If not FDA regulated, all electronic regulatory files are expected to be housed in a system that has an audit trail. The system does not have to specifically be 21 CFR part 11 compliant. Example: a non-validated REDCap database.
  • If using a hybrid format, any regulatory documents that originated as paper, must be retained. Examples of some documents that could be originally signed on paper: FDA form 1572, protocol signature page(s), delegation of authority forms, signed informed consent forms.
  • Use sponsor binder if applicable.
  • Add new or updated documents as appropriate.
  • Identify required regulatory and sponsor mandated documents.
  • Determine which documents must be original and which may be copied or scanned.
  • Retain copies of all original and revised documents.
  • Retain copies of all submissions and correspondence associated with the study.

Keep regulatory binder in a confidential and secure location.

The basic list of clinical research regulatory files include*:

  • Curriculum Vitae – principal investigator and sub-investigators
  • Delegation of Duties/Authority
  • Financial Disclosure Forms
  • Form FDA 1572 (IND) or Investigator Agreement (IDE)
  • IRB-approved advertising/recruitment materials
  • IRB-approved informed consent/assent documents
  • IRB correspondence (e.g., email; Fax; phone communications)
  • All IRB submission documentation and determinations
  • IRB member list and/or FWA #
  • Investigational product accountability
  • Product shipping inventory
  • Dispensing log
  • Product return or destruction documentation
  • Investigator’s Brochure, Product Insert, Device Instruction for Use
  • Laboratory certifications
  • Laboratory normal values – for all laboratories utilized in the protocol
  • Licenses as appropriate i.e., MD state license, RN state license
  • Monitoring logs
  • All versions of IRB-approved protocols
  • Protocol correspondence – all communication between investigative staff and sponsor (e.g., email; Fax; phone communications)
  • Required regulatory approvals (i.e., Radiation Committee)
  • Screening logs
  • Serious adverse event reports and IND/IDE safety reports
  • Sponsor correspondence – all correspondence between Sponsor and investigative staff
  • Subject enrollment logs
  • Signature pages
  • Telephone logs

There may be required updates or renewals for long-term studies, such as CVs, protocol amendments, laboratory certification(s), or laboratory values. Ensure that a copy of outdated information is kept. Historical information is important.

*There may be different or additional files required by the sponsor.

Ensure that all documentation and materials associated with the study are provided to assigned study personnel. Connect with the sponsor/CRO to find out which study personnel they will want to meet. Collaborate with the sponsor/CRO to schedule a mutually convenient date and time when all required parties can attend; save this correspondence in your regulatory files.

Prepare for and meet with the Clinical Research Associate (Study Monitor). They will want to:

  • Conduct a final protocol review.
  • Ensure that the study team is familiar with the protocol.
  • Ensure that staffing and the physical environment is the same as documented during the pre-study site evaluation.
  • Ensure that study procedures are compatible with site routines or that special plans have been made to accommodate the protocol.
  • Ensure that the study team is comfortable with the process to complete the case report forms.
  • Confirm that the study team understands and is willing to follow all regulatory obligations.
  • Verify that all needed supplies are present and ready.
  • Familiarize the study team with the monitoring plan.

The study team should:

  • Obtain answers to any final questions.
  • Clarify communication procedures with the sponsor/CRO.
  • Discuss process and requirements for monitor/CRA onboarding and Epic access.
  • Discuss the frequency and type of study visits that will occur during the course of the study.

If all preparatory activities are complete:

The sponsor/CRO will issue an official notification that the PI is free to begin the study. This document will be signed by sponsor/CRO, can be paper or electronic, and will be saved in the regulatory files. The study and administration of the test article cannot begin until this is received.

Completing case report forms:

  • Assure that all personnel writing in the Case Report Form (CRF) have signed the delegation of authority log and it is placed in the regulatory binder.
  • Identify data to be collected from appropriate primary source documentation. Ensure that there is a data source for each CRF entry.
  • Transcribe data to the CRF as soon as possible after data has been collected.
  • Enter data in black ink (paper CRF) unless otherwise directed.
  • Do not leave data points blank. If data does not exist, use required sponsor categorization (i.e., ND = not done, NA = not applicable) or single horizontal slash mark if so directed.
  • Do not add any extraneous data to a CRF.

GCP best practice for completing case report forms and other primary source documents:

Paper

  • Use black ink unless instructed otherwise. Never use pencil.
  • Include name and date of person completing the case report forms.
  • Correct errors by striking through errors with a single line. Write correct entry next to the incorrect one, date, and initial change(s).
  • Do not write over an entry to attempt to correct it.
  • Do not erase, do not use white-out.
  • Obtain PI signatures as required.
  • Report loss of data immediately.

Electronic case report forms

  • Ensure that staff are appropriately trained according to sponsor specifications when using electronic data capture.
  • Complete forms as instructed by sponsor.
  • Include name and date of person completing the case report forms.
  • Do not leave computer unattended.
  • Do not allow anyone to use computer access code.
  • Report any loss of electronic hardware immediately.

De-identifying subject treatment or diagnostic records before sending to sponsor leaving study specific identifiers:

  • Remove all identifiers based on the HIPAA identifier list.
  • Remove identifiers within a document body as well as the name and medical record number.
  • Ensure that personal identifiers cannot be discerned when covered.
  • Ensure that personal identifiers cannot be seen if source record is copied (wax pencils or “grease markers”) are highly recommended for paper copies.

A copy of the study’s informed consent form, when appropriate, should be placed in the participant’s Epic medical record. There are specific studies where adding the consent to the participant’s medical record is not appropriate; be sure to connect with the PI and study sponsor to ensure that if applicable, the consent is added.

Informed consents being added to a patient record should include the patient’s name and MRN on each page of the consent; often that is accomplished by creating a label with the information and adding it to the upper right-hand corner of each page.

There are two options for adding informed consent forms to the medical record:

  • On campus confidential interoffice mail: These are blue envelopes that are also used by the hospital. These envelopes are marked to be sent to the Health Information Management (HIM) department. They can be obtained from HIM.

DO NOT leave blue folders in an open mail slot, either add them to a pile of already outgoing blue folders in the hospital clinic or take them to HIM on Shapiro S7 and put them in the locked box

  • Electronic mail: HIM accepts electronic requests to upload informed consent forms. The consent forms must still be labeled on each page. Be sure to provide information in the email about the documents that need to be uploaded. Send to: HIMOperations@hcmed.org

How to place an Epic FYI:

If the study is a clinical trial that is providing an intervention to a participant and it is important that the hospital clinic staff is aware of the study, an Epic FYI research banner should be added to the participant’s medical record. To do this:

  • Go to the FYI
  • Choose the RESEARCH/PROTOCAL FYI
  • Insert critical information about the study that may affect the participant’s care
  • Be sure to add PI and other study staff contact information

A green banner will appear on the major Epic reports and will remain on the chart across all encounters.

Study personnel MUST deactivate the banner when the participant has completed the study.

Yes. Ensure that the protocol or study SOPs provide information about expectations when an electronic system will be used:

  • Maintain a listing of the hardware and software used for each trial along with the provider of the hardware and software.
  • Ensure the sponsor has provided SOPs and training on how to use the electronic system
  • Ensure the data points the sponsor is requesting to be entered into the electronic system are the data points listed in the IRB approved protocol/submission
  • For FDA regulated research or research data that will be submitted to the FDA in the future as part of a marketing application or other FDA related application, the electronic consent process and platform must meet the requirements of 21 CFR part 11. See also: FDA – OHRP Guidance on Electronic Consent

Use sponsor provided Electronic Data Capture (EDC) system as described in the IRB approved protocol/submission and study SOPs:

  • Work with the sponsor to facilitate set-up.
  • Ensure training is provided for using the software.
  • Ensure that the software is 21 CFR 11 compliant, as required.
  • Assign a unique and secure user ID for each clinical research team member that will be entering electronic data.
  • Establish and maintain a password-changing schedule.
  • Invalidate stolen, lost, or compromised user IDs and/or passwords immediately.

