Current developments in clinical research in India

Dr S K Gupta,
Galpalli Niranjan D

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 the international market, India is now on the helm of taking up the challenge of proving its efficiency as the capital for global clinical trials. Numbers of factors favour the recognition of India as a hub for clinical research, 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 centres for multi-centred 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 utilised. 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 percent 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 programmes 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 favours 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, and homeopathy are practiced with equal fervour 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, India is globally attracting collaborative contract proposals for conducting clinical trials and many have already come forward to set up their clinical research organisations (CRO's).

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 clinical research to support its launch. Thus, whether it is a new chemical entity or an existing drug that is being marketed for a new indication, clinical studies have to be conducted. Similarly, launch of new formulations, drug delivery systems or even new fixed dose combinations, require clinical data before they can be marketed. Hence, it is obvious that the area of clinical research holds immense scope and promise, for without the supporting data, drug launches are not feasible. Clinical research 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/bio-equivalence).

Clinical research 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 clinical research (market value, revenue, staff requirement) for the next five years, promise a growth at a rate greater than 20 percent (Table 1).

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 four to five 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 disco-uraged 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 introductions in India with the rest of the markets worldwide.

Product patent regime

The draft National Pharmaceuticals Policy 2006 is committed to making Indian laws and policies relating to IPR, including data protection, fully complaint with TRIPS provisions. 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 I trials is being granted after thorough appraisal of the protocols, products and claims. Favourably, 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.

Bioethics

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 Honourable Justice Shri M N Venkatachaliah by the Indian Council for Medical Research (ICMR) to address this dilemma and set a framework for future clinical research. 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 minimisation, professional competence, accountability, maximisation of public interest and totality of responsibility and compliance (ICMR, 2000). The trial may be a randomised 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.

The DCGI is responsible for regulatory approvals of clinical trials in India and his office depends on external experts and other government agencies for advice. Additional permissions are required for the export of blood samples to foreign central laboratories. All this usually takes about three months in India. The ICMR guidelines for clinical trials insist on the setting up of ethics committees at the institutional levels.

India's regulatory agency, the DCGI, has responded to the demands of industry and tried to bring India in line with international standards. Changes include recommended adoption of a set of internationally recognised ethical and scientific quality requirements. (Table 2)

In January 2005, India adopted a new rule that will allow pharmaceutical companies to begin phase II and phase III trials concurrently with trials of the same phase conducted abroad, thereby reducing clinical development time. Under the old rule, phase II and III trials were only permitted after those phases were completed elsewhere. The rules were intended to create a "phase lag" between India and the rest of the world to prevent foreign pharmaceutical companies from using Indians to test their unproven therapies. With the latest amendment (20th January 2005) to the Schedule Y of Drugs and Cosmetic Act 1945, the reporting of adverse events from clinical trials has become clearer and unambiguous. There is of course a quantum leap between the old and the new version and the serious intentions of the DCGI regarding stricter compliance are clearly palpable.

ICH-GCP compliance

Good Clinical Practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected, consistent with the principles enshrined in the Declaration of Helsinki and ensures that clinical trial data are credible. High level of International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use, Good Clinical Practice (GCP) and US Food and Drug Administration (FDA) standards compliance—since 2001, the DCGI has implemented conformity to ICH GCP/good laboratory practice (GLP) guidelines. Generally, most competent authorities (CAs), including the FDA, will find the standards of Indian clinical trials acceptable.

Clinical trial registry

Two independent incidents underscored the need to have a serious re-look at the way clinical trials are conducted and reported. An early stage trial of TGN1412, a monoclonal antibody to treat leukaemia, went seriously wrong in Britain with a dozen patients hospitalised due to multiple organ failure necessitating hospitalisation. Coming as it did close on the heels of the intense controversy that Merck withheld critical data from trials of Vioxx, these incidents put the pharma industry firmly in the dock. In fact, there have been several reports that all is not well with clinical trials, that aim to develop new therapeutic or preventive measures, assess or evaluate an existing medical treatments and techniques vis-à-vis a new one.

As a series of incidences of unfortunate events associated with clinical trials came to light, there has been a growing call for transparency, accountability and accessibility of clinical trials and their results in order to re-establish public trust in clinical trial data. All these appear to be possible only by mandatory registration of all clinical trials, with the ultimate goal of ensuring that all trial results, positive or negative will be released to the public. Several trial registries are already in place the world over, such as the ACTR, ClinicalTrials.gov, ISCRTN, etc. Furthermore the WHO is promoting an international initiative to develop a meta register of controlled trials that would offer a one step search portal fed from existing registers and provide a unique identification number for clinical trials from certified registers that needs standard criteria for the exchange of essential trial data. Keeping with the times and its demands, a registry, Clinical Trial Registry-India (CTRI), funded jointly by DST, WHO and ICMR has 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. Primary objectives are to establish public record system by registering all prospective clinical trials conducted in India on health products including drugs, devices, vaccines and herbal drugs which will made publicly available on the internet at no cost.

(Source: CTRI Bulletin; July 2007)

National pharmacovigilance programme

The Government of India, with the World Bank, has initiated the National Pharmacovigilance Programme. The Central Drugs Standard Control Organization (CDSCO) is coordinating the countrywide pharmacovigilance progra-mme under the aegis of DGHS, Ministry of Health and Family Welfare, New Delhi. With the number of new drugs being regularly approved for marketing in India, there is a need for a vibrant pharmacovigilance system in the country to protect our population from the potential harms that may be caused by some of these new drugs. Besides, with the patent regime coming in force from 2005, it is widely believed that India would become the global hub for new drug trials. These situations make it pertinent for the Indian central drugs regulatory authority to have a vibrant pharmacovigilance system in the country.

(The authors are from Institute of Clinical Research (India). For queries contact skgupta@icriindia.com)