Year : 2013 | Volume
: 4 | Issue : 1 | Page : 75--79
Research ethics in real world studies
Independent Medical Research Consultant, Mumbai and Pune, Maharashtra, India
Medical Research Consultant, Mumbai and Pune, Maharashtra
|How to cite this article:|
Nanivadekar A. Research ethics in real world studies.Perspect Clin Res 2013;4:75-79
|How to cite this URL:|
Nanivadekar A. Research ethics in real world studies. Perspect Clin Res [serial online] 2013 [cited 2020 Jan 19 ];4:75-79
Available from: http://www.picronline.org/text.asp?2013/4/1/75/106396
Since 1996, good clinical practice (GCP) has become the global standard for doing clinical research. The initiative to forge this standard was taken by the International Conference on Harmonization (ICH). Although the focus of ICH-GCP was clinical trials of drugs, similar guidelines have been adopted by governmental and non-governmental organizations that sponsor, support and oversee clinical trials as well as other types of clinical research. For example, the Indian Council of Medical Research (ICMR) has issued its guidelines  with a scope that is much wider than that of ICH-GCP. One of the main objectives of these guidelines is to protect the human subjects participating in research.
The GCP guidelines issued by regulatory bodies in various countries differ in some details, mostly minor, and require an ethics committee (EC) to review each clinical research proposal before any work begins. Regulatory agencies, grants committees, and medical journal editors consider such review essential for any further consideration of the proposal. Thus, EC approval has become the first traffic signal that all clinical research projects must cross.
Ethics Committees in India
The ethics committees (ECs) that exist in India at present are named in various ways. If you come across the acronym IEC, you need to find out whether the "I" means independent or institutional, although even an institutional EC needs to be independent. The term institutional review board is not common in India though it would connote the same thing as IEC.
Institutional ECs (IECs) are set up by their heads who invest them with the required authority. Being institutional, they are located within the institution's premises and receive both financial and administrative support from them.
Some institutional ECs were formed afresh post-1996, especially in non-teaching but well equipped hospitals getting increasingly involved in national and global clinical trials. Their emphasis has been to meet ICH-GCP criteria and be acceptable to drug regulatory authorities.
However, most teaching hospitals already had some sort of committees primarily to appraise research proposals from both staff members and outside sponsors. Their primary function was to sanction financial support for non-sponsored proposals and to decide on the acceptance and utilization of funds for sponsored projects. Post-1996, the existing committees were transformed into institutional ECs to meet GCP requirements.
Besides institutional ECs, we also have non-institutional ECs (NIECs) in the country. These came into existence to provide ethical review services to investigators and research sites that did not have access to their own ECs. However, it has not always been quite clear from whom these ECs derive their authority and to whom they are accountable for their operations.
Mandate of Ethics Committees
Although ECs are expected primarily to protect the research participants, they also need to consider scientific aspects of the proposals, especially if these have relevance to ethical issues. As I shall discuss a little later, these scientific-ethical aspects of research proposals have many facets that reflect various financial, social, political and philosophical hues of human existence. Being able to deal with them is also an implicit function of an EC.
All GCP guidelines emphasize that independence and competence are the two hallmarks of an EC. These are simple words with profound practical implications. How ECs try to cope with these ideals, and how far they succeed, determines how well they live up to the trust reposed in them.
The ICH-GCP states that at least one of the EC members should be from outside the institution. This is the minimum requirement for independence. It may be valid and enough in a legal sense, but it is worth pondering what other conditions are necessary to render an EC truly independent or free from any influence that may jeopardize its role as the fiduciary of participants' protection.
Most IECs have an outsider as a chairperson. This fact is often cited or accepted as evidence of the EC's independence. Such may be the case if the chairperson is sufficiently familiar with the nature and methods of clinical research and the conflicts of interests to which it may be exposed. If this condition is not satisfied, then an outsider chairperson ensures mere formal independence of the EC, but not its true and material independence. Sometimes the conflicts of interests are perceived palpably and circumstantial, but they cannot be proved legally. A perspicacious chairperson can steer the EC's deliberations in the right direction if he has sufficient insight into the subject matter, and if there are more outside members in the EC besides himself. There is no magic ratio of the numbers of institutional and outside members, but in my view just one outsider does not seem to be enough.
