Dr YK Gupta, Professor and Head, Department of Pharmacology, AIIMS, New Delhi expounds on the measures taken to revive clinical research in India and shares his recommendations to better the situation
Clinical research has grown exponentially over the past decade in India because of cost advantage, treatment naïve patient, qualified doctors conversant in English etc. India was the second most preferred country to conduct clinical trials outside the US in 2009. However, recent years have witnessed a decline in number of trials in India (529 in 2010; 253 in 2012). The number of drugs entering the Indian markets had been gradually reducing even before the current slump in clinical research activity (270 in 2008;140 in 2011; 44 in 2012 and 25 in 2013). This necessitates a relook on the strategy so as to optimise clinical research in Indian context. The problems and possibilities around the clinical research arena can be broadly grouped as capacity building issues and ethico – regulatory ones.
In India, Drug Controller General (India) (DCGI) is the competent authority for approving clinical trials as well as manufacturing and marketing drugs. DCGI grants approval after appropriate clinical trials are conducted in India with adequate number of trial subjects. To begin with, there are scant training resources to train adequate number of researchers so as to carry out research activities as per the international standards. There is a need to build dynamic training modules and platforms which confirm to international regulations and best practices while addressing peculiar national needs. The training infrastructure needs to be flexible enough to accommodate ever changing
regulatory landscape. We have a thriving knowledge base of traditional medicine systems which cater to a large segment of the population are regulated by a separate Department of AYUSH. There is a requirement of involving AYUSH practitioners in collaborative research and reorient the research regulations so as to effectively monitor research in AYUSH. Recent draft notification regarding regulations for ‘Phytopharmaceuticals’ is a step in this direction.
Though India has a robust regulatory apparatus, it is perceived that Indian patients being poor and less informed are vulnerable. While isolated instances of unethical clinical trials cannot be ignored, a more informed debate and perception management is the need of the hour. The confidence building amongst all stake holders has now assumed paramount importance.
The Govt of India has taken a lot of steps to ensure participant safety by introducing major changes in regulatory landscape of clinical research. Some such changes are as follows.
Registration of all clinical trials with Clinical Trial Registry India (CTRI) is mandatory w.e.f Feb 01, 2013. The protocol, enrollment and the final report also need to be uploaded at the registry. This is a welcome step aimed at putting trial related information in the public domain. However, there is a case for broadening the ambit of CTRI by capturing the subsequent trial results (positive, negative or inconclusive termination) too in the national database. This step shall go a long way in ensuring optimum publicity of trial results thereby mitigating publication bias.
W.e.f. Jun 07, 2013, audio-visual recording of the informed consent process is now mandatory to make the process more transparent and maintaining confidentiality. Reservations on logistics of this notification has been expressed by stakeholders, however amendments are awaited.
Registration of Institutional ethics committees (IECs) is mandatory w.e.f. Feb 08, 2013. IECs have been empowered and made more accountable. Now, they are required to actively monitor and participate in reporting of SAEs. Strict timelines for reporting of Serious Adverse Events (SAEs) have been mandated in which IEC has to give their report including opinion on compensation within a fixed time frame. Investigators are required to report SAEs to the IEC within 24 hours followed by a detailed report within 14 calendar days. Within next 30 days, IECs have to analyse and forward these reports to national expert committee with opinion on financial compensation. In order to fulfill their responsibility, IEC should be competent. Therefore training of IECs needs to be undertaken so as to empower them about their roles and responsibilities.
For the first time in the world, the financial compensation based on no – fault principle calculated as per defined formula has been made the mandatory responsibility of the sponsor for trial related injuries or death. This comprehensive and dynamic formula has been so devised that younger participants get more compensation as compared to older participants. The final order regarding compensation is given by the DCGI which has to be complied within 30 days. If the trial related injury is discerned after the completion of trial, still the compensation has to be given. The financial compensation to be paid is over and above free medical management of injury that has to be provided to the participant. In addition, trial participants have to be provided ancillary care if they suffer from for any other illness during the trial. The calculation of compensation for trial related injury is derived from the one applicable in case of trial related deaths. It is based on the assumption that death is the maximum injury possible to an individual and the amount in case of injury has to be less than the amount that would have been applicable in case of death in similar circumstances. According to this formula, the trial related SAEs for deciding the amount of compensation have been divided into following four categories – permanent disability; congenital anomaly or birth defect, chronic life-threatening disease; or reversible SAE in case it is resolved. The compensation applicable in all these scenarios has to be calculated differently.
Accreditation of principal investigators (PIs), IECs and the trial sites has been recommended to ensure competence of investigator(s), IEC members and the capacity of the site. For drafting the principles of accreditation, a committee, steered by Dr Ranjit Roy Chaudhury and Dr YK Gupta has been formed. To ensure adequate trial supervision, the number of trials per investigator has been restricted to three.
This spate of well intended regulatory overhaul has also made pharma companies apprehensive and skeptical about doing trials in India. Once the grey areas and contentious issues are addressed, it is envisaged that clinical research in our country will quickly scale up in a much safer, regulated and enabling environment.
Besides the regulatory action, patient, the most important stake holder, needs to be sensitised too. There is a need to generate informed and balanced debate in electronic and print media. The entire spectrum of clinical research needs to be made transparent with seamless knowledge sharing and information exchange. Regulators also need to act more as facilitators of research and not merely as law enforcers. The regulations have been made after detailed deliberations, consultations and analysis of the situation. These steps were essential to fill the gaps in the regulations, in absence of which there can be potential harm to the trial participants, who are relatively less informed as compared to their counterparts in the developed world. However, it is perceived that at few points, there is some over-correction which needs to be adjusted based on the evidence and detailed discussion with all the stakeholders, so that the progress of science is also not affected.
While the arena of clinical trials is under close watch, other types of clinical research such as observational studies, population based studies, outcomes research etc. also deserve equal emphasis. We need to formulate standardised protocols and SOPs for these activities and train adequate manpower. In the country of our size and magnitude, this is where the clues and leads are likely to emerge from.
Another important issue is to align the clinical research activity in our country as per our national health needs. Research in India specific problems (such as JE, Dengue, malaria, MDR TB) should be incentivised by way of faster approvals, liberal funding and extended marketing rights. It is good to have a vaccine against HPV but one against JE may be needed more and sooner.
Clinical research is essential not only for developing medicines for emerging health concerns (such as XDR TB, antibiotic resistant pathogens, H1N1, Ebola virus, etc) but also for finding safer and better medicines for entrenched diseases such as HIV, malaria, diabetes, hypertension etc. India, with its large patient population, unmet health needs, and limited resources, needs to make newer and better treatment options available to its population in a quick, economical and dependable manner. For this, India must take proactive part in clinical research and assume leadership role globally. We must ensure that clinical research in our country is carried out as per global scientific standard, is moored in sound ethical foundations befitting a liberal democracy but is optimally oriented towards addressing national medical and health needs.
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