Introduction: "Clinical Trials" and debates associated with it have been in headlines since past few months pursuant to the strict view taken by the apex court on the matter. The number of deaths in India resulting from clinical trials has increased to an unendurable figure of 2,868 during the period 2005-20121. If on the one hand this figure relating to number of deaths resulting from clinical trials is fearful, on the other hand the decline in the number of clinical trials and approval given for conducting such trials in last few months is equally shocking. Till April 2013, only 12 (twelve) clinical trials have been approved by the authority as compared to almost a three digit figure in last year2. This certainly raises a concern for the future of clinical trials in India- country which once was perceived as a fertile place for growth of clinical trials by most of the multi-national corporations. Currently estimated at USD 500 million, India's clinical research market was projected to more than double and cross USD one billion mark by 2016 driven by favorable factors like diverse and accessible population, availability of low cost and effective resources3.
The controversies relating to clinical trials are not something which can be decided in black and white. Rather it's an interface of elements like law, ethics, scientific development, human rights and social good. As these scientific tests and trials involve application of advanced technologies, there is a need for well framed rules and laws for the conduct of these tests and trials. Certainly it's not easy to set an order of priority or precedence among these elements.
This Article is an attempt to analyze the current controversy revolving around the clinical trials in India and to come out with feasible suggestions to ensure the ethical conduct of such clinical trials without undermining the need of scientific research and development and its benefits to society. However before proceeding further, it is necessary to understand in nutshell what does "clinical trial" actually means and how are they regulated in India.
What are "Clinical Trials"? Clinical trials in layman's language mean any investigation on human subjects carried out by pharmaceutical experts in order to discover or verify the clinical and pharmacological effects of any investigational medicinal product(s) and/or to identify any adverse reactions of such medicinal products(s) and/or to study such investigational medicinal product(s) with the object of ascertaining its safety and/or efficacy. Like any standard scientific and research activity, clinical trials are carried out with a definite aim through well- defined procedure and under closed conditions.
Applicable laws and regulatory framework: Clinical trials, in addition to national laws, are governed by well established guidelines and directives at international level like EU regulations and directives, ICH- Good Clinical Practices (GCP) guidelines, recommendations of World Medical Association Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practices and ICMR guidelines. These guidelines, recommendations and opinions are considered as "soft law" and are not legally binding but play an important role in regulating these clinical trials. Most of the multi -national corporations carrying out clinical trials worldwide voluntarily and as a good practice follow these guidelines and recommendations. These guidelines and directives primarily aim at protecting the subject from taking undue risk in participating in a clinical trial; enforce both voluntary consent to research and the continual assessment of risk and benefit. In India, Central Drugs Standard Control Organization (CDSCO) (headed by Director Control General of India) is the primary authority and "Drugs and Cosmetics Act, 1940" (along with the rules framed there under) is the principal legislation for the regulation of clinical trials. Schedule Y of the Drugs and Cosmetics Rules, 1945 ("Rules") provides for the detailed conditions, and compliances relating to clinical trials in India.
Recent amendment to Schedule Y of Drugs and Cosmetics Rules, 1945: Recently on 30th January 20134, Government of India came out with certain amendments to Schedule Y of the Rules with a view to tighten the norms relating to the conduct of clinical trials especially in terms of taking informed consents from the trial subjects and providing them or their legal representatives (as the case may be) compensation in case of any trial related injury or death. The amendment has imposed complete and ultimate liability on the sponsor of the clinical trial to reimburse any cost incurred by the trial subjects for the medical treatment of "any injury" suffered by the trial subjects as well as financial compensation for such injury or death. Further in case the sponsor fails to provide the proper medical treatment and/ or the financial compensation as per the orders of the licensing authority to the trial subjects (or their representatives as the case may be), then the authority may cancel or suspend the license of the sponsor to carry out the clinical trials and may even debar it from carrying any clinical trial in future in India. The amendment also mandates GCP compliance and adverse event reporting. The amendment has certainly acted as a deterrent on the multi-national corporations and is a negative catalytic agent to the prospects of clinical trials in India.
Ins and outs of the amendment: The aforesaid amendments to Schedule Y of the Rules came as a response to demands from the apex court, which were outraged by the lack of supervision and regulation of these clinical trials in India. As per the law existing prior to the said amendment, sponsors of the clinical trials were required to pay compensation "for deaths that results from clinical trials". Further there was no prescribed formula or minimum amount for determining such compensation and the time lines for making such payments by the sponsor in the Rules. Consequently only 45 out of 2,868 were reported to receive the compensation by the sponsors in last 7 years5. Additionally, there were no minimum clinical standards for trials prescribed under the law, for instance the requirement of registrations of the entities/ clinical research organizations conducting such trials, defined conditions and ethical standards to be complied with while conducting such trials.
After instances of unethical trials and unpaid compensations reached the courts and CDSCO early this year, CDSCO as a measure to bring about a planned change to the law relating to clinical trials in India decided to bring on table the amendments to schedule Y of Rules.
