Param Dave, MPharm

	The drug approval process in India has faced challenges in recent years, some around compulsory licensing of patents, government price control and narrow standards for patentability. Other issues have also occurred in the clinical trials area, which, despite India’s high treatment-naïve population and emerging economy, have reduced pharmaceutical sponsors’ interest in India as a priority area in which to conduct clinical studies. 

	A cursory overview of the Indian drug regulatory process is as follows:

	Currently, the Drug Controller General of India (DCGI) requires a confirmatory Phase III study that includes a proportion of local patients, although if Indians are included in multinational trials this can be avoided and decided on a case-by-case basis. The Central Drug Standard Control Organization (CDSCO) handles the approval process. Apart from the CDSCO approval, DCGI has given rights to each state’s drug control authority to regulate the manufacture, sale and distribution of drugs. The states include North India: Jammu and Kashmir, Himachal Pradesh, Uttaranchal, Haryana, Panjab; South India: Kerala, Tamilnadu, Karnataka, Andhrapradesh; East India: West Bengal, Assam, Arunachal Pradesh, Nagaland, Manipur, Mizoram,Tripura, Jharkhand, Bihar, Orrisa; West India: Gujarat, Rajasthan, Maharashtra; and Middle India: Madhya Pradesh, Chhattisgarh. However, final authority does rest with DCGI.

	As noted above, challenges emerged between 2011-2013, when the Supreme Court of India had asked for several justifications from the Health Ministry around the conduct and continuance of clinical trials in India after a series of troubling events. The first occurred when a principal investigator was found to have generated fraudulent data and referring patients from a government hospital where he was working, to his private clinic to gain more income. 

	Meanwhile, amendments to clinical trial regulations under the Drugs and Cosmetics Rules (Third Amendment) were introduced in February 2013. The objective was to improve patient safety, reporting timeliness of serious adverse events including deaths during clinical trials, and the payment of compensation to patients. The amendment resulted in several concerns for researchers and research organizations around the areas of financial compensation and liability of the trial researchers. 

	Because of these changes to the regulatory framework, many multinationals withdrew their clinical studies from India. This resulted in a standstill for the entire clinical research industry in India.

Regulatory Stance to Eliminate the Bottle Neck

	The Health Ministry and stakeholders-including sponsors, CROs, investigators, and the regulatory agency-made a concentrated effort to address the concerns and formed a Subject Experts Committee (SEC, formally known as New Drugs Advisory Committee), Technical Committee and Apex Committee to examine applications for clinical trials in India. All of the studies approved by the DCGI were then evaluated and approved by these committees prior to commencement.

	The Technical and Apex Committees consist of experts like SEC, however, each acts on the recommendations received from the SECs. The committees review the protocol application and further passes its recommendations to the DCGI. Basically, the SEC acts as a gateway in the clinical trial approval process by advising the DCGI in the following matters:

		To undertake in-depth evaluation of non-clinical data, including pharmacological toxicological data, clinical trial data (Phase I, II, III, and IV) furnished by the applicant for approval of new drug substances of chemical and biological origin, global clinical trials, fixed-dose combinations and those of two or more drugs.

		Defining roadmap for research industry for appropriate development of new drugs relevant to Indian population.

	The Committees formed are Anesthetics and Rheumatology, Antimicrobial-Antiparasitic-Antifungal-Antiviral, Cardiovascular and Renal, Dermatology and Allergy, Gastroenterology and Hepatology, Metabolism and Endocrinology, Neurology and Psychiatry, Oncology and Hematology, Ophthalmology, Pulmonary, Reproductive and Urology and Vaccines.

	The SEC Committees in oncology and hematology, for example, had been conducting meetings several times a year between 2011 to 2014. However, the functioning and proceedings of meetings were not satisfactory to all the stake holders, so the ministry of health has taken efforts to streamline and increase the number of meetings, in addition to separating out the oncology and hematology therapeutic areas. As a result, in 2014, 31 SEC meetings were conducted and in 2015, 92 SEC meetings were held.

	The number of drug approvals also increased in 2015 after three-tier reviews based on the cases. Analyzing this, we can say that scenario of clinical trial approval has improved by DCGI as compared to 2014 and earlier.

