Global Perspective India The Future Clinical-Trials Destination India is, at the moment, a preferred destination for clinical research because of its huge, heterogeneous patient population; its English-speaking, Western educated investigators (physicians); a track record of sincerity in meeting regulatory and recruitment timelines; and, most importantly, well-accepted, good quality, auditable data. The Global Perspective Just a few years ago, Eastern Europe was the preferred destination for clinical research because of the low-cost and fast-recruitment potential it offered. But a sharp rise in costs in the area, stemming from fierce competition among sponsors and CROs, and increased expectations of clinical-research professionals has led companies to look for other clinical-research destinations. Today, major European and U.S. pharmaceutical companies are looking seriously at Asian and African countries to speed their drug-development processes. Over the past few years, India has proved to offer advantages over other Asian countries, as well as African nations, because of its huge, heterogeneous patient population; English-speaking, Western-educated investigators (physicians); track record of sincerity in meeting regulatory and recruitment timelines; and, most importantly well-accepted, good quality, auditable data. Cost-effectiveness, competition, and greater confidence in the quality of India’s clinical-trial procedures have propelled many global pharmaceutical players — Pfizer, Novartis, AstraZeneca, Eli Lilly, GlaxoSmithKline, Aventis, Novo Nordisk, and so on — to expand their own clinical-research investments and infrastructures in India. According to research-service firms such as Ernst & Young, McKinsey, Strategic Associates, and others, while global pharmaceutical companies and CROs are opening up branches in the country, small biotech, pharmaceutical, and R&D companies are looking for preferred partners to conduct their research activities in India. While these companies are highly enthusiastic about carrying out high-quality research in India, they still have a list of concerns aside from the distance and time difference. These include disease prevalence patterns (see box on this page), resources and infrastructures, regulatory frameworks and guidelines, regulatory protection of intellectual property and patents, and audit and inspection of clinical studies. The Infrastructure India has 14,000 general hospitals, of which about 150 have served as sites for clinical trials in recent years. Most studies are conducted in medical colleges and hospitals, though others are carried out in private hospitals and clinics. Most of these hospitals have state-of-the-art infrastructures and instruments to perform the rigorous tests and procedures necessary for a clinical trial. The personnel also are in place. There are 600,000 physicians practicing in these hospitals and clinics, and more continue to graduate. For example, the Medical Council of India awards 75 postgraduate degrees per year in cardiology, 62 in neurology, and 21 in oncology. In super-specialty areas, there are about 2,000 psychiatrists, 500 neurologists, 500 oncologists, and 400 diabetologists. Many of the physicians and specialists are motivated to be part of international studies. The standards of treatment and healthcare practices in India are lauded by the global medical fraternity, which takes into account the capabilities, knowledge level, high-quality research papers, and Western education of these investigators, as well as their English skills. Additionally, there are a few central laboratories in India that have national and international accreditation. The Regulatory Framework India started its voyage into global good clinical practice (GCP) trials in the last decade, when the country had no clear-cut regulatory guidelines. Because of pressure from the industry and proactive initiatives of the regulators, the Central Ethics Committee on Human Research (CECHR) of the Indian Council of Medical Research (ICMR), New Delhi, issued Ethical Guidelines for Biomedical Research on Human Subjects in 2000. In 2001, a committee was set up by the Central Drugs Standard Control Organization (CDSCO) to develop Indian GCP guidelines in line with the latest guidelines from the World Health Organization (WHO), International Conference on Harmonization (ICH), U.S. Food and Drug Administration (FDA), and Modern Humanities Research Association (MHRA). There have been other proactive government policies in recent times, such as a revised Schedule Y to allow concurrent trials, a patent act that started in January 2005, stringent regulations to deal with spurious drug manufacturers, and mandatory GMP compliance to further support clinical-development initiatives. For new drug substances discovered in India, clinical trials are required to be carried out in India from Phase I, and data should be submitted to the licensing authority, the Drugs Controller General of India (DCGI). For new drug substances discovered in countries other than India, Phase I data from other countries should be submitted along with the application. After submission of Phase I data to the licensing authority, permission may be granted to conduct Phase II trials and subsequently Phase III trials with other global trials for that drug. Phase III trials are required to be conducted in India before permission is granted to market the drug in India. The Indian regulatory framework allows concurrent submissions of applications for regulatory and ethics committee (EC) approvals. Clinical trials on a new drug are initiated only after the licensing authority has granted permission and the approval has been obtained from the respective ethics committee(s) of the site(s). Application for permission to undertake clinical trials is made in Form 44, and data specified in Appendices of the Schedule Y (amended in 2005) of the Drugs and Cosmetics Act, 1940, are to be submitted to the DCGI along with the application for import of new drugs. The DCGI’s office takes eight to 12 weeks to provide the approval for the conduct of clinical trials in India. Concurrently, the essential documents, including translation of informed consent forms and patient information sheets, are submitted to the institutional EC. Most institutional ECs meet once a month and require the documents to be submitted one week before the meetings. The EC approval letter is issued within one week of the meeting. There are a few centralized ECs in India, and most investigators prefer to have the EC approval from their institutional EC, unless the study is done in a private clinic, in which case the investigators go to the centralized EC. The Schedule Y allows the site(s) to accept the approval granted to the protocol by the EC of another trial site or the approval is granted by an independent EC, provided that the approving EC(s) is/are willing to accept responsibilities for the study at such trial site(s) and the trial site(s) is/are willing to accept such an arrangement and that the