Year : 2013 | Volume
: 4 | Issue : 4 | Page : 199--203
Injury and death in clinical trials and compensation: Rule 122 DAB
Ravindra B Ghooi
Scientia Clinical Services, Pune, Maharashtra, India
Ravindra B Ghooi
G 801, Rohan Nilay (1), Aundh, Pune - 411 007, Maharashtra
Three amendments to the drugs and cosmetics rules were published in quick succession in 2013. These addressed the issues of compensation of injury and death in clinical trials in addition to the role and registration of Ethics Committees. Of the three, the first and the third make an impact on the clinical research activities in India. The second amendment has codified the conduct of clinical trials, putting together rules, which appeared in different sections of Schedule Y. The first amendment deals with the compensation for injuries and deaths taking place during clinical trials while the third deals with registration of Ethics Committees. Despite the long delay in the issue of compensation rules, there appears significant room for improvement. The most problematic are conditions of injury and death in which compensation has to be paid. When compared with other countries, the Indian rules seem unduly harsh on sponsors and are at significant variance with those in UK. The rules are very generous toward subjects and compensation is likely to become an alternative to insurance in terminally ill subjects. The implementation of these rules will make clinical trials in India more expensive and hurt the industry that is already struggling through other handicaps. There is an urgent need to make the the environment more industry friendly to attract more clinical work.
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Ghooi RB. Injury and death in clinical trials and compensation: Rule 122 DAB.Perspect Clin Res 2013;4:199-203
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Ghooi RB. Injury and death in clinical trials and compensation: Rule 122 DAB. Perspect Clin Res [serial online] 2013 [cited 2019 Nov 13 ];4:199-203
Available from: http://www.picronline.org/text.asp?2013/4/4/199/120167
The need for new drugs continues unabated and drug developing agencies are continually working toward this goal. In the development of drugs, clinical trials are essential, without which a drug cannot be allowed to be used clinically. These trials are usually conducted on patients suffering from the disease (except some Phase I trials, which are conducted on healthy individuals); that the new drug is intended to treat. Some subjects do suffer from injury or even death while in a trial and such an occurrence calls for consideration of payment of compensation. So far, there were no rules in India to decide which subject deserves compensation and in what amount. The first amendment of 2013 to the drugs and cosmetics rules (known as Rule 122 DAB) contains directives regarding compensation for injury and death during the clinical trials.
While the clinical trials themselves have a long history, the first trial to use a design now considered the gold standard was that of streptomycin in 1948.  This trial was a randomized one and recruited 107 patients suffering from pulmonary tuberculosis. The trial was reported by the Medical Research Council and ushered in the new era of clinical trials. It was conducted since pulmonary tuberculosis was the most important cause of death of young adults in Europe and North America and streptomycin had been demonstrated to have a good anti-tubercular action in guinea pigs. 
The post-war England in 1948 was limited in resources, including the trial drug and these had to be used very judiciously. In order to design the trial, a number of people were roped in, including Geoffrey Marshall, Philip D'Arcy Hart and Austin Bradford Hill. That it was the use of statistics that unequivocally demonstrated the efficacy of streptomycin is another story; it is the death rate in the trial that needs examination. In the streptomycin group, 4 out of 55 patients died while in the bed rest group the death rate was 15 out of 52 patients. The hypothetical question is, should these 19 patients' relatives or nominees been compensated? As per the Rule 122 DAB, they would have to be.
Compensation is a very tricky issue! Let us consider the possible fate of 19 patients had they not entered the trial. Most probably they would have all died; hence, it cannot be said that they died because they entered a trial. A more correct assumption would be that the 4 patients died despite the use of streptomycin while 15 died due to a progression of the disease. If streptomycin were not used the death rate in the control group may have remained unchanged, but it would have gone up in the active group.
