Department:

UAMS Human Research Advisory Committee

Policy Number:

7.6

Section:

Procedures for Study Review

Effective Date:

July 31, 2002

Revision Date:

October 11, 2002

SUBJECT:  Continuing Committee Review

Periodic review of research activity is necessary to determine (i) whether the risk/benefit ratio has changed, (ii) whether there are unanticipated findings involving risks to subjects, and (iii) whether any new information regarding the risks and benefits should be provided to subjects.  All research protocols (except protocols determined by the HRAC to qualify for exempt status) must be periodically reviewed, not less than one time per year [38 CFR16.109(c)], unless the following conditions have been met:

Research Closed to Accrual of New Subjects.  A research protocol for which no new subjects will be enrolled must be periodically reviewed until such time that:

  1. Initial analysis of the data has concluded that no new information needs to be provided to enrolled subjects; and

  2. There is no need to re-contact enrolled subjects to obtain additional research information.

 

Primary Reviewer System.  When conducting continuing review by full HRAC Committee (i.e., when the protocol may not be reviewed using an expedited review procedure), the HRAC Committee may use a primary reviewer system for continuing review.  However, the full HRAC Committee must be informed of the reviewers' findings at a convened meeting.  Primary reviewers should receive and review a copy of the complete protocol including any modifications previously approved by the HRAC Committee and any monitoring or audit reports conducted since the last review.  Even when using a primary reviewer system, the full, convened HRAC Committee must discuss the protocol and make a determination with recorded vote.  Based on its review, the HRAC Committee may require that the research be restricted, modified or halted altogether.  Alternatively, special precautions or HRAC-imposed restrictions may be relaxed.

How Is The Continuing Review Date Determined?  HHS regulations at 45 CFR 46.108(b) and 109(e) require, respectively, that (1) except when an expedited review procedure is used, each HRAC must review proposed research at convened meetings at which a majority of the members of the HRAC are present, including at least one member whose primary concerns are in nonscientific areas; and (2) an HRAC must conduct continuing review of research at intervals appropriate to the degree of risk, but not less frequently than once per year. The HRAC should decide the frequency of continuing review for each study protocol necessary to ensure the continued protection of the rights and welfare of research subjects. 

Several scenarios for determining the date of continuing review apply for protocols reviewed by the HRAC at a convened meeting. To determine the date by which continuing review must occur, focus on the date of the convened meeting at which HRAC approval occurs. (These examples presume the HRAC has determined that it will conduct continuing review no sooner than within 1 year).  

Scenario 1: The HRAC reviews and approves a protocol without any conditions  at a convened meeting on October 1, 2002. Continuing review must occur within 1 year of the date of the meeting, that is, by October 1, 2003. 

Scenario 2: The HRAC reviews a protocol at a convened meeting on October 1, 2002, and approves the protocol contingent on specific minor conditions the HRAC chair or his/her designee can verify. On October 31, 2002, the HRAC chair or designee confirms that the required minor changes were made. Continuing review must occur within 1 year of the date of the convened HRAC meeting at which the HRAC reviewed and approved the protocol, that is, by October 1, 2003.  

Scenario 3: The HRAC reviews a study at a convened meeting on October 1, 2002, and has serious concerns or lacks significant information that requires HRAC review of the study at subsequent convened meetings on October 15 and October 29, 2002. At their October 29, 2002 meeting, the HRAC completes its review and approves the study. Continuing review must occur within 1 year of the date of the convened meeting at which the HRAC reviewed and approved the protocol, that is, by October 29, 2003.  

The continuing review expiration date may change from year to year.  Each time the convened HRAC conducts continuing review, the study calendar is reset to the date of the meeting.  

Example:  A study’s continuing review date expires on June 1, 2000.  The HRAC convened on May 15, 2000 and granted protocol approval.  The next continuing review approval will expire on May 15, 200l.

Notices are mailed to the PI approximately 8-12 weeks prior to the project’s continuing review expiration date with a required return deadline.  However, unforeseen problems may result in a renewal notice not being received by the PI.  Therefore, an investigator should not depend solely on HRAC notification as a prompt for submitting the CRR and request for renewal. Investigators are required to submit continuing review reports at least 5 weeks prior to expiration to allow sufficient time for processing the report prior to the project’s expiration. 

