Development of new drug involves two phases, namely drug discovery and drug development. The growth of an idea into a product may take over a decade of dedicated research by team of researchers including organic chemists, pharmacists, pharmacologists, toxicologists and clinicians. This is a target oriented multi-stage ongoing process of critical importance as each new discovery means relief to millions.
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 increased in leaps and bounds. 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, namely preclinical and clinical. Preclinical evaluation involves rigorous testing of efficacy and safety of the new molecule by various in vivo assays using animals. The necessary data for evaluation in humans is generated here and the test drug is now ready for its last and most crucial stage of evaluation, i.e., 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 one or clinical pharmacology forms the basis for clinical trial for any new drug and provides the link between pre-clinical and clinical research (Kuhlmann, 1997). Finally, the application for FDA review and approval may be applied and the approval 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 200 million USD in early nineties to over 800 million USD in the new millennium.
Clinical research (CR) may be defined as an organized research conducted on human beings and is intended to provide adequate information on drug use as a therapeutic agent on its safety, efficacy and adverse effect. Globally, CR is becoming a thrust research area as it is essential for development of not only new drugs but also for new formulations, drug delivery systems, dosage regimen, surgical and diagnostic techniques, devices and therapies. With the advent of high throughput screening, drug discovery programs have speeded up making clinical evaluation as the rate-limiting step towards final product development.
Globally there has been a paradigm shift in the pharmaceutical market, and nearly 2/3rd of the R&D costs go towards drug development. Of this, CR accounts for 70% of time and resources spent in drug development.
India: Hub for clinical research
The Indian pharmaceutical industry is one of the fastest growing sectors of the Indian economy and has made rapid strides over the years. From being an import dependent industry in the 1950s, the industry has achieved self-sufficiency and gained global recognition as a producer of low cost high quality bulk drugs and formulations. Having proved its mettle in international market, India is now on the helm of taking up the challenge of proving its efficiency as capital for global clinical trials.
Number of factors favor the recognition of India as hub for CR due to which the multinational companies have identified it as their ideal destination. Firstly, there are numerous government funded medical and pharmaceutical institutions having state-of-the-art facilities, which can serve as ideal centers for multi-centered clinical trials. Secondly, India can boast of a large well-trained and qualified manpower that is well versed in English as a means of communication. Most importantly, there is vast clinical material, which can be utilized. In terms of the cost efficiency, India works out to be a cheaper option as the cost to conduct a trial here is lower by 50 to 75% than that in either United States or European Union. R&D costs in India are much less than those in the developed world and it is possible to conduct both New Drug Discovery Research and Novel Drug Delivery System programs at competitive rates. Additionally, while clinical trials cost approximately $300 to 350 million abroad, they cost about Rs.100 crore in India. There is a good communication link which, favors fast recruitments and approvals. Thus, the studies can be completed quickly and provide edge over competitors.
Moreover, India is a land of diversity where alternative systems of medicine like ayurveda, unani, siddha, homeopathy are practiced with equal fervor as allopathy. Thus, clinical studies for their evaluation can also be conducted with ease. Internationally, there has been recognition of the Indian advantage which is luring pharmaceutical companies to adopt collaborative outsourcing strategies so as to tap the potential to its fullest. Owing to these factors the India is globally attracting collaborative contract proposals for conducting clinical trials and many have already come forward to set up their clinical research organizations (CROs).
Scope of clinical research
Irrespective of the fact that a drug has been developed in India or abroad, or whether its clinical studies have already been conducted abroad, every new drug needs evidence from CR to support its launch. Thus, whether it is a new chemical entity or an existing drug that is being marketed for new indication, clinical studies have to be conducted. Similarly, launch of new formulations, drug delivery systems or even new fixed dose combination, requires clinical data before it can be marketed. Hence, it is obvious that the area of CR holds immense scope and promise for without the supporting data drug launches are not feasible. CR should not be merely viewed as a subsidiary to pre-clinical research. On the contrary it is of prime importance for it has to be conducted even in cases where pre-clinical studies are not warranted (new formulations/fixed dose combinations/ bioequivalence).
CR holds tremendous scope and opportunities not only for trained medical, pharmaceutical and paramedical professionals but also for regulatory authorities, government and the society at large. A mechanism of knowledge transfer can be worked out which would lead to a definite improvement in hospital infrastructure. It will make available the state-of-the-art therapy for many deserving Indian patients who were hitherto deprived of such therapeutic advances.
Consequently, the projected figures for the various aspects of CR (market value, revenue, staff requirement) for the next five years, promise a growth at a rate greater than 20% (table 1).
It is certain that in future as the number of clinical projects expands, there will be a demand for qualified personnel. According to McKinsey report the global clinical trial outsourcing opportunity in India in pharmaceutical industry is estimated to be around 2 billion USD by the year 2010 and there will be requirement of 50,000 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.
Current regulatory requirements
In 1988, the government made it mandatory for all new drug introductions as a regulatory requirement for getting NCE's approved. Schedule Y stipulated that the first applicant for any new drug should generate data in local clinical trials conducted in approximately 100 patients at 4-5 centres. This schedule also indicates that permission for such clinical trials would be given for one phase behind the development status in the rest of the world. However, for a second and subsequent applicant for the same compound, no clinical trial would be required since they could show bio-equivalence to the first product approved and introduces their brand of the generic in the market. Due to this lack of protection, innovator companies have been losing money by virtue of not being able to introduce their new and cutting edge research in the Indian market due to the presence of generic brands of innovator compounds. Moreover, it also discouraged the pharmaceutical companies from carrying out global clinical studies by their local subsidiaries in India and preferred to wait for their innovator brands to be approved in source countries and then carry out limited bridging studies for local approvals. Consequently, there has been a gap between their introduction in India with the rest of the markets worldwide.