Electronic system logging in/out:

  • Use own unique user ID and password combination when logging in.
  • Do not give out a user ID or password to another individual.
  • Do not use another individual’s user ID or password.
  • Log off the program when finished with computer entries.

Electronic system use:

  • Confirm that changes to electronic records are documented through an audit trail and that the original entries are not overwritten.
  • Ensure that all entries are attributable with date, time, and electronic signature stamps.
  • Electronic medical records and/or documents converted to electronic form are considered equivalent to an original paper record.
  • Electronic signatures are considered legally equivalent to a full hand-written signature, initials, or other signing.

See also: section 6. Obtaining informed consent - 6.14 Can I conduct consent electronically? for more information about requirements for electronic signatures.

Inpatient drug research studies:

  • Complete and submit an Investigational Drug Data Form to the Hennepin Healthcare System (HHS) Investigational Pharmacist, per HHS policy # 005361 Investigational Medications. Contact EQ, eq@hhrinstitute.org, for more information.
  • Work with Investigational Pharmacist to enter investigational drug orders into Epic. Provide the protocol title to differentiate it from other medication orders.
  • Develop an inpatient drug accountability form if one is not supplied by the sponsor.
  • Investigational drug will be stored in the Inpatient Pharmacy.
  • Investigational Pharmacist will be responsible for maintaining Drug Accountability Records for all investigational drug products delivered to the pharmacy, including perpetual inventory, dispensing of drugs to research subjects, and the return to the sponsor or alternative disposition of unused product.
  • Study drug will be dispensed by an HHS dispensing pharmacist.
  • Study drug is to be administered only by an individual licensed within the state of Minnesota and so authorized by their professional scope of practice. They must ensure that:
  • Study drug is to be administered in accordance with the research protocol.
  • Study drug is to be administered in accordance with any other hospital policies pertaining to medication administration.
  • Administration of all doses of an investigational drug must be documented. Either in the participant’s electronic medical record (EMR) or if it should not be part of the participant’s EMR, then documented in the participant’s study file.
  • Ensure that the blinds (if applicable) are enclosed or that access to unblinding is defined.

Outpatient drug research studies:

  • Complete and submit an Investigational Drug Data Form to the Hennepin Healthcare System (HHS) Investigational Pharmacist.
  • It is preferable that study drugs for research performed in an HHS Clinic be housed in the HHS Investigational Pharmacy.

If not:

  • Ensure that the information on the packing slip corresponds exactly with what has been shipped to the site, report any discrepancies, breakage, or evidence of tampering to the sponsor. Retain all packing/delivery slips.
  • Ensure that the blinds (if applicable) are enclosed or that access to unblinding is defined.
  • Investigational drug should be stored as specified by the sponsor and in accordance with regulatory requirements.

Ensure that:

  • Study drug is kept in a storage area that has been identified to the investigational pharmacist
  • Study drug is kept in a storage area that is large enough for the supply of study drug
  • Study drug is kept in a storage area that must be locked
  • Study drug is stored with access that is limited to study staff identified to the investigational pharmacist
  • Study drug is stored separately from other drugs
  • Non-dispensed drug is stored separately from returned drug
  • Inventory control procedures are used
  • Study drug is kept in a storage where environmental controls are maintained (maintain a storage area temperature log if applicable)
  • Controlled substances are stored in a locked location
  • An outpatient drug accountability form is developed if one is not supplied by the sponsor. A template is available from EQ. Contact them at EQ@hhrinstitute.org.

Drug labels must comply with federal and state regulations:

Federal

The immediate package must have a label with the statement “Investigational Use Only”.

State

Investigational drugs, not dispensed in unit dose, must comply to Minnesota Rules on labeling for any drug dispensed to or for a patient and will include:

  • Name, address, and telephone number of the principal investigator
  • Subjects name
  • Name of prescribing practitioner
  • Title of study
  • Directions for use
  • Unique prescription number
  • Name of the manufacturer or distributor of the finished dosage form of the drug
  • Auxiliary labels as needed
  • Date of original issue or renewal
  • Generic or trade name of drug and strength, or study name to identify drug, except when specified by prescriber to the contrary

Additional requirements:

  • There must be an order entered into Epic in order to dispense study drug.
  • Study drug is to be dispensed by an individual licensed within the state of Minnesota and so authorized by their professional scope of practice.
  • Study drug is to be administered in accordance with the research protocol.
  • Study drug administered in an HHS clinic must be documented in the participant’s EMR or in participant’s study file.
  • Study drug is to be administered in accordance with any hospital or clinic policy pertaining to the administration of medications.
  • Fill out the drug accountability form each time study drug is dispensed or returned. Documentation should include, but not be limited to:
  • Protocol number
  • Lot number dispensed
  • Name of individual returning study drug
  • Date and time of returning drug
  • Amount dispensed
  • Expiration date
  • Name of individual dispensing study drug
  • Subject’s study ID number
  • Date and time of dispensing drug
  • Lot number returned
  • Amount returned
  • Retrieve and store used drug containers (if required by sponsor). Document the reason and amount if drug container is missing or not returned.
  • Monitor subject compliance by noting any discrepancies between amount of drug used and the amounts expected to be returned. The % compliance may be calculated with the following formula: (# of pills or vials returned)/(# of pills or vials dispensed)
  • Notify the sponsor when additional study drug is needed.
  • Ensure that unused product is to be returned to the Sponsor or disposed of per Sponsor’s requirements.
  • Retain the shipping slip when the monitor returns study drug to the sponsor during the study termination visit.
  • Ensure that if unused product is to be disposed, it may only be done by the Investigational Drug Pharmacist or Principal Investigator in accordance with the Sponsor’s investigational protocol and/or HHS Pharmaceutical Waste Policy #001832.
  • Ensure that a copy of all study drug delivery slips, return receipts, dispensing documents, or destruction records are placed in the regulatory binder.

Related: 643 TEMPLATE Investigational drug accountability form (OEQCR)

Accountability Requirements:

  • Upon receipt of investigational study devices:
  • Ensure that the information on the packing slip corresponds exactly with what has been shipped to the site, report any discrepancies, breakage, or evidence of tampering to the sponsor.
  • Ensure that the blinds (if applicable) are enclosed or that access to unblinding is defined.
  • Maintain an investigational device accountability form. Sponsor may provide form or contact EQ, EQ@hhrinstitute.org, for a form template.
  • Maintain proper storage for the investigational device:
  • Establish and maintain access controls for essential and/or appropriate research personnel.
  • Store the investigational device in a secure, locked environment along with controlled access.
  • Ensure the investigational device is stored at the appropriate temperature and maintain a storage area temperature log if appropriate.
  • The PI must assure that an investigational device is used only with participants under the PI’s personal supervision or under the supervision of a sub-investigator.
  • Study personnel must collaborate with appropriate personal (i.e., operating room, Radiology, Clinic Manger) to discuss the protocol and develop procedures appropriate to the study protocol and area in which the device will be placed.
  • Ensure that information is completed in the investigational device accountability form each time the study device is dispensed/used. At minimum, document the following:
  • Subject’s study ID number
  • Date
  • Person dispensing the study device
  • Notify the sponsor when additional study devices are needed.
  • Return any unused devices, or any retrieved devices that are used or opened to the sponsor according to the study protocol.
  • Ensure that a copy of all study device return receipts and dispensing documents are placed in the regulatory binder.

