Chirag Shah

	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

Articles

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.

Regulatory Approval in India: An Updated Review

	In developing a clinical trial program, the need to include global sites is necessary, as are the subsequent study feasibility tasks. The current regulatory environment of a particular country plays an important role in the geographic selection. For India, it is very relevant because of problems in clinical trials approval and conduct issues during last few years. However, there have been some changes made to that country’s trial review process to make it more streamlined, which is allowing quicker trial approvals.

	This article will highlight our experience performing study feasibilities in India. A detailed feasibility study is critical for the planning and conducting of successful large-scale global clinical trials. Increasingly, study sponsors and contract research organizations (CROs) are recognizing the value of performing a comprehensive feasibility assessment in mitigating risks involved with a clinical trial.

	A feasibility study helps to promote better trial design and study execution, thus ensuring that trials avoid unnecessary delays by identifying the potential investigator, meeting their planned schedules and patient recruitment targets.

	When performed well, sponsors and CROs have found that a feasibility study is invaluable in contributing to the success of a clinical trial and produces many significant benefits when finding that just-right clinical site. Poor site selection can be considered a key reason of clinical trials completed late; and eventually become costly in terms of resource and time allocation.

	In global feasibility, India has many benefits. The country has a large population, with high numbers of patients with many diseases such as hypertension, diabetes, cardiovascular disease, as well as many types of cancers and rare diseases. Additionally, many patients are treatment naïve or newly identified. These facts release the main pressure of patient recruitment, where the only effort left is to find the right site.

	The main attributes for India also include 2,000 GCP-trained investigators, who have conducted structured research. More and more sites, including medical institutes and hospitals, have strengthened their policies to accept research proposals. There are increasing numbers of trained clinical research professionals contributing to the development of this industry and growing clinical research environment.

Conducting a successful feasibility study  

	Many times, pharmaceutical sponsors look to use the expertise of CROs in conducting the initial feasibility for their project at global level. In our experience, when sponsors perform feasibility on their own, there can be a high possibility of potential bias with the particular site. There can be a persuasion from the other cross-functioning departments, such as marketing, who are in direct contact with a particular investigator.

	CROs can help provide those unbiased and objective feasibility assessments ranging from exploratory country specific data relevant to the therapeutic area through to detailed protocol and site information. 

	We recommend a dedicated team of persons from different backgrounds and expertise are involved in planning and conducting a detailed feasibility study. The first prerequisite of such a team is the detail understanding of the particular therapeutic area, disease modality, available epidemiological data and information related to ongoing competitive studies in a country or region. It can be beneficial to include experienced managers from project management, clinical monitoring and medical affairs who can underpin both unrivalled feasibility and operational risk assessments.

	In general, feasibility starts with the review of protocol in consultation with medical experts; and they would be able to check if the proposed study is rational-scientifically as well as ethically. The core idea of the study design and the related requirement should be propagated to the feasibility team. The operations team, then, would be able to gather those challenges, sort out possible solutions. The regulatory team is responsible for identifying the regulatory aspects. This would help to decide the scope and extent of the feasibility study and design a step wise process and documents to carry out the task.

	It is advisable to have a database or a repository of clinical investigators, which can help to shortlist few potential investigators. Here the past performance of the site and track record must be examined, if available. The sites must be differentiated on the need basis, and one must be careful in selecting the site that has representation of a Key Opinion Leader (KOL) in a particular therapeutic area, and also have stringent research policy e.g., major academic institutes. Before short listing a renowned KOL for the study, his or her time and interest must be evaluated. Although investigators can claim to recruit high numbers, the investigator’s capacity to perform the trial with the available resources and staff must be weighted.

	An initial phone discussion is the first and simplest way to get in touch with the investigators to ask them the right questions related to study. This conversation can be a good point to check for the investigator’s interest, as well as provide further information.

	In most of the cases, investigators are too busy to answer every specific details over the phone, although, a short discussion can be a source of valuable information. This certainly helps having an establish rapport, when there is a paucity of time. This initial discussion with the investigator can provide vital information on the possibility of conducting the study at sites. It can also serve as a quick epidemiological survey, which can give better approximation on subject accruals.

