Clinical Drug Trials and Ethical Dilemma in the Indian Context

Introduction The world of Medicine is making progress in the diagnosis and treatment of many diseases, which have plagued mankind for centuries. The pace of progress is really overwhelming. New drugs are introduced continuously. The evaluation of their efficacy and safety is an arduous and costly process that involves laboratory work, animal studies and human trials. Someone must take a new drug first hence, human experimentation is unavoidable. Indian Scenario The fact that India has the largest pool of patients suffering from cancer, obesity, diabetes and metabolic syndrome is leading the country to an altogether different destination of the global hub of outsourcing of clinical trials. In recent years, India has made tremendous progress in the international pharmaceutical arena as a preferred destination for leading global companies to conduct clinical trials and there exists a basic regulatory regime governing the conduct of clinical trials. Adequate knowledge of good clinical practice (GCP) requirements along with ethical concerns has resulted in a need of stringent regulatory requirements. Almost all majors in the pharmaceutical world have their division in India, setting up clinical trial facilities in major cities. Some of them are Eli Lilly, Pfizer, Roche, SIRO Clinpharm, Wellquest (clinical trials division of the Nicholas Piramal), Clinigene International Research being conducted by pharmaceutical and biotechnology companies in India has been on the increase. Added to this, has been the mounting quantum of outsourced research facilitated by Contract Research Organizations (CROs) with the promise of cheaper and faster conduct of trials as compared to the west. This is

largely due to the countrys lower costs and various other advantages. Moreover, many domestic pharmaceutical companies have increased their R&D spending for new drug development and are outsourcing clinical trials to various CROs. With this rapid increase in clinical trials outsourcing, the market is set to exhibit steady growth in future, thus providing players an opportunity to increase profitability. This have concerns about little benefit or relevance to the public health needs of the country. The allegations of unethical conduct in clinical trials have again brought a focus on the need for regulatory reform and stringent ethical safeguards. From 40 to 50 trials in 2003, the country saw around 2000 trials registered with the government registry up to January 2012. Ethical Dilemma As per a recent news report, as many as 2,469 people in India have died because of the clinical drug trials they were subjected to in the past five years. Only 38 of them have been compensated. No action has been taken so far against any pharma company or ethics committee that oversees clinical trials or CROs that conducts the trials, which have been found guilty of unethical practices. The information became public during the hearing of a Right to Information petition by the Central Information Commission on June 29. This is the first time that the office of the Drugs Controller General of India (DCGI) has also admitted to not paying compensation for any of the deaths that have occurred so far except in 2010-2011. A recent revelation by a leading daily that in the year 2011 alone, 438 people died due to serious adverse events during drug trials in India, but drug companies provided financial compensation in only 16 such cases. The total amount paid in compensation in all the 16 cases adds up to only Rs. 34.88 lakh with the highest amount being Rs. 5 lakh and the lowest being Rs. 50,000. This makes 2011 only the second year, for which data are available, when any

compensation was paid in cases of deaths caused during drug trials, the other being 2010, when 22 cases were compensated. Even though, the escalating research quantum has served little to benefit the Indian population which now is undergoing a demographic transition with both infectious and non-communicable diseases being commonplace; it has also raised concerns that ethical conduct is often forgone when the primary interest increasingly is profit generation rather than subjects welfare. The presence of unethical trials being frequently reported is a reflection of an ailing and substantially ineffective research regulation system in India. While clinical drug trials in the country have increased exponentially in the last decade, reforms in regulations have only occurred at a snail's pace. Even drugs continue to be approved in India without having undergone proper clinical trials on the local population. Just months after the parliamentary standing committee on health exposed how the country's highest office on drugs, Central Drugs Standard Control Organization (CDSCO), approved 33 new drugs between January 2008 and October 2010 without testing them through trials on Indian subjects. Union health minister recently admitted that between January and July 2012, the CDSCO has approved 14 new drug molecules of which 5 of the drug has been approved without clinical trials. This situation is very pathetic and it has to be believed that Indian authorities are least bothered about the health of the people. A number of news articles have also appeared in leading newspapers of the country with regard to irregularities in the conduct of clinical trials in India. Notable among these are dubious consent taking procedures and allegations of

