India is fast emerging as a favoured destination for clinical trials in new products by multinational pharmaceutical companies. Two major reasons for its popularity are: easy access and availability of a large, diverse and therapy-naïve population with vast gene pool and lower cost of technical services resulting into lowest per patient trial cost. It is well documented that the average costs of doing Phase I/II/III drug trials in US are $20/50/100 million respectively whereas in India they are 50-60% of the same and could be up to 75% faster (Table I). India also has the advantage of having a large pool of highly trained physicians, nurses, and technical personnel; numerous world-class medical facilities; broadly developed information technology infrastructure; a favourable IPR environment after signing the WTO and use of English as the primary business and medical language making it an attractive option for health care companies for clinical trials.

Table I.  Cost of clinical trials in US vis-a-vis in India
Study	Average US cost (In millions)	India Cost
Phase 1 (normally tests on small groups of healthy humans)	$20	50% less than the average cost in US
Phase II (tests on individuals afflicted with the condition for which the drug was developed)	$50	60% less than the average cost in US
Phase III (tests on large groups of afflicted patients)	$100	60% less than the average cost in US

In fact, a number of pharmaceutical companies have successfully used clinical trial data generated from India for US FDA New Drug Application (Table-II).

Table-II- US FDA New Drug Application data  generated from India
Drug Company	Molecules Researched
Alcon	Vegamox
AstraZeneca	Merenem
Cangene	Hepatitis B Vaccine
Eli Lilly	Alimta Gemcitabine (breast cancer) Cialis (erectile dysfunction) Xygris (Septicemia)
Glaxo	Lamictal
Jannsen	Resperidal
Novartis	Tegaserod
Pfizer	Voriconazole
Roche	Peg-Interferon
Santen	Quixin
Wyeth	Influenza A Vaccine

What is a clinical trial

A clinical trial is a research study to answer specific questions about vaccines, new therapies or new ways of using known treatments. Clinical trials are used to determine whether new drugs or treatments are both safe and effective. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people. Trials are conducted in four phases: Phase I tests a new drug or treatment in a small group for its safety; Phase II expands the study to a larger group of people and checks its effectivity; Phase III expands the study to an even larger group of people; and Phase IV takes place after the drug or treatment has been licensed and marketed. Though the system of carrying out Phase IV trials would still take time to be widely accepted, it has paid rich dividends in cases of withdrawal of Rotavirus vaccine due to intussusception and anti-arthritic drug, Vioox in India as it was found to have side effects on cardiac system. Post Marketing Surveillance has been added to Schedule Y of the Drugs and Cosmetics Act, 1940 in 2002.

Clinical trials are the buzzword today. In most of the boardrooms promoting "Destination India" by business mediators, "Clinical Trials in India" are being offered as a greater advantage, next only to its well-educated human capital. What's amazing is- how much these promoters understand "clinical trials" and more profoundly the ethics associated with it? The "access to lots of patients", "wide gene pool", "meager incentives", (due to poverty or other economic compulsions) and "illiteracy" sound more like washing dirty linen in public than actual "Advantage India"

Clinical trial ethics

Traditionally, clinical trials are associated more with serving the humanity, as they tend to understand disease patterns and seeking solutions for the dreadful diseases in terms of better diagnostics, drugs, vaccines and devices. However, having gone to the private hands in a major way, the outlook and ambitions of the clinical trials have undergone sea change. It is now regarded as one of the foremost lucrative business. Historically, clinical trials are reminiscent of some of the most appalling human experiments conducted by Germans on Jews and US on black men and students (Tuskegee syphilis and the Willowbrook hepatitis studies). At the same time, they resulted into laying of the most elaborate ethical norms and codes in the form of The Nuremberg Code, 1947 that made voluntary consent a requirement in clinical research studies; The Belmont Report, 1949 setting forth three underlying ethical principles - respect, beneficence and justice for the volunteers; The Helsinki Declaration making it mandatory for the medical community to essentially think about the benefit and non-benefit research and assess the benefit/risk ratio before initiating the trials and International Ethical Guidelines for Biomedical Research involving Human Subjects by Council for International Organisations of Medical Sciences (CIOMS) covering interests of local community and appreciation of cultural ethos after internationalisation of research.

However, it is well known that ethics and commerce often do not go together and this conflict is most evident in pharmaceutical sector when one uses humans in medical research. Pharmaceutical companies have a tendency to exploit regulatory loopholes in a bid to enter the market quickly. Ethics are sidestepped in favour of overriding commercial interests. Firms in India and abroad who spend millions on developing products want to maximise profits at the earliest. As a result, cases of clinical trials without ethical approval have emerged in countries where legislation is either inadequate or not implemented. A recent survey of more than 200 health researchers concluded that a quarter of clinical trials conducted in developing countries do not undergo ethical review.