Recently, amends in the regulatory requirements have been made and the thrust has shifted from just safeguarding Indian subjects to providing them access for biomedical innovation. India has signed the Trade Related Intellectual Property Rights (TRIPS) agreement as a part of the WTO regulations, which will guarantee intellectual property rights and patent protection to companies holding the patent from 2005. In the present Intellectual property right (IPR) regime, it has become extremely important for conducting timely clinical research. Increasingly, permission for phase 1 trials is being granted after thorough appraisal of the protocols, products and claims. Favorably, the government has also relaxed the duties that are levied on clinical trials samples. These steps indicate the commitment of the government in strengthening India's position and propelling it as world leader in clinical research. The Government is likely to exempt pharmaceutical companies from seeking Genetic Engineering Approval Committee (GEAC) clearance for undertaking clinical trials in the case of "purified products" of genetically modified organisms (GMOs) that are used in drugs such as vaccines, interferons and diagnostics. This is in line with what a joint committee comprising officials from the Department of Biotechnology, Ministry of Environment and Forests, has suggested to the national task force headed by the CSIR Director-General, Dr R.A. Mashelkar. This move will primarily decrease the number of steps in the clearance procedure for pharmaceutical companies.
Ethical requirements
Before opening its gates international pharmaceutical houses for conducting contract CR in India, the critical issue of ethical considerations for conducting biomedical research on human subjects needs to be addressed. The aim of the entire exercise should be to avoid the denigration of naïve Indian masses to the status of experimental guinea pigs. On the other hand it should not be deterrent for new scientific innovations for the benefits of mankind. Thus, a sensitive balance between risks involved and benefits to be gained needs to be achieved.
The Central Ethics Committee on Human Research was conceived and constituted under the chairmanship of justice M.N.Venkatachaliah by the Indian Council for Medical Research (ICMR) to address this dilemma and set a framework for future CR. A set of guidelines were developed and released in September, 2000 by the committee. The guidelines specially focus on issues regarding clinical evaluation of drugs/ devices/diagnostics/vaccines/herbal remedies. Sensitive issues of human genetics, transplantation and epidemiological studies have also been dealt with in great detail.
While conducting the research, CROs need to bear the following principles in mind-essentiality, voluntariness, informed consent, non-exploitation, privacy, risk minimization, professional competence, accountability, maximization of public interest and totality of responsibility and compliance (ICMR, 2000). The trial may be a randomized single or double blind controlled study conducted at one or different centres either for new chemical entity, new fixed dose combination or new indication/ route/ dosage regimen. First the proposal has to be reviewed and approved by Institutional Ethics Committee (IEC), or Institutional Review Board (IRB). Following ethical approval, the proposal has to be submitted for approval to Drugs Controller General of India (DCGI), as is necessary under the Schedule Y of Drugs and Cosmetics Act, 1940. Need for developing clinical training institutes
Despite the availability of infrastructure and manpower in India, the area of CR is still in its infancy here. Although there has seen satisfactory development of the drug industry and health care facilities in India but not of CR. This calls for the development of its capacities and capabilities in terms of infrastructure, regulatory structure, and formulation of specialized pool of research investigators.
Increasingly, a need is being felt for development of institute(s) that may provide training and education in the clinical research segment and meet the growing demands skilled manpower by the industry. If we desire to keep pace with the global advances in the field of pharmaceutical research, we need to set-up training institutes that can impart innovative and intellectually challenging education of the highest academic standards. In a survey conducted on training needs, around 40% of the respondents felt that there was a need for training centres in clinical research methodolgy. Further analysis reveals that the professionals perceive course content and its duration of utmost importance. Thus, the institute(s) that are developed should have all modern infrastructural facilities of library, computer laboratories, audio-visual facilities, on-line training, and placement cells. The institute(s) should aim to generate such professionals who can represent India in good light, which attracts further international collaborations. Also, this will help to organise this sector in a well-defined mould, whose interests will have to be catered at both local and international level. This will go a long way in launching and boosting India as a major player in this area of research and ensure that it does not lag behind for want of trained manpower.
Recently, one such non-profit institution, Institute of Clinical Research (India) has been launched from the environs of Dehradun. It is hoped that it will act as a center of excellence and contribute significantly by producing proficient manpower. Number of full-time and part-time courses are available to suit the needs of both fresh graduates and working professionals. It is hoped that India will see the emergence of many such institutions in future.
Considering the fact that less than one third of the drugs tested in clinical trials actually reach the market, the study of drugs in humans needs to be an logical, with sound scientific basis in both conception and execution (Berkowitz, 2004). The rigors of research should be adopted so as to maximize the benefits to mankind at minimum costs and risks. The challenge lies in integrating physician, regulatory authorities and pharmaceutical houses to optimise the risk-benefit profile with experience and not empiricism so as to minimize the abuse/misuse of the subjects (Cohen, 1994; Nowak, 1994). The drugs to be tested should conform to Good Manufacturing Practice guidelines and tested pre-clinically with Good Laboratory Practice and finally clinically in accordance with Good Clinical Practice. We still have a long way to go in resolving all the issues pertaining to clinical research for the only constancy is the constancy of change and at no stage the last and final word can be said.
(The author is with Institute of Clinical Research (India)