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deepak balakrishnan nair is a post-graduate in law from CUSAT with specializations in Administrative and Corporate laws.
Clinical Trial Regulation In India: The Reality
What would possibly happen if all the drugs and vaccines are removed altogether from our world? Quite intimidating. Ebola, Aids, Swine flu... all will feed voraciously on the human population. To stop them we need medicines; good and improved medicines. But how could we do that? Significance of Medical Research and Clinical Trials should be seen under this perspective.
Drug development is a process that calls for utmost care. An error can cause fatal result. Clinical trials are developed in such a way that it not only helps the discovery of new drugs but also ensures safety profile of such drugs.
A clinical trial in simple terms can be defined as a set of practice that helps certify a new drug molecule as safe and efficacious before reaching the market.
In fact "any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes" can be defined as a clinical trial.
Clinical interventions include drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioral treatments, process-of-care changes, preventive care, etc.
To determine the safety and efficacy of drug research on humans is always warranted, but one needs to be cautious and vigilant as to how the players in this field undertakes the process. Adherence to the principles of good clinical practices or GCPs, including adequate human subject protection universally recognized as a critical requirement to the conduct of research involving human subjects. Most countries have adopted good clinical practice principles as laws or regulations. In India, compliance with GCP guidelines issued by the Central Drugs Standard Control Organization or the CDSCO is recommended.
This article aims to give a brief outline of the Indian scenario regarding Clinical Trial initiation, current regulatory framework and its effectiveness in reality.
Medical Research and Trials: Indian position
India has long been identified as a major resource center for conducting clinical trials and data management services. Plus points include its large patient population, well-trained, enthusiastic and foreign-educated investigators, and significantly lower cost.
The average cost of Phase I/II/III trials in the US is over $20/50/100 million, respectively. But in India, one may do it at half (50%-60%) the said cost and 75% faster. Lowest per patient trial cost coupled with an extensive gene pool and extremely lower cost of technical services is doing the job here.
According to McKinsey report, Indian medical research industry is poised to grow up to Rs. 5,000 crores by the end of 2010. What makes India a hot spot for researchers is the presence of treatment-naive patients with a wide spectrum of diseases spanning from Multidrug-resistant pneumonia, Hepatitis B, Diabetes, to rare cancers than in the West.
Volunteer enrollment is also high, as people believe that participation in research trials could offer them access to quality health care and medicines, which otherwise would not be affordable. As result, subjects are compliant and keenly attend all study visits.
Data generated in India is accepted by all major conferences and journals; and that all Indian hospitals and private institutions store comprehensive source data, mostly in English adds to the advantage. Above all, India's increased regulatory control and acceptance of the International Conference on Harmonization or ICH guideline for good clinical practice further enhances India's status as a perfect location to conduct clinical trials. 
Going by the numbers, at least eighty Indian hospitals are currently engaged in conducting clinical trials. The figure is likely to go up to 14,000, which means involvement of five-lakh doctors, seven-lakh beds, and 17,000 medical graduates in 160 medical colleges. India, by 2011 is forecast to be conducting over 15% of the total global clinical trials. 
Need for Regulatory Frame Work
One major advantage of participating in the global drug trials is that it places us in an advantageous position to bargain for a lesser price tag when such drugs are marketed in India. Say, if a new cancer drug is developed by a multinational company from research in India, we naturally acquire a claim on it. This line of thinking is of course beneficial, but we should be able to limit exploitation and prevent fraud in the process. What requires here is a strict regulatory framework to provide proper administrative and monitoring mechanism.
In India, regulations pertaining to clinical trials are placed in Schedule "Y" of the Drugs and Cosmetics Act 1940, and the rules framed thereunder. It deals with regulations relating to clinical trial requirements for the import, manufacture and obtaining marketing approval for a new drug in India. Earlier, it required that all foreign drugs be retested at one phase below the highest phase of testing abroad. But, after the 2005 amendment to the Schedule Y of the Act, parallel global clinical trials are possible and India now permits concomitant phase 2 and phase 3 trials.
Drugs & Cosmetics Rules
New chemical entities cannot be administered to human subjects in a clinical trial without permission from the Drugs Controller General of India. Such permission may be obtained by submitting to the DCGI an application for a clinical trial. The application must include a protocol for the study, a draft of the Informed Consent Document, a list of proposed investigators who have agreed to participate in the study, and background information about the drug in accordance with Schedule Y of the Drugs & Cosmetics Rules.
