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| REVIEW ARTICLE |
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| Year : 2013 | Volume
: 4
| Issue : 1 | Page : 17-20 |
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Ethics committee member: Reviewing the 'Ethics' in clinical research
Raakhi Tripathi
Member Secretary, Independent Ethics Committee, Mumbai, Maharashtra, India
| Date of Web Publication | 23-Jan-2013 |
Correspondence Address:
Raakhi Tripathi
Member Secretary, Independent Ethics Committee, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2229-3485.106371
How to cite this article:
Tripathi R. Ethics committee member: Reviewing the 'Ethics' in clinical research. Perspect Clin Res 2013;4:17-20 |
 Introduction | |  |
Institutional Review Board (IRB) whose primary mandate is to protect the rights and safeguard the welfare of the subjects. In their deliberations, IRBs are expected to take into account the nature, content, and design of the research and ensure that they are compliant with the ethical principles of the Belmont Report, Declaration of Helsinki, Ethical Principles of Biomedical research (Indian council of medical research (ICMR), 2006) [1] and, when appropriate and applicable, the regulatory requirements of India. In today's scenario with India being portrayed as hub for global clinical research has lead to the mushrooming of several non institutional ethics committee's (NEC) all over the country. Both the IRB and NEC form the foundation stone for initiation and conduct of Ethical human research. The groups of diverse individuals forming the members of the IRB/NEC are entrusted with the valuable task of protecting human subjects and promoting ethically sound research.
Most of us when invited to be an Ethics Committee (EC) member readily accept to be one, rationalizing this as our way to serve the society by ensuring that no harm is done to patients participating as potential research subjects. During our tenure as EC member most of us learn on the job-to perform the ethical review of the research project. Although, the IRB/NEC system attempts to be perfect, conscientious ECs reassure the public that the rights and welfare of human subjects are seriously considered by people who do not have a vested interest in the outcome of the research. The EC member participates in the process of research review and approval, conduct to ensure that the human safety is not jeopardized and rights of the research participant are not violated and are accountable for their decisions. To perform this magnanimous task the EC member must be competent, vigilant, vocal, active, independent, trained to pick up unethical aspects and refine and modify them.
While reviewing the research projects there are multiple issues which can perplex the member and he/she is either left powerless/clueless in coming to the decision. This article attempts to focus the day to-day challenges the EC member faces during the initial and continuing review of projects.
Suitability of trial site and investigator
During the initial review of the research project, apart from the review of the trial related documents the competency and suitability of the investigator and the research team is to be evaluated. This may sound simple for an institutional Ethics committee member where in the investigator and research team members belong to the institute and the EC members are aware about them. This task can be complex for a non institutional EC where in the investigator and trial site are not known. Such non institutional EC may be vigilant enough to ask for additional documents-such as site profile enlisting the emergency and routine facilities, along with the curriculum vitae (CVs) and training certificates of the research team and state medical registration certificates of the investigator. To be 100% sure that trial site has all facilities ideally a preapproval monitoring of the site for facilities will be ideal, but is it always feasible for the EC to do this for all projects and if fallacies are detected what action can be taken are also not clear to the member. The NEC may be proactive and develop standard operating procedure (SOPs) for preapproval monitoring of trial sites and may guide the EC member to propose the action plans in this scenario.
Assessment of risk-benefit ratio
For research to be ethical, any risks must be balanced by the benefits to subjects/society, and/or the important new knowledge society will gain. This valid comparison is expressed as risk-benefit ratio. Mitigating risks to participants in research and enhancing benefits (direct to participants and to science) constitute one of the core objectives of the ethics review. Thus, the objectives of the ethics review, relevant to topic are: Ensuring scientific merit of the research; identifying probability and magnitude of all potential risks and benefits; assessment of risks and benefit ratio; determining whether the method of research proposed would effectively minimize harms and maximize benefits and determining the method and periodicity of monitoring of research process and results in order to ensure continued balance between the risks and benefits. [2]
The task of evaluating the risks can be cumbersome for an EC member. The researcher/sponsor presents all the risks in a voluminous document called the investigator brochure (IB) or in simplified manner in the Informed consent form for the non medical EC member to review. The medical EC members have to review the IB vigilantly and ensure that findings of the IB are reflected in the risks section of the informed consent document (ICD). The incidence of the risks/adverse events must be mentioned in the ICD. The extensive review of the IB and formal calculation of the risk benefit ratio may pose difficulties to the EC member. Is EC member (though medical members are entrusted the task of evaluating risk-benefit ratio) trained to this calculation effectively or there will be high element of subjectivity among different EC members will be a debatable issue.