This is the other hallmark of a GCP-compliant EC. Competence means not only a qualification in one's field, training and experience, but rather their application to the problems of clinical research. In other words, non-medical or non-scientist members such as lawyers, priests, sociologists or lay persons need to have an interest in health care research, be aware of prevailing controversies in important areas of research, be willing to study them if necessary, and be prepared to spend time and efforts to familiarize themselves with the important issues concerning a proposal received for review and due for discussion.
There are several operational aspects of an EC's working that have an impact on whether or not it fulfills its raison d'κtre.
Finding members who are willing to work on an EC, to spend adequate time for studying the proposals, to attend the meetings regularly, and to make efforts for familiarizing themselves with the subject of research as well as the evolving trends in regulations is a difficult task. It is my experience that for an active and willing person, with access to internet resources, it takes about two full days' work to read the documents related to a proposal and to form reasoned opinions on the issues involved.
In an IEC, the head of the institution may nominate internal members depending on his perception of their interest, expertise and competence, and they have generally little choice but to acquiesce. For outside members, the matter is different. They need to be identified, invited and persuaded. Those who are active in their current professions or jobs do not afford to spare adequate time or effort for the EC's work. On the contrary, those who are fully retired do not have sufficient interest and resources to discharge their duties as EC members. Because both agree to join the EC almost as a favor, the chairperson cannot be firm with them. These inherent problems in forming an EC tell upon the quality of their review of proposals and overseeing of the approved projects.
With NIECs the problems are even more varied. The person who moots the idea and convenes the committee has to identify and motivate first a chairperson and then various other members. Because the NIEC lacks institutional support, the convener has to organize the entire setup comprising the premises, the secretariat, membership, standard operating procedures (SOP), financial arrangements, etc.
Registration and accreditation
Initially there was no mechanism for registering and accrediting either IECs or NIECs. Each tried to follow the ICH-GCP or the local regulatory GCP so that it could face an audit or inspection should it occur. As a result, the various ECs had little in common except for the name. However, efforts now seem to be underway to identify, register, accredit and audit all ECs in the country,  but until this happens we will need to assess the independence, competence and efficiency of each EC from our own experience of dealing with it.
EC members need to be trained for their new role. Most are usually persuaded to attend a one-day session on GCP with emphasis on the structure and function of the EC. In my opinion, this turns out to be only an awareness program, not a competency program. It is just enough to document that all EC members have attended a training program. Whether they have been enabled and empowered to play their role competently is neither asked nor verified.
Training of EC members is not a one-time affair. It is a continuing process requiring exposure to newer ideas and developments as novel or unprecedented proposals come up for review. Besides, the scope of proposals received by an EC can vary from very narrow to very wide. For example, the EC of a contract research organization (CRO) dedicated to bioequivalence (BE) studies receive proposals that are very much stereotyped. The variation consists mainly in the molecules to be assayed, the doses that to be administered to volunteers to obtain measurable plasma concentrations, the total volume of blood to be collected from each volunteer, and the washout period between two periods of a crossover study. On the contrary, the EC of a large hospital can receive a gamut of research proposals comprising case registries, retrospective, cross-sectional and prospective surveys, trials to evaluate drugs, diagnostics and devices, dissertation projects of post-graduate medical students, and complex community-wide intervention trials lasting over years. All these make continuing self-training essential for EC members, if they have to do justice to their roles.
This is the hub of the EC operations. Receiving proposals, verifying their completeness before accepting them, preparing an agenda for the meetings, circulating proposals to the members, scheduling meetings such that the dates and times are suitable for most or all members, taking down notes and writing accurate minutes, corresponding with investigators, managing incomes, expenses and accounts, preparing for audits or inspections, and other related activities imply both volume and variety of the jobs to be done. Therefore, administering an EC secretariat is not a part-time responsibility but a full-time job. To run efficiently, such a secretariat needs space, equipment, funds and authority which are often not provided or available. As a result, the working suffers from delays, inefficiency or both. I believe an EC review is not yet taken seriously either by the EC or by the authorities, but rather accommodated as a legally necessary ritual that has somehow to be gone through.