It takes almost 12 weeks to obtain permission for a clinical trial for most investigatory drugs. The duration may be longer for drugs with special significance to the healthcare concerns of the country or those that may be considered controversial since these are liable to be referred to the Indian Council of Medical Research for comments. If clinical supplies are to be imported, a "Test-Import License" must also be applied for. Import and manufacture of clinical trial supplies is governed by Rules 33 & 34 and provisions contained in Part X-A of the rules. 
The procedure for applying for marketing approval depends on the status of the new drug, which broadly fall within three categories:
(i) new drug substances discovered that are already approved/marketed in other countries, for which it is sufficient if phase III or confirmatory trials are conducted to obtain data about the efficacy and safety of the drug in a sufficient number of patients, in comparison with a standard drug or a placebo, to confirm efficacy and safety claims made in the product monograph.
(ii) new drug substances discovered but are not approved/marketed in other countries, for which permission for clinical trials is granted with a "phase lag". It means that permission to conduct phase I trial is allowed only if the drug has completed phase I and moved to phase II in other countries. Likewise, phase II is allowed in India only after completion of phase II in other countries and phase III has commenced.
Phase I trials cannot be initiated in India for new drug substances discovered in other countries unless phase I data from other countries is available. The phase I trials are carried out on healthy human volunteers to determine the maximum tolerated dose in humans, adverse reactions, etc.
(iii) new drug substances discovered in India; for which clinical trials have to be carried out as human or clinical pharmacology trials. Exploratory trials, or phase II trials, are carried out on limited number of patients to determine therapeutic uses, effective dose range and further evaluation. Confirmatory trials, or phase III trials, are conducted to obtain sufficient data about the efficacy and safety of the drug in a larger number of patients, again in comparison with a standard drug or a placebo, to confirm efficacy and safety claims made in the product monograph. If the new drug substance is not marketed in any other country, phase III trials should be conducted on a minimum of 500 patients spread across 10-15 centers. In the case of new drug substances discovered that are not approved or marketed in other countries, clinical trials are now allowed to be carried out in India simultaneoulsy with trials abroad.
Regulation of Trials
For registering new drugs for marketing in India, submission of data generated on Indian patients is essential. For this purpose, a 100-patient non-comparative open-label study on patients treated for the primary indication is sufficient. For drugs that treat rare conditions, a lower sample size is usually adequate.
In conducting research, informed consent is the most basic and complex principle of clinical research ethics. An ethically valid informed consent has four key components: disclosure, understanding, voluntariness, and competence. In that case, the usual question that arises is whether the concept of informed consent extends to research involving the critically ill, because in many cases, critically ill patients are incompetent or unable to make a sound decision. Sometimes, the family members may not know the patient's wishes, or may not be legally authorized to give consent for the patient's involvement in research. All such issues create challenges for researchers in pediatrics, psychiatry, emergency and critical care medicine. 
A major threat India faces in this area is its low literacy levels, which has always kept regulators skeptical about the possibility of the volunteers being not adequately informed about the risks they are undertaking. However, compliance to International Conference on Harmonization-Good Clinical Practice or ICH-GCP norms, trained investigators, a growing population of experienced monitors and exposure to international protocols seem to provide some relief to such issues. The legislative framework governing medical research in India are:
Drugs and Cosmetics Act – 1940 (Schedule Y)
Drugs And Cosmetics (II Amendment) Rules, 2005
ICMR guidelines, DBT guidelines
Medical Council of India Act - 1956, (amended in the year 2002)
Central Council for Indian Medicine Act - 1970
Guidelines for Exchange of Biological Material (MOH order, 1997)
Right to Information Act – 2005
The Constitution of India
The Biomedical Research on Human Subjects (regulation, control and safeguards)
Acts, rules and codes of ethics of professional bodies regulating the practice of medicine in India, such as the Medical Council of India, Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH). Bill - 2005
Apart from these legislation's, The Indian Council of Medical Research or the ICMR, which was established with a view to foster a research culture, improve and develop infrastructure and foster community support, plays a significant role in controlling clinical trials in India. The Drugs and Cosmetics Act and The Medical Council of India Act states that all clinical trials in India should follow the ICMR guidelines of 2000. The ICMR has a mechanism of review for its own institutions, and so do other government agencies.
The Drugs Controller General of India or the DCGI is responsible for regulatory approvals of clinical trials in India. The DCGI's office depends on external experts and other government agencies for advice. The ICMR has a Central Ethics Committee on Human Research. This committee audits the functioning of this Institutional Ethics Committee or the IEC. The recently amended Schedule Y of Drugs and Cosmetic Rules order the composition of the IEC as per the ICMR guidelines. 
