Clinical trial reforms – two steps forward, one step back

Dr Chandrashekhar Potkar

Professor Ranjit Roy Chaudhury Committee’s report on the topic of ‘To Formulate Policy and Guidelines for Approval of New Drugs, Clinical Trials and Banning of Drugs’ was recently uploaded on the CDSCO website. Post the notification of the Compensation Guidelines on January 30, 2013, this Expert Committee was entrusted a task, by the Ministry of Health & Family Welfare, to formulate policy guidelines and SOPs for approval of new drugs, clinical trials, and banning of drugs. The committee met with various stakeholders during the first half of the year toward this objective and submitted its report in July to CDSCO. This report was perhaps the most anxiously awaited report from the clinical research community in the context of declining research fortunes in India.

Key recommendations from this report can be broadly classified in two categories – positive recommendations and areas of concern. Even under positive recommendations, there are a few challenges that need to be addressed to enhance the impact of these recommendations.

First, this report makes several recommendations to provide reassurance and confidence to the general public on the clinical research process. A number of these recommendations are unprecedented and bound to have a long term impact on the research community. These changes include:

• Establishment of a central accreditation council
• Conduct of clinical trials only at accredited sites and by investigators under oversight of accredited ethics committees
• Creation of a framework for registration of studies, which includes recommendations for situations in which no trials may be justified, data from global trials can be relied on, and where local data generation will be mandatory
• Requirement of post approval studies over four to six years to gather real world safety experience on a new drug
• Clarifications on compensation definition including adopting relatedness as a critical determinant of compensation eligibility
• Simplification of regulatory review process with a technical review committee replacing 12 New Drug Advisory Committees (NDACs) and an assurance on turn-around time for review
• Improving robustness of the informed consent process through audio-visual (AV) recording in cases of vulnerable subjects
• Adoption of information technology at each step to improve transparency

The Expert Committee has appropriately identified the above areas as critical themes, which when implemented correctly, will have a significant impact on improving the quality of research and public faith in the research process. This is perhaps the first comprehensive articulation of all gaps in the research processes in India that will work towards restoring public confidence. However, there are a few challenges even in these positive recommendations. These include:

• Inconsistencies leading to different interpretations: An example of inconsistency is the proposal on audio visual recording of informed consent. In the salient recommendations, on page 2-3, the report states the requirement of audio visual recording of informed consent while later on, in page 79, it states this requirement is for vulnerable subjects. Another area is about the proposal on the sample size of subjects required for registration. On page 21, the report mentions the requirement of a statistically significant number of subjects in India, whereas on page 23 it states the need for adequate number of subjects to show an effect. These inconsistencies can lead to differences in the interpretations of regulatory requirements, impacting compliance.
• Unwarranted over regulation: The recommendations on the randomisation cell of the Ministry of Health & Family Welfare recommending a list of accredited sites for inclusion in a protocol after approval from the technical review committee is an example of getting carried away after beginning with a good intention. This will be in deviation from GCP and a logistical nightmare.
• Absence of a roadmap for translating intent to action: While the Expert Committee’s remit was to put forth proposals for policy reforms, these recommendations may only remain as such, without an operational plan to convert them into reality. Even the best of intentions are not useful when the roadmap for their implementation is not available. Recommendations on clinical trials to be done at accredited sites are an example of this category. Without information on how the central accreditation council would come into being, these recommendations appear to be distant dreams.

Also, there are a few areas of concern in the way they appear in the report.

• Sample size for registration studies: In either scenario – Indian patients’ data from global trials or local phase III requirement for registration – the proposal on statistically significant or adequate (where we have highlighted the inconsistency in an earlier section) negates the basic premise of International Conference on Harmonization (ICH) which evolved to avoid duplication and ensure consistent standards. The requirement for significant numbers in Indian studies will, in fact, lead to a duplication of the entire clinical programs leading to increased cost of development with no added scientific value. This may in effect adversely impact global clinical development in India.
• Provision for medical care: While provision of medical care to patients suffering an AE/SAE is humane and is aligned with a physician’s duty and responsibility to providing care, putting a blanket financial responsibility of this care on investigator/sponsors is unjustified and not aligned with global practices. When an AE/SAE is assessed to be related to a study, this proposal would be ethical and valid, however, for non-related AE/SAEs an alternate mechanism must be put in place.

Overall, this report is a step in the right direction. With several recommendations bound to overhaul the clinical research system in India, this report is seminal in its intent. Unfortunately, areas of inconsistencies, a few critical red flags and absence of linkage with an implementation roadmap might derail the intended transformation. The next steps on this report would be to include fixing the issues cited and a quick communication of the Ministry of Health & Family Welfare’s position on these recommendations. Quick and swift action would help arrest the decline of research in India.