Device labeling:

If the study falls under FDA oversight, the Principal Investigator is responsible for ensuring the device follows FDA labeling regulations for investigational devices. See the following link for FDA guidance: Device Labeling | FDA

Related: 644 TEMPLATE Investigational device accountability form (OEQCR)

Preparing for an audit

  • Notify the following:
  • All study personnel
  • HHRI VP of Operations
  • Appropriate Grant Administrator
  • Office for Education and Quality in Clinical Research
  • Complete a Cayuse Incident submission, as applicable: see 133 GUIDANCE New information/Incident reporting
  • Study sponsor if the audit is by a local, state, or federal agency.
  • Ensure that all study documentation, including, but not limited to, consent forms, source documents, x-rays and ECGs, study drug or investigational device dispensing records, case report forms, and the regulatory binder are accurate, complete, and available. If this is an FDA audit, the inspector can audit all clinical trial documents.
  • Conduct a review of study procedures, protocol, and case report forms.
  • Ensure that records of staff qualifications and training are available.
  • Assign an escort to the auditor or inspector to facilitate document copying, retrieving requested materials, and navigating the campus. This is especially important in an FDA audit.

Participating in an audit

  • Meet with the auditor, request appropriate identification. Request the FDA Form 482 if this is an FDA audit.
  • Wear your institutional ID badge at all times.
  • Know the contents of your job description.
  • Ensure that the auditor has a suitable area to work in, preferably a private area.
  • Auditors should not be left unattended unless a specific work space has been provided.
  • Provide all requested documentation.
  • Be aware of what items an auditor may or may not ask to examine.
  • Questions posed by the auditor should only be answered by the appropriate study personnel.
  • Seek clarification if a question is not understood.
  • Answer only the questions asked. Do not offer extraneous answers or comments.
  • Remain calm and focused.
  • Do not fill in any silences.
  • Be aware of negative body language. Attempt to avoid mannerisms that may depict nervousness or anger such as repeatedly clicking a pen, hair twirling, standing with crossed arms, or avoiding eye contact.
  • Do not stay in the audit room to chat with the auditor after answering audit related questions.
  • Make photocopies of any study documents only if requested. Redact any personal information as defined by HIPAA regulations using a grease marker to completely obliterate the protected health information (PHI). If this is an FDA audit, FDA employees may receive records that identify subjects upon notice that the FDA has reason to suspect that adequate informed consent was not obtained or that reports required to be submitted by the investigator have not been submitted or are incomplete, inaccurate, false, or misleading. Make additional copies for the research site, this often assists study personnel when responding to questions from the auditor.
  • Participate in the exit interview. If this is an FDA audit and an FDA Form 483 is issued, be sure to review the FDA Form 483 with the FDA inspector before they leave the site

After the audit

  • Respond to the audit report as soon as possible.
  • Reply to each item in the report; provide clarification or steps that will be taken to institute corrective action.
  • Responses should be simple, direct, and dispassionate

Items that can be shared with an auditor

Internal auditor

  • All documents, procedures, notes, etc.

Sponsor auditor

  • All records pertaining to their study
  • SOPs governing the functional aspect of the trial
  • CVs, monitor visit reports, drug/device accountability records
  • No documents pertaining to another study

Regulatory (FDA) auditor/inspector

  • All records except financial documents, administrative meeting minutes, and internal audits

Items that can be taken by an auditor

Sponsor auditor

  • SOP index (not SOPs)
  • Organizational charts
  • Copies of any study specific documents/records (redact all PHI identifiers)

Regulatory (FDA) auditor/inspector

  • Federal inspectors may take copies of any record, photographs, CDs, samples, etc.
  • Any documents provided to the FDA should ensure PHI has been redacted.

Related: 645 TEMPLATE Audit preparation checklist (OEQCR)

Arrange a mutually convenient date and time for the sponsor/CRO study close out visit:

  • Ensure that all regulatory documents and case report forms are present and completed.
  • Ensure that all data queries to date have been resolved to the extent possible.
  • Ensure that all investigational product accountability records are completed.
  • Notify research pharmacist of study termination (if applicable).
  • Establish specific procedures for addressing any additional queries that develop during sponsor/CRO processing of case report forms and data review.
  • Discuss the sponsor/CRO requirements for subject follow-up for serious adverse events after closure of the study.

Dispose of investigational product and investigational supplies per sponsor/CRO instructions:

  • The Clinical Research Associate (monitor) will likely pack and ship investigational product; if not, research personnel are responsible for return of the investigational product to the sponsor.
  • Consult with the HHS investigational pharmacy if sponsor/CRO directs research team to dispose of investigational drug.
  • Retain copies of investigational product shipping slips and shipment receipts with study records.
  • Return or destroy all other study-related supplies as directed by the sponsor/CRO.

Inform ancillary departments of study closure:

  • These could include laboratory services, Sponsored Research Administration, etc.
  • Complete a Cayuse HE Closure submission for the study

Arrange for study record storage:

  • Follow sponsor and/or HHRI requirements for storage and/or destruction of study information.
  • Destroy any unneeded protected health information (PHI) by disposing in commercial shredding container or by personally shredding with a (preferably) crosscut shredder.
  • Collect all documents or add a note to file to the regulatory binder of where documents are being securely stored.
  • Source documents that must be retained per applicable FDA regulations include, but are not limited to:
  • Case report forms
  • Signed informed consent forms
  • Study drug/device accountability records
  • Subject diaries
  • Regulatory files
  • Medical files
  • If the sponsor/CRO had an electronic data capture (EDC) system, the sponsor/CRO must provide access to the site’s case report forms.
  • Notify the sponsor/CRO of any change in record location.
  • Notify the sponsor/CRO of any change in responsibility for study files. If the principal investigator leaves the institution, the responsibility must be delegated to another investigator and the sponsor/CRO notified.
  • Retain documents for no less than the amount of time required by federal regulations.
  • Obtain written authorization from the sponsor/CRO before destroying any records. Check with the appropriate Grant Administrator for contractual obligations.
  • Review requirements for whether the study is required to post the study’s consent form on clinicaltrials.gov.
  • Office for Human Research Protections (OHRP):https://www.hhs.gov/ohrp/regulations-and-policy/informed-consent-posting/index.html
  • NIH Office of Extramural Research (OER): https://grants.nih.gov/grants/guide/notice-files/NOT-OD-19-110.html

Record retention:

  • Retain all records used in the study as outlined in federal or ICH regulations, as applicable.
  • Check with Grant Administration to verify that the sponsor does not want records to be kept for a longer period.
  • Check with the sponsor before destroying records.

Long-term record storage:

  • Store records so that a request to view records by a sponsor, regulatory agency, or internal auditor may be met promptly.
  • Storage facilities should be secure with access limited to appropriate personnel.
  • If records are stored in an off-site facility, ensure that the records are handled securely and that only authorized personnel has access to them.
  • Notify the sponsor of any change in personnel responsible for stored records.
  • Notify sponsor of any change in record storage location.

Record destruction:

  • Shred paper documents with a mechanical (preferably crosscut) shredder or use a commercial shredding company to ensure that documents are destroyed in a way that information cannot be reconstructed.
  • Physically destroy disks, CDs, or other transportable memory devices.
  • Permanently delete files and data from internal and external hard drives using commercial scrubbing software or physically destroy hard drives. Connect with HHRI IT for best practices for destruction of electronic files.
  • Permanently destroy video or audio tapes.