Compliance with GCP guidelines issued by the Central Drugs Standard Control Organization or the CDSCO is recommended although this does not have statutory status at the present time. A report on the status of the study with details of enrollment and safety issues also needs to be submitted annually and on completion of every study.
These measures suggest that India do have guidelines and regulations at par with the international standards; but, the insufficiency lies with regard to the implementation of these control mechanisms. The shortfall is mainly due to the lack of sanction attached to such provisions in case of violations. The regulatory mechanisms available in the country are scattered in various guidelines having less or sometimes no force of sanction.
ICMR Guidelines and Ethics Committee
The ICMR guidelines for clinical trials mandates setting up of Ethics Committees or EC's at the institutional levels, for the purpose of scrutinizing and approving a clinical trial before it begins; and to to conduct periodic reviews of the progress of the trial. Ethics Committees are not merely ethics advisors and facilitators of clinical trials. They not only reflect on ethical aspects of research, but also play the role of ethics regulator for the DCGI. Their power to conduct ethics review, including the power to reject trials not conforming to ethical standards laid down in the ICMR's ethical guidelines, flows from the legal requirement wherein the DCGI provides clearance to clinical trials only on the condition that they will be reviewed and certified by an EC. But, since the ICMR guidelines are not legislated, ECs do not have the power to punish those who violate ethics in clinical trials.
Also, approval by the Ethics Committee is not a necessary precondition for regulatory permission to conduct a clinical trial provided the applicant submits an undertaking that the study will not be initiated at individual sites without prior EC approval. 
An example to show the gravity of administrative irregularity in this area is the official statistics published by the Indian Council of Medical Research itself. In 2002, the ICMR conducted a survey of 149 ICMR-supported ongoing clinical research/trials in 71 institutions but interestingly, despite ICMR being the funder, only 36 institutions responded. While all 36 claimed to have institutional ethics committees in place, only 23 had standard operating procedures for their review functions and only 14 claimed that they had trained IEC members in research bioethics. Besides, of the 149 research projects analyzed in this study, only 107 (72%) researchers had furnished IEC clearance certificates. This data alone gives proof that despite the presence of broad guidelines and means of its enforcement, India lacks proper regulatory mechanism to put them in force.
Ironically, though the DCGI fully depends on ECs for implementing ethical standards in clinical trials, there is absolutely no direct linkage of any kind between the DCGI and ECs. The DCGI neither cares for the proper functioning of ECs nor assures their competence as these tasks are left to institutions which have a direct interest in trials. In most cases, the legal regulator has no idea how well the ethics regulator is working or whether it is working at all. Thus, the present decentralization of clinical trial governance is a highly an irresponsible one, exposing the legal regulator to the criticism of effectively abandoning its obligations to regulate.
Further, ECs do not report to an independent public authority that is responsible for supervising these committees and ensuring their proper and competent functioning. Nor is their expenditure financed by public funds. Thus they are, in reality, either self-sufficient private bodies obliged to the institutions or independent private entities charging for their services. There is no transparency of their functioning and no public scrutiny of their review and regulation of clinical trials. So, despite a substantial period after forming the EC's in India, it still remains an enigma. Hence, it is high time to make these ethical review panels truly independent.
Shocking Violation of Human Rights
Informed consent is an essential requirement of medical trials, which denotes that the patient undergoing treatment as part of the study should be made aware of the trial being conducted, the drugs being administered on him and its possible side effects. But the country has, at several instances witnessed gross violations of human rights and ethical values while conducting trials on volunteers enrolled in studies. In 1999, without obtaining consent of the patients who were under treatment in the government-run Regional Cancer Centre in Trivandrum, an experimental drug tetraglycinyl nor-dihydro-guaiaretic acid was administered on them. Though there was an established treatment for their condition, they were not informed that they were taking part in an experiment or that they were being denied an established treatment.
Similarly, in 2002, the pharma giant Novo Nordisk conducted multi-centre phase III clinical trials of a diabetes drug even before receiving the results of animal studies. The study report found that the drug, ragaglitazar, caused urinary bladder tumors in rats; and this should have been known before the drug went for phase I trials. The trials were conducted on 650 people from North America, 200 from Latin America, 100 from Australia / New Zealand, 800 from the European Union, and 200 from non EU Europe; and 550 from Asia.
In 2003, Mumbai-based Sun Pharmaceutical Industries Ltd. launched a promotional-cum-research programme by getting private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women as a fertility drug for ovulation induction. The company then publicized the doctors' reports to other doctors as "research", using their network of medical representatives. The drug was prescribed despite the fact that it was known to be toxic to embryos.