Attendance and quorum
Getting adequate and appropriate members to attend a meeting is a trying task for the member-secretary. Full-time institutional members often send in last-minute apologies as they are busy with more pressing professional duties. Non-institutional members may also do so as their normal professional demands obviously take precedence over an EC meeting. On occasions such members condescend to make an appearance towards the end of the meeting to sign the attendance muster though not contributing much either to the discussion or to the decision. Rushing in to attend such meetings, the members are often quite unaware of the proposals to be discussed or the issues related to them. No wonder then that the EC review of a research proposal sometimes becomes just an exercise in documentation rather than deliberation and considered decision.
Some ECs try to solve the problem of attendance and quorum by having alternates for each member. However, such alternate members have to be identified, listed and enlisted in a planned manner just like the primary members. They cannot be picked up ad hoc on the eve of the meeting. Further, if they are to attend a meeting to fill in for the primary members, they need to receive the proposal documents well in advance to go through them, mull over the issues, and contribute to the deliberations at the meeting. Such planning presumes that the primary member's inability to attend a meeting will be known sufficiently in advance and that either the primary member or the secretariat will have enough time to brief the alternate member adequately. How far these expectations are met, in reality, is anybody's guess, but I believe the performance on such predicaments leaves much room for improvement.
An IEC is normally constituted to review and oversee the research carried out in the institution. Should it undertake to review a proposal for research to be done outside the institution if that location or investigator does not have an EC? This issue may not be common, but it is probably not rare. I believe the answer will depend on the constitution of the EC. The constitution may have a provision to accept outside proposals, but such acceptance must be subject to the condition that the applicant institution and investigator accept the EC's authority to visit, audit and inspect their facilities, and to oversee the conduct of the study.
For a NIEC, the issue would be routine because that is the reason why it is formed. Such an EC needs to be even more vigilant about verifying the qualifications, training, experience and facilities of the investigator, and the feasibility of having an effective control over the conduct of the study. I believe there is much that needs to be done in this area.
The protocol of a research proposal has many aspects that are primarily scientific or regulatory, but laced with ethical issues. I shall list and discuss some of them in brief though their order does not necessarily indicate either their frequency or their importance.
In some BE studies the proposed dose is almost the maximal permitted dose, and if the drug has prominent pharmacological effects on vital functions, the EC may be concerned about the tolerability of the dose. The justification for the dose is usually to obtain measurable plasma concentrations. Only a clinician who has employed the proposed dose in his patients might be able to guess how well healthy volunteers may tolerate it and what precautions ought to be taken to ensure that any serious adverse event is avoided. Such expertise may not be available within the EC, and an outside expert who is willing to provide a written and signed opinion may have to be invited before making a decision. Even then, to protect volunteers from unnecessary exposure to high doses of very active and potent drugs, the development of more sensitive assays would be a better alternative that should be constantly pursued.
The number of subjects needed for a BE study or a non-inferiority (NI) study depends on the equivalence or the NI margin acceptable to the regulators and the expected variance of the data. The regulatory requirements peg the risk to consumer (α) at 5%, leaving the manufacturer to manage the risk to himself (β) through adequate sample size. Now, as the sample size begins to exceed figures such as 64 or 128 in BE studies, and 600 or 900 in NI studies, EC members begin to wonder whether the clinical significance of such an exercise is worth the cost, effort and human participation. Would it not be better to ask whether society really needs the products to be tested and whether it would not be prudent to improve the products so that the variance of data is considerably reduced or the margin between the reference and the test product is minimized as much as possible? To settle this issue, both clinical, pharmacological, analytical and statistical expertise is needed in unison.
How many products?
If an EC receives proposals mostly or entirely for BE studies, NI studies or phase 3 studies of new fixed dose combinations, the members gradually begin to wonder whether so many more-or-less similar products are indeed needed for the society's health care. How many of such studies deserve the usage of human subjects when genuinely new drugs, therapies or strategies may be in need of them? These value judgments are difficult to make, and the EC can take the easy way out by following the letter of the law. This is a challenge that only vigilant and committed members can handle.