GLOSSARY

Definitions that are specific to a federal agency or an international committee are accordingly noted.

Adverse Event (FDA): Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

Adverse Event (Common Rule): Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research (modified from the definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice).

Allegation of noncompliance: Non-compliance that is suspected and/or reported.

Amendment (FDA): A written description of a change(s) to, or formal clarification of, a protocol.

Analysis Set (FDA): A set of subjects whose data are to be included in the main analyses.

Approval (in relation to institutional review boards): The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and applicable regulatory requirements. Also known as “Favorable Approval”.

Arm: A planned sequence of elements, typically equivalent to a treatment group.

Assent (HHS): A child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.

Assent (FDA): A child's affirmative agreement to participate in a clinical investigation. Mere failure to object may not, absent affirmative agreement, be construed as assent.

Assessment: A measurement, evaluation, or judgment for a study variable related to the status of a subject. Assessments are usually measured at a certain time, and may be derived by combining several simultaneous measurements to form an assessment (e.g., BMI).

Audit: A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirements.

Audit Report: A written evaluation (by the auditor) of the results of the audit.

Audit Trail: Documentation that allows reconstruction of the course of events. May be a secure, time-stamped record that allows reconstruction of the course of events relating to the creation, modification, and deletion of an electronic study record.

Authorization (HHS): Required by HIPAA Privacy Rule for uses and disclosures of Protected Health Information (PHI) not otherwise allowed by the Rule. Where the Privacy Rule requires patient authorization, voluntary consent is not sufficient to permit a use or disclosure of PHI unless it also satisfies the requirements of a valid authorization. An authorization is a detailed document that gives covered entities permission to use protected health information for specific purposes, which are generally other than treatment, payment, or healthcare operations, or to disclose protected health information to a third party specified by the individual. An authorization must specify a number of elements, including a description of the protected health information to be used and disclosed, the person authorized to make the use or disclosure, the person to whom the covered entity may make the disclosure, an expiration date, and in some cases the purpose for which the information may be used or disclosed. With limited exceptions, covered entities may not condition treatment or coverage on the individual providing an authorization.

Base: A number or value used as a standard or reference against which other values are compared.

Baseline Assessment: Assessment of a subject as they enter a trial and before receiving any treatment.

Baseline Data: Data collected for certain clinical parameters (study specific) performed on clinical trial subjects usually prior to treatment.

Batch: FDA: A specific quantity of drug or other material that is intended to have uniform character and quality within specific limits, and is produced according to a single manufacturing order during the same cycle of manufacture.

Bias - statistical & operational (ICH): The systematic tendency of any factors associated with the design, conduct, analysis, and devaluation of the results of a clinical trial to make the estimate of a treatment effect deviate from its true value. Bias introduced through deviations in conduct is referred to as “operational” bias. The other sources of bias listed above are referred to “statistical.”

Blinding (ICH): A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware; double blinding usually refers to the subject(s), investigator(s), monitor, and in some cases, data analyst(s) being unaware of the treatment assignment(s).

Blinded Medications: Products that appear identical in size, shape, color, flavor and other attributes that make it very difficult for subjects and investigators to determine which medication is being administered.

Business Associate: In relation to HIPAA, a business associate performs on behalf of a covered entity any function or activity involving the use or disclosure of protected health information, and is not a member of the covered entity’s workforce.

Bonus payments: Payments designed to accelerate recruitment that are tied to the rate or timing of enrollment.

Case History: A record of a subject’s medical history and relevant study data gathered and maintained by an investigator. The case history includes the case report form and informed consent documentation.

Case report: A case report is a retrospective analysis of a clinical case.

Case Report Form (CRF) (ICH): A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

Central File: The file that contains all of the key documents relating to a clinical study, usually maintained by the sponsor or sponsor representative. Also known as the “Trial Master File.”

Central Laboratory: The laboratory used for the analysis of laboratory samples from more than one study site.

Certified Copy: A copy of original information that has been verified with a dated signature as an exact copy with all the same attributes and information as the original.

Children (HHS): Persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. In Minnesota a person must be 18 years of age or older to legally consent to treatments or procedures. There are certain exceptions allowing children to give consent for treatments involving emergency care, or care related to pregnancy, sexually transmitted diseases or contraceptives.

Children (FDA): Persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted. In Minnesota a person must be 18 years of age or older to legally consent to treatments or procedures. There are certain exceptions allowing children to give consent for treatments involving emergency care, or care related to pregnancy, sexually transmitted diseases or contraceptives.

Clinical investigation (FDA): Any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of part 58, regarding nonclinical laboratory studies. The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous for purposes of this part.

Clinical Trial/Study: Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s), and/or to study absorption, distribution, metabolism, and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy.

Code of Federal Regulations (CFR): The Code of Federal Regulations is the codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. It is divided into 50 titles that represent broad areas subject to Federal regulation. Each volume of the CFR is updated once each calendar year and is issued on a quarterly basis. Title 21 relates to Food and Drugs (FDA).

Common Rule: The Common Rule is a short name for “The Federal Policy for the Protection of Human Subjects” and was adopted by a number of federal agencies in 1991. The Department of Health and Human Services (DHHS), now known as HHS, adapted the policy into its own code of federal regulations: 45 CFR Part 46, Subpart A.

Compliance: Adherence to all trial-related requirements, Good Clinical Practice (GCP) requirements, and applicable regulatory requirements.

Concomitant Medication: Current medication, other than the investigational drug, that the study participant receives during the trial. Also known as “Concomitant Therapy.”

Confidentiality: Maintenance of the investigator’s agreement with the subject about how the subject’s identifiable private information will be handled, managed, and disseminated (prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity and medical information).

Continuing non-compliance: An episode or episodes of repeated non-compliance.

Contract: A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.

Contract Research Organization (CRO): A person or organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions.

Control Group: Subjects in a controlled study that receives no treatment, standard treatment, or placebo.

Curriculum Vitae: Document that outlines an individual’s educational and professional history.

Data and Safety Monitoring Board (DSMB): See data monitoring committee.

Data Clarification: Answer supplied by the investigator in response to a query.

Data Integrity: An attribute of data pertaining to clinical trials depending on the quality of processes for data capture, correction, maintenance, transmission, and retention. Key dimensions of data integrity include that data be attributable, legible, contemporaneous, original, and accurate.

Data Monitoring: Process by which clinical data are examined for completeness, consistency, and accuracy.

Data Monitoring Committee (DMC) (FDA): A group of individuals with pertinent expertise that reviews, on a regular basis, accumulating data from an ongoing clinical trial. The DMC advises the sponsor regarding the continuing safety of current participants and those yet to be recruited, as well as the continuing validity and scientific merit of the trial. A DMC can stop a trial if it finds toxicities or if treatment is proved beneficial.

Database Lock: Action taken to prevent further changes to a clinical trial database. Locking a database is done after review, query resolution, and a determination has been made that the database is ready for analysis.

Data Verification: In clinical monitoring, data verification is the comparison of entries on CRFs with the source documents performed by monitors (CRAs) at investigational sites.

Digital Signature (FDA): An electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.

Dechallenge: A method used to determine if an adverse event (AE) is casually related to a drug treatment. The drug is stopped and the subject is carefully monitored to observe if the event resolves. Compare to “Re-challenge.”

Derived Data: Data that is based on conclusions and interpretations of raw data collected. Compare to “Raw Data.”