This risk benefit ratio assessment was a part of the initial review, what happens when this risk benefit ratio changes during the conduct of the trial. How can the EC member detect and propose the action plan is challenging. During continuing review the EC member may review Protocol amendments, amended IBs, SAE reports, safety reports, data safety management board (DSMB) reports all of which may hint a change in the risk benefit ratio. Should the EC member rely on the DSMB findings that the trial can be continued and there is no change in the risk benefit ratio? What if a given trial does not have DSMB then the herculean task of assessing the risk benefit ratio on an ongoing basis is it left to the EC member? The ideal solution will be that EC members undergo training in risk-benefit evaluation techniques or form in house (subcommittees of EC members)/institutional Data safety monitoring committees (independent of EC members) which can review only the safety data and assess the risk benefit ratio and guide the EC in this task.
Reviewing and monitoring the informed consent process
Reviewing patient information sheet and the ICD form the crux of ethical review. The goal of 'informed consent' is making sure a participant has the opportunity to be an informed participant in decisions affecting their welfare. With the implementation of ICMR guidelines [1] and Schedule Y all researchers do incorporate the basic elements of 'informed consent'-
- Disclosure : Includes information about the nature of the decision/procedure; reasonable alternatives; relevant risks, benefits, and uncertainties related to the research.
- Voluntariness : Free of coercion, fear, inducement and right to withdraw from the trial.
- Comprehension : Participant must be competent to make the decision and the discussion should be carried on in layperson's terms with the participant's understanding assessed along the way.
Many IRBs have been proactive and developed template consent forms to incorporate all the ethical principles of research. Standard language has been typically developed for those elements that deal with confidentiality, compensation, answers to questions, and the voluntary nature of participation. Researchers use this template ICD, modify the ICD as per their trial and submit the ICD for review making the work of the EC member simpler.
The EC member can suggest changes to the ICD to make the language more simple, non technical and layman friendly. The challenges faced by the EC member will be in reviewing the vernacular consents. Often the EC relies on documentary evidence as translation certificates and back translation ICD to ensure that information stated in vernacular consents is matching with English ICD. Monitoring the implementation of the consent process will be a crucial task for an EC member. Is it feasible for the EC member to monitor independently the recruitment process, the 'informed consent' process, and debriefing of research participants about the risks and benefits at the trial site for all the projects approved by them? This may be still be feasible for an institutional EC member to monitor the consent process and interview the research participants but for a NEC member to conduct monitoring the feasibility may be low as taking administrative approvals for monitoring the site, logistics may pose problems.
Subject selection
All the ethical guidelines including the ICMR guidelines (2006) and international guidelines namely 45 CFR 46 requires that when prospective research subjects are likely to be vulnerable to coercion or undue influence, such as mentally disabled or sick persons or those who are economically or educationally disadvantaged, additional safeguards have been included in the study to protect the rights and welfare of these subjects. However, regulations offer little practical guidance on what constitutes appropriate additional safeguards, leaving it up to local ECs, in consultation with researchers and others, to provide specific appropriate safeguards in a particular research study. Vulnerability constitutes a major hurdle to be tackled by the EC member [3] especially in an Indian scenario. The issue is not being economically or educationally disadvantaged [4] (when compared with the west), our social system (family head takes the decision) also makes us unable to take the decision of No/yes for participating in a clinical trial.
To make the matters on subject selection worse; are the non therapeutic trials where in the expected benefits are negligible. [5] Volunteers in Indian context may be participating for the monetary gains and there are multiple agencies which provide volunteers for phase I and bioequivalence studies. How can the EC member monitor the source of these potential volunteers and ensure that no harm is done to them? The IEC/NEC can ask for documentary evidence for the source of procurement of these volunteers and be still proactive and monitor/interview the volunteers during the consent process and ascertain the vulnerability. The EC can request the investigators not to take professional volunteers from agencies but enroll them from advertisements (with prior approval from EC) or by word of mouth.