Compensation Rules in India
By sweeping application of the compensation dictum, the Rule 122 DAB would demand payment for all subjects who died in the trial. This is exactly where the Rule errs. It states that a subject is entitled to compensation if injury or death is due to:
Adverse effect of investigational product (s) (IP);Violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;Failure of IP to provide intended therapeutic effect;Use of placebo in a placebo-controlled trial;Adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;For injury to a child in-utero because of the participation of parent in a clinical trial;Any clinical trial procedures involved in the study.In the streptomycin case, the 15 patients in the bed rest group would have to be compensated under clause (d) above and the 4 patients in the streptomycin group compensated under clause (c). The British guidelines (issued by the Association of the British Pharmaceutical Industry in 1994) state specifically the limitation as:
3.1 No compensation should be paid for the failure of a medicinal product to have its intended effect or to provide any other benefit to patient.
3.3 No compensation should be paid to patients receiving a placebo in consideration of its failure to provide therapeutic benefit.
Another drawback of the Rule 122 DAB appears in clause (a). Normally the violation of an approved protocol, scientific misconduct or negligence on the part of the investigator should be the responsibility of the investigator and not of the sponsor. In fact, the investigator has made a commitment in Appendix VII (ii) stating "I agree to conduct the study in accordance with the current protocol." Yet the Rule 122 DAB states that patients who suffer injury or death due to the above reason must receive compensation and that the compensation must be paid by the sponsor.
The rule also mandates that the subject shall be given free medical management as long as required and that the sponsor shall pay for the same. While in principle this is excellent, the rule does not specify, which injuries qualify the subject to free medical management. It is probably intended that the subjects should receive medical care irrespective of the cause of the injury, for as long as required. Now if a subject is detected to have diabetes or hypertension during a trial, such a subject would be entitled to free treatment for life. The only condition should be that there is reasonable evidence that the disorder was not present or not detected when the subject entered the trial.
The rule puts some conditions for classifying death or injuries as trial related or unrelated for deciding eligibility for compensation, but for availing free treatment of injuries there is no requirement of relatedness. This appears to be an anomaly that has not come to the notice of those framing the rules. The sponsor is also required to give an undertaking to provide for medical treatment for injuries and compensation for death or injuries occurring during the clinical trial.
As of today 138,664 studies are registered with Clintrials.gov, of these 2543 (1.83%) are in India while 67791 (48.88%) are in the US. There has been so much clamor in the press and electronic media in India while there are no compensation guidelines or rules in the US. A popular belief fuelled by the media is that poor Indians are being exploited in the name of clinical trials. The call for compensation becomes all the more loud due to this.
In the US, where the bulk of clinical trials are conducted, there are no laws for compensation to clinical trial subjects. Compensation if any is sought by a trial subject is settled in courts under the law of torts. , This is certainly not the ideal situation and a number of scientists and ethicists have called for guidelines for compensation.  The Code of Federal Regulations (45CFR 46.116) (a) (6) states that:
"(6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained."
This rule makes it clear that if there is a mechanism for compensation it should be included in the informed consent form. On the contrary, many European countries have well-framed guidelines that are ensuring compensation to subjects injured during clinical research. 
In so far as compensation to clinical trial subjects is concerned, a few questions need to be asked. Firstly, which patients qualify for compensation, secondly who should decide the compensation and lastly what should be the amount of compensation? The Rule 122 DAB has attempted to answer these questions, but the answers may not meet the approval of the drug industry, hospital authorities or even patients.
Let us first consider the subjects whose injury or death should be compensated for. Subjects involved in clinical trials may die due to a variety of causes, each of these and the culpability of the trial will be discussed briefly.
Injury or death unrelated to trial
Accidental injuries and death are sometimes seen in subjects enrolled in clinical trials. These cases should not be considered for compensation. The Rule 122 DAB does not provide for compensation for such cases, but does provide for free treatment at the expense of the sponsor. However, the rule 122 DAB states "In case of an injury occurring to the clinical trial subject, he or she shall be given free medical management as long as required."
The wording of the rule raises an interesting question. Let us assume that a subject is detected to have developed hypertension (or diabetes) during the trial of an IP, does the sponsor have to support the medical treatment of the subject as long as required? Treatment for such disorders may be needed lifelong!