Direct Access: Permission to examine, analyze, verify, and reproduce any records and reports important to the evaluation of a clinical trial. Any party (e.g., regulatory authorities or sponsor’s monitors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary information.

Disclosure: The release, transfer, provision of, access to, or divulging in any other manner of information outside the entity holding the information.

Discontinuation: The act of concluding participation, prior to completion of all protocol-required elements, by an enrolled subject. Four categories of discontinuation are defined: A) dropout: active discontinuation by a subject; B) investigator-initiated discontinuation; C) loss to follow-up: cessation of participation without notice or action by a subject; D) sponsor-initiated discontinuation. Subject discontinuation does not necessarily mean the exclusion of subject data from analysis.

Discrepancy: The failure of a data point to pass a validation check.

Documentation: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.

Dosage: The amount of drug administered to a patient or test subject over the course of the clinical study; a regulated administration of individual doses.

Dosage Form: Physical characteristics of a drug product that contains a drug substance, possibly in association with one or more other ingredients.

Dosage Regimen: The number of doses per given time period; the elapsed time between doses, the time that the doses are to be given, and/or the amount of a medicine to be given at each specific dosing time.

Dosage strength: The proportion of active substance to inert substance, measured in units of volume or concentration. The strength of a drug product tells how much of the active ingredient is present in each dosage.

Dose: The amount of drug administered to a patient or test subject at one time or the total quantity administered.

Drug: An article other than food intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; or intended to affect the structure or any function of the body. Not a device, component, part, or accessory of a device. Substance recognized by an official pharmacopeia or formulary.

Drug Classification System: A system established by the FDA designed to assist the agency in prioritizing its reviewing assignments in order to help expedite the evaluation of drugs that offer potentially significant therapeutic gains over existing treatments.

Drug-Drug Interaction (HHS): A modification of the effect of a drug when administered with another drug. The effect may be an increase or a decrease in the action of either substance, or it may be an adverse effect that is not normally associated with either drug.

Drug Reconciliation: Process of comparing dispensing records, CRFs, and source documentation to ensure that all records are accurate and drug has been disposed of properly.

Effect: An effect attributed to a treatment in a clinical trial. In most clinical trials, the treatment effect of interest is a comparison (or contrast) of two or more treatments.

Efficacy: The capacity of a drug or treatment to produce beneficial effects on the course or duration of a disease at the dose tested and against the illness and patient population for which it is designed.

Electronic Case Report Form (e-CRF): An auditable electronic record designed to record information required by the clinical trial protocol.

Electronic Data Capture (EDC): A computerized system for the collection of clinical trial data. There are many different providers of EDC software systems; in addition, some pharmaceutical, biotech, medical device, and contract research organizations choose to develop proprietary EDC systems. See also “Remote Data Entry.”

Electronic Record (FDA): Any combination of text, graphics, data, audio, pictoral, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.

Electronic Signature: Any computer data collection of symbols or series of symbols that are authorized to be the legally binding equivalent of an individual’s handwritten signature.

Essential Documents: Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data.

Exclusion Criteria: List of characteristics in a protocol, any one of which may exclude a potential subject from participation in a study.

Emergency use (FDA): Emergency use is defined as the use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval [21 CFR 56. 102(d)].

Family member (FDA): Any one of the following legally competent persons: spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship.

Food and Drug Administration (FDA): The US Department of Health and Human Services agency responsible for the enforcement of the Food, Drug & Cosmetic Ace of 1938 (FD&C Act), the FDA Modernization Act of 1997 (FDAMA), and the Food and Drug Administration Amendments Act of 2007 (FDAAA). The FDA is authorized to monitor the safety and efficacy of all drugs, biologics, and medical devices, and to grant marketing approval in the US.

Federalwide Assurance (FWA): The only type of new assurance of compliance accepted and approved by the Office for Human Research Protections (OHRP) for institutions engaged in non-exempt human subject’s research conducted or supported by the Department of Health and Human Services (HHS).

Finder’s fees: Payments in exchange for referral of potential subjects.

For-Cause Inspection: An inspection or audit conducted when the FDA receives a report or becomes aware of suspicious behavior at a clinical research site or IRB. Inspection triggers include complaints from a sponsor, subject, or competitor; history of non-compliance; conducting clinical trials outside of one’s area of expertise; or reporting study results that are significantly different than other investigators conducting the same study. Also called a “Direct Inspection,” “Compliance Inspection,” “Investigator-Related Inspection.” Or “Investigator Directed Inspection/Audit.”

Formulary: The list of therapies that a healthcare plan covers.

Generalizability, Generalization (ICH): The extent to which the findings of a clinical trial can be reliably extrapolated from the subjects who participated in the trial to a broader patient population and a broader range of clinical settings.

Good Clinical Practice (GCP) (ICH): A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. ICH GCP is developed around 13 key principles.

Good Laboratory Practice (GLP): A standard that ensures the quality of non-clinical laboratory studies, both in vitro and in vivo (e.g., animal studies), and the resultant data. GLP requirements apply to drug company laboratories, private toxicology laboratories, academic and government laboratories, and all other facilities under which laboratory studies are planned, performed, monitored, recorded, and reported. GLP is monitored in the US by Title 21 CFR Part 58.

Guardian (HHS): An individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care. In Minnesota, a guardian is most frequently appointed by a court, although they may also be appointed by will or by a spouse. Note: When a child is a ward of the State (parental right terminated—no adoptive parent—a guardian is required to consent on the child’s behalf). If you have questions concerning this determination of authority to consent on behalf of the child, please consult the HSRC.

Guardian (FDA): An individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care when general medical care includes participation in research. For purposes of subpart D of this part, a guardian also means an individual who is authorized to consent on behalf of a child to participate in research. In Minnesota, generally either of the married parents of a child may give consent for medical care and for research. If the patient/subject is the child of a woman who was not married when the child was born, the woman is generally the sole legal custodian of the child and may consent on the child’s behalf. If the parents of the child are divorced, then the divorce degree should establish legal custody of the child, upon which you may rely. If you have questions concerning this determination of authority to consent on behalf of the child, please consult the HSRC

HHS: Health and Human Services federal agency previously known as the Department of Health and Human Services.

HRPO: Human Research Protection Office of Hennepin Healthcare System, Inc.

Human subject (HHS): A living individual about whom an investigator (whether professional or student) conducting research obtains: (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (e.g., venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (e.g., a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. [45 CFR 46.102(f) (1) (2)]

Human subject (FDA): An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. This definition also includes an individual on whose specimen an investigational device is used.

ICH GCP Guidelines (FDA): A set of international guidelines developed by the International Conference of Harmonization (ICH) to govern the conduct of clinical trials

Independent Ethics Committee (IEC) (ICH): An independent body (a review board or a committee, institutional, regional, national or supranational), constituted of medical/scientific professionals and non-medical/non-scientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favorable opinion on, the trial, protocol, ant the suitability of the investigator(s), facilities and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

IND Safety Report: A sponsors written, telephone, or facsimile notification to the FDA by the sponsor of a clinical trial of any adverse experience associated with the use of the drug that is both serious and unexpected. A written IND safety report should be filed as soon as possible and in no event later than fifteen calendar days after the sponsor’s initial receipt of the information. A report describing and unexpected, fatal, or life-threatening event, must be made to the FDA no later than seven calendar days after the receipt of the information.

