Paradigm Shift in Clinical Trial Regulations in India

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the conduct of clinical studies are predicted to bring a paradigm shift in the overall regulatory ... surfaced pointing at poor enforcement of clinical trial (CT).

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Review Article

Paradigm Shift in Clinical Trial Regulations in India Sandeep Lahiry, Rajasree Sinha1, Shouvik Choudhury, Ayan Mukherjee, Suparna Chatterjee Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 1Department of Pediatrics, Medical College and Hospital, Kolkata, West Bengal, India Received: September, 2017 Accepted: November, 2017 Published: February, 2018

Address for correspondence: Prof. Suparna Chatterjee, Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244 A. J. C. Bose Road, Kolkata ‑ 700 020, West Bengal, India. E‑mail: [email protected]

Abstract India has the potential to contribute meaningfully to global clinical drug development. A  critical enabler to achieve this potential is a balanced, predictable, and scientifically robust regulation involving clinical studies. In the past few years, the country’s regulatory milieu has witnessed a positive transformation to favour ethical conduct of clinical trials, while appropriately supporting patient safety. Numerous amendments to existing policies governing the conduct of clinical studies are predicted to bring a paradigm shift in the overall regulatory scenario. In such view, it is important for us as academicians, to be abreast of such changes. We, therefore, discuss major regulatory highlights involving clinical research in India. Key Words: Clinical trials, guidelines, India, regulatory environment

Introduction Over the last few years, a slew of legal litigations have surfaced pointing at poor enforcement of clinical trial  (CT) regulations in India. Specifically, irregularities in reporting of CT‑related data and violations of ethical guidelines have highlighted the need for amendments to existing regulations. Moreover, there were unnecessary delays in study protocol approvals (usually 6-7 months) which often lead to huge financial losses, particularly in the pharmaceutical sector, causing major investors to shy away from Indian markets. There was a need to bring in major overhauls to existing regulations, therefore; Government of India has recently brought several amendments in Schedule Y of Drugs and Cosmetics Act  (1940), to address such issues. Timeline of such key regulatory changes has been summarized in Table 1.

Approval process To cater to the problem of unnecessary time lag in the approval process of CTs in India, starting February 2013, a “three‑tier” review process has been implemented, wherein CT applications will now be reviewed by the “technical committee” followed by the “apex committee,” after an initial approval from a “subject expert committee”  (SEC). Only on receipt of approval in all three stages, final approval will be granted by the Drug Controller Access this article online Website:

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General of India (DCGI). This new system will ensure faster dispensation of protocol approvals since previously it used to take 6–7  months for the DCGI office to arrive at an informed decision. Since August 2014, there exist nearly 25 panels of SECs across various therapeutic domains.[1]

Clinical trial‑related injury Any Injury or death due of a subject to following reasons is considered as “clinical trial related injury,” (i) adverse effect arising out of usage of an investigational product(s); (ii) violation of approved protocol, scientific misconduct, negligence by the sponsor or investigator; or in case  (iii) failure of investigational product to provide intended therapeutic effect where standard care, though available, was not provided to the participant as per CT protocol; or  (iv) use of “placebo” in a placebo‑controlled trial, where standard care, though available, was not provided to the participant as per CT protocol;  (v) adverse effect due to concomitant medication excluding standard care, necessitated as part of approved protocol; (vi) injury to a child in utero for participation of parent in CT; or  (vii) any CT‑related procedures. In case of CT related injury or death, the participant or nominee is entitled to compensation.

Causality assessment of adverse events Assessment of causality or relatedness of an adverse event  (AE) due to a suspect medication(s) is commonly This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited and the new creations are licensed under the identical terms. For reprints contact: [email protected]

DOI: 10.4103/injr.injr_110_17


How to cite this article: Lahiry S, Sinha R, Choudhury S, Mukherjee A, Chatterjee S. Paradigm shift in clinical trial regulations in India. Indian J Rheumatol 2018;13:51-5.

© 2018 Indian Journal of Rheumatology | Published by Wolters Kluwer - Medknow

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Table 1: Timeline of important regulatory changes involving clinical studies in India GSR/notification with date SO 1468 (E); September 06, 2005 GSR 53 (E); January 30, 2013

Amendment/gazette notification/regulation Devices such as cardiac stents, heart valves, intravenous cannulas, catheters, orthopedic implants, and internal prosthetic replacements specified as “drugs” Introduction of “compensation” for clinical trial‑related injury or death

GSR 63 (E); February 01, 2013

Introduction of SAE analysis and timelines for reporting SAEs Requirement conditions for conduct of clinical trials

GSR 72 (E); February 08, 2013 File No GCT/20/SC/ClinJ2013 DCGI; November 19, 2013 File no 12‑01/14‑DC Pt 47; July 03, 2014

File no. ECR/Misc/Indt.EC/007/2013; July 30, 2017 GSR 889 (E); December 12, 2014 GSR 611 (E); July 31, 2015 GSR 313 (E); March 16, 2016 File 12‑01/14‑Pt 47; August 02, 2016

Introduction of clinical trial inspections and actions in case of noncompliance Registration of ECs with DCGI made mandatory Introduction of AV recording of informed consent process of clinical trials Clinical trial waiver for approval of new drugs already approved outside India specified under certain conditions ‑ national emergency, extreme urgency, epidemic and orphan drugs and drugs indicated for diseases in which no therapy exists Independent ECs registered by CDSCO to oversee BA/BE studies only Clarification regarding compensation in case of trial‑related injury Change in timelines for SAE reporting Modification and relaxation of AV consenting norms ‑ for “vulnerable” populations only and where a “NCE” or “NME” is being studied A “new” drug undergoing a clinical trial for IIS no longer needs approval from the DCGI. Approval from the IEC would suffice The only three trials per investigator norm revoked

The condition that trials could not be conducted at sites with2000 ECs have been registered in India, and the number is ever increasing.[6,7] However, as per the recent DCGI notification, CDSCO registered independent ECs can now give clearance for bioavailability/ 52

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bioequivalence (BA/BE) studies only.[8] In other words, it mandates all institutions to have a registered IEC in order to conduct and oversee clinical studies.

ECs of the country are now primarily responsible for recommending the compensation for any trial‑related death/injury; thus, it is pertinent that the cause‑effect relationship of the investigational product and AE is established. The EC’s opinion to the expert committee or DCGI is only in the form of 'related' or 'unrelated'. Latter applies when it is definitely judged that there is no possibility of the trial intervention/procedure of having contributed to the event.

2. SAE causing permanent disability In case of 100% disability, the quantum is fixed at 90% of the amount which would be due for payment in case of death of the individual.[13,14] In case of