Injury or death due to negligence
Such cases are few and far between. Most sponsors would argue that negligence by investigators should be paid for by the investigator, but they have been reported to bear the expense in the interest of patient.  The Indian law requires compensation to be paid by the sponsor if the injury or death is due to the negligence of the sponsor, his representative or the investigator.
Injury or death due to exacerbation of pre-existing disease
This is the most common cause of injury or death and the incidence of such deaths in trials is quite high. This type of death can take place due to failure of test or standard drug.
The trial drug fails to produce its efficacy
When a trial is planned, it is not known whether the IP is as good as or better than the standard drug.  Under the Indian rules any injury or death in the IP treated group qualifies for compensation. Rule 122 DAB 5(c) states that compensation has to be paid for "Failure of IP to provide intended therapeutic effect."
Standard drug fails to produce its effect
Injury or death could take place in a trial where the control is the standard therapy. However, there is no mention about compensation for injury or death due to failure of the standard drug to demonstrate efficacy, though failure of IP is mentioned as a qualification to receive compensation in Rule 122 DAB 5(c). It is left to the imagination of the concerned parties, what is to be done. Such deaths are as common as in IP treated groups if not more in cancer trials.
Death in the placebo group
The Declaration of Helsinki, permits the use of placebos only in trials where subjects who "receive placebo or no treatment will not be subject to any risk of serious or irreversible harm" (clause 32).  Nonetheless if death were to take place in the placebo arm of the trial, compensation needs to be paid to the subject's nominees (Rule 122 DAB 5(d)).
Death in the trial of a drug not meant to treat the disease
Palliative therapy is not aimed at the disease. Its role is to provide comfort to the patient and freedom from symptoms of the disease or adverse effects of drugs. Among the newer drugs under trial in India is a cannabinoid Sativex® , which is being tested for its interaction with opioid induced analgesia in patients with advanced/chronic cancer pain (Clinical Trials Registry-India CTRI/2009/091/000336, CTRI/2012/11/003160, CTRI/2012/11/003169). In these trials, Sativex® is not expected to prevent death (or hasten it). Would a death in this trial attract the compensation clause?
Death due to adverse effects of the IP/standard drug/
Injury or death due to adverse effects of the IP should logically attract compensation and it does under the Indian rule. However curiously the subject receiving standard therapy does not warrant compensation. Any death taking place in the placebo arm should be attributed to exacerbation of disease (no compensation) or as unrelated to the trial
It is difficult to imagine other causes of death in subjects involved in a clinical trial. Yet serving as the Chairman of an Institutional Review Board, the author has noted the death of subjects due to homicide, suicide and accidental death. All these cases should have been legally pursued, but it is noted that they weren't. The Indian rules do not demand payment of compensation in these cases and none was paid.
One of the first news articles to highlight clinical trial deaths appeared on August 12, 2008 in Times of India headlined "49 babies die during clinical trials at All India Institute of Medical Sciences (AIIMS)". These deaths were not classified by cause, hence gave an impression to the readers that these healthy babies were sacrificed on the altar of drug trials. Nothing can be further than the truth. Firstly, these deaths were among the 4142 babies admitted to the hospital. The article does not clarify the number of babies recruited in clinical trials, which would have been a more relevant number to consider. The newspaper's website received a number of comments, many of which argued that this was nothing, but sensationalizing the issue. The National Human Rights Commission issued a notice to AIIMS and the government of India ordered an inquiry into infant deaths. Subsequently, AIIMS was cleared of any unethical conduct, but the damage had been done to the clinical research industry.
The lay press has been vocal in criticizing clinical research and demanding compensation for deaths. The press has discriminately printed articles against clinical research, but ignored those challenging or explaining the real situation. Articles by the author to the Times of India were never published when allegations about unethical research were made. Rule 122 DAB would satisfy these critics, yet it is necessary to examine how these rules will affect clinical research in India.
The Indian rules are tougher on the industry than the Guidelines of Association of the British Pharmaceutical Industry in UK and the CFR in US makes no mention of compensation for death or injury in clinical trials. The International Conference on Harmonization guideline E 6 states in 5.8.1 as follows:
"If required by the applicable regulatory requirement (s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence."
