Article

Malady of Clinical Trials in India

Anoop Pillai S.*, Balamuralidhar V., Pramodkumar T.M., Pooja M.B.
Pharmaceutical Regulatory Affairs Group, Dept. of Pharmaceutics, J.S.S. College of Pharmacy, J S.S. University, Mysore.

Indias medical tourism is proudly declared as an upcoming industry while a disturbing silence is maintained about clinical trials which was estimated at Rs 1,500 crore in 2010 and is expected to touch Rs 2,760 crore in 2012. Multinational drug companies have been shifting their clinical research from developed to developing countries. The present article highlights how India has emerged as a hotspot for foreign drug companies and the critical success stories driving the industry. It also provides an insight into the issues relating to the Government regulations governing clinical trials i.e. Schedule Y, government support initiatives in India to encourage the clinical trials and the outsourcing opportunities. These drugs testing often prove lethal which can be gauged from the fact that there have been 1,725 deaths during clinical trials in India over the past 4 years. Clinical trials have now emerged as a business opportunity and lucrative way to make money for investigators. The article opines that Government should reinvent Schedule Y via amendments that would make the foreign drug companies realize that The safest way to double their money is to fold it over once and put it in the pocket. Keywords: Schedule Y, CROs, Clinical Trials,

Introduction:
The pharmaceutical industries of the US and Europe are facing severe financial constraints since the past few years, which are expected to worsen in the coming years. With pressures such as increasing cost of introducing (>1 billion USD) New Molecular Entity, tightening regulatory pressures resulting in fewer FDA approvals, blockbuster drugs worth more than $100 billion set to expire by 2014 and drying pipelines of the pharmaceutical industry, cost cutting pressures are mounting on pharmaceutical companies, especially big pharma. Over the past 2 decades, drug manufactures have increasingly shifted trials for drugs intended for the U.S. market to developing countries like India where it is easier and cheaper to recruit trial patients and where oversight is minimal. While outsourcing drug trials may save significant money for the pharmaceutical companies, the cost of human lives and suffering for both the participants of drug trial and American drug users is likely horrendous. The lower-income countries are the clinical trial mill for higher-income countries. India over the last decade has developed significant capabilities in clinical trials, along with certain capabilities in project management and data management. India is able to provide significant cost savings in the range of 50-60% for clinical trials. As the financial and regulatory pressures grow on the US and European pharmaceutical industry, it is expected to further propel the growth in the Indian clinical trial market. This situation creates a major conflict of interest that threatens the well-being of patients.

are desperate for better quality and affordable care. Patients choose public hospitals due to burden to afford the private hospitals services. Various surveys have found that medical expenses are a major factor forcing many Indians below the poverty line1. In this situation, government moves to encourage clinical trials in India must be viewed with concern. Changes have been made in the law to permit international trials. Public hospitals are being promoted as clinical trial sites2. The government has not expressed a stand on the manner in which the clinical research industry is growing in India. Clinical trials are conducted by contract research organisations (CROs) which are developing the infrastructure for trials by making inroads into small towns, identifying trial sites in small private hospitals and developing databases of potential trial participants. Medical professionals are given substantial incentives to recruit their own patients into clinical trials. This situation creates a major conflict of interest that threatens the well-being of patients. India is viewed as a favoured global site for international clinical trials of drugs. In addition to its medical infrastructure and trained, English speaking human-power, it has a large, diverse and treatment-nave [untreated] population with six out of the seven genetic varieties of the human race.3The Indian government has seized upon this opportunity and is taking steps to change the regulatory climate here to accommodate the needs of international clinical trials.

Regulatory Framework For Clinical Trials In India

CTRI (clinical registry of India) is the online registry of prospective clinical trials in India started by the Indian Council of Medical Research and become mandatory for all applicants to register their trial from June 15, 2009 onwards. The purpose of this registry is i. To improve the internal validity of trials ii. Conform to accepted ethical standards iii. And reporting of all relevant results of all clinical trials in India and the region4,5.