Recycling of subjects
The above questions assume importance because once a subject has participated in a study, he is usually not eligible to participate in another study for at least 3 months, which means he is inaccessible or in quarantine for that duration. Further, unless there is a national registry of persons participating in clinical research studies, with a unique ID for each, it is difficult to verify whether a subject had indeed participated in another study within the preceding 3 months. This is one area in which all ECs need to cooperate with one another, but whether and how far they do or will is not known.
Choice of outcome variables
For comparing two groups, one may choose either an interval variable or a binomial variable. For example, fasting plasma glucose or the presence of diabetes mellitus by accepted criteria. With an interval variable, the study generally needs a smaller number of subjects than with a binomial variable. The real issue is which outcome variable is materially important to patients, their doctors and public health guardians? Which variable will make statistical and clinical significance congruent? The issue may be overlooked for marketing license, but it is one, which will ultimately determine whether the drug, product or procedure will stand or fall in the real-world dynamics.
Even with interval variables such as visual analog scale (VAS) score of pain, I believe there is a threshold value for each patient above which it becomes a problem needing relief and below which it is not a problem demanding treatment. Rather than comparing the average reduction in VAS score in two groups, I think comparing the proportions of patients who move from above the threshold to below the threshold is more meaningful to patients, doctors and public health guardians. Whether I am right or wrong, how do we include in the protocol some weight for their values in deciding the choice of outcome variables for comparing two devices, drugs, procedures or strategies?
Informed consent document
Written informed consent has become the "open sesame" for participant enrollment. The principle is impeccable; it is the practice that is problematic. The informed consent documents (ICD) may be legally and scientifically flawless, but empirically a nightmare. One of the most tedious, uninteresting and exasperating document to read is the ICD, especially when the patient or his kin is in a state of mind that needs assistance and succor rather than legally defensible but incomprehensible jargon. Writing it in English is of course the first hurdle, but translating it into the participant's language and back into English to verify its veracity is a trial for the translator. I believe each EC needs an expert in local language who knows enough medicine and psychology of patients to advise and demonstrate what really needs to be told and how to strike the optimum balance between legality, morality and propriety. I have done a few such exercises and learnt much to my chagrin. I think this is one area in which an EC must partner with the sponsors and the investigators to break new ground and to create new models.
What about other ethics committees?
While reviewing a research proposal, a question that often crops up in the members' minds is whether the same proposal has been submitted to or reviewed by other ECs, and if so, what their queries or decisions have been. This is especially so in multicenter studies. The question seems legitimate, but if the EC of every site were to ask this question and ponder the answers, the review process can be very protracted and frustrating. Maybe each multicenter study should be reviewed primarily by one EC, which may seek the views of the ECs of other participating centers before finalizing its review and conveying the decision to all. Perhaps the agency entrusted with the registration, accreditation and inspection of ECs could select the most appropriate primary EC for a multicenter project, and its decision accepted by other ECs unless there are very strong grounds for not doing so.
Conflict of interests
If a project consists of maintaining a case registry of patients who have been exposed to a drug, device or procedure, the compensation paid to the investigator per case becomes a sensitive issue. Is it just adequate to the expense and effort involved or is it such as to act as an incentive to prescribe, recommend or use a particular drug, device or procedure? How to avoid bias in these decisions is certainly an issue that an EC needs to consider.
Full disclosure of the research grant ought to be a concern of the EC because financial interests can drive people over the boundaries of morality. It is not uncommon to come across proposals in which the grant details are not adequately disclosed. Whether the grant should be paid directly to the investigator or should be administered by the accounts department of the institution is also an issue. Besides, grants can be not only in cash but also in kind, and full disclosure can be essential but elusive.
Whether a project is completed or not, a final report describing its outcome must be on the record of the EC that initially reviewed and approved it. I doubt that ECs at present receive such reports from all the investigators. Some reports may be simply filed by the sponsor and never get published. However, they represent a body of knowledge that ought to be available to someone embarking upon a meta-analysis of the available data. Here also, the site that registers a research project should have a provision to incorporate its final report in a standard format that would make its use for meta-analysis feasible.
The formation and working of ECs is but one step in making research on humans morally and scientifically sound. However, legality has never been an effective method of imposing or ensuring morality in any community. Morality can grow only as the value systems of people themselves undergo a slow, subtle and sustained change. In that effort, ECs have an important role to play, and this is what its members need constantly to keep in mind.
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