It should be noted that the ICH does not make any recommendation about compensation to subjects for injury or death, but merely suggests that regulatory requirements be fulfilled. It also clarifies that any injury or death caused by negligence of investigators is not required to be compensated for by the sponsor; this is in contradiction to Rule 122 DAB 5(b).
Sponsors are likely to think twice before outsourcing trials to India. In 2004, India and China were neck to neck in the number of clinical trials conducted. As of now China has gone about 4 times ahead of India and with regulations which don't exist elsewhere in the world, the trial work in India is likely to be further hit.
There is a growing feeling in some sections of the society that since the sponsor is expected to profit from trial related activity, the sponsor should be made to pay for any death or injury to subjects. In principle, this may be fine, but the practical impact of this would be an increase in trial expenses. Any such increase will directly reflect on the cost of the drug when it is eventually marketed. This would mean that the compensation to subjects will actually flow out of the pockets of patients who will use the drug in the future.
It should also be remembered that drug development is a very risky business proposition. When around 10 drugs enter the clinical phase of development, only one enters the market (this statistic differs from company to company and therapeutic group).  Increasing the cost of drug development is not in the interest of patients since this eventually leads to more expensive therapy.
Rule 122 DAB envisages that the amount of compensation to be given to a particular subject for trial related injury or death is to be computed by the Ethics Committee and the Expert Committee constituted by the Drugs Controller General of India for this purpose. Registration of Ethics Committees has been initiated under Rule 122 DD published in the drugs and cosmetics (third amendment) rules 2013, published on 8 th February 2013. Many Ethics Committees have applied for registration and are awaiting registration. Under the drugs and cosmetics (second amendment) rules 2013, Ethics Committees that are not registered cannot review any research proposal. Thus, approvals of proposals are deferred until registration takes place. Any case of compensation arising during the period 8 th February 2013 (when the second amendment was published) until registration of ethics committees (ECs) is complete, cannot be attended to by ECs.
As per the Rule 122 DAB, reporting of serious adverse event (SAE) leading to death has to be reported by the investigator to the sponsor within 24 h of its occurrence. A large number of trials currently underway are out-patient trials, in that patients go home with medication, or go home between medication cycles. Often, deaths take place either at home or in nearby hospitals and clinics; the information about the death of the subject doesn't reach the investigator immediately. In these circumstances it might have been prudent to use the words "24 h of receiving information of death" rather than "24 h within the occurrence of death" in the rules.
Compensation and Insurance
Insurance is a form of risk management primarily used to hedge against the risk of a contingent, uncertain loss. The key word being 'uncertain', if the possibility of loss is absolute, then few insurers will cover the risk. A healthy individual can obtain a cover against death at a nominal premium, but as the health deteriorates, the premium moves higher and higher. In case of a cancer patient, probably no insurance company will be ready to cover the life of the patient since the possibility of death in the near future is very high.
However, relatives of patients in clinical trials would be handsomely compensated in case of the death of the patient. With Rule 122 DAB in place, every cancer patient dying in a drug trial will be assured of compensation. Thus, patients who have been denied insurance due to pre-existing disease could still use the compensation route to make good their loss. In fact, Rule 122 DAB would become an alternate insurance at the expense of the sponsor. The Belmont report speaks of autonomy, beneficence and justice,  it is suggested that the principle of justice be extended to all stakeholders of research and not limited to subjects only.
There certainly are cases of subjects harmed in clinical trials, who deserve compensation. However, these cases do not justify sweeping application of compensation rule for each and every case where a subject is injured or dies. Every individual case has to be examined on merits and decision about compensation to be reached. In particular, the Section 5 of the rule needs serious reconsideration. Secondly, the reporting system for SAEs and unexpected ADRS is clumsy and needs streamlining. Compensation for deserving cases must be paid, but this should not be allowed to become an alternative to insurance which many people with serious illnesses cannot avail of.
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