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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.

India’s 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, CRO’s, Clinical Trials,

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 hospital’s 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-naïve [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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Once CRO obtained the approval from DCGI. • In post marketing stage. considering data emerging from earlier phases. 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). researchers can seek consent from the patient’s legally authorized representative. 2. Phase III trials are required to be conducted in India before permission to market the drug in India is granted. government made it mandatory for all new drug introductions to get NCE approval.  Need for expertise on Data Management related specialized services. If the patient is unable to consent for him/herself. Threats / Challenges  Need for a strong centralized regulatory regime to effectively monitor GCP guidelines. Drugs controller General of India (DCGI) 6 3. The government has relaxed duties levied on clinical trial samples which indicates its commitment in strengthening India’s position and propelling it as world leader in clinical research. new methods of administration or new combination etc. For new drugs distributed outside India. 2. phase 1 as per required in schedule Y should be submitted along with the application.  Current law talks of compensation. but its precise definition may still vary. Local Ethical review committee (EC) 7 To conduct trials in India. Permission to carry out these trials shall generally be given in stages.  Lack of adequate mechanisms to safeguard illiterate and vulnerable patients.  Diverse genetic pool and disease variation. SCHEDULE Y: (Clinical Trial Regulation in India) In 1988. In the present Intellectual Property Right (IPR) regime. Pharma Times . In India clinical trials are conducted by CRO and regulated by: 1. prevent informed consent violations. it does not specify the details. The local ethics committee has discretion on how it will supervise nonintervention studies (observational studies or those using already collected data). (One of the IRB’s main functions is ensuring that potential patients are adequately informed about the clinical trial). Schedule Y of the Drugs and Cosmetics Act. 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. 1. Clinical Research Organizations8 (CROs) have to obtain ‘No Objection’ letter from the DCGI at New Delhi and import license to import the research drug.  Cost efficiency (up to 60%) in comparison to USA/ Europe. As per Schedule Y of D&C Act.  Removal of phase lag and permission to conduct Phase I trials concurrently in India along with rest of the world.No. Increasingly. it has become extremely important for conducting timely clinical research. Export NOC is also obtained from DCGI to export the biological samples to central lab outside India for testing purpose.  No guidelines as to who can set up the ethics committee (EC) and ensure proper functioning of EC’s.December 2012 17 .Vol. clinical trial designed to explore new indication. clinical trial has to be carried out in India right from phase 1 and data should be submitted as per Schedule Y requirements. 44 . And other legal requirements of schedule Y are like: • Definition of phase I-IV • Concurrent phase II –III • Central lab and trial samples. English speaking manpower. are considered as trials for new pharmaceutical products. Clincial Trials in India: A Swot Analysis Strengths  Resource pool of welltrained. • 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.  Establishment of Clinical Trial Registry. for new drug substances discovered in India. To be ethical. as a regulatory requirement. 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. state drug control office has to be garnered. interferon and diagnostics.SWOT Analysis of Clinical Trials in India.  Registered CRO’s has gone up from 60 to 150. researchers must obtain the full and informed consent of participating human subjects. If the research drug is narcotic drug. additional approval from various agencies like Central Bureau of Narcotics13 (CBN). 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. Opportunities  Relaxation of duties on import of clinical trial samples. used in drugs such as vaccines.  Fast recruitment of large number of patients. After phase I data generated outside India to the licensing authority. qualified. 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. permission for Phase I trial is being granted after thorough appraisal of the protocols. Also if it is required. products and claims. Ethics Committee9 Clinical trials are closely supervised by appropriate regulatory authorities. provided the local Ethics committee gives approval to conduct studies.  Numerous government funded and private medical and pharmaceutical institutions with state of art facilities. 12 . Central Excise and state excise. The notion of informed with consent of participating human subjects10 exists in many countries all over the world. Weaknesses of Schedule Y  No mechanism to monitor clinical trials. they can start their research.