protocol version is the same at all trial sites. An application for importing drugs (investigational products, comparators, placebo, etc.) must be made concurrently with the regulatory permission letter to DCGI. The application needs to be made in Form 12 of the Drugs & Cosmetic Rules, 1945. The application should give a detailed calculation of the quantity of drugs required for the study and from which country these drugs are to be imported. The DCGI issues a test license (popularly known as a T license) in Form 11 of the Drugs and Cosmetic Rules for the import of drugs. Since this application is made concurrently, the T license is obtained along with the permission for the clinical trial. Drugs cannot be imported without DCGI approval and the T license, which is valid for one year. Similarly, if the study demands the export of human biological specimens, for example tissues or blood, to a laboratory outside India, an application in Form 16 giving the detailed justification of the quantity of specimens to be exported and with a declaration from the laboratory stating that the specimens will not be used for genetic testing, must be submitted to the Director General of Foreign Trade, (DGFT) New Delhi. DGFT issues export permission only after obtaining a copy of the DCGI permission and this may take an additional two to four weeks after clinical-trial permission. Intellectual Property/Patents In January 2005, the Indian government issued an ordinance amending the Patent Act, 1970, to make it compliant with the Trade Related Intellectual Property Rights (TRIPS) under the World Trade Organization (WTO) mandated product patent regime. As a signatory to TRIPS and WTO, India has moved from an era of process patent to product patent regime. This commitment by the Indian government has changed the business environment, increased R&D initiatives by both local and global companies, and encouraged investment by global companies. India has positioned itself as a global R&D and manufacturing hub, which attracts global investment because of lower-cost manufacturing that is supported by adequate regulatory protection of intellectual property (IP). India’s success in attracting global companies can be attributed to the number of patents filed with the FDA in recent years. India has filed 126 DMFs with the FDA, accounting for 20% of all drugs coming into the U.S. market. Of the 108 abbreviated new drug applications (ANDAs) pending approval from the FDA in February 2004, as many as 52 were patent challenges, and nearly half of these were for first to file (180 days market exclusivity). The large success of Indian generic pharmaceutical companies is thanks to their capabilities in the manufacturing and process chemistry business. Hence, many global companies have decided to source their bulk requirements from India and outsource their manufacturing to local companies. By embracing IP protection and amending the patent act to accommodate product patents rather than process patents, India has witnessed growth in foreign direct investment and increased R&D. The enforcement of this robust patent protection system is a positive step for multinational companies to tap the Indian market without fear of their products being copied. Audits and Inspection India has conducted many global, multicenter clinical trials in the past eight to 10 years. Although there are not many FDA audits or regulatory inspections to substantiate the quality of data, there are several mock audits and quality assurance audits being carried out by the sponsors in each of these global studies. The reports about data quality, integrity, and accuracy from assurance auditors and/or the third-party independent auditors are positive. PharmaVOICE welcomes comments about this article. E-mail us at [email protected]. Dr. Umakanta Sahoo Umakanta Sahoo, Ph.D., MBA, General Manager, Chiltern International Private Ltd., India, has experience working with global CROs and has monitored and managed several studies in India. Dr. Sahoo discusses the expectations of the global fraternity and addresses many common questions regarding disease prevalence patterns, resources and infrastructures, regulatory frameworks and guidelines, regulatory protection of intellectual property and patents, and audit and inspection of clinical studies. For more information, Dr. Sahoo can be reached at [email protected], or visit chiltern.com. The Prevalence of Diseases in India; Realistic Recruitment practices India is a vast country with a population of more than 1 billion. Based on prevalence/incidence rates, there are estimated to be 2 million to 2.5 million cancer patients, more than 35 million cardiac patients, 30 million to 35 million diabetic patients, and 3.8 million to 4.5 million HIV/AIDS patients. There also are huge numbers of patients in all other therapeutic areas. Past experience of many global, multicenter Phase II and Phase III studies suggests that most trials in India have the potential to recruit four to five times more patients, at a faster rate, than any center in Europe or the United States. Even some of the difficult diseases in the oncology area could recruit 200 patients in a two-year recruitment frame or faster, and from fewer than 10 centers. This recruitment is possible through referral networks and without any outreach campaigns and advertisements. July 2005 Cost Advantages There are several estimates of cost advantage — ranging from 40% to 60% — for doing trials in India compared with western countries. Although cost is one of the important deciding factors, just as important is the quality of services. The major indirect cost advantage is patient recruitment, which is four to five times faster than the rate of recruitment in the United States and Europe in any therapeutic area. The cost of treatment, including the tests and procedures, may be 40% to 50% less than the comparative cost in the United States and Europe. The cost of skilled labor in India is very low in comparison. A clinical-trial monitor typically earns about 10% to 15% of his or her U.S./European counterpart. While it is certain that there will be savings in per-patients-cost because of fast recruitment and the low cost of tests and procedures, the cost savings may vary. For example, if the sponsor wishes to use the services of a global service provider such as World Courier, the cost of the service in India may be low, but may not be 40% to 50% less in comparison to western countries. Similarly, CRO fees are dependent on many factors, including the cost of the skilled employees and the other overhead needed to create and maintain a global standard infrastructure, such as broadband connectivity, access control, adequate working space, ambient working environment for monitors, and so on. And there are important variants such as increased air travel cost and more travel time as most of the sites are geographically spread out in diverse locations. Overall, however, cost savings can be generated.

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