Informed Consent (IC):

1.(HHS definition) The voluntary confirmation of a subject’s willingness to participate in a particular trial, and the documentation thereof. This confirmation should only be sought after the information has been given about the trial including an explanation of its objectives, potential benefits, risks, inconveniences, alternative therapies available, and of the subject’s rights and responsibilities in accordance with the current version of the Declaration of Helsinki. Key elements of informed consent include disclosure of information, comprehension of the information being disclosed, voluntariness of the subject’s choice, competence of the subject to make decision, and consent by the subject. Informed consent is an ongoing process, not a one-time event.

2.(ICH definition) A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form.

Informed Consent Form (ICF): The document prepared by the investigator and/or the sponsor, and approved by the IRB/IEC, which must be signed by the subject or legally authorized representative (LAR) before entry into a clinical trial. The informed consent form is the legal written record that the subject agrees to voluntarily participate in the clinical trial.

Inspection (ICH): The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract establishments deemed appropriate by the regulatory authority(ies).

Institutional Official: The individual legally authorized to represent the institution.

Institutional Review Board (IRB) (ICH): An independent body constituted of medical, scientific, and noon-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing the continuing review of trial protocol and the documenting of informed consent of the trial subjects. Also called “Independent Ethics Committee” and “Human Subjects Review Committee.”

Institutional Review Board Approval (FDA): The determination of the IRB that the clinical investigation has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements.

Inter-rater Reliability (ICH): The property of yielding equivalent results when used by different raters on different occasions.

Intra-Rater Reliability (ICH): The property of yielding equivalent results when used by the same rater on different occasions.

Investigator: An individual responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.

Investigator Agreement: The formal, legal agreement, including financial commitments, between the investigator and sponsor, describing the terms and conditions under which the investigator will conduct a study. Also referred to as a “Clinical Trial Agreement,” and “Investigator Contract.”

Investigator’s Brochure: A collection of clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human subjects.

Investigational Device Exemption (IDE): Allows an investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification [510(k)] submission to the Food and Drug Administration (FDA). Clinical studies are most often conducted to support a PMA. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

Investigator Meeting: A meeting held either prior to the start of or during a clinical trial that is attended by sponsors, and/or their representatives, and preferably all participating investigators. Sponsors generally hold three kinds of meetings with investigators for the purpose of: (1) Providing input and feedback at the stage of protocol development; (2) To help ensure the consistency of procedures across all study sites; and (3) To show appreciation to the investigators and study staff for their work/progress in a clinical trial.

Investigational New Drug Application (IND): The IND is a proposal through which a sponsor obtains FDA approval of its plans to test a new drug in human clinical trials. If the FDA does not contact the sponsor within 30 days of the IND submission, the trial may commence.

Investigational Pharmacy: A specialized pharmacy which coordinates receipt, storage, preparation, and distribution of investigational drugs.

Investigational Product: A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. May also be an investigational device used in an Investigational Device Exemption (IDE).

Investigator Recordkeeping and Record Retention (FDA):

  1. Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under Sec. 21 CFR 312.59.
  2. Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.
  3. Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.

Laboratory Accreditation: A process resulting in a document issued by authorized agencies, which indicates that, a clinical laboratory has met certain performance criteria, generally evaluated by the use of blinded-test samples.

Laboratory Certification: A process resulting in a document issued by authorized agencies (e.g. CMS’ CLIA Certification and College of American Pathologists - CAP), which indicates that a clinical laboratory has met certain performance criteria, generally evaluated by the use of blinded-test samples.

Laboratory Normal Ranges: Statistically and biologically significant qualitative measurements of cellular and clinical components of the body based on averages provided by a survey of presumably healthy persons. Commonly used values include red and white blood cell counts, lipids, cardiac markers, coagulation, hemodynamic parameters, and general chemistry (glucose, folic acid, sodium, iron, etc.). Normal ranges are documented at the clinical research site. Also called “Normal Laboratory Values” and Laboratory Reference Ranges.”

Legally authorized representative (DHHS and FDA): An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. In Minnesota, a legally authorized representative of an incapacitated individual includes the following: a health care agent named in a duly executed Health Care Directive or a guardian of the prospective subject appointed by a parental or spousal appointment or by the court.

Life-Threatening Adverse Drug Experience (FDA): Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.

Longitudinal Study: Investigation in which data is collected from a number of subjects over a long period of time.

Lot (FDA): A batch or specific identified portion of a batch having uniform character and quality within specified limits or, in the case of a drug product produced by continuous process, a specific identified amount produced in a unit of time or quantity in a manner that ensure its having uniform character and quality within specific limits.

Monitoring (ICH): The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Monitoring Visit Report Form: A sponsor-specific form used by sponsor personnel to document activities conducted and new information gathered during a routine monitoring visit to an investigational site, including issues discussed, issues requiring follow-up, commitments made by and to the study staff, and progress to the study at the site.

Multicenter Trial: A clinical trial conducted according to a single protocol but at more than one site, and, therefore, carried out by more than one investigator.

National Bioethics Advisory Commission (NBAC): A commission established by executive order in 1995 to advise the National Science and Technology Council and other government entities on “bioethical issues arising from research on human biology and human behavior, and the applications, including clinical applications, of that research.” Topics of the Commission’s reports include stem cell research, human cloning, and newborn screening.

National Institutes of Health (NIH): The agency within the Department of Health and Human Services that is the primary US federal agency for conducting and supporting medical research. NIH is composed of 27 institutes and centers.

National Research Act of 1974: US legislation establishing IRBs and mandating informal consent.

New Drug Application (NDA): The compilation of all information and data about a new drug, including non-clinical, clinical, pharmacological, pharmacokinetic, and stability information, which is submitted to the FDA for review. The FDA mush approve the NDA before the new drug can be marketed in the US.

Nuremberg Code: An internationally accepted code of ethics for conducting medical research set forth in 1947. This was the first societal event that led to the development of current regulations and best practices for human research protections. In response to war crimes committed during World War II, the Nuremberg Code was formulated as a ten-point statement outlining permissible medical experimentation on human participants, including capacity to consent, absence of coercion, minimization of risk/harm, properly formulated scientific experimentation, and beneficence towards experiment participants.

Objective: The reason for performing a trial in terms of the scientific questions to be answered by the data collected during the trial. The primary objective is the main question to be answered and drives the statistical planning for the trial. Secondary objectives are goals of a trial that will provide further information on the use of the treatment.

Office of Human Research Protections (OHRP): The federal agency that protects the rights, welfare, and well-being of subjects involved in research conducted or supported by the Department of Health and Human Services (HHS) and helps ensure that such research is carried out in accordance with the regulations decribed at 45 CRF Part 46.

Patient Log: A list of all patients who were considered to be candidates for a study, regardless of the inclusion/exclusion criteria. This log is used to demonstrate a lack of bias in the selection process and to demonstrate efforts to find patients. Sometimes referred to as the “Screening Log.”

Patient Reported Outcome (PRO): Report coming directly from patients or subjects through interviews or self-completed questionnaires or other data capture tools such as diaries about their life, health condition(s), and treatment.

Pharmacodynamics (PD): The branch of pharmacology that studies reactions between drugs and living structures, including the process of bodily responses to pharmacological, biochemical, physiological, and therapeutic effects.

Pharmacogenetics: The study of the way drugs interact with genetic makeup or the genetic response to a drug.

Pharmacogenomics: The study of the use of biomarkers for drug efficacy, toxicity, and method of action. The goal of pharmacogenomics is to maximize efficacy and minimize adverse effects for an individual patient.

Pharmacokinetics (PK): The study of the way in which drugs are absorbed, distributed, metabolized, and excreted from the body.