The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. Category A trials will get fast track approval i. including its safety and adverse reactions. 44 . 3. 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. must be noted in the Clinical Trial Registry of India. monitoring sites. there seems to have been a sharp rise in the number of Contract Research Organizations functioning in India. An ICMR survey found that only 40 of 179 Institutional Ethical Committees follow the prescribed legal provisions and function as per various ethical guidelines. “Independent databases” are also developed through physician referrals. 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. 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. They are conducted for various purposes including monitoring for drug interactions and testing for new uses of the drug. Trial sites that do not have institutional review boards may approach “stand alone” ethics committees not affiliated to any institution. that clinical trial documents be reviewed by an ethics review committee. discussions are currently on to introduce phase 0 and phase 1 trials. identifying recruiting sites and investigators. As of January 2005. A two-tier approval process is already put in place. has announced various short-term. Phase II trials11 evaluate the effectiveness and safety of a drug on patients. Phase I trials collect information on the drug. Additional ethical concerns are present when conducting clinical trials on children (paediatrics). within 6 to 8 weeks whereas category B trials from other countries will get approval in eight to 12 weeks. single window clearance for applications is planned in order to reduce the approval procedure to between two and six weeks. EU and Japan. The DCGI Loopholes in Schedule-Y:  All clinical trials. The sponsor is not obliged to inform an EC – or the DCGI – if the protocol being submitted to it has been rejected elsewhere. The DCGI announced plans to recruit subject experts and has also got approval for 60 new drug inspectors. the DCGI is not equipped to monitor existing clinical trials in India. patient education programs and community outreach through social workers and NGOs. Some CROs commit to drafting journal articles and getting them published. launched in 2007. and mandatory registration of clinical trials. a “robust” review process. For this approval. inspection of sites. Drug companies conduct clinical trials through Contract Research Organizations (CROs). There is no central register of EC decisions and if a protocol is rejected by one local EC it may be submitted elsewhere. training clinical trial site inspectors. Amendments to Schedule Y13: Till January 2005. submitting data for marketing approval and drafting study reports for submission to journals. Some organizations focus exclusively on providing data management and statistical analysis. These activities may also be split up and handled by different organizations.e. The government’s long term goals as stated by the DCGI include changing the law to permit phase 0 (micro-dosing) and phase 1 trials. Cro (Contract Research Organization): Clinical trials are conducted by contract research organizations (CROs). Revised guidelines published in 2006 states that the ethics review committee is also responsible for monitoring trials. Phase 1 trials of foreign drugs were not permitted.No. Site maintenance organizations12 (SMOs) are focused exclusively on recruiting patients and coordinating the work of investigators conducting clinical trials. The government will grant a license to import supplies within 2 weeks of the application being made.December 2012 18 . Government Steps to Promote Clinical Trials In India: In addition to changes in the law (that have already taken effect). These include guidelines for ethical review. The short-term goals include developing guidelines for registering CROs. and meeting timelines. guidelines for registering ECs. The trial sponsor must obtain approval from the DCGI before starting a trial. As of now.Vol. However. Now the law requires that all ECs register with a Biomedical Research Authority. except for drugs of special relevance to India like phase 1 trials for HIV Vaccines in India. the sponsor must submit data from pharmacokinetic and animal studies and previous phase trials. However. commercial entities whose job it is to get the research done and to meet regulatory requirements. Since the early 2000s. Before 2005. the Pharma Times . and penal provision for CRO fraud. A clinical trials export promotion council may be setup to achieve the above mentioned goals. health camps. approved by the DCGI. They are usually conducted on a small number of healthy volunteers.Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. 12 . 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. data entry and management. the DCGI has stated that the estimated number of Contract Research Organizations in India registered with the USFDA has gone from 60 to 150. the Drugs and Cosmetics Act does not permit phase 1 trial of foreign drugs in India unless the drug is of local relevance. 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 registry only gives information on the purpose of the trial. medium-term and long-term goals towards encouraging international clinical trials in India. Most of the CRO’s agrees that clinical trials contribute a major fraction to the country’s international income. Medical professionals are given substantial incentives to recruit their own patients into clinical trials. The DCGI also stated that fingerprints of trial participants is planned to prevent them from entering more than one trial. This authority will also evaluate the functioning of ECs. but did not require. and advertisements in the media. 20 of these inspectors will be responsible exclusively for auditing clinical trials. There are no longer any restrictions on “concurrent phase” clinical trials in India. Phase IV trials are conducted after a drug obtains marketing approval. The DCGI has also promised that local EC review will be completed in 6 to 8 weeks. Trials cannot be started without clearance from the local ethics review committee (EC) at each site. Mid-term goals are registration of CROs. United Kingdom (UK). Category A protocols consist of protocols from the US. Further. which may handle some or all aspects of a sponsor’s project including: regulatory approvals for trials. 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. Other long-term goals include a central drug authority. the Drugs and Cosmetics Rules suggested. The Indian Council of Medical Research (ICMR) first published detailed guidelines for biomedical research in 2000.

