indian journal of medical ethics

ISSN 0974 - 8466 (print) ISSN 0975 - 5691 (online)

INDIAN JOURNAL OF MEDIC AL ETHICS Vol IX No 1 January-March 2012 (incorporating Issues in Medical Ethics, cumulative Vol XX No 1) www.ijme.in

ENTERING OUR 20TH YEAR Hunger, ethics and the right to food Impact of disability certificates on privacy and welfare Ambiguities in the Declaration of Helsinki Mainstreaming AYUSH: ethical and governance issues Challenges in the regulation of medical education Film review: 404-Error not found

INDIAN JOURNAL OF MEDICAL ETHICS VOL IX NO 1 JANUARY-MARCH 2012

(incorporating Issues in Medical Ethics, cumulative Vol XX No 1)

Editor Emeritus Sunil K Pandya Editor Amar Jesani Consulting Editor Sandhya Srinivasan Editorial Coordinator Meenakshi D’Cruz Editorial Board Divya Bhagianadh, Mumbai Mala Ramanathan, Thiruvananthapuram Nobhojit Roy, Mumbai Prabha Chandra, Bangalore Prathap Tharyan, Vellore Sanjay Nagral, Mumbai Sanjay A Pai, Bangalore Editorial Advisory Board Amit Sengupta, Delhi Chhanda Chakraborti, IIT Kharagpur Deepa Venkatachalam, Delhi Dhanwanti Nayak, Manipal G D Ravindran, Bangalore Neha Madhiwalla, Mumbai Parthasarathi Mondal, Mumbai Sridevi Seetharam, Mysore Sujith Chandy, Vellore Suneeta Krishnan, Bangalore Vasantha Muthuswamy, Delhi Vikram Patel, Goa Vinay Chandran, Bangalore International Advisory Board Aamir Jafarey, Pakistan Aasim Ahmad, Pakistan Abha Saxena, Switzerland Aliya Naheed, Bangladesh Angus Dawson, UK Antony Zwi, Australia Anurag Bhargava, Canada Bashir Mamdani, USA Bebe Loff, Australia Fatima Castillo, Phillipines Fiona Miller, Canada Helen Sheehan, USA Jacob Leveridge, UK Julian Sheather, UK Richard Cash, USA Ruth Macklin, USA Sisira Siribaddana, Sri Lanka Solomon Benatar, South Africa Administration and Subscription Santosh Tirlotkar ijmemumbaiATgmail.com Editorial Correspondence Meenakshi D’Cruz ijme.editorialATgmail.com Subscription Rates Period

Indian

International

Individual Institutional Individual Institutional One year Rs 400 Rs 800 US$35 US$70 Two years Rs 750 Rs 1500 US$60 US$120 Five years Rs 1,700 Rs 3,000 US$150 US$300 Life Rs 15,000 Rs 30,000 US$1,500 US$3,000 Subscribers from other SAARC countries (Bangladesh, Bhutan, Maldives, Nepal, Pakistan and Sri Lanka) may please pay the Indian rates adding Rs 200 per year extra for postage. Special one-year subscriptions for Rs 250 are available to students in India. Subscription payments by Demand Draft and Cheque in favour of Indian Journal of Medical Ethics, Forum for Medical Ethics Society, 0-18. ‘Bhavna’, Veer Savarkar Marg, Prabhadevi, Mumbai, 400 025 INDIA

Looking back to move forward This apparently contradictory step may be inadvisable while crossing the street or driving, but is essential for IJME when entering its 20th year of publication. The same applies to any social organisation or movement, unless it wants to replicate past blunders. India in the 21st century is becoming a battlefield of contradictions: the total population surges ahead while girls are going missing in large numbers; massive stocks of foodgrains rot in the open while people starve without the basic right to food being implemented; and a comprehensive scheme exists for integration of traditional medicine into healthcare, with little practical implementation on the ground. All these gaps have been analysed in this first issue of 2012. Can a research study which aims to reduce suffering caused by a serious health problem be said to be successful if it has exposed participants to unnecessary harm? A study from the 1970s has been revisited and discussed from varied standpoints in this issue, re-examining the ethical standards of healthcare research. Only public probing into the ethical responsibilities of researchers and clinicians, as also researcher-clinicians, can prevent current and future tragedies in the name of public welfare. We also need a medical education system which selects and equips doctors to heal the sick in the best possible way. An editorial and a comment both look into attempts to reform this system. Promising legislations await the attention of parliament in several areas. The draft National Food Security Bill has finally been tabled in the Lok Sabha, the culmination of a long struggle by several organisations. This is the right time to analyse them and press for improvements. We carry an analysis of the new Mental Health Care Bill by a group of practitioners. We have also a strong plea for removal of ambiguity in the Declaration of Helsinki on the existence of placebo-controlled trials so as to make universal standards in healthcare a real possibility. With an issue bursting with energy and ideas, IJME wishes it readers a fruitful and active new year, with the hope that the movement for ethical healthcare and research will stride ahead with increasing confidence.

The Indian Journal of Medical Ethics (formerly Issues in Medical Ethics) is a platform for discussion on healthcare ethics, with special reference to the problems of developing countries such as India. It hopes to involve all cadres of, and beneficiaries from, this system, and strengthen the hands of those with ethical values and concern for the underprivileged. The Journal is owned and published by the Forum for Medical Ethics Society, a not-for-profit, voluntary organisation. The FMES was born out of an effort by a group of concerned doctors to focus attention on the need for ethical norms and practices in health care. Contributions to the journal, in the form of original papers, research findings, experiences in the field, case studies, debates, news and views on medical ethics, are welcome. All submissions must be in English and are subject to editorial review. Contributors are requested to refer to the detailed guidelines for submission available on the journal website, www.ijme.in Printed and published by Sanjay Nagral on behalf of the Forum for Medical Ethics Society Printed at Vibha Offset, Royal Industrial Estate, Wadala, Mumbai 400 031 Published at FMES, 0-18, ‘Bhavna’, Veer Savarkar Marg Prabhadevi, Mumbai 400 025 Editor: Amar Jesani

Indian Journal of Medical Ethics Vol IX No 1 January - March 2012

Contents

Indian Journal of Medical Ethics Vol IX No 1, January-March 2012 (incorporating Issues in Medical Ethics, cumulative Vol XX No 1)

EDITORIALS

IJME’s 20th year: some new directions.......................................................................................................................................................... 2 Amar Jesani The legacy of scandals and non-scandals in research and its lessons for bioethics in India.................................................................. 4 Mala Ramanathan, Amar Jesani MCI’s VISION 2015 and PG medical selection: continuing to produce square pegs for round holes? .................................................. 7 Prabha S Chandra, Sowmyashree

ARTICLEs

International collaborative trials, placebo controls and The Declaration of Helsinki: need for clarification in Paragraph 32 ......... 13 AY Malik, F Ghafoor Less equal than others? Experiences of AYUSH medical officers in primary health centres in Andhra Pradesh.............................. 18 JK Lakshmi Continuing oversight through site monitoring: experiences of an institutional ethics committee ................................................... 22 in an Indian tertiary-care hospital Yashashri C Shetty, Padmaja Marathe, Sandhya Kamat, Urmila Thatte

COMMENTs

Finding and using evidence that you can trust........................................................................................................................................ 27 Prathap Tharyan Hunger, ethics and the right to food......................................................................................................................................................... 32 Srijit Mishra Attempts at regulation of medical education by the MCI: issues of unethical and dubious practices ............................................... 37 for compliance by medical colleges and some possible solutions Ananthakrishnan N, Shanthi AK Disability certificates in India: a challenge to health privacy ................................................................................................................. 43 NN Mishra, LS Parker, VL Nimgaonkar, SN Deshpande Ethical aspects of public health legislation: The Mental Health Care Bill, 2011.................................................................................... 46 Harish Thippeswamy, Kausik Goswami, Santosh Chaturvedi

CASE STUDY

Observational study of cervical cancer..................................................................................................................................................... 50 From Casebook on Ethical Issues in International Health Research

CASE STUDY RESPONSES

Knowledge vs ethics in clinical research in resource-poor settings: a clinician’s perspective.............................................................. 51 B Subha Sri Lost opportunities...................................................................................................................................................................................... 53 Priya Satalkar Observational research where it is most needed..................................................................................................................................... 57 Sujit D Rathod Some ethical issues here: demands of informed consent and ethical justification for research......................................................... 59 Pravesh Jung G

