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8 IRB/IEC Roles and Responsibilities

P. Michael Dubinsky

GCP Key Point

The absence or failure of researchers to follow or have in place ethical standards and safeguards resulted in several key policy documents, e.g. Declaration of Helsinki being developed. The IRB/IEC functionally implements ethical expectations contained in those documents.

8.1 Introduction

In other chapters the authors touch on some details about historical events which resulted in the development and issuance of policy documents which define the ethical expectations associated with the conduct of clinical trials. The Nuremburg Code, Declaration of Helsinki and Belmont Report were all developed and put in place in reaction to ethical abuses by researchers. Institutional Review Boards (IRBs) were the operating or functional demonstration of ethical oversight beginning in the US circa the 1960s. The US FDA put regulations in place circa 1971 and in 1974 the National Research Act formalized the requirements for having IRBs review planned clinical research. Regulations governing both the IRBs and requiring informed consent of trial subjects were in place circa 1981. The US IRB system was initially developed and implemented by academic medical institutions. In Europe the system of ethical oversight was largely developed by governments and became known as independent ethics committees (IECs). Since the ICH E6 (R2) was a work product of the both the US FDA and the EU EMA along with the Japanese health authority both titles were included in the ICH Glossary.

The roles and responsibilities of the IRB/IEC as spelled out in section 3 of the guideline involve a range of activities from making the decision as to whether a proposed trial is approved for implementation to what constitutes required record keeping for the IRB/IEC. The IRB/IEC roles and responsibilities section are fittingly at the very beginning of the guideline since without their approval the trial cannot begin.

8.2 Objectives

The objectives of this chapter are to review the requirements/expectations for IRB/IEC as found in the ICH E6 (R2) Guideline at section 3. The GCP expectations speak to:

1 Responsibilities of the IRB/IEC

2 Composition, functions, and operations of the IRB/IEC

3 Procedures for the IRB/IEC

4 Records that the IRB/IEC is expected to maintain

In addition, the chapter will highlight some of the areas where IRB/IECs have not adhered to these expectations. Such information should be useful as the risk assessment for a trial is prepared.

8.3 Responsibilities of the IRB/IEC

The IRB/IEC first and foremost is responsible for safeguarding the rights, safety, and well‐being of the human subjects participating in the trial. If a trial involves a population that is considered vulnerable, e.g. children, then the IRB/IEC must apply an even more rigorous approach to their review and assessment of documents, people, processes, and places.

8.3.1 Documents

All the critical and essential documents which define the clinical trial are provided to the IRB/IEC for assessment and approval. That includes the Protocol, Informed Consent Form, Investigator’s Brochure, subject recruitment materials such as advertisements, and the investigator’s qualifications. Their conclusions about the acceptability of the investigational plan and the supporting materials are determinative when it comes to starting the trial. Absent their approval the trial cannot proceed. The IRB/IEC must provide their approval/favorable opinion. The IRB/IEC can require modifications to any of the essential documents as well as disapproving a study. In addition, their review must be ongoing which usually means annually but can differ if the IRB/IEC so decides. Vulnerable populations such as children call for the IRB/IEC to be even more attentive to details such as the circumstances under which the subject’s consent is obtained and who may give consent on behalf of the subject. Compensation for participation in a trial is permitted in some form by most regulatory authorities. However, the method and monetary value of compensation associated with payment often calls for close review to ensure that subjects are not coerced or enticed in a manner which violates ethical standards. And it is not just the amount of a payment that could be problematic but also any claims related to the effect that the investigational product may have on the disease or injury being treated.

8.4 Composition, Functions, and Operations

Membership or makeup of the IRB/IEC as described in the guideline focuses on two aspects. A minimum number of members is set at five with one having a nonscientific background and one being independent of the institution or trial site. The investigator and sponsor must not have a voting representative on the IRB/IEC but can provide information about the trial as part of the IRB/IEC evaluation process. Outside experts can be invited to participate in the information gathering process if needed. The exact number of members and their credentials may be controlled by regulation or law for the country or region where the trial is to be conducted and those requirements must be followed.

The IRB/IEC should have written procedures (SOPs) in place to direct its operations. There should be written records of all meetings including decisions. Meeting minutes should list the members present and whether a quorum was achieved. The number of members constituting a quorum will be defined in an SOP.

8.5 Procedures

SOPs are a key part of meeting ICH E6(R2) across the board and the IRB expectations are no exception. The IRB/IEC’s role in ensuring that ethical practices and policies are built into every trial is documented in part by having written procedures and records documenting that those procedures were followed. The procedures that are expected to be in writing include:

 Determining the composition such as qualifications for members and under what authority the IRB/IEC is established.

 How scheduling will be handled. This might include timing, notification procedures, and how members will be notified.

 How the Committee will conduct initial and ongoing reviews of trials.