Background of Clinical Trials in India

For more than a decade, government policy has been to reduce public support for healthcare services, and these services are underresourced. Health economists have pointed out that only 15% of the Rs. 1,500 billion spent in the health sector in India comes from the government. Two-thirds of health care users bear 100% of their health care expenses. 70% of these health care users are poor3. Patients who visit either government hospitals or private hospitals

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SWOT Analysis of Clinical Trials in India.

Clincial Trials in India: A Swot Analysis Strengths Resourcepool of welltrained, qualified, English speaking manpower. Diverse genetic pool and disease variation. Numerous government funded and private medical and pharmaceutical institutions with state of art facilities. Cost efficiency (up to 60%) in comparison to USA/ Europe. Fast recruitment oflarge number of patients. Establishment of Clinical Trial Registry. In India clinical trials are conducted by CRO and regulated by: 1. Schedule Y of the Drugs and Cosmetics Act. 2. Drugs controller General of India (DCGI) 6 3. Local Ethical review committee (EC) 7 To conduct trials in India, Clinical Research Organizations8 (CROs) have to obtain No Objection letter from the DCGI at New Delhi and import license to import the research drug. Also if it is required, Export NOC is also obtained from DCGI to export the biological samples to central lab outside India for testing purpose. Once CRO obtained the approval from DCGI, they can start their research, provided the local Ethics committee gives approval to conduct studies. If the research drug is narcotic drug, additional approval from various agencies like Central Bureau of Narcotics13 (CBN), Central Excise and state excise, state drug control office has to be garnered. And other legal requirements of schedule Y are like: Definition of phase I-IV Concurrent phase II III Central lab and trial samples. Flexibility in data requirements for new drugs for life threatening / serious condition or disease of relevance to India Classification of fixed dose combination for clinical studies. In post marketing stage, clinical trial designed to explore new indication, new methods of administration or new combination etc. are considered as trials for new pharmaceutical products. Weaknesses of Schedule Y No mechanism to monitor clinical trials. No guidelines as to who can set up the ethics committee (EC) and ensure proper functioning of ECs. Current law talks of compensation, it does not specify the details. Lack of adequate mechanisms to safeguard illiterate and vulnerable patients, prevent informed consent violations. Opportunities Relaxation of duties on import ofclinical trial samples. Removal of phase lag and permission to conduct Phase I trials concurrently in India along with rest of the world. Registered CROs has gone up from 60 to 150. Threats / Challenges Need for a strong centralized regulatory regime to effectively monitor GCP guidelines. Need for expertise on Data Management related specialized services.

1. SCHEDULE Y: (Clinical Trial Regulation in India)

In 1988, as a regulatory requirement, government made it mandatory for all new drug introductions to get NCE approval. 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 centers. The 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. As per Schedule Y of D&C Act, for new drug substances discovered in India, clinical trial has to be carried out in India right from phase 1 and data should be submitted as per Schedule Y requirements. For new drugs distributed outside India, phase 1 as per required in schedule Y should be submitted along with the application. After phase I data generated outside India to the licensing authority, permission may be granted to repeat phase I trials or /and to conduct phase II trials and subsequently phase III trials concurrently with other global clinical trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted. Permission to carry out these trials shall generally be given in stages, considering data emerging from earlier phases. In the present Intellectual Property Right (IPR) regime, it has become extremely important for conducting timely clinical research. Increasingly, permission for Phase I trial is being granted after thorough appraisal of the protocols, products and claims. The government has relaxed duties levied on clinical trial samples which indicates its commitment in strengthening Indias 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 case of purified products of genetically modified organisms (GMOs), used in drugs such as vaccines, interferon and diagnostics.

2. Ethics Committee9
Clinical trials are closely supervised by appropriate regulatory authorities. All studies that involve a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise nonintervention studies (observational studies or those using already collected data). To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRBs main functions is ensuring that potential patients are adequately informed about the clinical trial). If the patient is unable to consent for him/herself, researchers can seek consent from the patients legally authorized representative. The notion of informed with consent of participating human subjects10 exists in many countries all over the world, but its precise definition may still vary.