SELECTED SUMMARY

William Osler’s medical ethics in the 21st-century .................................................................................................................................. 62 Richard L Golden

REVIEWs

Back to the future: Towards a critical medical practice............................................................................................................................. 64 Dhruv Mankad Medical students as guinea pigs: 404 Error not found.............................................................................................................................. 65 Vivek Jain, Rashmi Naudiyal

FROM THE PRESS....................................................................................................................................................................................................................................10 FROM OTHER JOURNALS.....................................................................................................................................................................................................................66 LETTERS.................................................................................................................................................................................................................................................... 69 CLINICAL TRIALS WATCH......................................................................................................................................................................................................................73

[]

Indian Journal of Medical Ethics Vol IX No 1 January-March 2012

Editorials

IJME’s 20th year: some new directions Amar Jesani Trustee, Anusandhan Trust, Sai Ashray, Aaram Society Road, Vakola, Santacruz East, Mumbai 400 055 INDIA e-mail: [email protected]

With this issue of January 2012, the Indian Journal of Medical Ethics (IJME) is entering its 20th year of uninterrupted publication. In the last 19 years, the journal has never had to combine two issues, and has been published regularly in the first month of each quarter. This has been a remarkable feat for a journal on medical ethics and bioethics on a shoestring budget, with voluntary contributions of time and material resources from individuals. IJME has been able to afford some part-time staff support only for the last six years. More heartening than its survival has been the support, goodwill and enduring contribution of its readers and well wishers from India and abroad. Their number is so large that to mention every one of them is impossible. Many may not even like to be named as they have merely done what they considered right and relevant. Their support in the process of growth in quality and content allowed the journal to contribute meaningfully to the debate on improving the health system, medical care and the conduct of health professionals, and in the taking forward and strengthening of bioethics discourse in the country. While the first issue of the journal was published in August 1993, the processes that led to its publication began in 1989, with the coming together of doctors and health activists to intervene in the healthcare system to improve ethical standards, and to bring the concerns of patients, particularly of the most vulnerable segments, to the centre of healthcare. None of these individuals had any formal training or qualifications in bioethics, but they were studying it in their practice, in research and in the discussion of bioethics and the literature. The journal, therefore, became, not just a medium to share views, conclusions and research, but also a platform to learn. Over the years, the sharing and learning aspects of the journal have only been strengthened, and that is what we intend to consolidate. In the beginning, most of us did not harbour any illusion that the journal would be able to carry on for long. In fact, we suffered from insecurity and the fear that it would die in its infancy or in childhood. Its survival and growth was made possible through sustained collective effort. With such support, over the last 19 years, IJME was carefully nurtured by four editors. Its executive editor, who worked with exceptional dedication for 14 years (1998-2011) helped the journal to make the transition from an amateur activity to a professional publication. However, all this was in the spirit of voluntarism, without having any of the administrative and financial support that professionally produced journals normally enjoy. The dedicated efforts of these individuals, with the support of members of the editorial and advisory boards, both national and international, and, indeed, of its writers and readers, have taken IJME from an 8-page newsletter in 1993 to a 64-page, peerreviewed, indexed journal. Increasing numbers of submissions, theme issues and special issues for activities like the National Bioethics Conferences (three so far, in 2005, 2007 and 2010) on the platform of the journal, have often pushed the number of pages to 80 and more than 100. In the year 2000, through voluntary contributions of time and resources by members, the website of the journal was established, scanned copies of past issues were made available, and IJME became an online open-access free journal. At present, the online edition is used substantially by interested readers. In 2010, the journal website received 4.9 million hits, had 330,090 unique visitors with 434,180 visits with over one million pages being viewed and 192 GB volume of material was downloaded.

The transition The strength of IJME is its organic, gradual growth. It was not something that a commercial publisher with professional, highly paid staff brought forth one fine day for everybody to read and appreciate. It has grown along with the consciousness and commitment to ethics of health professionals and health activists. It has also grown alongside the development of bioethics as a discipline in the country and in the developing world. Perhaps by being both a platform for expressing critical views on ethical issues and a fully peer-reviewed indexed academic journal, it has been a part of bioethics activism as well as of the academic development of bioethics. In that sense, its feet are firmly planted on the reality of the developing world and in movements struggling to improve people’s health and uphold their rights. []


In the future, as the journal builds on this strength, there are some changes in the offing. These changes have been necessitated for various reasons. Given the complexities and demands in terms of time and resources for ensuring effective and efficient peer review of an increasing volume of submissions for publication, copy editing and many other complex components of the production process, it is very difficult for only one or two individuals, despite their dedication, to do everything. We have to gradually put in place a more complex division of labour and adopt the appropriate technology, including an online submission management and production system. While this process started two years ago, we are now required to consolidate it by establishing an independent office of the journal with some full-time support staff, and pay more attention to fund raising. This will mean that some editors and members of the Forum for Medical Ethics (FMES) will have to commit more time to establishing physical structures and work systems for the journal, and also make efforts to raise funds. At the same time, those who have voluntarily shouldered the responsibility of work for the last several years needed a temporary break or respite from the heavy workload they have attended to. This 20th year is, therefore, devoted to such consolidation and transition. We are in the process of establishing an independent office for the journal in Mumbai. In the coming year, we will strive to establish an on-line system for submission, review and production. George Thomas, who has borne the responsibility of editing the journal for the last six years, has stepped down as editor. Sandhya Srinivasan, who has done the back-breaking work of being executive editor for the last 14 years, will continue to provide her expertise and guidance in editing the journal as consulting editor. We are in the process of enlarging the IJME editorial and administrative teams to tackle the new challenges. Two new members have joined the editorial advisory board. We welcome Dhanwanti Nayak, who is an anthropologist with a deep interest in the medical humanities. She teaches at the Manipal Institute of Communication at Manipal University, Karnataka. We also welcome to the board Deepa Venkatachalam. Her key interests are women’s health, technologies and bioethics, and she works with the women’s group Sama in Delhi. Another new member has joined the international advisory board. We welcome Jacob Leveridge, who is school research facilitator at the University College London, London, UK. We are very happy that these three members have joined us in IJME, and that their support and individual contributions will enrich the journal. During the coming year, we also intend to invite other individuals to be guest editors of our theme-based and special issues, to garner national and international bioethics expertise for the development of the journal. Changes are also occurring in the FMES, the owner and publisher of IJME. This is essential as the FMES, as a non-profit society and public trust, is actually a product of the medical ethics and bioethics movement, and is to some extent shaped by it. In 2011, it invited many individuals from the bioethics movement to be its members, and is thus, involved in a process of transformation from a small, primarily Mumbai-based group to a national level society. In addition, Vasantha Muthuswamy, the distinguished bioethicist, will be taking over as chairperson of the FMES in the latter part of 2012.

The broadening of horizons around bioethics The primary focus of the journal continues to be medical ethics and bioethics. From within the healthcare system, the ethical concerns and issues of many healthcare professionals, such as nurses and AYUSH professionals, demand attention. In the pluralist healthcare system of India, the quest for healthcare ethics must be enriched and strengthened by including their specific issues and concerns. At the heart of the medical ethics and bioethics movement are the patients, the people, and the more vulnerable they are, the greater the need to be ethical. Normative ethical guidelines, rules and regulations, therefore, find their rationale only in so far as they protect and empower the vulnerable in healthcare relationships. However, as our experiences in India and in many developing countries testify, the mere existence of guidelines and rules and, for that matter, even laws and the power of regulators are not, in themselves, sufficient to improve ethical standards and professional conduct. The high pressure of work in the closed environment of health institutions, the pursuit of excellence in technology instead of humane caring, the high status enjoyed by medical professionals in society, their increasing wealth in the unregulated market of healthcare, etc, have insulated many of them from the living reality of patients and the widening inequities in society. In such a context, those making efforts to achieve an equity-based, humane healthcare system with universal access, are contributing to the strengthening of healthcare ethics. To achieve this, systemic reforms, changes in the conduct of professionals, and greater involvement of patients, and the people in general, in healthcare decision making is necessary. This process could be greatly enriched by interaction with the perspectives of the social sciences, law, philosophy, art, literature, and the media. For the development of holistic and humanistic medicine, it is crucial to open it to public scrutiny and the gaze of other professions. Those perspectives may vary but their interaction with medicine will be mutually beneficial, leading to a better understanding and appreciation of each other’s contribution. More so for bioethics, as it is multi-disciplinary, with medicine being only one component. Such interactions could contribute positively in the acceptance and observance of ethics by healthcare professionals. They could also act to deepen and widen the processes of building ethical guidelines and rules, which are often dominated by medical professionals. Therefore, IJME will endeavour to expand its scope by including the field of humanities in addressing issues in medical ethics and bioethics. We hope that such an inclusive approach, will, without diluting our focus, enrich the journal as well as the concerns and disciplines it represents. []