What Occurs If A Continuing Review Expires?  The HRAC and investigators must plan ahead to meet required continuing review dates. If an investigator has failed to provide continuing review information to the HRAC or the HRAC has not reviewed and approved a research study by the continuing review date specified by the HRAC, the research must stop, unless the HRAC finds that it is in the best interests of individual subjects to continue participating in the research interventions or interactions. Enrollment of new subjects cannot occur after the expiration of HRAC approval.  

When continuing review of a research protocol does not occur prior to the end of the approval period specified by the HRAC, HRAC approval expires automatically. Such expiration of HRAC approval does not need to be reported to OHRP as a suspension of HRAC approval under HHS regulations.

Type of Review.  Review by the full, convened HRAC Committee, with recorded vote, is required unless the research is otherwise appropriate for expedited review or is exempt. 

  1. Standard Review.   The full HRAC Committee must conduct a continuing review of a protocol using standard review procedures when that protocol originally was reviewed using standard review procedures. A protocol does not need to be reviewed if it has been modified such that it can be reclassified as eligible for expedited review.  Alternatively, research activities that have previously been judged as exempt, or were qualified for expedited review, may change such that standard review would be required for the continuing review  (see HRAC policy 7.4). 

  2. Program Grants.  An umbrella grant, for example, a grant to fund a program or center, requires HRAC approval.  Each grant included in the umbrella grant requires its own individual HRAC approval.  Certain types of applications for grants, cooperative agreements, or contracts are submitted to departments or agencies with the knowledge that subjects may be involved within the period of support, but definite plans would not normally be set forth in the application or proposal. These include activities such as institutional type grants when selection of specific projects is the institution's responsibility; research training grants in which the activities involving subjects remain to be selected; and projects in which human subjects' involvement will depend upon completion of instruments, prior animal studies, or purification of compounds. These applications need not be reviewed by an HRAC before an award may be made. However, except for research exempted or waived under 38 CFR16.101 (b) or (i), no human subjects may be involved in any project supported by these awards until the project has been reviewed and approved by the HRAC, as provided in this policy, and certification submitted, by the institution, to the department or agency (38 CFR18.118).

  3. Expedited Review.  A protocol that originally was reviewed using expedited review procedures may receive its continuing review on an expedited basis. Research that meets the following criteria may be permanently closed to the enrollment of new subjects:

    a.       All subjects have completed all research-related interventions;

    b.       The research remains active only for long-term follow-up of subjects; or where no subjects have been or will be enrolled and no additional risks have been identified; or where the remaining research activities are limited to data analysis.

    c.       When conducting research under an expedited review procedure, the HRAC Committee Chair or designated HRAC Committee member conducts the review on behalf of the full HRAC Committee (see HRAC policy 7.5). 

  4. Exempt Research Activities.   Once a research protocol has been determined by the HRAC to qualify for exempt status, that protocol need not be periodically reviewed by the HRAC  (see HRAC policy 7.3).

Criteria.  Continuing review must be substantive and meaningful.  The criteria for continuing review are the same as those for initial review.  Therefore, the HRAC Committee (or the reviewer for protocols reviewed under an expedited procedure) must determine:

  1. That the risks to subjects continue to be minimized and reasonable in relation to the anticipated benefits;

  2. That the selection of subjects continues to be equitable;

  3. That informed consent continues to be appropriately obtained and documented;

  4. That there are:

a.   Adequate provisions for monitoring the data collected to ensure the safety of the subjects, when appropriate

b.    Adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data, when appropriate, and

c.    Appropriate safeguards for vulnerable populations. 

  Materials to be Reviewed.   