have access to the latest medicines for their patients.  After approval by the DCGI. 10% of the daily cost of developed nations). with large-scale incidences of cancer. a draft bill on the guidelines is yet to be examined before it is tabled in Parliament. it would be worthwhile to understand the benefits of clinical research. 7.  Deaths over the years Factors that Continue to make India attractive for Future Clinical Trial Outsourcing15: 1. it becomes difficult to trace those who participated in the trial. reveals data put out by the Union health ministry. India has  a large. a third of which is spent on patient recruitment. Personnel in these roles oversee studies in a growing number of Indian sites. As patent protection periods include time spent in R&D. and they develop our continuing marketing outreach to clients in India. average development time is now approaching 15 years. Shorter recruitment timelines and increased patient compliance are prevalent in India. 3. India possesses a world class data-processing infrastructure for biostatistics and bioinformatics. and a well-trained medical community. and other infectious diseases. according to the Directorate General of Health Services. Because of these factors. and the places or sites where the trial will be conducted.000 specialty hospital beds (at approx. They may be easily influenced by the doctor’s advice. Increasing government incentives and regulatory support for research and an increasing number of qualified investigative sites are all major benefits of conducting clinical trials in India. 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.No. The drug companies have accepted only 25 cases where death was caused because of the trial.  There have been cases where the consent of the participant was not taken. personnel. get extensive training in the internationally accepted GCP and GLP guidelines. But a report in “The Indian Express” dated 26th September. Typical clinical studies take up 30-50% of R&D time. the date on which it will start and end. 5. lower trial costs. there are no guidelines on who can set it up. But. it does not specify the details. India possesses large generic drug manufacturing facilities. compensation has been given only in five cases. a trial has to be approved by an ethics committee. 2011 states that. 221 medical colleges and English-speaking medical Pharma Times . 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. In other words. 76% of patients said the trial’s principal investigator was their primary physician and 21% said they were referred by their primary care physician. When the trial’s principal investigator is also the person’s primary physician. it is crucial to streamline the development process as much as possible.  Though the ICMR has framed guidelines on conducting clinical trials on humans. 12 . There is increasing adoption of GCP Guidelines. As of October 2008. World Class Facilities: India currently has over 700.  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. In 2004 Criterium established a Data Management Centre in Pune. the Indian sub-continent is desirable because of its large population of qualified patients. There is no mechanism to monitor clinical trials. 4.In US. 525 patients from 40 sites had been interviewed. Criterium India added monitoring. diabetes. there is scope for a direct conflict of interest. India is now on par with developed nations by becoming compliant with the Trade Related Intellectual Property Rights Act (TRIPS). Current law talks of compensation. receive more frequent and focused consultations leading to an improvement in the quality of healthcare. Clinical trials in India have also occasionally undergone regulatory or sponsor audits proving superior in meeting international and Regulatory standards.  The testing of foreign drugs has become much easier in India after changes were made to the Drugs and Cosmetics Rules in 2005. Bright Future for Clinical Trials in India14: For studies in many therapeutic areas. 6. 97% of patients entered the trial because of their primary care physician. ‘ Indians are treated as guinea pigs for clinical trials by multinational pharma majors and very few cares to compensate the victims of the trials. get free medical care which includes costs of investigations and medicine. Clinical Liaison and Business Development functions to the Pune office. or where the consent form has been filled by a person other than the participant. especially if physicians are paid recruitment fees to recruit their patients into trials16. use of English as the primary language. Moreover.  Sites/Hospitals where the research is conducted get infrastructural development and get global recognition. This survey was of patients participating in trials run by the CRO Excel Life Sciences and began in July 2008.’  1593 people died during clinical trials of drugs conducted by various multinational pharmaceutical companies in 2008-10. In 2005. India as a continuation of its strategy for having a worldwide team provide 24-hour coverage on clinical research projects.  Patients/study subjects who participate in clinical trials have access to the latest medication or treatment modalities. heterogeneous population pool of over 1 billion.  There is a laxity of norms governing these trials which has resulted in gross injustice to the poor. They may also believe that refusal to follow the doctor’s advice to enter a trial would affect their access to care. In such cases. Before jumping into any ill-informed conclusions.Vol. Increasing Global R & D Costs 2. Increasing Pharmaceutical Development Time. clinical trials industry in India is expected to grow at a CAGR of almost 40%. with the maximum amount being Rs 3 lakh. 44 . Patent Protection and Intellectual Property Rights Issues have been resolved.December 2012 19 .number of people participating in the trial. This represents the best and most experienced team of medical professionals throughout India. Since January 2005. or where the forms have been filled incorrectly. Most were treatment naïve (untreated for the condition for which the drug was being tested) when they entered the trial.