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Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. Additional ethical concerns are present when conducting clinical trials on children (paediatrics).

has announced various short-term, medium-term and long-term goals towards encouraging international clinical trials in India. The short-term goals include developing guidelines for registering CROs, training clinical trial site inspectors, a robust review process, and meeting timelines. Mid-term goals are registration of CROs, inspection of sites, guidelines for registering ECs, and mandatory registration of clinical trials. Import duty has been lifted on clinical trial supplies and permission for export of clinical trial specimens will be granted at the same time as the protocol is approved by the DCGI. The DCGI also stated that fingerprints of trial participants is planned to prevent them from entering more than one trial. The governments long term goals as stated by the DCGI include changing the law to permit phase 0 (micro-dosing) and phase 1 trials. As of now, the Drugs and Cosmetics Act does not permit phase 1 trial of foreign drugs in India unless the drug is of local relevance. However, discussions are currently on to introduce phase 0 and phase 1 trials. Other long-term goals include a central drug authority, and penal provision for CRO fraud. A clinical trials export promotion council may be setup to achieve the above mentioned goals.

3. Drug Contoller General Of India (DCGI)

Trial sponsor must obtain approval from the DCGI before starting a trial & should submit data from pharmacokinetic and animal studies. Phase I trials collect information on the drug, including its safety and adverse reactions. They are usually conducted on a small number of healthy volunteers. Phase II trials11 evaluate the effectiveness and safety of a drug on patients. Phase III trials are conducted on larger numbers of people to confirm the evidence from earlier phase trials towards obtaining marketing approval of the drug. Phase IV trials are conducted after a drug obtains marketing approval. They are conducted for various purposes including monitoring for drug interactions and testing for new uses of the drug.

Cro (Contract Research Organization):

Clinical trials are conducted by contract research organizations (CROs), which may handle some or all aspects of a sponsors project including: regulatory approvals for trials, identifying recruiting sites and investigators, monitoring sites, data entry and management, submitting data for marketing approval and drafting study reports for submission to journals. These activities may also be split up and handled by different organizations. Some organizations focus exclusively on providing data management and statistical analysis. Trial sites that do not have institutional review boards may approach stand alone ethics committees not affiliated to any institution. Site maintenance organizations12 (SMOs) are focused exclusively on recruiting patients and coordinating the work of investigators conducting clinical trials. Some CROs commit to drafting journal articles and getting them published. Independent databases are also developed through physician referrals, health camps, patient education programs and community outreach through social workers and NGOs, and advertisements in the media. Medical professionals are given substantial incentives to recruit their own patients into clinical trials. Drug companies conduct clinical trials through Contract Research Organizations (CROs), commercial entities whose job it is to get the research done and to meet regulatory requirements. Since the early 2000s, there seems to have been a sharp rise in the number of Contract Research Organizations functioning in India; the DCGI has stated that the estimated number of Contract Research Organizations in India registered with the USFDA has gone from 60 to 150. Most of the CROs agrees that clinical trials contribute a major fraction to the countrys international income.

Amendments to Schedule Y13:

Till January 2005, clinical trials of new drugs being developed outside India were permitted only with a phase lag: a phase 2 trial could be conducted in India only after phase 3 trials were completed elsewhere. Phase 1 trials of foreign drugs were not permitted, except for drugs of special relevance to India like phase 1 trials for HIV Vaccines in India. As of January 2005, an amendment of Schedule Y of the Drugs and Cosmetics Rules did away with the phase lag in international clinical trials conducted by foreign sponsors. There are no longer any restrictions on concurrent phase clinical trials in India. Phase 2 and phase 3 trials of drugs discovered abroad may now be conducted in India in the same phase and at the same time as they are conducted in other parts of the world. The trial sponsor must obtain approval from the DCGI before starting a trial. For this approval, the sponsor must submit data from pharmacokinetic and animal studies and previous phase trials. Trials cannot be started without clearance from the local ethics review committee (EC) at each site. Before 2005, the Drugs and Cosmetics Rules suggested, but did not require, that clinical trial documents be reviewed by an ethics review committee. The Indian Council of Medical Research (ICMR) first published detailed guidelines for biomedical research in 2000. These include guidelines for ethical review. Revised guidelines published in 2006 states that the ethics review committee is also responsible for monitoring trials. Now the law requires that all ECs register with a Biomedical Research Authority. This authority will also evaluate the functioning of ECs. An ICMR survey found that only 40 of 179 Institutional Ethical Committees follow the prescribed legal provisions and function as per various ethical guidelines. There is no central register of EC decisions and if a protocol is rejected by one local EC it may be submitted elsewhere. The sponsor is not obliged to inform an EC or the DCGI if the protocol being submitted to it has been rejected elsewhere. Further, the DCGI is not equipped to monitor existing clinical trials in India.

Government Steps to Promote Clinical Trials In India:

In addition to changes in the law (that have already taken effect), single window clearance for applications is planned in order to reduce the approval procedure to between two and six weeks. A two-tier approval process is already put in place. Category A protocols consist of protocols from the US, United Kingdom (UK), EU and Japan. Category A trials will get fast track approval i.e. within 6 to 8 weeks whereas category B trials from other countries will get approval in eight to 12 weeks. The government will grant a license to import supplies within 2 weeks of the application being made. The DCGI has also promised that local EC review will be completed in 6 to 8 weeks. The DCGI announced plans to recruit subject experts and has also got approval for 60 new drug inspectors. 20 of these inspectors will be responsible exclusively for auditing clinical trials. The DCGI

Loopholes in Schedule-Y:
All clinical trials, approved by the DCGI, must be noted in the Clinical Trial Registry of India, launched in 2007. However, the registry only gives information on the purpose of the trial, the

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number of people participating in the trial, the date on which it will start and end, and the places or sites where the trial will be conducted. There is no mechanism to monitor clinical trials. After approval by the DCGI, a trial has to be approved by an ethics committee. But, there are no guidelines on who can set it up. Though the ICMR has framed guidelines on conducting clinical trials on humans, a draft bill on the guidelines is yet to be examined before it is tabled in Parliament. The testing of foreign drugs has become much easier in India after changes were made to the Drugs and Cosmetics Rules in 2005. There is a laxity of norms governing these trials which has resulted in gross injustice to the poor. Current law talks of compensation, it does not specify the details. The drug companies have accepted only 25 cases where death was caused because of the trial. Moreover, compensation has been given only in five cases, with the maximum amount being Rs 3 lakh. There have been cases where the consent of the participant was not taken, or where the consent form has been filled by a person other than the participant, or where the forms have been filled incorrectly. In such cases, it becomes difficult to trace those who participated in the trial.

personnel. There is increasing adoption of GCP Guidelines. 5. Patent Protection and Intellectual Property RightsIssues have been resolved. Since January 2005, India is now on par with developed nations by becoming compliant with the Trade Related Intellectual Property Rights Act (TRIPS). 6. India possesses aworld class data-processing infrastructurefor biostatistics and bioinformatics. 7. India possesseslarge generic drug manufacturing facilities. Because of these factors, clinical trials industry in India is expected to grow at a CAGR of almost 40%.

Why People in India Participate in Clinical Trials:

A CRO-conducted survey of the informed consent process in clinical trials provides some interesting information on the patient recruitment procedure and the quality of informed consent in clinical trials in India. This survey was of patients participating in trials run by the CRO Excel Life Sciences and began in July 2008. As of October 2008, 525 patients from 40 sites had been interviewed. Most were treatment nave (untreated for the condition for which the drug was being tested) when they entered the trial. 76% of patients said the trials principal investigator was their primary physician and 21% said they were referred by their primary care physician. In other words, 97% of patients entered the trial because of their primary care physician. They may be easily influenced by the doctors advice. They may also believe that refusal to follow the doctors advice to enter a trial would affect their access to care. When the trials principal investigator is also the persons primary physician, there is scope for a direct conflict of interest, especially if physicians are paid recruitment fees to recruit their patients into trials16.