  1. The full HRAC Committee should receive and review, at a minimum:

a.    A continuing review application;

b.    A status report on the progress of the research within the continuing review application should include:

                                     i.         Maximum local subject enrollment approved

                                     ii.         The total number of subjects enrolled since the study began

                                     iii.         The total number of subjects withdrawn from the study since the previous review;

                                     iv.         A summary of any unanticipated problems involving risks to subjects or adverse events that were serious or unanticipated, and resulted in a change to the risk/benefit ratio since the previous review;

c.   An explanation of any complaints about the research since the previous review;

d.   A summary of any recent literature, findings obtained thus far, amendments or modifications to the research, reports on multi- center trials and any other relevant information, particularly information about risks associated with the research since the previous review; and

e.    A copy of the current approved informed consent document(s).

f.     Recruitment materials and advertisements

 

2.         In addition, primary reviewers should receive a copy of the current, approved HRAC Application that includes any prior modifications previously approved by the HRAC Committee and supporting documentation such as an investigator’s brochure, sponsor’s protocol, or a grant application.  They should also receive copies of any monitoring or audit reports conducted since the last review.

Consent Document.  Review of the currently approved consent document must ensure that the information is still accurate and complete. Any significant new findings that may relate to the subject's willingness to continue participation should be provided to the subject in an updated consent document. Review of currently approved or proposed consent documents must occur during the scheduled continuing review of research by the HRAC Committee but may be done more frequently if new information becomes available.

New Amendments to Protocol Submitted at Time of Continuing Review.  Amendments and addenda to a research protocol may be submitted at the time of continuing review.  A separate cover letter describing the change and all appropriate documentation (approved consent form) must accompany the continuing review application.  The amendments may not be implemented by an investigator prior to review and approval by the HRAC Committee.  

Process for Reviewing Changes in Ongoing Research During the Approval Period.  In accord with 21 CFR 56.110(b), an HRAC may use expedited review procedures to review minor changes in ongoing previously approved research during the period for which approval is authorized. An expedited review may be carried out by the HRAC chairperson or by one or more experienced reviewers designated by the chairperson from among members of the HRAC.  

When a proposed change in a research study is not minor (e.g., procedures involving increased risk or discomfort are to be added), then the HRAC must review and approve the proposed change at a convened meeting before the change can be implemented. The only exception is a change necessary to eliminate apparent immediate hazards to the research subjects [21 CFR 56.108(a)(4)]. In such a case, the HRAC should be promptly informed of the change following its implementation and should review the change to determine that it is consistent with ensuring the subjects' continued welfare.

Cooperative Protocol Research Program (CPRP) protocols.  Continuing HRAC review is required as long as individually identifiable follow-up data are collected on subjects enrolled in HHS-supported Cooperative Protocol Research Program (CPRP) protocols. This remains the case even after a protocol has been closed at all sites and protocol-related treatment has been completed for all subjects.

CPRP protocols are those projects, which involve more than one institution.  In the conduct of cooperative research projects, each institution is responsible for safeguarding the rights and welfare of human subjects and for complying with this policy.  With the approval of the department or agency head, an institution participating in a cooperative project may enter into a joint review arrangement, rely upon the review of another qualified HRAC, or make similar arrangements for avoiding duplication of effort (38 CFR16.114).

Continuing Review of Data Safety Monitored (DSM) Clinical Trials.  When a multi-site clinical trial is subject to oversight by a DSM, the HRAC Committee may rely on the most recent report(s) from the DSM indicating that it has reviewed study-wide adverse events, interim findings and any recent literature that may be relevant to the research.

Multi-Center Trials Monitored By A DSMB, DMC, Other Similar Body, or Sponsor.  Continuing review of research by the HRAC should include consideration of adverse events, interim findings, and any recent literature that may be relevant to the research.  OHRP recognizes that such information may not be readily available to local investigators participating in multi-center clinical trials or to their local HRACs. However, OHRP notes that such trials are often subject to oversight by a Data and Safety Monitoring Board (DSMB), Data Monitoring Committee (DMC), other similar body, or sponsor whose responsibilities include review of adverse events, interim findings, and relevant literature.