The legacy of scandals and non-scandals in research and its lessons for bioethics in India Mala Ramanathan1, Amar Jesani 2 1 Additional Professor, Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala 695 011 INDIA e-mail: [email protected] 2 Trustee, Anusandhan Trust, Sai Ashray, Aaram Society Road, Vakola, Santacruz East, Mumbai 400 055 INDIA e-mail: [email protected]

A case study entitled “Observational study of cervical cancer”, on research undertaken in a south Asian country, published in a compilation of case studies by Cash and others (1), is the subject of a collection of commentaries in this issue of IJME. The range of responses reflects the commentators’ individual disciplinary orientations and views on the state of medical practice in those times, and the ethical standards that applied. While reviewing this compilation of case studies, Macklin critiqued the use of historical case studies as they may not resonate with knowledgeable physicians and researchers who would want material that is relevant to their current or future experience (2). Another possible criticism is that case studies based on developed world scenarios may not seem as relevant to researchers from developing countries working within developing world settings. They may respond with “What if this happens in our setting?” rather than the more evocative “There but for the grace of God, go I!” which facilitates changes in perceptions and practices.

Bioethics training and international case studies Indeed, the case studies employed in bioethics training within India, as well as in other parts of the world, are often “international research cases” from developed countries on issues relevant in their contexts. They may also describe the experiences of researchers from developed countries in the developing countries. As there are very few case studies identifying an Indian location and research sponsored by Indian agencies, trainees from the Indian subcontinent may feel that violations in ethics primarily occur elsewhere, and are perpetrated by “others” on our people. This belief results in the reiteration of faith in our own morality and ethics, without the realisation that we can learn from such scandals only after in-depth inquiries, research and debate. The history of the Belmont Report is rooted in the inquiry into the Tuskegee study. This report initiated reforms in the way clinical research was conducted in the United States of America. It is also part of the bioethics literature. However, inquiries and scandals that occurred in India are not the subject of bioethics teaching in India. This is not because they do not occur, but because they are not written about, debated or discussed. This shortcoming needs to be corrected and the truth needs to be told as part of the development of the bioethics movement in India. We need to retell history, not as part of a witch hunt to blame or punish those involved, but to teach ourselves and set the record straight, based on the adage: “Those who cannot remember the past are condemned to repeat it”. The case study presented in this issue had women in different stages of dysplasia who were followed up for an extended period, without treatment; even after evidence for offering such treatment became available. The research was based on the rational assumption that it was important for a country with limited resources for health to determine which of the dysplasias would develop into carcinoma in situ (CIS), thereby identifying the high risk cases who could be given preference in provision of treatment. The study lasted 12 years. This again is reminiscent of the observational study of syphilis in African-American males in Tuskegee, Alabama, USA. In the Tuskegee study syphilis patients had been observed for 40 years, without providing treatment.

Research similar to that described in the case study We know of two research studies conducted in the 1970s and 1980s on carcinoma cervix that are similar to the case study discussed in this issue. One well documented study that was acted upon and followed up was done in New Zealand. The other was carried out in India. The research project that was a matter of public debate in New Zealand was on carcinoma cervix but with slightly different objectives and possible outcomes than the case study published in this issue. This was an observational study on the invasive potentiality of cervical CIS initiated in the mid 1960s at the National Women’s Hospital in Auckland; the patients were not offered standard treatment. This study was brought to light in 1987, by two women’s health activists and journalists, Sandra Coney and Phillida Bunkle, through an article in New Zealand’s Auckland-based magazine Metro (3). Following a public outcry, this study became the subject of a judicial enquiry by Judge Silvia Cartwright (4). The public hearings took place between August 1987 and January 1988 and the report was released on August 5, 1988. The findings of this inquiry set the pace for reform in medical research in New Zealand, and the understanding of ethics in health research within the country (5). A system of research ethics committees in which 50% of members came from the lay public was []


established; their functions included the supervision of clinical observational studies. A successful population-based cervical screening programme based on cytological smears began. New Zealand enacted the Code of Patients Rights as a part of the Health and Disability Commissioner Act, 1994. This provided an independent external enforcement system in the Office of the Health and Disability Commissioner (6). Thus, the controversy, the inquiry, and subsequent follow-up created a lasting legacy that enhanced patients’ rights and reformed medical practice. The research carried out in India, like that in the case study published in this issue, observed women with cervical dysplasia, without offering treatment. It was supported by public funds and carried out by Indian researchers, and it lasted over a decade. The Indian medical and scientific community was aware of the research when it was being carried out. After its completion in 1987, its findings were reported in international journals. At the time it was on in the 1970s and 80s, researchers would have been aware of the international furore generated by the revelations about the Tuskegee trial. When the findings of the Indian study were being published, the controversy regarding the New Zealand study was being reported in the medical literature. Yet, there was no critical reflection within the community of Indian researchers on what was not done; nor were measures taken to provide recompense to the participants in the study. Instead, the country waited long for a public controversy. Ten years after the completion of the study, when some participants started reporting to hospital with cervical cancer, a newspaper report revealed that those participants were the ones who had not been provided treatment during or after the study, nor followed up in the long term (7). The report described it as “the use of women as guinea pigs”. The researchers defended the study by saying that “no one died” (8) due to any medical intervention as there was none. However, like any other big scandal on health and research, this one too died down, was soon forgotten, and hardly anything has been written on it since then.

The perils of ignoring history Among the cancers in India, carcinoma of the cervix is a major killer of women. There is absolutely no doubt that more research for its prevention and treatment is needed in the country. Ours is also a resource-poor setting, and so the argument in justification as given in the case study can be applicable to the research that was done in India. Indeed, the identification of dysplasia that would most likely turn into CIS makes the intervention selective and thus resource saving. In the absence of evidence to the contrary, we may assume that such good intentions motivated the researchers to undertake the study in India. However, a research design based on observing the progression of disease in patients over a period without offering standard treatment during or after the research exposes patients to the risk of suffering from that disease. Such a research design does not offer any benefits to patients who are recruited only for the benefit of science and the benefit of future patients. This produces a serious imbalance in the risk-benefit ratio. This imbalance does not get corrected even when researchers are confident of obtaining written and witnessed informed consent from patients for participation. This inherent imbalance in risks and benefits to participants caused harm to patients; and so the public furore it aroused was fully justified. This situation could have been prevented only by questioning this harmful research design, which could have forced the researchers to look for alternative research designs to generate the kind of evidence they needed. It has been argued that research of the kind described in the case study was essential for making treatment available to those who needed it the most. However, the government, which sponsored the research, did not follow this up with a genuine implementation of the universal cervical screening programme. Even a quarter century after the completion of the research, and 15 years after the reporting of the ethics controversy in the media, the universalisation of cervical screening with the provision of treatment to those who need it the most remains a distant dream. If the research is described as “sacrificing a few now in order to save many millions later” – an argument deeply problematic in ethics and indeed unacceptable – in this case “sacrifice” did not usher in the provision of real care for all women who needed it, though some did benefit from it. Unethical research, even when it is on correctly identified health problems and produces useful outcomes, not only poses potentially serious harm to the participants, but also sometimes affects the priority accorded to these health problems. When a few scientists and physicians show lack of respect for vulnerable participants, future potential participants and society in general become suspicious of the motives and credibility of all researchers. Therefore, a short-lived media controversy on such research is not sufficient to correct the situation. What is needed is efficient and transparent investigation of such cases to bring out the facts in public, making those responsible for violations accountable. Further there is a need to use the findings of these inquires to improve the governance of research and ethics education of all stakeholders. Apparently, nothing of the sort that New Zealand did was done in India. And despite the numerous other controversies in biomedical research after this study – more so after 2005 when corporate- sponsored clinical trials increased in number – the governance of research and ethics education remain abysmal in India. We have recently witnessed another controversy about ethics violations arising out of research into carcinoma of the cervix. This relates to the manner in which the phase IV clinical trials and demonstration project on HPV vaccines used for the prevention of carcinoma of the cervix were conducted. The public outcry surrounding it resulted in the suspension of the project and institution of an inquiry to investigate ethics violations and the deaths of participants. Of course, the institution of an inquiry is a step forward []


when compared with the handling of the earlier controversy on the research into this disease. However, the report of the inquiry has still not been made public, though it was formally submitted to government by the committee. The facts of that research still remain disputed due to such secrecy; nobody is held accountable for violations, and of course no learning for researchers emerges from even such a controversial case (9).