	The DCGI suggests that reviewing and approval timelines for all types of applications in consultation with SEC be 180 days. CDSCO has issued a checklist (link checklist to 

http://www.cdsco.nic.in/forms/list.aspx?lid=2053&Id=3

) for various categories such as bioavailability and Bioequivalence (BA/BE), global clinical trial of all phases, subsequent new drugs (SND), new drug, medical device and test license application. 

	Another regulatory concern in India was in regard to compensation in cases of trial-related injury or death. As noted earlier, the Third Amendment provided free medical treatment to these patients by sponsors irrespective of whether the impairment was related or not related to a clinical trial.

	However, this created a legal uproar among pharmaceutical companies and contract research organizations (CROs). An updated amendment, the Sixth Amendment, stated that “In case of injury occurring to the subject during the clinical trial, free medical management shall be given as long as required or until such time it is established that the injury is not related to the clinical trial, whichever is earlier.” It additionally stated, “In case, there is no permanent injury, the quantum of compensation shall be commensurate with the nature of the injury and loss of wages of the subjects.” The compensation formulas have been judiciously developed based on the Workman Compensation Act, and the industry has accepted this.

	Other corrective measures taken by the Health Ministry include the mandatory registration of ethics committees with DCGI; only institutional ethics committees can review and grant approval for the conduct of clinical studies at any site. It also changed the responsibility of reporting serious adverse events to the licensing authority from the sponsor to the investigator within 14 days. 

	Other possible changes are expected in the near future and include a restriction on investigators being able to conduct only three ongoing clinical studies at a given time. Another condition that may be changed is that of having at least 50 beds to allow sites to be selected based on availability of proper infrastructure along with the emergency facility.

	The removal of audio video consent of trial subjects (except for vulnerable population) and online submissions of clinical trial applications are also under review in India. The DCGI has already started the online application submission process for medical devices. This has not yet started for clinical trial submissions. 

	The updated guidance of conducting clinical trials in India (

http://www.cdsco.nic.in/writereaddata/cdsco-guidanceforindustry.pdf

) is steadily improving, as DCGI is committed to amend and upgrade the policies to encourage research in India. In recent years, Indian regulatory authorities have been quite aggressively working toward all fronts, with the goal of enhancing the quality and integrity of research through optimization of approval timelines. An implementation of online dossier submission by DCGI is a step toward reducing dossier review and approval timelines.

	Chirag Shah, PhD, PGDPM, is Associate Director & Head – Clinical Trials, Cliantha Research Ltd, Ahmedabad, India

	Param Dave, MPharm, is a Clinical Research Associate, Cliantha Research Ltd. He can be reached by email at pdave@cliantha.in 

	Authors would like to acknowledge the help of Mr. Ayan Neogi and Ms. Chandani Rajyaguru for support of compilation of regulatory details.  

		CDSCO (2010a) Central Drugs Standard Control Organization. Available from: 

http://www.cdsco.nic.in/writereaddata/Notificatiohn%20on%20		Compensation%20on%20clincial%20trial%20

		Krishnan V (2013) SC asks why got approved 162 global clinical trials in India. Available from: 

http://www.livemint.com/Politics/hFfKjL9PP51TKf6wEiYDcJ/SC-asks-why-government-approved-162-global-clinical-trials-i.html

		Mahapatra D (2013) SC orders video recording of clinical trials of new drugs. Available from: 

http://articles.timesofindia.indiatimes.com/2013-10-22/india/43287135_1_technical-committee-clinical-trials-apex-committee

		Sivaramakrishnan V, Bhide M (2013) A Comparative Analysis of Drug Lag in Emerging Markets. Available from: 

http://www.raps.org/focus-online/news/news-article-view/article/2947/a-comparative-analysis-of-drug-lag-in-emerging-markets.aspx 

		Major hurdles “cleared” for clinical trials in India: Experts. Available from: 

http://articles.economictimes.indiatimes.com/2015-07-23/news/64773370_1_clinical-trials-suneela-thatte-iscr

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Issues concerning the drug approval process in India have occurred in clinical studies resulting in a reduced interest from sponsors. The Drug Controller General of India (DCGI) has been working to amend and update it’s policies to stimulate growth in this sector.

Param Dave, MPharm

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