Phase 0 Studies: A relatively new designation, Phase 0 refers to the clinical evaluation of new molecular entities in humans to determine early indicators of pharmacokinetics and pharmacodynamics. In Phase 0 Studies, ultralow doses are utilized in very small groups of humans. Part of the FDA’s Critical Path Initiative to accelerate the development of promising drugs, the agency’s 2006 guidance “Exploratory Investigational New Drug (IND) studies” allowed companies to explore Phase 0 Studies. Though Phase 0 is designed to determine early on whether a drug will behave in human subjects as expected from animal studies, there is debate as to whether the ultralow doses are useful as a pre-clinical tool. Also known as “Microdosing Studies.”

Phase I Studies: The introduction of a new drug or biologic into a small group of humans at a stage when only in vivo and in vitro data are available. The primary emphasis of a Phase I study is safety, and the determination of pharmacokinetic and pharmacodynamics effects on humans. Traditionally, Phase I Studies are conducted on subjects who are free from clinical conditions (“healthy volunteers”) that would complicate clinical interpretation. The objective of a Phase I study is to determine human toxicity, absorptions, distribution, metabolism, and elimination (ADME). Pharmacological properties and dose range are determined so as to maximize therapeutic utility. Typically, the starting dose in a Phase I Study is considerably lower than the predicted therapeutic dose.

Phase II Studies: Phase II Studies evaluate the safety and efficacy of a drug or biologic in a select population of patients who have the disease or condition to be treated, diagnosed, or prevented. The ultimate aim of a Phase II study is to determine whether there is a therapeutic justification and commercial rationale for moving to larger, more expensive Phase III studies. Specifically, data is gathered in patients to determine and confirm safety, effectiveness, clinical endpoints, dose, toxicity, short-term adverse effects, pharmacological effects, pharmacokinetics, and possible drug interactions.

Phase III Studies: Phase III is the last and most expensive pre-marketing testing stage; it may include the comparative evaluation of the new drug or biologic versus the standard therapy. These are large multi-center studies of patients for whom the treatment is eventually intended. During these full-scale evaluations, the new drug, biologic, or medical device is tested under conditions most closely resembling those under which it would be used if approved for marketing. Phase III Studies often provide much of the information needed for the package insert and labeling of the medication.

Phase IIIb Studies: Phase IIIb Studies are conducted just prior to or during regulatory filing. The purpose of a Phase IIIb Study may be to gather additional safety data, to provide additional evidence that will support the product claims, and/or to develop data on the use of an investigational product in a patient subgroup such as children, pregnant women, or the elderly. A Phase IIIb Study may be conducted voluntarily, or as a condition of regulatory approval.

Phase IV Studies: Studies conducted after the drug or biologic has been approved for marketing. The purpose of these studies includes comparing the product to a competitor, exploring use in additional populations, exploring adverse events, or evaluation formulations, dosages, durations of treatment, drug interactions, and other factors. Some use “Phase IV Studies” and “Post Marketing Surveillance Studies” interchangeably, while others distinguish between the two terms.

Pilot Study: A pre-clinical study conducted in a small number of animals or human subjects to determine the feasibility of pursuing larger-scale pre-clinical or clinical development of a project. A pilot study may reveal deficiencies in study logistics and/or design.

Placebo: An inactive preparation identical in appearance to the investigational drug unwittingly taken by a control group to rule out psychological effects clinical testing may cause.

Placebo Control Studies: Studies where the investigational drug is compared with an inert substance, usually in a double-blind study. Also called “Placebo Concurrent Control Study.”

Primary Source Documents: Original documents, data, and records contained in, but not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm, or magnetic media, x-rays subject files, and records kept at the pharmacy, laboratories, and at medico-technical departments.

Prisoner (HHS): 45 CFR part 46.303 (c) Any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures that provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing.

Privacy: Refers to persons and their interest in controlling the access of others to themselves (e.g., based on their privacy interest people may want to control: (1) time and place where they give information, (2) the nature of the information they give, (3) the nature of the experiences that are given to them, and (4) who receives and can use the information).

Protected health information (PHI): Information about an individual in combination with health data that could identify the individual.

Protocol: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents.

Protocol Amendment (ICH): A written description of a change(s) to or formal clarification of a protocol.

Protocol Deviation: Failure to adhere to the pre-specified trial protocol.

Protocol Violation: A serious departure from protocol that may result in subject data being excluded from a study. Generally, protocol violations compromise subject safety and/or the quality of data.

Quality Assurance (QA):

  1. Systems and process established to ensure that a clinical trial is performed and the data are generated in compliance with GCP, including procedures for ethical conduct, SOPs, reporting, and personnel qualifications.
  2. Proactive and retrospective activities that provide confidence that requirements are fulfilled (FDA Staff Manual Guide 2020).
  3. GCP ICH: All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and the applicable regulatory requirement(s).

Quality Control (QC):

  1. In a clinical trial, quality control refers to the observational techniques and activities used to fulfill requirements for quality. Quality control activities concern all members of the investigational team.

2.(FDA) The steps taken during the generation of a product or service to ensure that it meets requirements and that the product or service is reproducible (FDA Staff Manual Guide 2020).

3.(GCP ICH) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

Quality Improvement (QI): A continuous process that identifies problems, examines solutions to those problems, and regularly monitors the solutions for improvement.

Quality improvement activities: Quality improvement activities are projects that are completed to improve quality of programs, improve services, or improve the provision of medical care, customer service, etc. and are usually done for internal purposes only.

Query: A request for clarification on a data item collected for a clinical trial; specifically a request from a sponsor or sponsor’s representative to an investigator to resolve an error or inconsistency discovered during data review. May also refer to the activity of creating programming language to generate data from a database, i.e., querying the database.

Query Resolution: The closure of a query usually based on information contained in a data clarification.

Randomization: The assignment of experimental subjects to treatment (or control) groups in such a way that each subject has equal chance of being assigned to each treatment group.

Raw Data: Records of original clinical and laboratory findings, observation, measurements, and activities. Examples are physician’s notes, X-rays, and data recorded by laboratory instruments. Compare to “Derived Data.”

Rechallenge: A method used to determine if a drug treatment is casually related to an adverse event. The subject, who has been taken off of the drug so that the adverse event has subsided and the suspected drug has been eliminated from their system, takes the drug suspected of causing the adverse event, and is carefully monitored to observe if the event reoccurs. Compare to “Dechallenge.”

Recruitment Plan: A summary of the steps to be taken to ensure recruitment of adequate numbers of subjects within the target time frame. This might include, for example,

Redact: The act of selecting or adapting for publication. To prepare a document or report for inspection by an auditor by removing all identifying information the auditor is not legally entitled to see.

Regulatory Authorities: Any federal, state, local, or tribal bodies having the power to regulate clinical research.

Reliability: Pertains to questions concerning whether an instrument is accurate, repeatable, and sensitive. Reliability is distinguished from validation, which answers whether the instrument actually measures the selected construct.

Remote Data Entry: A computerized system designed for the collection of data in electronic form. See also “Electronic Data Capture.”

Research (HHS): A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Research involving a human being as an experimental subject: An activity, for research purposes, where there is an intervention or interaction with a living individual for the primary purpose of obtaining data regarding the effect of the intervention or interaction. Research involving a human being as an experimental subject is a subset of research involving human subjects. This definition does not include activities that are not considered research involving human subjects, activities that meet the exemption criteria, and research involving the collection or study of existing data, documents, records, or specimens from living individuals.

Research activities involving de-identified data and/or human biological specimens: Projects that involve data and/or human biological specimens where all direct personal identifiers are permanently removed from the data or specimens, no code or key exists to link the materials to the original source(s), and the remaining information cannot reasonably be used by anyone to identify the source(s).