Learning from history and ethics cases On October 1, 2010, the United States secretary of state, Hilary Clinton, and the health and human services secretary, Kathleen Sebelius, expressed regret and tendered their apologies to Guatemalans who were harmed by the US Public Health Service sexually transmitted disease inoculation study of 1946-1948 (10). This was an outcome of painstaking research on the subject done by a historian, Susan Reverby, which exposed the deliberate inoculation of infective agents into many Guatemalan people as a part of a research project sponsored by US government agencies (11). One may say that an apology is insufficient to provide solace to those who suffered, and to bring back respect to the community and the country. But an admission of error, and the reaching out to those who suffered and their community, is a good beginning. One will want such apologies in all cases where nations have violated ethics in research. However, ethical practices and review in research, and the ability to learn from past mistakes, cannot be limited to a first world initiative, when the potential for unethical practices is universal. If we do not dust off old books on our own medical research, identify lapses, document them and discuss them, we will fail the stakeholders of such research – those who will participate either as subjects or as researchers in future initiatives or as regulators of such research in India. It is for this reason that we decided to publicise this case study and initiate discussion on it-- many decades after the event -- to obtain a better understanding of the need for ethics in research, and to facilitate an understanding of the issues among future researchers within the country. A case study of the kind published in this journal may not be sufficient to go into all the issues in the actual research, but it should be a sufficient trigger for historians to re-examine these concerns. References 1. Cash R, Wikler D, Saxena A, Capron A, editors. Casebook on ethical issues in international health research [Internet]. Geneva:World Health Organisation;2009 [cited 2011 Dec 13];124-5. Available from: http://whqlibdoc.who.int/publications/2009/9789241547727_eng.pdf 2. Macklin R. Casebook on ethical issues in international health research. Bull World Health Organ [Internet]. 2010 [cited 2011 Dec 13];88:716. Available from: http://www.who.int/bulletin/volumes/88/9/10-078469/en/index.html 3. Rosier P. The speculum bites back: feminists spark an inquiry into the treatment of carcinoma in Situ at Auckland’s National Women’s Hospital. Reprod Genet Eng [Internet].1989[cited 2011 Dec 13];2(2):121-32. Available from: http://www.finrrage.org/pdf_files/RepTech%20General/Carcinoma_In_Situ. pdf 4. Cartwright S. The report of the committee of inquiry into allegations concerning the treatment of cervical cancer at National Women’s hospital and into other related matters [Internet]. Auckland (New Zealand): Government Printing Office, Auckland; 1988 Aug 5[cited 2011 Dec 13]. 288p. Report No.:ISBN0-47300664-2. Available from: http://www.nsu.govt.nz/Current-NSU-Programmes/3233.aspx 5. Paterson R. The Cartwright legacy: shifting the focus of attention from the doctor to the patient. N Z Med J [Internet]. 2010 Jul 30 [cited 2011 Dec 13];123(1319):6-10. Available from: journal.nzma.org.nz/journal/123-1319/4239 6. Bunkle P. Patient-centred ethics, the Cartwright Inquiry and feminism: identifying the central fallacy in Linda Bryder, A history of the‘unfortunate experiment’ at National Women’s Hospital (2009, 2010). Women’s Studies Journal [Internet]. 2010[cited 2011 Dec 13];24(2):8-24. Available from: http://www. wsanz.org.nz/journal/docs/WSJNZ242Bunkle8-24.pdf 7. Mudur GS. ICMR let women guinea pigs get cancer. The Telegraph (New Delhi Ed). 1997 Mar 22. 8. Mudur GS. Gynaecologists refuse to buy “no one died” argument: Cancer trial stroke ethics debate. The Telegraph (New Delhi Ed). 1997 Mar 23. 9. Sarojini N, Shenoi A, Srinivasan S, Jesani A. Undeniable violations and unidentifiable violators. Econ Pol Wkly. 2011 Jun 11;46(24):17-9. 10. US Department of Health and Human Services [Internet].Washington DC: US Department of Health and Human Services. Joint Statement by Secretaries Clinton and Sebelius on a 1946-1948 study; 2010 Oct 1[cited 2011 Dec 13];[about 2 screens]. Available from: http://www.hhs.gov/news/press/2010pres/ 10/20101001a.html 11. Reverby SM. “Normal exposure” and inoculation syphilis: a PHS “Tuskegee” doctor in Guatemala, 1946-1948. J Policy Hist. 2011;23(1):6-28.

[]


MCI’s VISION 2015 and PG medical selection: continuing to produce square pegs for round holes? Prabha S Chandra1, Sowmyashree2 1 Professor of Psychiatry, 2 PhD student, Neurosciences, National Institute of Mental Health and Neurosciences, Bangalore 560 029 INDIA Author for correspondence: Prabha S Chandra e-mail: [email protected]

The need for better methods of selection for postgraduate (PG) medical seats in different specialties has never been more keenly felt than in the current scenario. Multiple entrance exams, management quota and paid seats, the urgency to get into a PG seat at any cost and the mushrooming of PG entrance exam coaching centres have added to the angst and woes of medical students. Currently the Indian medical education system is one of the largest in the world with around 250 colleges fully recognised by the Medical Council of India (MCI). The increasing demand for doctors trained in basic skills and the need to maintain the educational system on par with global standards is quite challenging, considering all the hurdles which come in the way of improving quality. One author of this editorial is a postgraduate teacher who has been involved in PG entrance examinations for several years and the other a medical student who has appeared for 30 entrance exams in the last two years! We have also taken the opinions of several students who have either got or not got a PG medical seat after going through several entrance exams across the country. Based on this, we speculate on the problems of the current system, review the VISION 2015 proposed by the Medical Council of India (MCI) to see if it improves the situation, and suggest some alternative strategies based on a review of literature on advanced and superior methods of selection in some other countries (1). Regarding the paper pattern for entrance exams, the current preference for multiple choice questions (MCQs) as a method of selection was initiated to enhance objectivity. However, even as late as the 1980s and ’90s, many institutions had recognised the need for getting to know the candidate either through an interview or through a brief clinical assessment. If candidates had qualified in the theory entrance exam, they had to undergo a face to face interview or some form of clinical assessment in several institutions. The suitability and aptitude of the candidate for the particular specialty would be discussed before the actual selection. While not being entirely fool proof, it was probably more gratifying for the selection panel and the student and resulted in a better fit. However, all these initiatives had to be abandoned in the name of objectivity and the use of only the MCQ test was proposed by the MCI as the preferred method. An ability to solve MCQs, however, does not reflect the abilities of a good doctor. Unfortunately, what was considered as the best method has now resulted in a bit of a Frankenstein-like situation. Students start worrying about a PG seat in the final year of medicine, and the internship is spent not in gaining clinical skills but in preparing for the entrance examinations. There are many students who, by their own admission, have not touched a patient during their internship, nor written a single prescription.

Objectivity -- but at what cost? The scope of the PG centralised entrance test (CET), as it is conducted today, does not include assessment for aptitude in the specialty desired by the candidate. Hence, students tend to neglect their undergraduate education and concentrate on the CET. The only deciding factor is the marks obtained in the CET, with the entrant accepting the subject available to her, not necessarily the subject she has an aptitude for, or the one she likes. As a result, many students drop out of courses that they join and several continue half-heartedly. All manner of scams are being revealed because of this method, including impersonation, students with high marks giving up their seats for a price, and of course much money changing hands. This is unheard of in most developed countries. Pursuing a medical specialty should be a calling and not a financial deal, and the consequence should not be the demoralisation of the medical student community.