Monitoring of trial sites
Continuing review of research project is an important mandate to be followed by any EC member. IRBs are expected to conduct monitoring of trial sites. [6] The challenge the EC member faces is whether to check accuracy of all trial documents or to monitor the research processes. If trial procedures are to be monitored, every NEC/IRB has to chalk out the following- which procedures, frequency of monitoring, development of checklists and action plan. If deficiencies/deviations are detected suggest the required rectification will also be vital task for the EC member. The EC not only has to develop an SOP for monitoring trial sites and follow it but also has to flag studies during the initial review process (especially studies in which subjects are exposed to high risk) for which it will conduct periodic mandatory monitoring.
Reviewing the safety reports and proposed compensation
As a part of continuing review the EC member has to review the serious adverse event (SAE) reports (occurring at trial sites approved by a given EC) and also the SAE reports (occurring at other trial sites). Reviewing the other trial site SAE reports submitted to the EC as extensive CIOMS reports, SUSAR, periodic safety listings do pose constraints. Is it practically possible for the EC member to review these reports and re-assess the risk benefit ratio? The solution could be as stated earlier that institutional Data safety monitoring committees (independent of EC members) which can review the safety data (including onsite and other site safety reports) and assess the risk benefit ratio OR the EC can appoint an SAE subcommittee composing of 2-3 EC members who will solely review this data and guide the EC in this task.
The other Herculean task the EC member faces is overseeing the compensation process being executed by the researcher/sponsor. With the advent of new (proposed) compensation guidelines the calculation of compensation is devised, the calculated compensation whether appropriate and is handed to the appropriate representative will be the challenging for the EC member. The EC will have to develop inbuilt mechanisms/vigilant operations to ensure that amount is in accordance with the regulations and the representative receiving the compensation is as per the Indian law. As stated by ICMR guidelines the EC will have to also look into composition, functions and setting up of arbitration committee to solve issues arising due to compensation paid for trial related injury. Setting of arbitration committee- its composition, functioning, SOPs, action plans to be done by EC in the midst of no clarity is a challenge by itself for the member trying to attempt to oversee the compensation process.
Compensation for trial participation
At present the amount to be paid as Compensation for trial participation is not very clear from the ICMR guidelines. The amount to be paid to compensate the time lost, inconvenience and discomfort caused to the patient at trial visits may sometimes pose as inducement which the EC member has to be vigilant to evaluate. The line between inducement and compensation for participation is very thin especially in Indian context where in subjects may perceive this compensation as benefits to him/her.
Reviewing the protocol deviation reports
Other document which an EC member reviews as a part of the continuing review process is the protocol deviation reports. At present the guidelines and regulations of India just mandate these protocol deviations and violations be notified to the EC. The EC member has to review and assess whether the deviation has impact on patient safety and data integrity. The challenge is that deviation reports are not submitted promptly to the EC (most of the time along with the annual reports); by the time EC reviews and suggests action plan either the damage is done or the patient has already completed/discontinued from the trial.
| Conclusion | | |
Thus, facing the day to day challenges along with changing guidelines and regulations, to keep abreast of the knowledge and action plans for unethical issues in research is a mammoth task for the EC member (may be more extensive for non medical members). Apart from this there are always burning ethical issues-use of placebo in trials, maintenance of standard of care, publication ethics, studies in special population-cancer, psychiatric illnesses etc, which can further perplex the EC member. Thus in today's scenario the EC member will require more commitment, dedication to be self trained, vigilant, and competent in executing its responsibilities to perfection.
| References | | |
| 1. | Indian Council of Medical Research. Ethical guidelines for biomedical research on human participants. New Delhi: ICMR; 2006. Available from: http://icmr.nic.in/ethical_guidelines.pdf [Last cited on 2006] 
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| 2. | Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A Review of quantitative risk benefit methodologies for assessing drug safety and efficacy. Value Health 2010;13:657-66.
[PUBMED] |
| 3. | Grady C. Vulnerability in research: Individuals with limited financial and/or social resources. J Law Med Ethics 2009;37:485-93.
[PUBMED] |
| 4. | Denny C, Grady C. Clinical research with economically disadvantaged populations. J Med Ethics 2007;33:382-5.
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| 5. | Miller FG. Ethical issues in research with healthy volunteers: Risk assessment. Clin Pharmacol Ther 2003;74:513-5.
[PUBMED] |
| 6. | Ananthakrishnan N, Shanthi AK. ICMR′s Ethical guidelines for biomedical research on human participants: Need for clarification. Indian J Med Ethics 2012;9:206-10.
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