Will the proposed compensation guidelines for research-related injury spell the death knell for clinical research in India?

CS Pramesh, RA Badwe 
 Department of Clinical Research Secretariat and TMC Research Administrative Council, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

Correspondence Address:
C S Pramesh
Department of Clinical Research Secretariat and TMC Research Administrative Council, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
India

Full Text

The Indian Council of Medical Research (ICMR) and the Central Drugs Standards Control Organization (CDSCO) of the Directorate General of Health Services of the Ministry of Health and Family Welfare have issued draft guidelines [1],[2] for compensation of research-related injury on their respective websites requesting feedback from interested parties. These guidelines, when finalized, are likely to be adopted by the Government as an amendment to the Drugs and Cosmetics Rules, 1945 under the Drugs and Cosmetics Act 1940. In the present form, they apply to all forms of clinical research, whether industry sponsored, funded by government or investigator initiated.

These guidelines have some clauses that raise several points of concern. Prominent among our concerns include what types of research-related injury are entitled for compensation, whether injury resulting from standard care should be entitled for compensation, whether causality needs to be established as a prerequisite for eligibility for compensation, whether all forms of research should have mandatory provision for compensation, the dangers of such recommendations being that they could be powerful inducement for patients to participate in clinical research and, finally, infringement of the patient's fundamental rights regarding what research he/she wishes to participate in. We will address each of these concerns point by point.

(1) The ICMR guidelines state that, "Compensation be provided to the research participants when temporary or permanent injury occurs due to participation in the clinical research, when injury is caused by a procedure which has been undertaken to manage an adverse reaction occurring during the research and to a child injured in-utero through the participation of the parent in clinical research." The guidelines define clinical research as "any research conducted on human participants or on material of human origin such as tissue, specimen and cognitive phenomenon, epidemiological and behavioral studies, and outcomes and health services research." The guidelines then go on to specify that compensation be paid irrespective of "the fact that the injury was caused by the comparator product(s) under investigation in the clinical research and …. the cause of injury and individuals/agencies responsible" with some exceptions. These exceptions include the investigational product not having its intended effect, the placebo not having therapeutic benefit, natural progression of disease and adverse events because of concomitant medications or routine procedures as part of standard of care.

The ICMR guidelines are explicit that injuries resulting from the standard "comparator" or control arm of a clinical trial are entitled for compensation. The standard arm of a trial is the treatment that the patient would have received even if he/she was not part of any clinical research. The logic behind these injuries (actually, side-effects of routine medical treatment) being eligible for mandatory compensation is difficult to fathom. This is especially so when injuries resulting from other procedures performed as standard of care are not eligible for compensation by researchers. How is the standard treatment in the control arm of the trial any different from these other procedures?

(2) The guidelines also state that compensation should be paid regardless of causality (with the exceptions mentioned above). This implies that any serious adverse event (SAE) occurring in clinical research should be compensated except when it can be attributed to adverse events from concomitant medications, routine procedures and natural progression of disease. If causality need not be established as grounds for compensation, will a clinical trial participant who is knocked down by a bus while crossing the street be entitled for compensation?

These recommendations could have two important repercussions: firstly, this could potentially become a strong inducement for poor patients to participate in clinical research, as they are assured of the best possible care and free treatment, both for the disease as well as compensation for the resultant side-effects, even those resulting from the "standard treatment" of the control arm. Secondly, the costs of clinical research would skyrocket, making it possible only for big pharma companies to conduct research and, effectively, stifle or kill investigator-initiated research by academic institutions and possibly even the government. These guidelines are not likely to affect commercial, industry-sponsored research, as compensation costs would be a small fraction of the overall costs in drug development. These would however decimate the conduct of academic research in the country for which there has been so far a strong impetus from the government. The search for cost-effective treatment options for common diseases would die a premature death - this would be especially unfortunate in a country like India where the vast majority of patients find the expensive "standard of care" of the western world completely out of reach. Surgical trials, which often compare two standard, accepted forms of surgery, would never be done - and this, despite a clarion call for more surgical research globally. Unless these guidelines are modified, it could very well spell the death knell of academic clinical research in the country.

The CDSCO draft guidelines go one step further (backward?) from the ICMR draft guidelines. They mandate that in addition to what is mentioned in the ICMR guidelines, the following are entitled for compensation: "failure of an investigational product to provide intended therapeutic effect, administration of placebo providing no therapeutic benefits, and adverse effects due to concomitant medications." This borders on the bizarre.

While we can understand that both these guidelines have been framed out of necessity, we can only hope that these recommendations are relooked at, and soon. If they are not, practically anything adverse occurring to a research participant after the informed consent process is entitled for compensation. If we were certain about the therapeutic benefits of the investigational product, where is the need for a clinical trial? How can a placebo be expected to consistently provide therapeutic benefits? Why should adverse events resulting from concomitant medications require to be compensated? Not only do these specific points of the CDSCO guidelines directly contradict the ICMR guidelines (which clearly recommend that these situations NOT be compensated), they also appear to contradict itself where later on in the CDSCO guidelines, it states that "in the event of an injury or death occurring during the trial, the sponsor or his representative shall prove before the Ethics Committee that the injury or death is not on account of the clinical trial within 30 days of receiving the report of injury or death from the investigator; failing which sponsor shall be liable to provide the compensation within 60 days as decided by the Ethics Committee." Does this now mean that causality needs to be established? If so, causality with relation to what? The investigational product (or treatment), failure of the product or the placebo to have therapeutic benefits or any of these? What does "injury or death on account of the clinical trial" mean?

Compensation guidelines do exist worldwide for clinical research, and differ based on the country's needs. Researchers and sponsors in the United States are not mandated to provide compensation for research-related injury to research participants. [3] The Association of the British Pharmaceutical Industry (ABPI) guidelines, [4] which is actually referenced in the ICMR draft guidelines, state that "Compensation should, be paid when, on the balance of probabilities, the injury was attributable to the administration of a medicinal product under trial or any clinical intervention or procedure provided for by the protocol that would not have occurred but for the inclusion of the patient in the trial" (emphasis ours). The ABPI guidelines also recommend that while participants suffering from research-related injuries be compensated, no compensation should be paid for injury caused by other licensed medicinal products administered to the patient for the purpose of comparison (i.e., standard treatment arm or control arm) with the product under the trial. This automatically implies that when two standard forms of treatment are being compared (as is done in many investigator-initiated studies), any injury or death while participating in the study need not necessarily be compensated.

It would be thus worthwhile to revisit the draft guidelines for compensation for research-related injury, which clearly need to be thought through carefully. Patients who understand that compensation will not be routinely provided but still decide to participate in clinical research out of altruistic motives (which is the only motive with which a research participant should really do so) would still be able to take part. This would also ensure that academic research continues and medical science and therapeutics progress in our country. We are at a crucial point in the Indian clinical research juggernaut - whether to let it roll on or grind to a tragic halt - depends on how these guidelines are shaped.

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