Is there an alternative? Several options exist and we have models from several countries which we can emulate. One possibility is to use marks obtained in the MBBS exams. Since it would be difficult to assess in depth the expertise of the student in the desired subject, it would be useful to consider the marks obtained by the student in that subject at the university examination. Monitoring the growth in knowledge of students indicates the contributions made by the different training phases (2). An aptitude test would also be useful, because that would match students to courses that require special skills, such as surgical courses, or those that require an abiding interest and aptitude, such as psychiatry (3). []


VISION 2015 – does it provide any solutions? The VISION 2015 document of the MCI suggests having an entrance examination soon after the final MBBS examination and just before internship. This has been proposed so that students are not preoccupied by the entrance exams during internship, and focus more on clinical skills (1). Several students we spoke to felt that the new policy of having an exam after the final MBBS will only add to the students’ burden, as the exam is in an MCQ pattern while the final MBBS exam is in a different format. They felt that two months of preparation time would be insufficient and, in the process, students might neglect the final MBBS exam and, in turn, perform poorly at both exams. Most students we spoke to, including the second author of this paper, had written an average of 30 entrance exams in a span of two years before getting admission into a PG course. In their experience, preparation to answer MCQs is completely different from that for a theory paper. It is an interesting observation because it gives us some idea that MCQs may not actually be testing the three attributes that they should be: knowledge, skills and aptitude of the doctor. Instead they seem to test the ability to think in a multiple choice format. VISION 2015 also states that, at the end of internship, the licentiate examination would assess skills. A laudable goal indeed and much needed. However, this may not solve all the problems. It is not yet clear if this would happen as a common exam or would be assessed at the level of individual medical colleges. What of students who did not qualify for PG seats before internship? What if students who feel they are not completely prepared for entrance exams take a year off before exams for studies? These situations may again lead to a waste of resources, with the hospitals lacking interns and patient care being affected. VISION 2015 is silent about assessing aptitude, matching courses to candidates and also about enhancing objectivity in assessment by methods other than the MCQ format of entrance examinations. There is also a lack of recognition of the postgraduate as a professional and a leader, and a focus only on technical knowledge. Ideally, students who have some leadership experience and those who have participated regularly in social/community health outreach programmes should receive extra credit in selection criteria. This will bring recognition to non-academic activities, which positively hone the personality and outlook of a doctor and are as important as knowledge. Research experience, conference presentations and/or publications in journals should also provide bonus points to PG examination candidates. This will help encourage more medical student involvement in research activities (4, 5). Rural work experience for a minimum number of years after completion of the MBBS is already being used as a criterion by some state governments for providing priority in PG course admissions. This is one way of encouraging fresh doctors to spend some time serving in underprivileged rural areas. VISION 2015 addresses various reforms which have to be implemented to improve the existing educational system. However, the students we spoke to felt that it would only minimally help in decreasing the existing burden on students in the race to get a PG seat. More exams would only mean more stress. The idea of having a new pattern of examinations with clinical questions is encouraging. However, we strongly feel that more evidence is needed regarding the nature of questions and responses that actually tap knowledge and skills. Even though hundreds of PG entrance exams have been conducted over the last several years, there is no database or research to guide examiners who set questions for these exams. Which questions appear to be the more discerning, what is the distribution of the nature of questions, what should be the right proportion of clinical versus theoretical questions and should all the questions simply be in the `one of four choices’ format, or will any other format of MCQ work better? It is time that the MCI actually looked at some of these issues and gathered evidence to guide future examiners. Examinations at this level need to focus on an in-depth assessment of the student’s knowledge and competency. Questions with multiple responses (with the possibility of more than one answer being correct) are much better than single correct response MCQs in this regard (5). When a candidate attempts such a question with multiple answer options, it tests her in-depth knowledge, observation skills and efficiency in time management. It often simulates a clinical situation where patients might present with comorbid conditions or multiple symptoms and signs relating to a medical condition. Students also felt that the newer changed terms in the VISION 2015, for various courses will not help to improve the quality of education. The proposed framework suggests introduction of a two year Master of Medicine (M Med) programme as the first level of specialisation with the focus on skill development and providing care to the community. These PG students will be trained mainly to enhance clinical skills rather than being engaged in basic research. A second exam after M Med will select students for an MD/MS. This would be a burden for students and many M Med students may again neglect learning skills in the process of trying to get a good score for an MD/MS seat. Another issue not clearly addressed is whether M Med is like a diploma course in a particular specialty, or a general training course in basic skills. If students have to prepare for another common exit exam after M Med, they will have no time to learn anything in a particular specialty in a period of one year after M.Med. Some of them might spend more than a year preparing for the PG entrance exam again. Some questions, which are not addressed by the VISION 2015, but are important in the lives of medical students we interviewed included: []


l Would entry to all seats come through the common entrance test? l Would there be reservations for seats as in the current selection pattern? l What is the pattern of counselling? l What would the fee structure be? Would each state’s fee structure be different? l Will the current management quota for seats in private colleges continue? l What about the private deemed universities and their seats? l What if some states do not want to be bound by the common entrance exam? l How will transparency be monitored?

Well-planned methods of selection in other countries Most other countries with well-planned postgraduate or residency programmes focus on the assessment of clinical skills and aptitude in addition to an MCQ paper for theory. Several centres in the United States have one exam related to clinical skills. Here, they video record the whole exam session and assess the student for all aspects of patient care -- history taking and examination, arriving at a diagnosis, explaining the prognosis and also prescribing treatment. The US is also planning to introduce new guidelines and more marks for communication skills from 2012. Students write letters to their universities of interest and once they get good percentile marks in the first and second steps of the medical licensing examination, they have interviews with deans of the various universities or the experts in the field. They are also required to send a letter of recommendation from doctors with whom they have previously worked. This process, which is called `matching’, is a good practice because candidates get to choose the subject of specialisation and also the university where they want to study, and the universities are allowed to choose the students who they feel will fit in with their system. In some other countries, while there is no separate live assessment of clinical skills, there is an exam which includes interpretation of videos, data tables, pathological slides and other investigations. This is a particularly good method for assessing aptitude and if one uses the objective structured clinical examination format this can be objective. However, this will require much thought, planning and training of large numbers of examiners across the country and some form of standardisation. It is sad to see the medical graduate’s plight, following soon after a rigorous course like MBBS. The anxiety of getting a PG seat and the inadequacies in the process of selection are a daunting combination. It is customary in many decision-making bodies the world over to have consumers as part of the process. Maybe it is time to have students and junior faculty as part of the VISION 2015 committee, to give an insider’s view about what is actually happening in the field. This may help the potential PG student and bring about more modern and evidence-based methods of selection. References 1. Medical Council of India. VISION 2015 [Internet]. New Delhi:2011 Mar [cited 2011 Dec 1]; Available from: www.mciindiia.org 2. van Leeuwen YD, Mol SS, Pollemans MC, van der Vleuten CP, Grol R, Drop MJ. Selection for postgraduate training for general practice: the role of knowledge tests. Br J Gen Pract. 1997 June;47(419):359–62. 3. Parulekar SV. Postgraduate entrance test reforms. J Postgrad Med. 2011;57:263-4. 4. Bhan A. Conduct of postgraduate medical entrance examinations: Amendments needed. J Postgrad Med. 2010;56:332-3. 5. Iyer DS, Bhan A. Postgraduate medical entrance system needs reforms. Natl Med J India. 2009 May-Jun;22(3):162-3.

