Is the drug regulatory situation in India unique?

The past couple of years have been very trying for the DCG (I) office. It started off with exposure of trial misconduct in Bhopal, escalated to questions in parliament about trial-related deaths, compensation to clinical trial subjects in case of injury or death during the study, the institution of a Joint Parliamentary Committee (JPC) to discuss the functioning of the Central Drugs Standard and Control Organization (CDSCO) and the recent Supreme Court rulings. The issue is kept permanently on the boil by certain broadcasting corporations showing two to three year old clips of the Bhopal case once every few weeks.

The DCG (I) office is almost paralyzed. The DCG (I) response has been kneejerk to say the least. It published various draft rules, guidelines and orders as if in reaction to every incident being noticed and publicized. Shukla A et al summarizes it well in their article (1). Here is a sample:

Date	Rule, Guideline, Order, Notice, Notification
19.01.2011	Draft Rules to include provisions pertaining to the registration of contract research organizations (“CROs”) under the Rules, and to include a Schedule Y-1 which covered the ‘requirements and guidelines for registration of CROs’. Stakeholder comments invited. Notification yet remains to be implemented
18.11.2011	Draft Rules to include provisions to award compensation to study subjects, by Sponsors of trials, in case of clinical trials related - injury or death and consequences of non-compliance
17.07.2012	Draft Rules to include provisions for registration of the Ethics Committees with the licensing authority prior to approving clinical trials, and to include, as part of Schedule Y-1, requirements and guidelines for registration of the Ethics Committees
03.08.2012	Draft Guidelines for determining quantum of compensation
16.08.2012	DCGI Order directing Ethics Committee to conduct surprise visit and keep vigil to see whether clinical trials are being undertaken as per Schedule Y / GCP Guidelines
16.08.2012	DCGI Notice drawing out a check list of essential elements in the informed consent document to be obtained from the study subjects and the format of the said informed consent document
12.12.2012	DCGI Order directing the Ethics Committees to mandatorily operate according to Good Clinical Practice guidelines issued by CDSCO
30.01.2013	Notification regarding compensation in case of injury or death during a clinical trial
08.02.2013	Notification regarding registration of Ethics Committees

Reactions to these developments are diverse. They range from despair at the thought of the clinical trial industry not being allowed to grow, agitation about the exploitation of trial subjects, to helplessness over the slow bureaucracy, lack of transparency and an unclear policy. One wonders why we need to have a JPC to set things right, or a New Drugs Approvals Committee (NDAC) when the deciding authority is the DCG (I) office. Also about where and when all this is going to end.

Is this situation unique to India?

Let us see what happened in US. This has been reported in the New England Journal of Medicine; the Institute of Medicine Report 2012 (2). After receiving appropriate permissions, GSK was marketing rosiglitazone in type 2 diabetes. A Meta analysis reported that rosiglitazone was associated with a higher risk of myocardial infarction and death from cardiovascular causes than placebo or nonthiazolidinediones. Other studies showed that another thiazolidinedione, pioglitazone was not associated with such effects.

In 2008 FDA ordered GSK to conduct a trial comparing the cardiovascular outcomes of long term treatment of rosiglitazone versus pioglitazone. This was the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial. Even before enrollment began, people argued that the trial was not ethically justified, based on the inferior safety of rosiglitazone. How could one seek informed consent in spite of knowing that one of the comparators was likely to have cardiovascular side effects?

Due to the public outcry on this issue, members of the Congress sent a letter to the FDA in February 2010, demanding a justification for the trial. They also indicated that the consent form did not provide sufficient risk information to the patient. In response FDA internally expanded the investigation on the safety of rosiglitazone. They also requested Institute of Medicine to set up a committee “to examine the ethics and science of FDA-required postmarketing safety research”. In September 2010 FDA halted the trial and placed stringent restrictions on the availability of rosiglitazone.

This committee made a number of actionable recommendations which the FDA could implement. It also recommended appointment of an ethics advisory board to strengthen the decision making of the FDA.

This compares well with the happenings in India. The parliamentary standing committee report on the functioning of the CDSCO is a clinically precise, incisive document based on hard evidence. It has commented on every aspect of the functioning of the CDSCO, beginning with the mission statement and going on to the necessary qualifications of the DCG(I) position, insufficient personnel, infrastructure, and method of granting permissions for marketing, permissions or waivers for and conduct of clinical trials, imports etc.(3).

Under every head the committee has reviewed data placed before it and made strong critique and recommendations based on evidence. It has laid bare the irregularities in the approval process and use of discretionary powers granted in the drugs act to the advantage of companies, both of Indian and foreign origin. If all the suggestions of the committee are implemented even partially, there will be a sea change in the functioning of this important office.

Let us revert for a moment to the Institute of Medicine Committee in the US. The committee noticed many deficiencies in the TIDE consent form. Interestingly, this trial was approved by 480 Ethics Committees and Institutional Review Boards (IRB). The fact that FDA had requisitioned this trial obviously played a major role in clouding their judgment. The committee has also provided guidance to ECs and IRBs for approving such and other trials by taking into consideration the stage in the lifecycle when the trial is being initiated, since the risks and ethics would change accordingly.

Don’t we find similar decisions being taken in our country where an EC approves a study because it has already been approved by many others? The culture of independent ECs, IRBs is still taking root in India. We can certainly give them time to develop and improve. The new legislation for registering ECs will help in enhancing the overall quality level of our ECs.

The DCG (I) has instituted therapeutic area-wise New drug Approvals Committees (NDAC). This has been considered by many as shirking of decision making responsibility by the authorities. Such advice from advisory committees is being sought by the FDA too. Mcintyre et al (4), mention, “the FDA Amendments Act of 2007 made public advisory committee meetings mandatory for new molecular entities and devices requiring clinical trials, unless the necessity of convening such a meeting has been waived by the FDA commissioner.”

The article reports a survey of how Advisory board members prepare for meetings and how sponsors should prepare themselves. Majority replied that they do read briefing books provided prior to the meetings. However on further probing they revealed that they would prefer briefing books with less than 100 pages and with summaries before each major section. Hence they advise sponsors to make a brief and clear presentation, and to be transparent, forthright and credible in all responses. How different is this from the Indian scene?

India is no different

India seems to be experiencing a social awakening about the rights and safety of patients in trials. We are going through a process of reorganization no different from what other countries faced earlier and are still facing from time to time. Every such issue will result in a sociopolitical churning resulting in streamlining of systems.

At the end of the tunnel we will have SOPs for various important activities with less scope for ambiguity and interpretation. Things will be more transparent and less uncertain. But to reach that end we will have to let bureaucracy take its slow course. It is frustrating for those currently affected by the change, but they have to grin and bear it.

References

• 1. Shukla A, Baxi K, CLINICAL TRIALS ON TRIAL; Pharma Hotline: January 30, 2013
• 2. Mello MM, Goodman SN, Faden RR, Ethical Considerations in Studying Drug Safety; The Institute of Medicine Report, The New England Journal of Medicine Downloaded from nejm.org on August 23, 2012
• 3. Rajya Sabha Department-Related Parliamentary Standing Committee On Health And Family Welfare 59th Report On The Functioning Of CDSCO, May 2012
• 4. McIntyre TD, Pappas M, DiBiasi JJ, How FDA Advisory Committee Members Prepare and What Influences Them; Therapeutic Innovation & Regulatory Science 2013 47: 32 originally published online 7 September 2012, downloaded Jan 2013
  

Dr. Vishwas Sovani, March 2013