The Indian pharmaceutical industry is fourth largest in the world in terms of volume and production and 13th in terms of value of sales. India produces around 400 active pharmaceutical ingredients (APIs) and has largest number of FDA approved bulk drug and formulation manufacturing units outside the USA. In recent years, pharmaceutical market in India is booming with a steady growth rate at 10-15 per cent and currently stands at US $6 billion. It is estimated that the market size of Indian pharma industry may reach US $25 billion by 2010 with an average spending of 5-6 per cent on research and development (R & D). Approximately 30 per cent of total new Abbreviated New Drug Applications (ANDA) to US FDA filed in 2006 are by India.
Drug discovery & clinical development
Development of new drug involves two phases - drug discovery and drug development. The growth of an idea into a product may take over a decade of dedicated research by a team of researchers, including organic chemists, pharmacists, pharmacologists, toxicologists and clinicians. The first stage of drug discovery involves the identification of the target, drug designing and synthesis followed by its preliminary in vitro screening. With the advent of high throughput screening technology, the number of new chemical entities (NCE) that are being generated has tremendously increased. NCE undergoes drug development that involves determination of its safety, efficacy, kinetics and developing formulation. There are two overlapping phases of drug development that can be differentiated. They are preclinical and clinical phases.
Preclinical evaluation involves rigorous testing of efficacy and safety of the new molecule by various in vivo assays using animals. During this stage, the necessary data for evaluation in humans is generated and the test drug is ready for its last and most crucial stage of evaluation - clinical evaluation. The clinicians in co-ordination with the pharmacists evaluates the efficacy and safety of the sample over four stages starting from healthy volunteers and moving on to small group of patients and then larger number of patients and special groups. Phase I or clinical pharmacology forms the basis for clinical trial for any new drug and provides the link between pre-clinical and clinical research. Finally, the application for FDA review and approval may be applied and sought. The successful development of a drug from laboratory to market may take well over 15 years. Drug discovery is an investment of millions of dollars and the cost involved in the development of a successful drug has been steadily increasing from around US $200 million in early 90s to over US $800 million in the new millennium.
With escalating pressure on R&D and cost-containment across the global pharmaceutical industry, there is increased focus on reducing the cost of clinical development. In addition, the problem of delayed development is also affecting new drug introductions and incremental revenues. This dual challenge of accelerating clinical development and reducing costs has forced major pharma companies to look at alternative destinations for sourcing patients for their global studies. Thus, global pharma industry is trying to take interest in the countries like Latin America, Eastern Europe and Asia. In Asia, India stands out prominently due to its huge treatment-naive patient population, English speaking doctors and a large pharmaceutical presence that is dominating the world market with cheap generics.
Pharmaceutical companies find it increasingly difficult these days to recruit enough patients to test the drugs coming out of their laboratories. On average, more than 4000 patients are required for FDA to approve an experimental drug for marketing. However, only fewer than 5 per cent of patients in the US are willing to participate in clinical trials. As a result, 86 per cent of all US clinical studies fail to recruit the required number of patients and in turn trials get delayed on average by 366 days. The delay in launching the product leads to loss of million dollars a day. According to the report, the global outsourcing opportunity in pharmaceuticals, which was about $24 billion in 2002, was expected to climb to $48 billion by 2007.
Center Watch estimated that against a 2005 demand for 56,000 investigators, only 48,000 were available, a shortfall of 15 per cent. The great challenge is to get large number of quality professionals in medical and clinical research. This challenge can only be met by cooperative and collaborative efforts between industry, academia and government. Besides the manpower efforts, the training activity needs financial support.
Demand for manpower
It is certain that as the number of clinical projects expands, there will be a demand for qualified personnel in future. According to McKinsey report, the global clinical trial outsourcing opportunity in Indian pharmaceutical industry is estimated to be around US $2 billion by the year 2010 and there will be requirement of 50,000 clinical research (CR) professionals. Trained pharmacists and clinicians can fill this wide gap. They will be involved in the various aspects of clinical research, starting from site monitoring, site management, clinical data management, data analysis, report writing, report submission, presentation and publication.
In the field of CR, there is an imbalance between demand and supply with the scales tipping in favor of demand. Thus, the pharmaceutical houses are hunting for trained professionals and are using bulky pay packages to lure them.
ICRI - A CR hub
To meet the requirement of trained clinical research professionals, Institute of Clinical Research, India (ICRI), the only premier institute of its kind, has started training students and corporates according to international standards.
The objectives of ICRI are:
■ Manifestation of the thoughts and well executed plans of an elite group of professionals
■ To create a world class academic institution
■ To produce professionals for clinical research, clinical trial administration, regulatory affairs, medical marketing and data management
Advantage India
The duration of clinical trials can be greatly reduced in India. The huge and skilled manpower available in India could revolutionize the clinical trial field.
■ The major advantage India has is its 3-4 million scientists, the second largest concentration in the world after US
■ Many of these scientists are English-speaking and willing to work for a fifth of the salary of their counterparts in the West
■ According to industry sources, India has about 500 investigators, over 572,000 doctors, 43,322 hospitals and dispensaries and about 8.7 lakh beds, both in private and public hospitals.