 Criteria for ongoing review of trials.

 Special procedures such as expedited review

 Specifications that apply to every trial such as: not enrolling subjects until a written approval for the trial is given; deviations from an approved protocol cannot be made without IRB/IEC approval; items that must be reported to the IRB in a timely manner such as protocol changes, changes which might increase subject risk, adverse experiences that are unexpected or serious, and new information.

 The IRB/IECs timeline for reporting decisions on approvals as well as reasons for decisions and any criteria for appeals of decisions.

8.6 Records

The IRB/IEC should maintain all records for a retention period of 3 years. That is a minimum timeframe listed in some regulations. The retention period may vary. In the United States the retention period for IRB records is 3 years [1] after completion of the research however in the European Union the archiving requirement is for 25 years [2] after the end of the clinical trial.

8.7 Noncompliance by IRB/IECs – Areas of Risk

IRB/IECs are generally regarded and viewed as professional organizations established by government legislation or within the structure of academic medical institutions where clinical trial research may be centered. There are however commercial or independent IRB/IECs that operate globally which have found a niche in the business of clinical trial conduct. The independent IRBs have become a substantive presence in the review of clinical trials and the ethics of using a commercial or paid entity to conduct a review that is intended to determine if there are among other things any ethical concerns about a clinical trial plan may seem a dichotomy. However independent IRB/IECs have been around for some time and offer a sense of continuity to the review process especially when there are multiple trial sites involved as with large phase III trials.

Irrespective of whether the IRB/IEC is independent or affiliated with the institution where the trial is occurring inspections of IRB/IECs have shown noncompliance in a variety of areas. Many of the deficiencies might be described as administrative but the primary role of the IRB/IEC is in a way just that – Administrative. A list of the types of deficiencies follows and it should provide a basis for deciding whether to add any risk assessment regarding the IRB/IEC review process for a given trial.

 Inadequate meeting minutes

 Inadequate membership rosters

 Inadequate initial and continuing review of research

 Inadequate written procedures for prompt reporting of noncompliance, suspension, or termination

 Quorum issues

 Failure to promptly report noncompliance, suspension/termination of a site

It is useful to point out that from a practical standpoint IRB/IECs have established administrative control mechanisms due to the detailed requirements and record keeping that they must adhere to. This administrative staff is not the IRB/IEC per se but they (the staff) often know the details of the regulatory requirements better than the IRB members themselves. While not foolproof, having such organizational units overseeing and directing the IRB’s functional activities can and does prevent noncompliance.

The US FDA publishes data from their inspections of the IRB/IECs that register with them. The items listed above are compiled from the inspections that the US FDA conducts and reported in FDA’s Good Clinical Practices webpage [3].

8.8 Summary

The IRB/IEC represents the unbiased third‐party reviewer for all the essential documents which comprise the clinical trial plan. The protection of the rights, well‐being and safety of human subjects is the primary role of the IRB/IEC.

In order that this role is performed in a manner which is credible the ICH E6(R2) guideline calls for certain criteria to be in place so that as needed the procedures that were followed, the qualification of the people who followed the procedures and the records maintained of the work are complete, reliable, and accurate.

Avoiding ethical pitfalls should be inherent in the culture of the medical community that conducts human clinical trials, but history has shown that is not always the case. The IRB/IEC requirements are necessary and not likely to be set aside.

Knowledge Check Questions

1 Why do you think that the IRB/IEC requirements call for one member to be independent of the institutional/trial site? Please provide a brief narrative explaining your answer.

2 While not a common practice today, in the past prisoners were often called upon to participate in clinical trials. Would you consider prisoners to be a vulnerable population? If so, what might be some of the issues which would envision arising when an IRB/IEC is reviewing a protocol which allows them to be subjects in a clinical trial?

3 According to ICH E6(R2) the IRB/IEC must have written standard Operating procedures in place for all the functions they implement. True or False?

4 A quorum for an IRB is always three members being present, Correct? If not where is the number for a Quorum found?

5 According to regulatory authority reports one common deficiency for IRB/IECs is inadequate ongoing review of studies. Can you briefly explain how you might avoid such a deficiency if you were part of an IRB/IEC.

References

1 1 FDA (2002). Code of Federal Regulations Title 21 CFR 56.115 (b). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.115 (accessed 6 April 2020).

2 2 EU Regulation (2014). REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/ECEU Regulation 536, Article 58 ‐ Archiving of the clinical trial master file. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol‐1/reg_2014_536/reg_2014_536_en.pdf (accessed 6 April 2020)

3 3 FDA Bioresearch Monitoring (BIMO)(2021). Inspection Metrics. https://www.fda.gov/science‐research/clinical‐trials‐and‐human‐subject‐protection/bimo‐inspection‐metrics (accessed 6 April 2020)