In such circumstances, HRACs conducting continuing review of research may rely on a current statement from the DSMB or sponsor indicating that it has reviewed study-wide adverse events, interim findings, and any recent literature that may be relevant to the research, in lieu of requiring that this information be submitted directly to the HRAC. The HRAC must still receive and review reports of local, on-site adverse events and unanticipated problems involving risks to subjects or others and any other information needed to ensure that its continuing review is substantive and meaningful. In addition, institutions and HRACs may require additional information for continuing review at their discretion.

Process for Dealing with Reports of Adverse Reactions and Unexpected Events

Written Procedures.   HRAC continuing review responsibilities include reviewing reports of adverse reactions and unexpected events involving risks to subjects or others. The HRAC should establish a procedure for receiving and reviewing these reports. The level and promptness of review may depend upon factors such as the seriousness of the event, whether the event is described in the study protocol and consent and whether the event occurred at a location for which the HRAC is the HRAC of record. The written procedures may include a brief form to be completed by the principal investigator when an adverse event occurs, asking for his/her opinion as to whether the event was related to the study and other information to aid the HRAC in an appropriate and efficient review of the event.

Researchers should be made aware of the HRAC's policies and procedures concerning reporting and continuing review requirements. This can be accomplished by notifying the investigator, in the HRAC's letter of approval, of the requirement to report changes and unanticipated problems in research activities. The HRAC's written procedures pertaining to continuing review and reporting requirements should be distributed to ensure that all individuals involved in research activities understand their obligations.

Process.  Unanticipated risks are sometimes discovered during the course of research. Information that may impact on the risk/benefit ratio should be promptly reported to, and reviewed by, the HRAC to ensure adequate protection of the welfare of the subjects. Based upon such information, the HRAC may need to reconsider its approval of the study, require modifications to the study or, revise the continuing review timetable.

HRACs are also responsible for ensuring that reports of unanticipated problems involving risks to human subjects or others are reported to the FDA [21 CFR 56.108(b)(1)]. Usually, this reporting is accomplished through the normal reporting channel, i.e., the investigator to the sponsor to FDA.  

Review Must Occur Not Less Than Once Per Year.  The HRAC Committees must conduct continuing review of protocols at intervals appropriate to the degree of risk, but not less than once per year.

  1. “Not less than once per year" means that the research must be reviewed within one year of the date of the HRAC meeting at which the research was approved (with or without specific revisions) even though the research activity may not begin until after the HRAC Committee has given approval.  This means the research must be reviewed, at a minimum, on or before the one year anniversary date of the HRAC review, not within one year of the receipt of the Final Action Letter from the HRAC.

2.   Factors to be considered by the HRAC in determining the appropriate interval for review may include, but are not limited to:

a.  Involvement of vulnerable populations;

b.  Research conducted internationally;

c.   The involvement of recombinant DNA or other types of gene transfer protocols;

d.  The use of waiver of informed consent procedures, e.g. surrogate consent;

e.  Classified research;

f.    Research for which subjects would be exposed to additional risks, e.g. breach of confidentiality, continual non compliance with federal regulations, Phase 1 studies, disproportionate number or severity of SAEs;

g.   Previous suspension of the researcher due to compliance, record-keeping or other concerns

h.  Recommendations from other institutional committees

 

No Grace Period.  There is no grace period extending the conduct of the research beyond the expiration date of HRAC approval. Extensions beyond the expiration date will not be granted. 

If the HRAC does not re-approve the research by the specified expiration date, subject accrual must be suspended pending re-approval of the research by the HRAC.    

  1. Enrollment of new subjects cannot ordinarily occur after the expiration of HRAC approval.  

  2. Continuation of research interventions or interactions in already enrolled subjects should only continue when the HRAC Committee finds that it is in the best interests of individual subjects to do so.  

  3. The HRAC Committee must address on a case-by-case basis those rare instances where failure to enroll new subjects would seriously jeopardize the safety or well-being of an individual prospective subject.  

Investigator Non-compliance.  If the HRAC has not reviewed and approved a research study on or before the study's current expiration date, HRAC approval will expire and all research activities, including enrollment, should stop. Written notification of the HRAC action will be provided to the investigator, appropriate institutional officials, the FDA and funding agency, when applicable.