[]


FROM THE PRESS Horror in hospital In a shocking tale of medical negligence, a 28-year-old woman suffered burn injuries after being cleaned with a toxic chemical following her delivery. The incident occurred at Lalbag sub-divisional hospital in Murshidabad district of West Bengal on November 1, 2011 after the woman, Sikha Biwi, apparently delivered a dead child. Initially it was suspected that carbolic acid was used to rub her clean. Deputy chief medical officer health Birendra Kumar Show issued a statement: “It was not done intentionally. The attendants washed the patient with the acid by mistake. The colour of the acid and the anti-infectant is almost similar. The bottles somehow got mixed. A sweeper must have kept the bottle of the acid there.” It now seems that the liquid may not have been acid but some other toxic chemical. Even as the hospital claimed that the child was born dead; allegations that the baby boy died due to the toxicity of the chemical have forced the Lalbag sub-divisional officer to probe further into the matter. Meanwhile, West Bengal continues to hog the news for the highest number of reported infant deaths in its state-run hospitals. In a re-run of the July 2011 incident when 21 babies died in three days at the B C Roy Hospital, Kolkata, 45 babies died in one week at two state-run hospitals in Kolkata and Burdwan from October 25 to 28, 2011. While 16 babies died at the BC Roy Children’s Hospital, the Burdwan Medical College and Hospital reported 12 infant deaths. Giving the hospitals a clean chit, the Minister of State for Health, Sudip Bandopadhyay, said, “I’ve totally given them a clean chit because I believe that this is not due to negligence of the authorities . . . . Infant mortality rate in West Bengal is 33 per thousand live births which is much better than other states.” Hospital authorities too maintain that there is “nothing abnormal” or “unusual” in the deaths because the babies, they claim, were brought in in an “extremely critical” condition. However, underlining the poor health infrastructure in the State once again, six more babies died in a Malda district hospital between November 9 and 10, 2011. While probes are routinely ordered, the government is busy defending the hospital authorities, amidst the rising public frustration at medical negligence. NDTV Correspondent, 45 infant deaths in one week in West Bengal, Mamata silent NDTV, November 1, 2011. Available from: http://www.ndtv.com/article/india/45infant-deaths-in-one-week-in-west-bengal-mamatasilent-145579&cp. PTI, Nurses clean woman with acid after childbirth, msn News, November 2, 2011. Available

from: http://news.in.msn.com/national/article.aspx?cpdocumentid=5563140. The Times of India, November 3, 2011. Available from: http://timesofindia.indiatimes. co m / c i t y / ko l k at a - / Tox i c - w a s h - N u r s e - s u s p e n d e d / articleshow/10600340.cms. Indo Asian News Service, Six more babies die in Bengal Hospital, NDTV, November 11, 2011. Available from: http://www.ndtv.com/article/india/ six-more-babies-die-in-bengal-hospital-148773

Gujarat’s polluted fields In some villages of Gujarat, borewells spew reddish brown water. Irrigated fields are contaminated with industrial effluents. Yet, say the villagers, the authorities have failed to bring to book those responsible for this situation. Residents of Nodhana in Bharuch district complain that seepage from a nearby effluent channel has been contaminating their fields for the last two decades. The Mukteshwar Mahadev Temple lake in Bharuch district has turned violet. 46 industries, mainly manufacturing chemicals and dyes, in Bharuch and Vadodara districts, release treated effluent into the channel. Residents claim that a number of these industries discharge untreated or partially treated wastewaters into the effluent channel. The channel was built by Effluent Channel Project Limited (ECPL) in 1983 to carry treated effluent to the Gulf of Khambhat. Currently, it is said to discharge 300 million litres of effluent treated at a common plant, every day into the Gulf. Following complaints from the villagers, the ECPL was reduced from 55 km to 46.5 km in 2004 and the route of the remaining part of the channel passing through Nodhana was diverted using an underground PVC pipeline. In May 2011, following a complaint from Nodhana panchayat that the pipeline had put irrigated fields and water sources at risk, the Bharuch district administration, along with the Gujarat Pollution Control Board, sent a notice to ECPL. ECPL, on the other hand, denies receiving any such notice. Luna, a village situated along the 55 km long effluent channel, once known as the vegetable basket of western India, tells a similar story. The residents of the village and its surrounding areas in Padra taluk, Vadodara district, claim that their borewells are not just contaminated but also filled with industrial effluents. Luna, in fact, faces pollution not only from the channel but also from the industries located nearby. In May 2011, the Central Pollution Control Board tested the groundwater and surface water in the region and found that of the 108 borewells, as many as 45 were contaminated by effluents comprising lead, mercury and ammoniacal nitrogen. However, according to the local administration in both the districts, a survey on the health effects of the contamination is still pending.

[ 10 ]


Anupam Chakravartty, Stinking for two decades, Down to Earth, November 30, 2011. Available from: http://www. downtoearth.org.in/content/stinking-two-decades. Anupam Chakravartty, Polluters get away by making ad hoc payments to farmers. Down to Earth, November 29, 2011. Available from: http://www.downtoearth.org.in/content/ polluters-get-away-making-ad-hoc-payment-farmers

Pill of contention Yasmin and Yaz, Bayer Pharmaceutical Company’s popular oral contraceptives, also prescribed in India, are fast gathering lawsuits in the West. Several women have taken the company to court for misleading them about the health risks posed by the pills. While Yasmin has been available in the US market since 2004, Yaz, a spin-off of Yasmin, was approved by the US Food and Drug Administration (FDA) in 2006. Research on the pills has reportedly revealed that women consuming them are prone to blood clots, heart attacks and strokes. Bayer faces more than 10,000 lawsuits over problems allegedly caused by these pills. The latest in the string of accusations against Bayer is that it may have pitched the Yasmin family of birth-control pills for unapproved use. According to company emails that were made public following litigation, Bayer officials had discussed how to promote Yaz as a treatment for all kinds of premenstrual syndromes (PMS) not just for premenstrual dysphoric disorder, for which regulators had approved it. Apparently Bayer officials sent emails to their sales people in 2006 saying that they should cite a Women’s Day magazine article which said that Yaz was a safe PMS treatment. According to the copy of the email produced, Matt Sample, a Bayer unit sales consultant wrote, “This article is a nice way of using Yaz for PMS treatment instead of just focusing on the specific” class of women struggling against the most severe form of PMS, that is. Besides the off-label marketing allegations, lawyers representing women suing Bayer have alleged that company officials withheld information from patients, doctors and regulators about the drug’s risk of causing blood-clots in their rush for profit. Apparently, Bayer’s contraceptives generated $ 1.58 billion in sales last year, making them the company’s biggest-selling drugs after Betaseron, a multiple sclerosis medication. An FDA study reveals that contraceptives that contain a particular synthetic hormone called drospirenone carry higherthan-previously-thought-of risks of blood clots. Drospirenone is an active ingredient in Bayer’s line of products. A study of 1.3 million Danish women revealed that pills containing drospirenone were linked to a six-fold increase in dangerous blood clots. In a review of 800,000 American women’s medical histories, the FDA found that women using Yaz had significantly higher rates of blood clots than women using the older pills. However, women using Johnson & Johnson’s patch, Ortho Evra, and Merck’s NuvaRing also experienced a higher rate of

complications, the FDA said, thus opening up debates about newer contraceptives available for women. Jef Feeley and Margaret Cronin Fisk, Bayer may have pitched birth control pill for unapproved use, Bloomberg, November 22, 2011. Available from: http://www.bloomberg. com/news/2011-11-21/bayer-may-have-touted-birthcontrol-pills-for-unapproved-use-e-mails-show.html. Tracy Staton, FDA study: newer contraceptives carry higher risks, Fierce Pharma, October 28, 2011. Available from: http://www.fiercepharma.com/story/fda-study-newercontraceptives-carry-higher-risks/2011-10-28