	The most important tool for the feasibility is a well-designed Feasibility Questioner Form (FQF). A FQF is an assessment of clinical trial site’s potential for patient recruitment. Sites are sent a brief protocol synopsis of the proposed trial and requested to answer various questions relating to the site’s clinical trial experience, its facilities, previous experience with recruiting for a particular therapeutic area, and its ability to access the required patient population. Based on these feasibilities, sites are chosen to participate in the proposed trial.

	An investigator’s team should be provided with the basic information in order to have an overall requirement of the study. FQF itself should be able to provide sufficient information about the study and the requirements to get realistic data about the site’s capability.

	Following essential information should be provided:

		Medication / Treatment provided to the subjects, including the placebo.

		Any other specific details (e.g. hospitalization, repeated blood sampling etc).

	The feasibility response will help to differentiate a site for an actual site selection visit. The response must be thoroughly assessed in order to comprehend and devise the true picture of the site, to assess the patient population and estimation of enrolment based on the inclusion and exclusion criteria. One should also check the staff availability, ethics committee details and site infrastructure. It can serve as a comprehensive validation tool.

	Another rule of thumb in feasibility is to generally select 60%-70% of sites with whom the CRO/sponsor team should have prior working experience. One of the most important aspects is the professional working relationships with such investigators that will help to get faster and clear responses.

	There are cases, where it was imperative to identify new sites in a new geographical area, depending on the expertise of investigators. These investigators, when selected and adequate training is provided, can perform very well.

A Success story of Gastroenterology study feasibility

	There is a wide variation in the prevalence of the peptic ulcer disease in India. One sponsor wanted to perform the clinical trial for their established generic drug for active Duodenal Ulcer as a monotherapy. The preliminary discussion with Indian gastroenterologists concluded that due to availability of the better drugs and formulations, the majority of clinicians were reluctant to use it as a monotherapy.

	Having many negative responses from the senior clinicians, the entire team was challenged to dig deeper into the reasons for it. The feasibility team modified the questionnaire based on the responses received from the investigators and regulatory guidelines, mainly related to the size of the ulcer. It means, based on the pathology of disease, the entire focus was made on the patient population having a specific size of ulcer, which can be considered for the study. The team decided to do the thorough discussion with prospective investigators, based on the new insights. Ultimately, the team was successful by not only getting accurate information from investigators on estimation of patients, but also convincing them about their participation in the study. Most of them have agreed to enroll the required number of patients in stipulated time.

	This example can substantiate how important it is to combine practical insights with the scientific information in a clinical trial.

	In clinical trials, the recruitment of right patient at right time is the most important factor for success. The selection of investigators to meet this objective can be difficult at times. Performing a thorough feasibility provides benefits throughout the course of the clinical research program. It can be inferred that feasibility is not just a ‘nice to have’ process, but an essential step to climb the ladder of project success. India, as a country with a large population, experienced number of clinical investigators, and their preference about particular class of drug/molecule also varies. This enables sponsors to have a variety of options available for their feasibility in particular area.  Hence, including India as part of the global clinical trials to achieve the timelines and better quality outcomes is helpful.

		Harper B., Zuckerman D. Critical Success Factors for Planning for Site Selection and Patient Recruitment Planning; 

BioExecutive International 2(6):S16-28, June 2006

		Non-communicable diseases in India; WHO India data, available at: 

http://www.who.int/nmh/countries/ind_en.pdf (accessed on Oct 13)

		Strengthening Clinical Research in India;  

		Harper B. Validate a Site’s Ability to Conduct a Study. 

	Fig. 1: A general approach of performing the study feasibility.

, is Clinical Team Leader at Cliantha Research Ltd, India. 

, is Head and General Manager – Clinical Trials, Cliantha Research Ltd, Ahmedabad, India. His email: 

The current regulatory environment of a particular country plays an important role in the geographic selection. For India, it is very relevant because of problems in clinical trials approval and conduct issues during last few years.

Chirag Shah

Articles

Regulatory Approval in India: An Updated Review

Role of India in Global Clinical Trial Feasibility