Continuous review for ethical conduct of clinical trial-are the ethics committees complying?

Abstract

Ethics committees (ECs) play a crucial role in safeguarding clinical trial participants through ongoing review beyond initial protocol approval. Although regulations require periodic monitoring of study progress, risk, protocol adherence, and informed consent processes, evidence from India indicates significant gaps in implementation.. Challenges such as limited resources, insufficient training, and lack of structured monitoring hinder effective continuous review. Strengthening EC capacity and accountability is essential to ensure ethical conduct and participant safety in ongoing clinical research.

The primary role of ethics committees (ECs) is to ensure the rights, safety, and well-being of research participants are fully protected. This protection is achieved through close collaboration between ECs and researchers, working together to ensure that all research adheres to the highest ethical standards.

To fulfill this responsibility, ECs are tasked with both the initial and ongoing review of research activities. Before any research begins, ECs must conduct a thorough ethics review and provide a favorable opinion on the proposal. In addition, ECs have a continuing responsibility to monitor the approved research throughout its duration to ensure ongoing ethical compliance.[1]

WHAT IS CONTINUING REVIEW?

Continuing review is the reevaluation of ongoing research at regular intervals. ECs determine the frequency of continuing review based on the level of risk that the research poses to human participants or as may be specified in the Standard Operating Procedure (SOP) of the EC and at the time of according approval.[1] The purpose of continuing ethics review is to monitor the progress of the study which was previously approved for any changes, to ensure continued protection of the rights and welfare of research participants, and to find out if the research (including recruitment and informed consent process) is being conducted in compliance with the approved protocol.

REGULATORY FRAMEWORK AND GUIDELINES FOR CONTINUING REVIEW

The regulatory framework governing continuing review of clinical trials emphasizes the ongoing responsibility of ECs to ensure that approved research remains ethically sound throughout its conduct.

In India, the New Drugs and Clinical Trials Rules, 2019[2] (Chapter 3, Rule 11[ii]) mandate that ECs must conduct an ongoing review of clinical trials at appropriate intervals. This review may be based on periodic progress reports submitted by investigators, monitoring and internal audit reports provided by the sponsor, or through site visits conducted by EC members.

Complementing this, ICMR Guidelines (2017)[1] stipulate that ongoing research should be reviewed at regular intervals, and at least once annually. However, if the level of risk is deemed high, more frequent reviews may be necessary. The frequency and conditions for review should also align with the EC’s SOPs and be clearly stated in the initial approval and communication documents.

National Accreditation Board for Hospitals and Healthcare Providers[3] in its guidebook to standards for Accreditation of EC (Standard 1.8) mentions that EC should follow documented procedures for monitoring and for-cause assessments. This could be done by the site visits and review of the following source records such as the informed consent process, visit details, investigational product storage, SAE records, monitoring reports from the sponsor, data safety monitoring board recommendations, and interview with an investigator.

On the international front, guidelines from the European Medicines Agency,[3] the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use – Good Clinical Practice,[4,5] and the United States Food and Drug Administration (USFDA)[6] reinforce the importance of regular, risk-based continuing review. These bodies recommend that Institutional Review Boards (IRBs) or ECs conduct continuing reviews at intervals appropriate to the degree of risk, but no less than once a year. Furthermore, USFDA regulations require ECs to establish and follow written procedures for conducting continuing reviews based on the degree of risk, with a minimum frequency of once per year. The review must be conducted at convened meetings at which a majority of the IRB members are present, including at least one member whose primary concerns are in nonscientific areas, unless the research qualifies for review through an expedited process (21 CFR 56.108(a)(1) and 56.109(f)).

SCOPE AND PROCESS OF CONTINUING REVIEW

Continuing review or Monitoring can be routine or “for cause.” The central aspect of continuing review is the assessment of the study’s progress, which is typically informed by annual progress reports or interim progress reports submitted by the investigators. These reports help ECs track whether the study is proceeding according to the approved protocol and timeline. Risk assessment is another crucial component. ECs must evaluate any new events or emerging information that could potentially alter the original benefit-risk ratio of the study.

Monitoring for protocol deviations or violations and protocol amendments which could compromise the integrity of the study or the safety of its participants is an important component of continuing review. Similarly, serious and unexpected adverse events whether related to the study product or its conduct are closely examined.

The adequacy of the informed consent process is continually evaluated to confirm that participants are being appropriately informed throughout the study. On-site monitoring may be conducted to observe the conduct of the study firsthand and to verify compliance with ethical standards.

On-site monitoring of an approved study by ECs ensures quality assurance and continued education of research staff and most importantly ensures that there are no breaches or lapses in the integrity of data. Submitting annual or progress reports is one of the key mechanisms through which investigators provide ECs with the necessary information for these assessments. Monitoring also helps to ensure equitable selection of participants with special attention to vulnerable and high-risk participants. At the same time, it gives an opportunity for improvement to the site in case of any deviation or violation.

For cause assessments shall be conducted following noncompliance and/or complaints from participants, adverse media reports, a high number of protocol deviations/violations, a high recruitment rate, scientific misconduct, and a high number of SAE reports.

ETHICS COMMITTEE DECISIONS DURING CONTINUING REVIEW

EC may suspend or withdraw a favorable ethical opinion of the research or ask for modifications to the project or to the informed consent form, which will require reapproval by the EC. It may request that new information, changes to the research, or changes to the balance of burdens and benefits be communicated to research participants to enable an informed choice or refusal to continue in the research.

CHALLENGES FOR CONDUCTING CONTINUOUS REVIEW BY ETHICS COMMITTEE

Conducting effective continuing review poses several challenges for ECs particularly in resource-constrained settings. One of the primary obstacles is the lack of adequate infrastructure and administrative support, an insufficient workforce which hampers the smooth functioning of EC operations. EC members often shoulder a significant workload, reviewing numerous protocols with limited time and, in many cases, without any form of remuneration. Some ECs might have very long monitoring form which the members find difficult to fill and in such cases, it is recommended to have short monitoring form which covers all necessary information of the trial. This overburdened structure makes it challenging to maintain the level of oversight required for continuous ethical review. Motivating members to participate in on-site monitoring visits becomes a critical component of ongoing review under these circumstances. Another major barrier is the limited training provided to EC members on monitoring procedures. Without proper guidance and capacity-building efforts, members may lack the confidence or skills needed to identify and address ethical or procedural violations during the course of a study.

FINDINGS FROM THE INDIAN CONTEXT

A study conducted by Shetty et al.[7] between 2008 and 2009, which involved monitoring seven research sites, highlighted several concerning ethical lapses in the conduct of clinical research. At six of the seven sites, issues related to the informed consent process were identified, indicating a lack of adherence to ethical standards in participant communication. Five sites demonstrated protocol deviations, while three sites failed to submit progress reports to the EC as required.

Further evidence from inspections carried out by the Central Drugs Standard Control Organization between 2011 and 2016 reinforced these findings.[8] These inspections revealed that many ECs were not conducting ongoing reviews of approved research projects as mandated. EC members had not visited study sites, and, alarmingly, no concerns were raised even when there were multiple instances of protocol deviations and noncompliance. These findings point to significant gaps in the implementation of continuing ethical review and monitoring by ECs across several institutions in India.

CONCLUSION

While ECs are mandated to conduct continuing reviews to safeguard research participants, evidence from India indicates significant gaps in compliance. Many ECs lack the resources, training, and enforcement mechanisms needed for effective ongoing oversight, leading to ethical lapses in clinical trials. Strengthening EC capacity and accountability is crucial to ensure continuous ethical conduct in research.

Funding Statement

Nil.