These are only a few of the numerous shocking human rights violations that have been exposed in the area of clinical trials. These instances throws light on the lacunae in the Indian legal system for penalizing drug companies that violate norms and mess up while conducting global clinical trials.
Another flaw in the Indian healthcare regulation is the lack of consistency in the licensing procedure. Currently, the interpretation and enforcement procedure varies from one state to another. This variation in procedures creates little accountability, in case an issue arises. At the same time, attempts by the Central government to create a Central Drug Authority is highly appreciable. Such a move gains significance in the context that the US and European drug giants are increasingly outsourcing their clinical testing to the rapidly developing economies like China, India and Africa.
The changing face of regulations in India
Though slowly, India has time and again been adopting new techniques to control the fast expanding medical research industry. As part, in 2004, India has launched the National Pharmacovigilance Programme with World Bank Financial assistance keeping Drug safety surveillance in mind. But unfortunately, the initiative has largely been ignored till date.
At present, the 21 pharmacovigilance centers operating in India is currently in the process of being interlinked with the new cells. A central team in the DCGI office would monitor and oversee co-ordination of the centers and cells.
However, setting up of such centres alone will not address the underlying issues, namely the absence of a robust, workable surveillance mechanism to report adverse events and from which evidence based decisions are made. This calls for proper technological and technical training to operate the proposed pharmacovigilance system.
Currently, the Clinical Research Organizations or the CROs operate using a voluntary process administered by the Indian Council of Medical Research along with World Health Organization. As this process has proved insufficient, the DGCI has now come up with plans for mandatory registration of CROs in a central registry.
The purpose of the Clinical Trials Registry-India is to encourage all clinical trials conducted in India to be prospectively registered before the enrollment of the first participant and to disclose details of the 20 mandatory items of the WHO ICTRP dataset. Nevertheless, the exact registration process and requirements are still in the development stage. The Registry is planned to be a freely available and searchable primary register. To register a study, trialists will submit information including the basic data required by the International Clinical Trials Registry Platform or ICTRP and will receive a WHO assigned unique identification number.
A major benefit of such registration surrounds the exchange of fingerprints of clinical trials volunteers. Fingerprinting of the volunteers is routinely undertaken by many companies in India to prevent people from enrolling in multiple trials. Submission of this data as part of the central registration process would facilitate easy access to the data by all stakeholders in clinical research.
Another initiative from the part of the Ministry of Health and Family Welfare is its decision to invest nearly Rs. 250 crore in an e-governance initiative for the CDSCO to operate efficiently and transparently. Some of the e-governance initiatives contemplated include online submission of all forms, a digitalised interactive portal, digitalisation of records and online approvals with digital sign.
With an exponentially growing clinical trial market, India promises to be one of the hottest destinations for global clinical trials. But, at the same time, to rely simply on minimum standards of non-binding and vague medical ethics is both naive and culturally insensitive. To address the challenges and key issues, India should devise policies and ensure implementation in legislative, Intellectual Property Rights structure and regulatory issues.
There is also a need to develop Clinical Research Organizations with adequate capacity and competency in carrying out research activities in compliance with ICH/GCP guidelines.
Many of the new initiatives for regulating pharma industry in India has been in the charts for quite a long time. What required is speedy implementation and, necessary investment and infrastructure support. India should realize the fact that laws alone would not suffice, there should be a proper administrative and monitory mechanism to ensure its working.
Lack of regulatory jurisdiction over private trial sites and absence of uniform application of the need for informed consent and proper ethics review have raised concerns about trials conducted in India. What we need here is to establish authorities such as the proposed Central Drug Authority and central licensing mechanism for manufacturing approvals. This would essentially help us keep a check over the activities of firms conducting drug trials in India.
   Shiv Raman Dugal, Chairman, BoD, Institute of Clinical Research, New Delhi - “India: Clinical research hot-spot”. www. biospectrumindia.ciol.com. Sept. 08, 2010.
  Kunal Kumar Kundu: “India leads in clinical trials”. AsiaTimesOnline, May 12, 2005.
  “Clinical Trials Regulation”: www.iscr.org.
 Cited by the Indian Brand Equity Federation, available at www.ibef.org.
  P. Sree Sudha (2007): “How ethical are clinical trials in India?” - India Law Journal.
 The Regulatory Affairs Journal – Pharma11. , 2008, 19(12), 840-841.
 e:gov online, 25 November 2008, www.egovonline.net/news/news-details.asp?News=INR-250-Cr.-For-12. e-Governance-Project-of-CDSCO&NewsID=15677
 Anthony Woodman, Suresh Gupta: “Is India Evolving to Support Global Drug Development?”. Jan. 2009
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