On Jan 30, 2013 while the country stood in silence as a mark of respect to the father of the nation on his 65th death anniversary, a gazette notification was passed which could have meant the death of good quality serious clinical research in India. It definitely meant the death of reasoning, the death of stakeholder engagement when after a year of deliberations and receiving suggestions from at least 32 organizations, they were summarily dismissed and not incorporated in the notification, which is now law. The ethical clinical research industry was faced with a Hobson's choice, the necessity of accepting one of two or more equally objectionable alternatives. To continue doing clinical trials in the light of the gazette notification, means being not compliant to the law, because some of the provisions are difficult to implement. To stop doing clinical trials, both ongoing and in the future, would mean being morally unethical as it won't be in patient and public interest.

The way I see it, good quality clinical research by the serious players will continue as patient and public interest is at the heart of what they do. They will soldier on in the interest of patients and the public. But they will not litigate. After all, public interest litigations (PILs) are filed not necessarily in the interest of the public. This industry believes in being industrious, hardworking, and committed to the unmet medical and clinical needs of the people who are eligible to be included in clinical trials so that they can serve an altruistic purpose of doing good for the larger community.

In the first place, let us understand that compensation is not applicable as a blanket provision in the world of good quality serious ethical clinical research as participants are fully informed, fully comprehend, and only then make a volitional decision to enter the trial. If they suffer from an adverse event related to this participation they are medically managed free of cost. Patients are insured and investigators are indemnified. Despite this, if there are reasonable and justifiable grounds for compensation, the same is done. Per section 2.4.7 of the Indian Good Clinical (Research) Practice (GCP) guidelines, if the clinical trial related injury is deemed related to the study or drug, and is endorsed by the ethics committee, the event is compensable and sponsors have compensated, although in many cases the patient's relatives, investigators and ethics committee members have wondered why is the sponsor doing so when the patient was well looked after by the sponsor.

This notification may have been hastily passed perhaps as a knee jerk reaction to the Supreme Court diktat that either clinical trials need to be stopped or overseen by the Health Secretary to assure that participant rights, safety and wellbeing are monitored. The notification seems to have internal and external inconsistencies. Some provisions are not feasible to implement. For example, it is mentioned that from the day of serious adverse event (SAE) occurrence the sponsor and investigator need to report to the DCGI's office within 24 hours and submit a detailed analysis of the same within 10 days. Often one comes to know of the event 10 days after occurrence. It is reported immediately but by this notification one is already non-compliant. Is the DCGI's office geared for e reporting of SAEs? It should have been worded as from the day one comes to know of the SAE, not from the day of its occurrence. Changes to informed consent forms, contractual changes, getting fresh approvals both internally and from ethics committees will pose operational challenges which can even take as long as 6 to 12 months.

The notification states that medical management of any injury needs to be paid for, for an indefinite period, even if not related to the trial. For example, a participant while traveling to a clinical trial site, has a road accident, and will now need to be medically managed free of cost for the life of that patient. Such blanket provisions do not exist in any part of the world. Compensation for lack of efficacy or intended therapeutic benefit of the investigational product goes against the basics of clinical research. Sometimes patients do not respond even to approved and marketed products. Use of placebo is generally done as an add-on to current standard of care. Why should a sponsor have to compensate if there is wilful negligence or protocol violation on the part of the investigator? Sometimes patients are not compliant. The sponsor does select the investigator, trains him and his team, monitors and oversees the trial conduct with a clinical research associate, quality standards manager and auditor, plus the US FDA, EMEA and the Japanese MOH inspect some sites. Even if the DCGI's office is unable to monitor, even if ethics committees don't have the time to oversee, the industry does a very thorough job of monitoring and its standard operating procedures are stricter than any law of the land.

Wouldn't such blanket compensation clauses promote research misconduct? Won't patients be induced to participate in clinical trials? There is no clarity on how would one determine causality, and accordingly determine the amount of compensation, and the sponsor may not have the opportunity of representing to an independent arbitration committee. Having written this, I must also add that so far we have not received any frivolous claims for compensation and the Expert Committee has adjudicated in some cases that the SAE was not related to the study, in line with the causality assessment of the sponsor, ethics committee and investigator.

While the ethical research minded industry does support the mandate for compensation for clinical trial related injuries/death in the new compensation rules, and this step will further strengthen human subject/participation protection systems in clinical trials, the gazette notification if not suitably amended will be difficult to implement. Access to new medical innovations for unmet medical needs will become an issue as no new drugs may reach the Indian market. The research/innovation culture recently propagated by the government may take a back seat for academic (including investigator initiated) research and we would miss this golden R & D opportunity to build research capacity and capability.

Thankfully the sustained advocacy by the Indian Society for Clinical Research along with other like-minded bodies has resulted in an amendment to the gazette notification which hopefully should become law on June 12 this year. The contentious clauses alluded to above have been suitably amended. The same has been posted for public comments for 45 days.

I wish to end by writing that clinical trials don't kill patients. Rather, if not for the clinical trial especially in oncology, many a patient would have died a premature death. Clinical trials are controlled and regulated to a much greater extent than clinical practice. Let's be balanced and understand the benefit to risk ratio, maximizing benefit, minimizing risk and optimizing the therapeutic experience for the patient. Primum non nocere - at least do no harm.