Also as a response to the public interest litigation(s) filed by few NGOs working for the human rights of the vulnerable sections, the apex court has acknowledged the lack of proper standard of care adopted by the clinical research organizations, lacunas in the existing legal framework and has shown serious concerns over the use of Indian subjects as "guinea pigs" in the conduct of clinical trials by the multi- national giants. This further triggered the CDSCO and Ministry of Health and Welfare to tighten the norms relating to the conduct of clinical trials and also the approval mechanism for such clinical trials.
While the human rights activists and NGOs are supporting the amendments to Schedule Y of the Rules, the pharmaceutical industry, sponsor pharmaceutical companies and clinical research organizations are certainly not unanimous with respect to supporting these amendments. As a result of stricter compliances and uncertain approval process, the number of clinical trials coming to India has decreased significantly in the recent past. One of the reasons for the decrease is due to the unpredictable nature of the regulatory timelines for clinical trial approval and the unreasonable demands of the authorities like protocol amendments, site selection etc. which in turn further increases the unpredictability and timelines associated with regulatory approvals. There are some who argue that this will just increase the cost of doing clinical trial in India, eventually pricing out local drug manufacturers and making India affordable only for multinational corporations. However it cannot be overlooked that as a result of aforesaid amendments and uncertain approval mechanism, the multi-national corporations would prefer other locations for carrying out the clinical trials like China, South Korea and Russia which provide a comparatively flexible and less strict regulatory atmosphere for carrying out clinical trials.
Not only the sponsors are affected by the change in regulatory scenario but also the doctors and investigators involved in the clinical trials are facing the consequences of these amendments. For example, as per the amended Schedule Y of the Rules, the investigators have an obligation to report any serious adverse effect of the drug under investigation within 24 hours of the "occurrence of such effect". Also sponsor has a responsibility to forward such reports within 10 days of the occurrence of such serious adverse event. However it is not practically possible to do so in most of the cases. Since such effects are not always physical or visible, it can be reported by the investigators only once they themselves became aware about the adverse effects of the drug through the subject or its representatives. Reporting of adverse effects and serious adverse effects are important since the same are directly related to the clinical trial injury and payment of financial compensation by the sponsors and hence the ambiguity in the amended language needs to be clarified by the authorities soon to avoid any ambiguity.
Striking out a balance between need for strict regulatory regime and the growth of clinical trials in India: Clinical trials not only contribute to the scientific research and development but also ensure better patient care than normal clinical practice and in long run is a boon for the society as it eventually leads to the development of new generic drugs and medicines. It is unfortunate that India is losing out the opportunity to other nations because of the uncertainties in the regulatory framework and approval mechanism.
Without undermining the need of amending the existing regulations relating to the clinical trials thereby making the clinical trials safer and preventing the exploitation of vulnerable subjects participating in such trials, it is necessary to appreciate that we as a developing economy with the conditions so suitable for clinical trials like diverse population, cost effective facilities and resources, presence of reputed pharmaceutical companies including subsidiaries of such multinational corporations willing to act as a sponsor and trained investigators, should not restrict the growth of clinical trials and instead try to promote a strong culture of research and development in the health sector in India.
No company or institution desires to be get publicized negatively or defend itself over ethical issues like violation of human rights or unethical treatment of patients, for any reason whatsoever. In today's diverse and competitive business environment, one must acknowledge that law often embodies ethical principles, but law and ethics are far from co-extensive. Regulators have to and should take into account other elements like social utility, economic growth etc. also while framing laws and hence it is not necessary that law would always prohibit something which is considered as unethical and the vice versa holds good.
There is a strong requirement for liberalizing the regulatory environment in favor of the sponsors conducting such trials and at the same time balancing the interest of the subjects involved in such trials. Further the approval mechanism needs to be more transparent and time efficient. Concerns raised by the human rights activist and NGOs are genuine, but rejecting or delaying the approval to the applications for conducting clinical trials is in no way a solution to the problem. Law should be for the "regulation" of the clinical trials and not for "restricting" the clinical trials. Instead of dismissing clinical trials or delaying the approval process, what is required is to identify and fix the loopholes in the regulatory framework and implement existing laws effectively to ensure that clinical trials are conducted with utmost transparency and diligence. Otherwise we would end up losing the prospects of growth of clinical research activities in India, which would certainly be a huge loss to our health care sector.
Way Forward: Following are some of the changes suggested in the existing law, which can go a long way to strike a balance between the interest of the subjects and the growth of clinical trials in India:
- Informed consent: Improvement in the system of obtaining informed consent from the subjects. Audio/ visual techniques of recording should be used while explaining the subjects about the process, the likely side effects and taking their consent. Further, subjects should be clearly informed about the past records of such clinical trials and number of adverse effects/deaths reported due to such clinical trials. Merely poverty and free treatment should not be the basis of engaging subjects in the clinical trials. Investigators and sponsor should be morally responsible in this regard.