Bright Future for Clinical Trials in India14:

For studies in many therapeutic areas, the Indian sub-continent is desirable because of itslarge population of qualified patients, lower trial costs, use of English as the primary language, and a well-trained medical community.Increasing government incentives and regulatory supportfor research and an increasing number of qualified investigative sites are all major benefits of conducting clinical trials in India. In 2004 Criterium established a Data Management Centre in Pune, India as a continuation of its strategy for having a worldwide team provide 24-hour coverage on clinical research projects. In 2005, Criterium India added monitoring, Clinical Liaison and Business Development functions to the Pune office. Personnel in these roles oversee studies in a growing number of Indian sites, and they develop our continuing marketing outreach to clients in India. This represents the best and most experienced team of medical professionals throughout India. Clinical trials in India have also occasionally undergone regulatory or sponsor audits proving superiorin meeting international and Regulatory standards.

Are Indians Being Used for the benefit of the Western World?
The use of Indians for the benefit of the Western world has extensively been criticized. Before jumping into any ill-informed conclusions, it would be worthwhile to understand the benefits of clinical research. Patients/study subjects who participate in clinical trials have access to the latest medication or treatment modalities, get free medical care which includes costs of investigations and medicine, receive more frequent and focused consultations leading to an improvement in the quality of healthcare. Investigators/physicians who conduct clinical trials get first-hand experience with the most recent drugs get global recognition working on the same platform as other international counterparts on the project, get extensive training in the internationally accepted GCP and GLP guidelines, have access to the latest medicines for their patients. Sites/Hospitals where the research is conducted get infrastructural development and get global recognition. But a report in The Indian Express dated 26th September, 2011 states that, Indians are treated as guinea pigs for clinical trials by multinational pharma majors and very few cares to compensate the victims of the trials, reveals data put out by the Union health ministry. 1593 people died during clinical trials of drugs conducted by various multinational pharmaceutical companies in 2008-10, according to the Directorate General of Health Services. Deaths over the years

Factors that Continue to make India attractive for Future Clinical Trial Outsourcing15:
1. Increasing Global R & D Costs 2. Increasing Pharmaceutical Development Time- In US, average development time is now approaching 15 years. Typical clinical studies take up 30-50% of R&D time, a third of which is spent on patient recruitment. As patent protection periods include time spent in R&D, it is crucial to streamline the development process as much as possible. 3. India has a large, heterogeneous population pool of over 1 billion, with large-scale incidences of cancer, diabetes, and other infectious diseases. Shorter recruitment timelines and increased patient compliance are prevalent in India. 4. World Class Facilities: India currently has over 700,000 specialty hospital beds (at approx. 10% of the daily cost of developed nations), 221 medical colleges and English-speaking medical

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 2008 288 deaths 2009 637 deaths 2010 688 deaths 22 cases alone got compensation, DGHS said in response to an RTI (Right to Information) query that Rupees 53 lakh compensation paid in 22 cases in 2010.