Nursing their discontent Around 250 nurses of the Asian Heart Hospital and neighbouring hospitals in Mumbai went on strike on October 19, following the suicide of a 22-year-old nurse, Beena Bebi, of the same hospital. Beena was said to have been driven to suicide following harassment after she misplaced a patient’s ultrasound report. However, the tragedy set off a wave of frustration among the nursing staff on issues such as a twoyear bond they were compelled to sign, the confiscation of their original certificates, and the condition that they pay Rs 50,000 in case they wished to leave their jobs at the hospital before completing two years of service. They also complained of abusive treatment from their seniors at work. During the strike period the nurses were lathi-charged by the police and 20 on-call nurses were evicted from their residential quarters at the hospital. As the majority of nurses were from Kerala, two Members of Parliament from that state visited Mumbai in an attempt to intervene and settle the dispute. They also wanted the management to take responsibility for Beena’s death and send her body to her home in Kerala for the last rites. Ultimately, the strike was called off after four days, with some demands being granted: the revocation of the two-year bond and work experience certificates to those with less than two years’ service. These certificates had earlier been given only to those with more than two years of service at the hospital. However, the nurses are said to have had to undergo interviews and sign fresh contracts at the end of the strike, as also pay a deposit of Rs 10,000. This was to be further supplemented by Rs 1,000 being cut from their salaries every month, the whole amount being forfeit in case they gave up their jobs in less than two years. The strike brought out the simmering resentment among the nursing cadre in even the more reputed private hospitals in the city. DNA correspondent, Mumbai’s Asian Heart Hospital nurse commits suicide; others strike work, DNA October 19, 2011. Available from: http://www.dnaindia.com/mumbai/ report_mumbai-s-asian-heart-hospital-nurse-commitssuicide-others-strike-work_1600768 HT Correspondent, Asian Heart Hospital nurses call off four-day-long strike, Hindustan Times, October 23, 2011. Available from: http:// www.hindustantimes.com/India-news/Mumbai/AsianHeart-Hospital-nurses-call-off-four-day-long-strike/ Article1-760527.aspx

[ 11 ]


What’s the right age for bariatric surgery? Bariatric surgery on an eleven-month-old child in Mumbai’s Breach Candy Hospital has set off a heated debate among doctors on the ethics of such surgery on an infant. The child, already weighing 19 kgs at eleven months, was suffering severe respiratory problems. She is said to have monogenic syndrome, a genetic disorder, which claimed the life of her brother at the age of 18 months. Given the loss of one child in the family, and the inability to control the weight gain as she grew older, the family decided to go in for a sleeve gastrectomy, performed by Dr Sanjay Borude. The doctor is quoted as saying that the surgery should control the baby’s weight gain for at least the next three or four years. However, others in the profession have expressed the view that since this is not a case of overeating, bariatric surgery may not have been the best option. They have said that since the genetic disorder continues to exist, merely reducing the size of the stomach is unlikely to do much good. Another area of doubt relates to the age of the patient. While India has no guidelines in place on the minimum age for bariatric surgery, in the US the minimum prescribed age is 18 years. According to Dr Borude, “She has already developed respiratory problems due to which she has been suffering from breathlessness. A little more weight can prove bad for her.” He added, “The surgery could have been done later but the child has to survive till then. We did not want to take any chances.” The child’s parents, who are not well off, are happy that the surgery, which was done free of charge, seems to have given her some hope of a normal future. Jyoti Shelar, Infant’s fat surgery leaves docs divided, Mumbai Mirror.com, November 25, 2011. Available from: http://www.mumbaimirror.com/index.aspx?page=article& sectid=15&contentid=2011112520111125090939157b01b 23a8

Surviving an archaic test Desperate for a job, Balaji Trimanwar, the son of a Yavatmal farmer, took part in a 26-km run, a required test for aspirants to jobs as forest guards. Just 23, he collapsed in a pit and died

the next day, apparently of exhaustion. Balaji’s family said he received medical aid only after a couple of hours. While thousands took part in this archaic test, 1,240 candidates fainted in the heat, according to Kishore Tiwari of the Vidarbha Jan Andolan Samiti. Tiwari stated this to counter the forest officials’ claim that Balaji may have died due to a kidney ailment. The Samiti has approached the state human rights commission to review the case and recommend compensation for Balaji’s family. It has also demanded that the Forest Department revise its recruitment rules and cut the length of the race. On the intervention of the state human rights commission, the department has now agreed to check all candidates after the first five km before allowing them to continue. It will also make it compulsory for applicants to produce a fitness certificate before running. The department has defended itself saying that the stringent provisions of the Forest Conservation Act and the Wildlife Protection Act prohibit the building of roads in the forest area, hence the work requires men who are fit enough to function under such conditions. They claim such tests help them to gauge a person’s capacity for the job. The Commission is said to have asked for the rules to be revised in writing. Meanwhile, the department has paid compensation of Rs two lakh to Balaji’s family. Yogesh Naik, 5-km ‘risk test’ in forest job marathon, Mumbai Mirror, October 26, 2011. Available from: http://www.mumbaimirror.com/article/2/ 2011102620111026020201404bc6fe9f5/5km-%E2% 80%98risk-test%E2%80%99-in-forest--job-marathon. html Mumbai Mirror Bureau, Yavatmal youth dies while chasing forest job, Mumbai Mirror.com, September 21, 2011. Available from: http://www.mumbaimirror.com/ article/2/2011102620111026020201404bc6fe9f5/5km%E2%80%98risk-test%E2%80%99-in-forest--jobmarathon.html?pageno=1

Contributions from Maithreyi and from Meenakshi Dcruz Compiled by Meenakshi Dcruz e-mail: meenakshidcruz@ gmail.com

[ 12 ]


Articles

International collaborative trials, placebo controls and The Declaration of Helsinki: need for clarification in Paragraph 32 AY Malik1, F Ghafoor 2 Wellcome Trust D Phil student, Ethox Centre, Department of Public Health, University of Oxford, Oxford, OX3 7LF UNITED KINGDOM e-mail: [email protected]. uk 2 Pakistan Medical Research Council, Sheikh Zayed Medical Complex, Lahore PAKISTAN e-mail: [email protected]

1

Abstract Inequities in socio-economic and healthcare systems between developed and developing countries have been thrown into sharp relief by globalisation. At the same time, pharmaceutical companies have started conducting clinical trials in developing countries in order to reduce their costs substantially. Together, these two developments create ethical challenges for sponsors and researchers of these trials. One such challenge is that of placebo-controlled trials (PCTs). In this paper we analyse Paragraph 32 of the Declaration of Helsinki referring to PCTs, identifying ambiguities in the wording, and then examine three arguments presented by sponsors of PCTs in developing countries, in defence of such trials. These arguments are: (i) a placebo control provides a definitive answer, and is therefore methodologically superior; (ii) placebo-controlled trials are ethical because they serve the principle of utility, and (iii) interpreting the “best current proven intervention” as the local standard of care allows PCTs to be conducted, if the local standard of care is “no treatment”. We argue that PCTs are not methodologically superior; nor are they ethically defensible. Other trial designs conforming to the ethics of research are feasible; the reason for conducting PCTs is expediency. We further propose that, given the global applicability of the Declaration of Helsinki, it is imperative to remove the ambiguities in Paragraph 32. In the context of collaborative trials, when a treatment exists, conducting PCTs is ethically unacceptable, irrespective of the geographic location of the trial. Universal standards ought to be applied universally.

Introduction Globalisation has brought to the fore inequities in socioeconomic and healthcare systems in the developed and developing worlds (1-2). Health spending in the least developed countries is US$11 per person per annum compared to US$1,900-2,000 per person per annum in high income countries. The expenditure in the former is well short of the US$30-40 per person per annum recommended by the World Health Organisation (3), required to cover basic treatment and care for major communicable diseases like HIV/AIDS, TB and malaria (4). Thus, in resource-poor countries, the meagre amount allocated for healthcare results in minimum healthcare provision – sometimes none – for its citizens. This creates a situation in which patients may view enrolling in a trial as the only way to access healthcare (5). From another point of view, the large pool of potential research participants in developing

countries is of interest to pharmaceutical companies. These companies reduce their costs substantially by conducting trials in developing countries. These factors together raise the possibility that patients in developing countries may be exploited (6-9), posing ethical challenges for researchers as well as sponsors of clinical trials. Some of the challenges are related to the provision of post-trial benefits to the host community, the use of a placebo in the control arm, and treatment and compensation for research-related injuries. The Declaration of Helsinki (DoH) is a key document in the ethics of international research involving human participants. It has been revised many times and each time important questions of clarification have arisen. Paragraph 32 of the DoH refers to the use of a placebo control. In this paper we focus on the use of placebo-controlled trials (PCTs) in developing countries. It begins with an analysis of Paragraph 32 of the DoH, and is followed by the enumeration of three justifications given in favour of PCTs, and our arguments against them. We use the paradigm case of the short course azidothymidine (AZT) trials in Africa as a backdrop to examine the arguments. In 1994, more than 12,000 HIV positive pregnant women in SubSaharan Africa were enrolled in randomised controlled trials of a treatment regimen to prevent mother-to-child transmission of HIV. Randomised controlled trials are considered the gold standard of research in order to establish the safety and efficacy of a drug. This treatment regimen using a short course of the drug AZT was based on the 076 regimen that had been found effective, a little earlier, by the AIDS Clinical Trials Group study 076. The 076 regimen was available to patients in the developed world. However, the short course regimen would be much cheaper than 076. Of the 12,000 women, half were given the test drug (short course AZT) and half were given placebo. This provoked a heated international controversy on the ethics of conducting placebo-controlled trials when an effective treatment – 076 – existed in the sponsoring country (10-11) and eventually led to a number of revisions in the Declaration of Helsinki. Finally, we conclude that Paragraph 32 of the DoH must state unequivocally that conducting a PCT when treatment exists is ethically tenuous, irrespective of the geographic location of the trial.