drug trials on the poor without subjects consent and information. Ethics Committees (ECs) have been entrusted with the responsibility to safeguard the rights, safety, and well-being of all trial subjects. The number of ECs in the country is also rising, but there is no clear estimation of the total numbers. The quality of conduct of ECs is often quite variable, and also there is no standardized training or orientation for members. Unless there is mandatory registration of ethics committees and an accreditation process, it would be difficult to ensure that ECs are optimally focusing on their core duty. According to a report published in the Bulletin of the World Health Organization, fewer than 40 Ethics Committees in India are properly constituted and functioning, which means that the safety of the subjects of clinical trials is on the back burner. These issues continue to highlight the importance of transparency, accountability and accessibility of clinical trials and their results. Most of the negative, ambiguous, adverse results of drug trials never came in the lime light. The Forum for Ethics Review Committees in India (FERCI), could serve as a platform to respond to the situation. Regulatory Reforms Recently, the ministry of health and family welfare has published the draft rules for the amendment to the Dugs and Cosmetic Rules, 1945 along with the draft guidelines for determining quantum of financial compensation to be paid in cases of clinical trial-related injury or deaths. By the look of it, The Drugs and Cosmetic Rules (4th amendment) are primarily aimed at regulating the Ethics Committees (ECs) by adding section 122-DD and Schedule Y-1 to the original rules. The draft Drugs and Cosmetic Rules (4th amendment) propose to make the registration of Ethics Committees mandatory and lay down detailed guidelines and requirements for the registration process.

The draft guidelines for financial compensation is aimed at providing a crucial amendment in the existing Drugs and Cosmetic Act 1940, which does not contain any provision for financial compensation in cases of drug trial-related injuries and deaths. At present the financial compensation is not mandated by law and is merely mentioned as a Good Clinical Practice in para 2.4.7 of the Indian Council of Medical Researchs GCP Guidelines for Clinical Trials in India. As per the proposed draft guidelines, the financial compensation will be calculated through a mathematical formula using four predetermined parameters, namely-age of the deceased; income of the deceased; seriousness and severity of the disease; and percentage of permanent disability. Additionally, the guidelines propose two categories of victims-those who were healthy at the time of participation in a drug trial and those who were suffering from a disease prior to participation. Accordingly, the compensation to the healthy category would be higher on account of the `loss of dependency to the family of the victims. In contrast, for the diseased category, the compensation amount would be a fraction of the amount for healthy people and would depend on seriousness and severity of the disease. Conclusion It is clear that there is a need for reform. Improvement has already been seen in certain areas, such as clinical trial registration in India through the medium of the Clinical Trial Registry. The increasing awareness about ethical requirements in research, as well as the role of activists when trial conduct seems exploitative, has also resulted in a positive change to some extent. This requires a multi-faceted approach and involvement of all the stakeholders with an aim for more robust science, which shall be supported by strong commitment to ethics.

The role of stronger legal oversight, in light of the guidelines not serving to be enough in curbing deviant research conduct, cannot be emphasized enough. Advocacy is needed, so that the draft bill on Biomedical Research on Human Participants (Promotion and Regulation) prepared by the Indian Council of Medical Research is put in the public domain for discussion and refinement, and is then tabled in the parliament on a priority basis. Such a law can provide mechanisms for legal remedy in the case of questionable and/or exploitative research. The need for Institutional Ethics Committee (IEC) resulted from the consciousness that affirms human rights as a privilege of all stake holders in the society. Individual physicians and research workers may not be able to do what is right in all instances as evidenced by the number of cases on record. There is also a need for ensuring that guidelines for constitution and functioning of IECs are implemented. (i. scientific evaluation should be completed before ethical evaluation ii. evaluate possible risk to the subjects with proper justification and expected benefit from clinical trials iii. adequacy of documentation for ensuring privacy, confidentiality and justice issues). The mechanism and credibility of a Central Independent Ethics Committee is on the anvil for granting ethical approval for clearing trials to be conducted at far off distant cities and must be re-visited as the ECs may not be conversant with the field situation. Transparency is also one of the core guiding principles in the Clinical drug trials. Pharma Companies, institutions and investigators need to give more information into the public domain such as the kind of research they are carrying out, the rationale for choosing a certain set of participants and the interventions, the standard of care in the research, ancillary care and post-trial obligations etc. The relevant ECs or IECs should insist on full information being provided.

References:

1. Clinical trials in India: ethical concerns. 3. Bull World Health Organisation 2008 2. Pandey A, Aggarwal AR, Seth SD, Maulik, M. Clinical Trials 4. Registry India: Raising the veil. Natl Med J India 2010; 23 : 187-8. 3. The Clinical Trials Registry- India (CTRI), hosted at the ICMR's National Institute of Medical Statistics (NIMS) http://ctri.nic.in 4. Developing Counties and clinical Trials, Tony Gilland, January 2010 5. Booming Clinical Trials Market in India, RNCOS, November 2007 6. KBuzz Sector Insights, Issue 18, June 2012 7. Rashmi Kadam, Shashikant Karandikar, Ethics Committees in India: Facing the challenges, Perspective in Clinical Research, Vol 3 April June 2012