■ Rapidly improving support industries such as labs and hospitals, apart from a world respected IT industry capable of picking up domain expertise to support R&D and clinical trials
■ Pharma giants are also attracted by the heterogeneity of the billion plus population, the fact that the country offers nearly 700,000 speciality hospital beds at about a tenth of the price in developed nations and 221 medical colleges.
Clinical trials in India
■ Dr Reddy's, Rheoscience has commenced phase III trial for oral anti-diabetic drug balaglitazone, which is an insulin sensitizer that acts as partial peroxisome proliferator-activated receptor (PPAR). The study is the first in the series of planned phase III trials, which will investigate the safety and efficacy of balaglitazone, as an oral antidiabetic drug.
■ MNCs like Pfizer, Eli Lilly, GlaxoSmithKline, Sanofi-Aventis and Roche have already started phase-I and II trails in India. Mumbai-based CRO, Metropolis Health Services, which conducts clinical trials in various therapeutic segments and offers a spectrum of clinical development services, is in the process of offering site management services to various pharma firms and other CROs.
■ Bangalore-based Lotus Labs has also completed more than 450 bio-studies and is conducting several phase III trials. It has set up research facilities in Bangalore and Chennai and has recently tied up with St John's National Academy of Health Sciences, Bangalore, for conducting phase I trials.
■ Mumbai-based ClinInvest Research focuses on all phases of clinical trials, mainly in the areas of oncology, neuro-psychiatry, cardiology and diabetes drugs.
■ Clingene International, a subsidiary of Biocon, concentrates on bio-analytical, bio-statistical and data management services to its clients.
■ Quintiles Spectral (India), a subsidiary of Quintiles Transnational, the clinical services segment, conducts studies in oncology, psychiatry, neurology and anti-infectives. The company has conducted over 90 clinical studies on 13,000 patients.
■ Pharma giant Pfizer has already chosen a city in one of the northeast parts of India to conduct clinical trials on 300 patients for a new malaria drug that combines chloroquine (to which several Indian malarial strains have developed resistance) and azithromycin, an antibiotic. It is also carrying out clinical trials for drugs to treat osteoporosis, breast cancer and schizophrenia. Pfizer is conducting around 20 clinical trials. It has independently conducted more than 40 good clinical practices (GCP) workshops and has trained more than 2,000 investigators.
■ According to industry sources, the pace at which drug trials are being instituted in the country is so fast that the Clinical Data Interchange Standards Consortium (CDISC), USA, a non-profit organisation committed to the development of clinical research organisations' standards the world over, is looking to set up a chapter in India.
■ Eli Lilly has over 17 large and small clinical research projects running in 40 hospitals across India. The company has already held clinical trials involving more than 600 patients for human insulin and insulin lispro. It is also conducting trials on oncology, besides developing a new molecule for lung cancer.
■ GlaxoSmithKline (GSK) Plc has started seven simultaneous clinical trials of its vaccine and pharma molecules.
■ Torrent Pharmaceutical Ltd has six projects in the pipeline. One of them, the New Safer Anti-arrhythmic Agents, is ready for phase II clinical trials.
Govt. initiatives
■ The Indian government is offering incentives to promote local pharmaceutical companies and attract foreign firms
■ India plans to create an independent drug regulatory authority that will emulate the U.S
■ Internationally, India became a member of World Trade Organization in 1995 and agreed to adhere to the product patent regime by 2005
Indian regulatory framework
■ Indian Patents Act 1970, as on January 01, 2005 provides product patent for drugs, food and agrochemicals
■ New drugs, imports, clinical trials and drug standards are approved by Central Government. Enforcement is handled by States
■ Upgraded Schedule M
■ Schedule Y amended for multi-centric concurrent clinical trials as per GCP
■ GMP realigned as per international guidelines GCP India's requirements on GCP published as guidelines
■ GLP monitoring authority set up for pre- clinical (toxicological) studies
Clinical trial registry
Clinical trial registry is a database containing entries with basic information about a clinical trial. Registration of clinical trial facilitates the information dissemination among physicians, researchers, patients and health regulators across the globe. It also helps to assure trial participants that the information that accrues as a result of their altruism will become part of the public record. Several trial registries are already in place the world over, such as ACTR, Clinical Trials.gov, ISCRTN etc. Keeping with the times and its demands, a registry, Clinical Trial Registry - India (CTRI), funded jointly by DST, WHO and ICMR have been initiated. The CTRI has been set up at NIMS (ICMR), New Delhi to provide a platform for registration of all clinical trials in India.
Of the several new opportunities created by India's compliance with WTO levels of patent protection, clinical research outsourcing has the most significant impact. Moreover, clinical trial outsourcing fits the classic requirements of outsourcing a process - it is standardisable, increases efficiencies of time and costs apart from improving organizational flexibility. Finally, India has country specific factors that favor global outsourcing of the R&D process. Due to amendment in patent law, it is no longer a barrier to outsource and the way is clear for global pharmaceutical companies to include Indian clinical research organizations in the global R&D network.
Indian CROs need to be more aggressive in marketing their skills externally and combat potential disinformation campaigns internally. If high ethical standards are adhered to, clinical research studies would help the poor in the country by giving them free access to the newest drugs and the highest levels of health care that even the middle class cannot afford.
(The authors are from Institute of Clinical Research, New Delhi)