their patent. (Online) Available at: http://www.dailyfinance. com/2011/02/27/top-selling-drugs-are-about-to-lose-patentprotection-ready/Accessed on: 5 November 2011 4. Satish A. The productivity tiger time and cost benefits of clinical drug development In India (Online) Available at: http://pharmalicensing. com/public/articles/view/1153412098_44bfac02291f1 Accessed: 3 January 2012 5. Duggal R. The out-of-pocket burden of healthcare. Agenda: Access to public health. Pune, India: Centre for Communication and Development Studies, 2005. pp 20-25. 6. Pandey A, Aggarwal AR, Seth SD, Maulik, M, Juneja A. Strengthening ethics in clinical research. Indian J Med Res. 2011 Mar; 133(3):339-40. 7. ScheduleY, Amendment version 2005, Drugs and Cosmetic Rules, 1945(Online) Available at http://cdsco.nic.in/html/schedule-y%20 (amended%20version-2005)%20original.htm Accessed: 24 December 2011 8. ICH Guideline for Good Clinical Practice: Consolidated Guidance (Online) available at http://www.ich.org/LOB/media/MEDIA482.pdf Accessed: 29 December 2011 9. Arun Bhatt, president, Clininvent (contract research organisation), interviewed in Mumbai, November 15, 2008 10. Website of IRL Research. Patient recruitment approach. Viewed on July 1, 2009 (http://www.irlresearch.com/patient-recruitmentapproach.htm) 11. Inaugural address of Surinder Singh, Drugs Controller General of India, at a conference of the Institute of Clinical Research (India), Mumbai, October 10-11, 2008. 12. http://criteriuminc.com/docs/Criterium_India.pdf 13. 14. Sinha G. Outsourcing drug work: pharmaceuticals ship R&D and clinical trials to India. Scientific American Online, August 16, 2004. (http://www.sciam.com/article.cfm?articleID=00033282DBF5-10F9-975883414B7F0000) Last Assessed December 21, 2011. 14. Lamberti MJ, Space S, Gammbrill S. Going global. Appl Clin Trials2004; 13:84-92. 15. Borfitz D. Lifting Indias barriers to clinical trials.Center Watch2003; 10(8): 1-9. 16. Presentation by Dan Mcdonald, vice president, business development, Excel Life Sciences, at a meeting of the Institute of Clinical Research (India), Mumbai, October 10-11, 2008.

Conclusion:
Due to restricted press freedom and the ease of suppressing negative results, the true scope of the harm caused to drug-naive patients in developing rescue countries is not fully known. However, numerous discoveries and reports of drug trial deaths, uninformed patients and other acts of abuse and deception leave no doubt that developing drug trial patients are being killed and abused. The infrastructure for regulation, ethics review and monitoring is insufficient. The governments priority seems to be ensuring that clinical research in India produces good quality data according to Good Clinical Practice standards & its own ethical guidelines seem to be of secondary importance. The Government policy to encourage international clinical trials without taking strong steps to develop a system to protect participants from harm; peoples desperation for affordable health care all this will only worsen the harm being done to trial participants in India. The existing regulatory apparatus therefore permits unethical trials of no benefit to Indians & unless we put in place systems that ensure safety of patients and good quality of trials, people will get away with whatever they can get away with and only a sustained and persistent will can help us attain global expectations of quality and speed! Until then, we have to be ready to bear the pangs of globalization!

References:
1. Iyer A. Ill and impoverished: The medical poverty trap, Agenda: Access to public health (Pune, India: Centre for Communication and Development Studies) 2005. pp 16-18. 2. Presentation by Surinder Singh, Drugs Controller General of India, at the meeting of the Institute of Clinical Research (India), Mumbai, October 10-11, 2008. 3. Melly A. The 10 biggest selling drugs that are about to lose

13th ISE report

Opening of the Indian Chapter of the International Society for Ethnopharmacology (ISE-INDIA)
The 13th International Congress of the Society for Ethnopharmacology was organized by the University of Graz, Institute of Pharmaceutical Sciences, in Graz, Austria, from 2nd6th September, 2012. The congress focused on the intercultural aspects of herbal medicine and its relevance in modern societies. Dr. Pulok K. Mukherjee was an invited speaker. There was a huge participation from the Indian scientists in the field of Ethnopharmacology. More than fifty Indian scientists attended this congress and presented their research work. The society will act as a forum of likeminded scientific and teaching professionals in ethnopharmacology and professionals of other area interested in developing the cost effective natural remedies, establish R & D centre for drug development and start a training program to impart theoretical, practical and technical education in adults and knowledge among the youths in the pursuit of self-employment and selfentrepreneurship and developing methods for validation of natural products.

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