There was a huge participation from the Indian scientists in the field of Ethnopharmacology.pdf 13. 2009 (http://www. “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. com/public/articles/view/1153412098_44bfac02291f1 Accessed: 3 January 2012 5. 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. Borfitz D. interviewed in Mumbai. 7. Mumbai. The Government policy to encourage international clinical trials without taking strong steps to develop a system to protect participants from harm. 2. Gammbrill S. Presentation by Dan Mcdonald.htm)  16. The government’s 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. Pharma Times . Duggal R. Drugs Controller General of India. at a conference of the Institute of Clinical Research (India). More than fifty Indian scientists attended this congress and presented their research work. from 2nd6th September. 3. uninformed patients and other acts of abuse and deception leave no doubt that developing drug trial patients are being killed and abused. Excel Life Sciences. Outsourcing drug work: pharmaceuticals ship R&D and clinical trials to India. (http://www. Maulik. Going Dr. 1945(Online) Available at http://cdsco. Conclusion: Due to restricted press freedom and the ease of suppressing negative results. 2004.• 2008 – 288 deaths • 2009 – 637 deaths • 2010 – 688 deaths  22 cases alone got compensation.cfm?articleID=00033282DBF5-10F9-975883414B7F0000) Last Assessed December 21. Pune. 2008. The infrastructure for regulation. November 15. Iyer A. at a meeting of the Institute of Clinical Research (India). However. 13:84-92. ICH Guideline for Good Clinical Practice: Consolidated Guidance (Online) available at http://www. “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. Institute of Pharmaceutical Sciences. vice president. 2008. 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.December 2012 20 .nic.irlresearch. 2011. Mumbai. 14.ich. Satish A. 2005. October 10-11. Lifting India’s barriers to clinical trials. 133(3):339-40. 12 . Clininvent (contract research organisation).   15. Schedule–Y. 6. Austria. Pulok K. Sinha G. ethics review and monitoring is insufficient. Viewed on July 1. Pandey A. India: Centre for Communication and Development Studies) 2005. at the meeting of the Institute of Clinical Research (India). http://criteriuminc. 2008. Aggarwal AR. the true scope of the harm caused to “drug-naive patients” in developing “rescue countries” is not fully known. 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. Mukherjee was an invited speaker. October 10-11. DGHS said in response to an RTI (Right to Information) query that Rupees 53 lakh compensation paid in 22 cases in 2010. 2008 10. Inaugural address of Surinder Singh. people’s desperation for affordable health care – all this will only worsen the harm being done to trial participants in India.” (Online) Available at: http://www. ‘Ill and impoverished: The medical poverty trap’. 2012. India: Centre for Communication and Development Studies. Website of IRL Accessed: 29 December 2011 9. Juneja A. 2011 Mar. com/2011/02/27/top-selling-drugs-are-about-to-lose-patentprotection-ready/Accessed on: 5 November 2011 4. Indian J Med Res. their patent.Vol. The out-of-pocket burden of healthcare. numerous discoveries and reports of drug trial deaths. Strengthening ethics in clinical research. Agenda: Access to public health (Pune. Drugs and Cosmetic Rules. pp 20-25. 10(8): 1-9. Drugs Controller General of India.dailyfinance. Scientific American (amended%20version-2005)%20original. pp 16-18. Amendment version 2005. Arun Bhatt. Lamberti MJ.  Appl Clin Trials 2004. establish R & D centre for drug development and start a training program to impart theoretical. The congress focused on the intercultural aspects of herbal medicine and its relevance in modern societies. in Graz. “The productivity tiger – time and cost benefits of clinical drug development In India” (Online) Available at: http://pharmalicensing. we have to be ready to bear the pangs of globalization! References: 1. Melly A.htm Accessed: 24 December 2011 8. Presentation by Surinder Singh. M. 14. business development.No. Seth SD. ‘Patient recruitment approach’.sciam. Agenda: Access to public health. 12. Space S. Center Watch 2003. October 10-11. August 16. Mumbai. 44 .