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editorial
. 2014 Nov-Dec;46(6):575–578. doi: 10.4103/0253-7613.144887

Clinical trials and evolving regulatory science in India

Y K Gupta 1, B Dinesh Kumar 1
PMCID: PMC4264069  PMID: 25538325

Few years ago, India was considered a preferred destination for conducting clinical trials. Both Indian and foreign pharmaceutical companies were utilizing “Advantage India” factor (large, diverse, treatment naive patient population, trained human resource, GCP compliant investigators/sites, and relatively low cost of conducting clinical trials when compared with developed world).

Unfortunately, there have been some isolated incidents of alleged unethically and incorrectly conducted trials. These incidents have made the patient community to believe that they are gullible and treated like guinea-pigs. A negativity came to be associated with clinical research in the country. The necessity of conducting clinical trials for better therapeutics were not effectively communicated to the public, patients, media and policy makers. Though the media plays a constructive role as a whistle blower, inadequately informed and unbalanced reporting has created an atmosphere not conducive for promotion of “clinical research” in general and “clinical trials” in particular, the country. This resulted in the sharp decline in the number of clinical trials (from 529 in 2010 to nearly 250 in 2012 to just over 100 in 2013) approved by Drug Controller General of India (DCGI).

The clinical trial issues generated debate from public to parliament in the country and also few public interest litigations by nongovernmental organizations (NGOs). The important concerns raised were regarding the process of informed consent in clinical trials, justifiable compensation to the trial participants for injury or death, and alleged exploitations of the Indian subjects in the clinical trials.

The government took several initiatives to address the loopholes in the existing regulations related to clinical trials in India through enforcement of ethical guidelines and norms for effective supervision of the trials by investigators and the regulators. The important regulatory changes introduced are: (a) Compulsory registration of all the trials in Clinical Trial Registry of Indian Council of Medical research (b) registering the Ethics Committees with DCGI (c) Provision of inspection and audit of ethics committees by the regulator (d) inspection and monitoring by ethics committee of the on-going trials (e) mandatory audio-visual informed consent process (f) declaration of financial arrangement and the payment received by the investigator in the trial (g) strict time lines for reporting SAE to Sponsor, Ethics Committee and the Regulator (h) restriction of a maximum three trials per investigator (i) compensation guidelines for clinical trial related injuries for SAE leading to death (j) compensation for clinical trial related SAE not resulting to death (k) strict time lines for reporting SAE to Sponsor, Ethics Committee and the Regulator etc.

Although most of the regulatory reforms have been widely appreciated by Indian and international stakeholders, some have generated strong debate amongst the scientists, academicians and pharmaceutical industry.

The issues that need to be addressed and require immediate attention of felt overcorrection are-compensation in case of clinical trial injury due to ineffectiveness of placebo, ineffectiveness of investigational drug under trial, negligence by investigator, logistic difficulties in audio-visual recording of informed consent in many situations, restriction of permissible trial numbers to three even in cases where the enrolment may be less or the trial may be of minimal risk.

Therefore, there is an urgent need to build a strong framework for regulatory science with new tools, standards and approaches to enable efficient and consistent assessment of safety, efficacy, quality and performance of products without impacting the research environment adversely. Several efforts are being made using State-of-the-art science and technology to ensure complete safety.

Indian Pharmacological Society is one of the oldest and largest professional bodies affiliated to INSA-ICSU, a Member Society in IUPHAR, which is making all attempts to understand the demands of the society and develop an atmosphere, that is conducive to promote good health among population without disturbing the environmental balance.

We are proud that Dr. Ranjit Roy Chaudhury, a well-known Clinical Pharmacologist and the Chairman of the Expert Committee to formulate policy guidelines, SOPs for approval of new drugs and clinical trials in India has been a committed votary of reforms in drug regulation and clinical trials.

The mass media, especially ‘The Hindu’ deserves appreciation for their role in taking up the onerous task of updating information on various topics of current debate. These are of great interest to the industry and are important for creating awareness among the members of civil society on contributions of scientists, regulatory agencies and others in developing effective as well as safe drugs while adhering to Good Clinical Practices.

Acknowledgment

On behalf of “India Pharmacology – Initiative Program’ of IPS, we acknowledge “The Hindu’ for permitting us to reproduce the article published on October 8, 2014 titled “a steel frame for clinical trials” by Prof. Ranjit Roy Chaudhury and Dr. Arghya Sengupta.

Footnotes

Source of Support: Nil.

Conflict of Interest: No.

Indian J Pharmacol. 2014 Nov-Dec;46(6):575–578.

A steel frame for clinical trials: Source: ‘The Hindu’ 8th October, 2014

The regulatory framework on clinical trials needs a coherent set of stand-alone rules. This will not only ensure adherence to the principles laid down by the Supreme Court but also give impetus to the clinical trials industry in India, currently languishing due to an uncertain regulatory environment.

In recent months, the quest for a safer, more transparent clinical trials regime has found new momentum. Fourteen notifications in July 2014, governing various aspects pertaining to a clinical trial — ranging from placebo-controlled trials to compensation awards — have been notified. Further, the Central Drugs Standard Control Organization (CDSCO) has proposed a forward-looking IT-enabled information system that will ensure transparency and protect the interests of trial subjects.