Clinical trials are necessary as they promote the health of the nation. They also bring in new technology and new treatments; bring down the costs of the new treatments and also sensitize the bio-medical community towards country's need to advance medical and clinical research. Quintiles, the largest CRO in the country for clinical trials has prepared trial field for nationwide Phase II and Phase III trials of psychiatry, oncology, neurology, anti-infectives, gastroenterology, diabetes, ophthalmology, cardiovascular indications and internal medicine. Almost every pharmaceutical/biopharma company in the country has its own clinical trial unit and is going out of the way to woo multi-nationals for conducting trials in India. However, three fundamentals are clear:

1. Despite much talk about R&D activities, there is hardly any New Chemical Entity (NCE) or New Biological Entity (NBE) developed by local pharma firms.
2. Most of the hoopla for clinical trial research, is, hence, being generated for laying grounds for molecules/therapeutics/devices developed abroad.
3. Trials are generally conducted on economic weaker section or on a population with other compulsions.

The suspension of clinical trials of a promising new anti-diabetes drug in humans following reports of drug-induced tumours in laboratory mice raises a host of ethical issues.

In India, many instances of unethical and illegal trials have been brought to the limelight between the infamous clinical trials on pre-cancerous cervical lesions on about 2250 women in late 80s (where no ethical committee approval was taken) and the suspension of the clinical trials in July 2004 of the new anti-diabetes drug ragaglitazar being conducted by the Danish multinational, Nova Nordisk after the discovery of urinary bladder tumor in mice (the drug having undergone "preclinical and some preliminary toxicology studies" but not completing the long term toxicological studies before initiation of human clinical trials as required in case of anti-diabetes drug). During the same period, many new national Codes and Guidelines have been issued by concerned government agencies: Schedule Y (1988), ICMR Code (2000), GCP guidelines by DGHS (2001), Amended Schedule Y (2002) etc. Through laying and adoption of these guidelines, the learning process has already started in the country and the subcontinent is poised to grab the opportunities. Most teaching hospitals have well constituted ethics committees that comply with ICH-GCP requirements for composition. Yet, cases of unethical trials keep appearing now and then! It probably looks that:

Ø There are too many overlapping guidelines issued by various Government agencies leading to confusion in the mind of investigators;
Ø Most of the guidelines and laws are written documents with loose implementation strategies;
Ø There is ignorance about the legal and ethical issues of human trials among the public and health care professionals;
Ø The Institutional Ethics Board (IRB) though constituted by most of the hospital as per the detailed "ICMR Code", remain very much within the control of the investigator;
Ø There is no proper evaluation of the study protocol by IRBs;
Ø Several hospitals, specially away from main researcher's hub, though not equipped with appropriate infrastructure and manpower undertake all kinds of trials compromising with the safety of the patients; it is such centres that are exploited the most by companies desirous of completing the trials fast;
Ø There is no independent Data Safety Monitoring Board established by most of the clinical trials teams, hence Adverse Drug Event or Serious Adverse Events are hardly reported;
Ø Even if SAE or AE are reported, there is no arrangement for compensation for study-related injury, disability or even death;
Ø There is no definite remedy provided in the law even if an incident of violation of the Rules or Guidelines comes to light;
Ø The regulatory agencies have no control in the manner trials are conducted; as no mechanism exists to go back once an approval is given;
Ø Mostly lapses come to the light when the company approaches for new approvals or reported through media;
Ø Many medical investigators share a cozy relationship with the sponsors or have financial interest in the company. Though such phenomenon is more widespread in US and other developed countries (as evident in the famous case of gene therapy trials conducted by the University of Pennsylvania vis-s-vis Gelsinger where researchers violated the trial's protocol by not reporting the "adverse events"), it is already making inroads in developing countries.

Amidst all these, there are some central planning bodies suggesting ease in regulations of clinical trials without proper understanding and groundwork. It needs to be noted that the drug approval agencies in developed countries such as the US Food and Drug Administration and EMEA (European Agency for the Evaluation of Medicinal Products) require ethics committee approval of trials for the sale and distribution of any drug. They have elaborate mechanisms to keep their IRBs totally unbiased and independent, have regular auditing and elaborate Case Record Forms. These are strong incentives to seek such approval. Efforts are under way to strengthen ethical review throughout the world through Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), an international project to develop the ethical review of biomedical research globally. WHO is involved in the project and in 2002 opened its own ethics unit, whose goals include harmonizing ethical review standards for clinical trials and ensuring such studies are effectively regulated in WHO's 192 Member States.

In case India has to really take commercial advantage of its huge patient load, it needs to be ensured that the outside companies conducting trials apply the same standards as they do while doing trials in their own country. This can come only through vigilant IRBs as they are closest to monitoring the protocol and can avoid exploitation of needy and sick population. There is also a need for making ethical review panels truly independent and to tighten laws governing clinical trials in true spirit.

References
1. www.rediff.com/money/2004/dec/22spec.htm
2. www.indeconomist.com/300704_pharma.html
3. www.aap.org/new/rotapublic.htm
4. www.lewrockwell.com/orig3/hogarth1.html
5. www.pharmacenter.ch/pdf/burri_c.pdf
6. India grapples with rules on clinical trials http://www.scidev.net/Features/index.cfm?fuseaction=readFeatures&itemid=278&language=1

-- The authors are from Department of Biotechnology, Ministry of Science and Technology, New Delhi