- Restricting the liability of sponsors: Restricting the liability of the sponsors to the injury or death of the subject which are resulting directly or sufficiently attributable to the participation of the subjects in the clinical trials. With as many as 2,868 deaths during clinical trials from 2005 to 2012, only 89 have been attributed directly to such trials6. The timelines for payment of compensation should be liberalized depending upon the case to case basis. A fixed timeline in all type of adverse events and claims may not serve the purpose. Further the amount of financial compensation (over and above the cost of medical treatment) should be quantified or objective criteria to determine the same should be ascertained. For example, a terminally ill patient who chooses to be the subject of a clinical trial need not be given the same compensation as a healthy individual who has opted to become the subject for clinical trial. It should not be left at the sole discretion of the licensing authority or ethics committee.
- Institutionalization and registrations: Independent research and trials should be restricted and only institutionalized clinical trials to be carried out. It is commonly seen that investigators and doctors at individual level carry out unregulated clinical research in private clinics and hospitals. This is required to be checked by the authorities. Registration of clinical trials with Clinical Trials Registry India and registration of clinical research organizations should be mandatory. This is already in place, however the effective implementation of the same should be ensured.
- Approval mechanism: Fast and time efficient approval mechanism is required. Objective criteria for accepting or rejecting the applications, transparency in the entire process and the decisions for rejection or pending applications should be supported with the appropriate reasons. It is to be noted that the approval time for initiating drug trials in India typically runs from six to eight months, compared to 28 days in Europe and Canada.7
- Transparency: Transparency from the side of investigators and institutions is also very important. It is one of the core guiding principles in the ICMR Ethics Guidelines. Institutions and investigators should be open to public about regarding kind of investigation, standard of care taken, subjects involved, etc.
- Inspection and auditing: Officials of the CDSCO or licensing authority carrying out the inspection of the site should be of the same field with adequate knowledge and expertise on the subject. Also the use of CCTV camera at the trial site to administer the whole procedure of trial should be implemented. Further, involvement of the experts from the industry and legal field in the ethics committee and more emphasis on institutionalization of the ethics committee is also necessary. These would help the ethics committee and regulatory authority to investigate the matter more efficiently.
- Applicability of stringent laws: Multi-national corporations which are voluntarily following the internationally recognized guidelines and directives or are governed by laws of other home countries which are materially equivalent strict in terms of following the good clinical standards and protecting the interest of the subjects, should not be made to comply with more procedural compliances and practices and should be provided a conducive regulatory atmosphere for coming to India and carrying out clinical trials.
- Drugs with serious side effects: It is seen that most of the deaths occurred in the past few years is due to some specific drugs which were time and again put to investigation and every time resulted in the severe adverse effects. Special care should be taken in approving the clinical trials of such drugs and only in exceptional cases and depending upon the utility of such drug the permission should be given.
- Role of media: Negative publicity of clinical trials and multi- national corporations involved in such trials should be avoided and discouraged. Media should be responsible in spreading any critical report relating to the clinical trials and same should be approved by the licensing authority in advance. In past it is seen that out of the 2,868 deaths reported only 89 of them were taken place due to clinical trials8. Rest were either remotely related to the trial or were in regular course due to the disease of the subjects. Such negative publicity discourages the sponsor and creates uncertainties in the mind of the subjects. Rather media should emphasize on spreading awareness about such clinical trials targeting the vulnerable sections who mostly get involved in trials as subjects.
- Pending actions from the side of Government: The proposal of Ministry of Health and Family Welfare with respect to forming a committee comprising of science and regulatory experts that would formulate policy on drug approvals, clinical trials and drug bans should be implemented promptly. Also the draft bill on Biomedical Research on Human Participants (Promotion and Regulation) prepared by the Indian Council of Medical Research should be tabled in the parliament on priority basis. It would be beneficial if the comments and suggestions of the experts from the industry are taken.
- Clarification: Removing the loopholes in the language of the amended schedule Y (for instance as mentioned above the time period with respect to the reporting of serious adverse events) and bringing clarity to the same.
The ethical concerns of the clinical trials cannot be removed completely. But the above suggestions, if implemented, can certainly give bright prospect to the growth of clinical trials and research in the health care sector in India and would help in regaining the lost confidence of the multi-national corporations interested in carrying out clinical trials in India. At the cost of repetition, I would like to reiterate: Law should be for the "regulation" of the clinical trials and not for "restricting" the clinical trials!
1 Please see : http://www.business-standard.com/article/pti-stories/only-45-of-2-868-clinical-trial-deaths-compensated-since-2005-113030500403_1.htm l; last visited on June 21, 2013
2 Please see : http://www.thehindu.com/sci-tech/health/policy-and-issues/post-stringent-norms-clinical-trials-in-india-plummet/article4639976.ece ; last visited on June 21, 2013
3 Frost & Sullivan report, please see http://www.thehindubusinessline.com/industry-and-economy/clinical-trial-market-to-reach-1-billion-by-2016-report/article3877317.ece ., last visited on June 21, 2013
4 Notification GSR 53(E) dated January 30, 2013 For more details please see: http://www.cdsco.nic.in/GSR%2053(E)%20dated%2030.01.2013.pdf , last visited in June 21, 2013
5 Supra foot note no. 1
6 Supra foot note no. 1
7 Please see http://www.pharmalive.com/india-losing-its-edge-clinical-trials , last visited on June 21, 2013.
8 Supra foot note no. 1
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