These developments are important steps for the clinical trials regime in India to satisfy the three principles laid down by the Supreme Court for approving trials — assessment of risk versus benefit to patients, need for innovation vis-à-vis existing therapeutic option and the unmet medical needs in the country. But for satisfying these standards, much more remains to be done. The entire regulatory framework pertaining to clinical trials needs to be overhauled and a clear, coherent and succinct set of stand-alone rules needs to be introduced for this purpose. This will not only ensure adherence to the principles laid down by the Supreme Court but also give impetus to the clinical trials industry in India, currently languishing due to an uncertain regulatory environment.

Accreditation and ethics

There are three key changes that are essential if the clinical trials regime in India is to be put on a firm foundation — instituting a structured accreditation process accrediting investigators, trial sites and ethics committees, making ethics committees function effectively and ensuring diligent adherence to guidelines concerning informed consent from trial subjects. Each of these three aspects has been studied closely by the committee headed by one of us, the Ranjit Roy Chaudhury Committee, with detailed recommendations provided.

Accreditation must become the centrepiece of a new clinical trials regime founded on the principle of patient safety. Accreditation ensures adherence to certain quality standards thereby instilling confidence not only in patients who will be trial subjects but equally in the industry, which is responsible for conducting the trials. Thus, principal investigators of trials should be accredited depending on their qualifications, experience and training; trial sites should be accredited on the basis of infrastructure, personnel and systems; finally, institute ethics committees must be accredited keeping in mind the experience of their members and the standard operating processes for review which are used. Guidelines in this regard have been prepared recently by an expert committee; these must be implemented post-haste. If this is done, India would be the first country anywhere in the world to institute such a structured process of accreditation.

Conflicts of interest and consent

Accreditation of ethics committees is an especially central element towards making such committees effective custodians of the safety and probity of all clinical trials. Several cases of casualties in clinical trials have emerged in the past few years, where compliance with standard operating processes were shoddy or such processes themselves were absent. In an Indian Council of Medical Research (ICMR) publication, the independence of ethics committees and conflict of interest questions were highlighted. To correct this, it is not only essential that ethics committees are accredited but also develop standard operating procedures that are capable of effective implementation. To follow such procedures, members of ethics committees need to undergo high-quality mandatory training. This requires a combination of men and women of wisdom and experience and training protocols that are succinct and geared towards ensuring safe and effective trials where all norms are strictly followed.

A key positive spin-off of accredited ethics committees would be to prevent conflicts of interest. The Ranjit Roy Chaudhury Expert Committee Report pointed out gross malpractices and unscrupulous decisions in clinical trials caused owing to ethics committee members having an interest in the trial itself. To offset this, a key facet of accreditation would be a strict adherence to finding independent persons to serve on ethics committees. This can be achieved by a combination of randomised allocation of experts to particular ethics committees together with a supplementary check by the accrediting body. A hybrid process, part-automatic with a supplementary human element, would not only ensure independence of the ethics committee in fact, but also create a positive perception of such independence in the minds of trial subjects.

Such a positive perception of the independence of ethics committees, it is believed, would become a key facet of securing informed consent of trial subjects. The need for informed consent was a key norm that was recently found by the United States Office for Human Research Protections (OHRP) to be flouted in a cervical cancer study funded by the U.S. National Cancer Institute and the Bill & Melinda Gates Foundation. Till April 2014, 254 women in unscreened control groups in these trials have died. The OHRP determined that insufficient information was provided in order for these and other women to give informed consent to participate in the trial.

Towards a new order

Culpability in this matter is still an open question that might require judicial intervention. However, at this stage, it is clear that the episode demonstrates the lack of effective protocols to ensure that informed consent is truly on the basis of relevant information and the lack of clear methods to ascertain the taking of such consent. This has been partially offset by CDSCO which issued draft guidelines earlier this year on audio-visual recording of informed consent process in clinical trial. This mandates audio-visual recording and safe storage of the taking of informed consent from trial subjects. This is a welcome move. However it is imperative to keep in mind the privacy of patients who might not wish to be recorded. Thus, it is recommended that such recording should be mandatory subject only to waiver by the trial patient or the ethics committee, keeping in mind the equally significant principle of patient privacy.

Not only is the substance of the changes mentioned significant, but equally the form it takes. Best practices worldwide demonstrate that having a succinct, stand-alone set of rules governing clinical trials promotes transparency and increases certainty. Currently, the legal architecture governing clinical trials is complex with several facets governed by the Drugs and Cosmetics Rules, 1945, a slew of notifications there under, and some facets regulated by the proposed Drugs and Cosmetics (Amendment) Bill, 2013, pending in the Rajya Sabha.

It is essential that the recommended reforms together with any other changes proposed by CDSCO are brought under a consolidated umbrella of rules governing clinical trials. This will give the clinical trials industry the necessary certainty to undertake trials in India with confidence. The benefits for India — in terms of development of new drugs, employment generation in the clinical trials industry and ensuring a safe environment for its citizens desirous of participating in clinical trials — would be tremendous. Most crucially, it would demonstrate the seriousness that the government attaches to effective public health systems and scientific progress, two goals of a well-functioning clinical trials regime that must also become the pillars on which modern India is built.

Prof. Ranjit Roy Chaudhury

National Professor of Pharmacology (NAMS)

Chairman of the Expert Committee to formulate policy, Guidelines,

SOPs for approval of new drugs and clinical trials and banning of drugs, New Delhi

Email: ranjitroychaudhury@gmail.com

&

Dr. Arghya Sengupta

Research Director

Vidhi Centre For Legal Policy

New Delhi, Email: arghya.sengupta@vidhilegalpolicy.in

Articles from Indian Journal of Pharmacology are provided here courtesy of Wolters Kluwer -- Medknow Publications

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