Research activities involving non-living individuals: Projects that collect information on deceased subjects.

Risk: In clinical trials, the probability of harm or discomfort for subjects. The level of acceptable risk varies depending on the condition for which a product is being tested.

Risk-Benefit Ratio (NIH): The risk to individual participants versus the potential benefits. The risk-benefit ratio may differ depending on the condition being treated.

Safety and Tolerability (ICH): The safety of a medical product concerns the medical risk to the subject, usually assessed in a clinical trial by laboratory tests (including clinical chemistry and hematology), vital signs, clinical adverse events (diseases, signs and symptoms), and other special safety tests (e.g., ECGs, ophthalmology). The tolerability of the medical product represents the degree to which overt adverse effects can be tolerated by the subject.

Screening:

  1. Regarding Subjects: The process of evaluating potential clinical trial subjects to determine if they meet protocol inclusion/exclusion criteria before enrollment.
  2. Regarding Investigators: The process of evaluation investigational sites for participation in a clinical trial.

Short Form: Used when written informed consent is not possible because the subject does not read or understand English. According to the Code of Federal Regulations: a short form written consent document stating that the elements of informed consent have been presented orally to the subject or the subjects’ legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is said to the subject or to the representative. Only the short form itself is to be signed by the subject or representative. However, the witness shall sign both the short form and a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form. See also “Informed Consent.”

Screen Failure: A potential subject who did not meet one or more criteria required for participation in a trial.

Serious Adverse Event: An untoward medical occurrence that: (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalization or prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, or (5) is a congenital anomaly/birth defect.

Serious Non-compliance: An action or omission in the conduct or oversight of research involving human subjects that affects the rights and welfare of subjects, increases risks to subjects, decreases potential benefits, or compromises the integrity or validity of the research.

Source Data (ICH): All information in original records and certified copies of original records of findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original data or certified copies).

Source Data Verification: The check performed by the monitor to ensure that the entries made on CRFs agree with the documentation of source data at the clinical trial site. Unlike source documentation verification, source data verification may also refer to verification of captured electronic data. In this case, there is no verification of source documents; rather verification occurs of the electronic instrumentation itself and its related software application. An example of this data captured and downloaded directly from equipment that electronically takes vital signs.

Source Documents (ICH): Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, the laboratories, and at medico-technical departments involved in the clinical trial).

Source Document Verification: The process by which the information reported by an investigator is compared with the original records to ensure that it is complete, accurate, and valid.

Sponsor: An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. A corporation or agency whose employees conduct the investigation is considered a sponsor and the employees are considered investigators.

Sponsor-Investigator (ICH): An individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the investigational product is administered or dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

Standard Operating Procedures (SOPs): Detailed, written instructions to achieve uniformity of the performance of a specific function.

Stopping Rules: Rigorous guideline criteria specified in advance of the start of the study in the protocol, outlining what interim evidence of a therapy’s inferiority or superiority may merit stopping the trial.

Stratification: Assignment of subject to groups based on some relevant factor (e.g., sex, age prognostic factors) in such a way that there are equal proportions in the test groups within each stratum.

Study Close-Out Visit: The final visit made to a site in the event that the investigator has completed the study, the sponsor has discontinued the study of specific study site’s participation, or if the investigator withdraws participation in the study. During the close-out visit, the sponsor seeks to ensure that the data has been properly collected and verified, that the unused study supplies have been returned, and the investigators files are complete and accurate. Also called a “Study Termination Visit” and a “Termination Visit.”

Study Initiation Visit: An on-site meeting conducted by a representative of the sponsor to ensure that the investigator and study staff are ready to start enrolling subjects. This is done when all company-required paperwork is in-house, the study has received IRB approval, and the investigator has received the clinical supplies. Generally, no subject should be enrolled until this visit has been made. Also called “Study Placement Visit.”

Sub-Investigator: (Sub-I) Any member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows).

Subject Identification Code: A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial-related data.

Subject/Trial Subject: An individual who participates in a clinical trial, either as recipient of the investigational product(s) or as a control.

Surveillance activities: Surveillance activities are projects that collect, analyze, and interpret health-related data essential to planning, implementing and evaluating health care practice.

Toxicity Studies: Studies designed to determine the onset, degree, and duration of adverse effects in animals. Information from these studies is used to predict the likelihood of similar effects in man (e.g., dose response, species response, prior experience of predictability); to correlate with pharmacology information of the efficacy and drug metabolism on ADME and kinetics and present to clinicians for use in making benefit-risk and starting dose decisions; and to present to regulatory bodies for the same purpose.

Translational Research:

  1. Applying discoveries made in the laboratory to understand more about mechanisms of action of new agents, appropriate targets of novel anticancer medicines, and applying knowledge of molecular biology and pathophysiology derived in the laboratory to more effective and safer therapy.
  2. National Cancer Institute: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity, and mortality.
  3. National Institute of Neurobiological Disorders and Stroke: Translational research is the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment of prevention of human disease.
  4. National Institute of Environmental Health Sciences: The conversion of environmental health research into information, resources, or tools that can be used by public health and medical professionals and by the public to improve overall health and well-being, especially in vulnerable populations.

Trial Monitoring: Oversight of quality of study conduct and statistical interim analysis.

Trial Site (ICH): The location(s) where trial-related activities are actually conducted.

Triple-Blind Study: A study in which knowledge of the treatment is concealed from those who organize and analyze the data, as well as from the subjects and investigators.

Unanticipated Adverse Device Effect (FDA): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

Unanticipated Problems (UP): Investigators are required to report the reviewing IRB reports of unanticipated problems for any source. Reports of unanticipated problems assist an IRB in determining whether the risk/benefit ratio of a study continues to be acceptable, whether appropriate informed consent has been provided to study participants, and whether the study should otherwise be allowed to continue without modification under 21 CFR 5 56.111. UP categories are available in FDA guidance documents.

Unanticipated Problem Involving Risks to Subjects or Others (UPIRTSO): A problem that is unanticipated or unexpected, involves risks to subjects or others, and is reasonably believed to be related to research participation.

Unblinding: The intentional or unintentional identification of the treatment code of a subject or grouped results in a blinded study. Procedures of how and why to unblind should be outlined in the clinical protocol and fully documented.

Unexpected Adverse Drug Reaction: ICH: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigators Brochure for an unapproved investigational product or package insert/summary or product characteristics for an approved product).

Unexpected Adverse Event: An untoward medical occurrence, the nature, severity, or frequency which is not consistent with the applicable production information.

Unexpected serious harm: Serious adverse event(s) that is/are not anticipated but is/are reasonably believed to be protocol related.

Validation (FDA): Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.

Vulnerable Subjects (ICH): Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include subjects with incurable diseases, persons in nursing homes, unemployed or impoverished persons, subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

Waiver: A written agreement to accept some deviation from applicable guidelines. Waivers from the FDA may be granted in regards to IRBs such as when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically sponsors utilize an IEC that operates in accordance with GCP. Waivers from an IRB may be granted in regards to informed consent such as when the clinical investigation involves no more than minimal risk to the subject.

Ward (FDA): A child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law.

Warning Letter (FDA): A written communication from the FDA notifying an individual of firm that the agency considers one of more products, practices, processes, or other activities to be in violation of the Federal FD&C Act, or other acts and that failure of the responsible party to take appropriate and prompt action to correct and prevent any future repeat of the violation may result in administrative and/or regulatory enforcement action without further notice.

Well-Being: The physical and mental integrity of the subjects participating in a clinical trial.

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