[ 13 ]


The Declaration of Helsinki The Declaration of Helsinki is the leading international standard of ethical principles for medical research involving human participants (12). Since it was first issued in 1964, it has undergone a number of revisions. The latest revision addresses issues related to post-trial benefits, research-related injuries and the use of a placebo control. However, the DoH has not resolved the question of whether the use of placebos in collaborative trials is ethical when there is a proven intervention in the sponsoring country for the condition that the experimental drug will treat. (This is of concern because in such circumstances, participants on placebo would be deprived of an effective treatment, thus subjecting them to harm.) As a result, PCTs are still conducted and the debate on the ethics of PCTs is ongoing (13-17). The DoH was last revised in October 2008. One important clarification was in Paragraph 32 concerning PCTs. The paragraph now reads: The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention except in the following circumstances: l The use of placebo, or no treatment, is acceptable in studies

where no current proven intervention exists; or l Where for compelling and scientifically sound methodological

reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option. (18: para.32)[emphasis added] Below, we argue that the interpretation of these phrases is not self-evident and, in the context of international collaborative research, these guidelines do not provide clear guidance. First, it is not clear what the locale is of the “best current proven intervention” against which the new intervention is to be tested. It could be the current proven intervention in the sponsoring country or the current (usual and available) intervention in the host community where the patients are enrolled. Second, it is not clear whether the phrase “studies where no current proven intervention exists” refers to the geographic location of the study, that is, when a study is conducted in locations where no current proven intervention or treatment exists. It can also be interpreted to refer to the disease under investigation for which no current treatment exists anywhere, and the purpose of the trial is to find a treatment. If the phrase means the latter, then the use of a placebo for the control group is acceptable. However, if the phrase refers to the geographic location of the studies, then it feeds into the assumption that a placebo control is permissible in studies conducted in locations where no treatment for that particular disease exists. In the context of international collaborative trials, it leads to the inappropriate conclusion that in countries where no proven intervention currently exists, conducting placebo-controlled

trials is permissible, even though the proven intervention exists in the sponsoring country. Third, the confusion is further aggravated if we permit PCTs for “compelling and scientifically sound methodological reasons”. These reasons too can be arbitrary. For example, some sponsors and researchers may have difficulty in designing non-placebocontrolled trials for developing countries. Following from the discussion above, depending on the interpretation of the phrases, placebo-controlled trials may or may not conform to the DoH’s ethical guidelines. Various arguments are made to support the use of PCTs in developing countries even though an effective intervention exists for the condition to be treated. We discuss these below.

I. Placebo control and definitive answers One argument in support of a placebo control is that comparing the test drug with a placebo provides a definitive answer to the efficacy of that drug; PCTs will show an absolute benefit. Interpreting paragraph 32 as referring to the geographic location where no treatment exists and supporting it for a “compelling and scientifically sound methodological reason”, it is argued that a PCT, unlike an active control trial (in which the control group is given another, effective drug), provides a definitive answer to the efficacy of the test drug (19). This implies that PCTs are able to distinguish between active and inactive treatments and therefore methodologically superior (20). Any study that shows the superiority of a treatment to a control (whether placebo or active therapy) provides strong evidence of the effectiveness of the new treatment (21). Therefore, conducting a PCT would provide a definitive answer and validate the provision of a proven effective test drug in the host country (as in the PCTs of short course treatment to prevent HIV transmission in Africa); governments require convincing evidence about treatment efficacy in order to make sound public health policy decisions regarding allocation of funds (22-23). However, a concern here is that since PCTs can only answer the question of whether something is better than “nothing”, even minimal efficacy would appear magnified. We suggest that alternative trial designs can be formulated in which an effective treatment (available in the sponsoring country) is provided to the control group. Conducting this active control trial would establish whether the investigational intervention is better or worse than, or equivalent to, the standard treatment in efficacy and safety (24-25). And that is what needs to be known: how does the new drug fare when compared with what we are using at present? A second alternative to PCT is using information sources external to the trial, which can provide a valid and reliable basis for evaluation of the new drug (21). This information can be from historical controls. Yet another methodology could be to start with a small cohort of patients and as soon as the efficacy of the intervention is determined, the data monitoring and safety board could expedite the use of the new drug for the rest of the patients. We suggest this possibility based on the

[ 14 ]


protocol followed by Sperling et al (26). Therefore, if paragraph 32 were interpreted to refer only to diseases for which no treatment exists anywhere, this would represent a justifiable, ethical, use of placebo controls. Once a treatment becomes established, the new drug regimen must be tested against it (27-28).This ought to be implemented wherever collaborative research is conducted, reiterating the ethical interpretation of the phrase; to deny patients effective treatment in order to influence health policy is as bad in developing countries as it is in developed countries (13).

II. Placebo controls and ethics The second argument in favour of conducting a PCT is based on a principle of ethics, that of utility, which is to always produce the maximal balance of “positive value” over negative value. Resnik argues that PCTs provide quicker and more reliable answers to scientific questions – PCTs are more efficient (29). However, using a utilitarian calculation to justify placebo use in conditions that result in morbidity, and/or mortality, violates the principle of beneficence, even if consent is obtained (30). Resnik further argues that ethical principles sometimes conflict with the scientific rigour of the trial: this argument was based on the assumption that PCTs are methodologically superior and hence beneficence and informed consent may be trumped by “scientific rigour, justice and social utility”(29:298). However, as shown above, in order that the principle of utility (and beneficence) is not compromised, alternative trial designs can be formulated. Moreover, statistical analysis shows that the number of participants required in an active control trial and a placebo-controlled one is similar (17, 31-32). It is noteworthy that the phenomenon of placebo effect, wherein the placebo mimics the active drug response (33), can contribute to the variability in outcome data (34). This has implications: if the placebo effect is strong then the number of patients required to overcome this effect will increase (35). Placebos and justice The principle of justice may be violated by conducting PCTs. It is plausible that if an active control trial in developing countries identified effective but less expensive and less toxic drugs, then these regimens would be implemented in the developed world (36). Or if the superiority of one drug were to be established over the other when both “ran” against each other, the result could have implications, both therapeutic and economic, in developed countries (37). This can have major financial implications for companies that have already established a market for one drug. If the cheaper regimen turns out to be more effective than the established treatment, or if it turns out to be equally effective, then the companies could lose substantially. In the case of the HIV/AIDS trials, the success rate in reducing mother-to-child transmission was considerably higher in developed countries where the 076 regimen was in use; but not in developing countries, where a short regimen was in use. However, the point to note here is that the knowledge generated through the use of the short regimen

in developing countries was used by researchers in developed countries to create more effective treatment regimens for patients in developed countries (38). Placebos and non-maleficence PCTs are also beset by another consideration that is both practical and ethical: participants in a trial need to be informed that during randomisation they may be assigned to the placebo arm. However, “potential participants may be more likely to consent to a trial where they are certain to receive an ‘active’ treatment than they are if they might get a ‘placebo’” (31: 43). There may be problems of noncompliance when these patients either do not take the “placebo medicine”, or withdraw, or covertly seek treatment (31). As stated earlier, it is the provision of treatment that impels patients to enrol in many trials in developing countries (5, 39-41). Even Miller and Brody who are proponents of PCTs write: “placebo controlled trials raise ethical concerns insofar as they have the potential to exploit the research participants by exposing them to excessive risks from placebo assignment.”(42:8). Placebo and equipoise An ethical prerequisite for starting a randomised controlled trial is clinical equipoise, a state in which the medical community, on the basis of available data, is equally poised between the two treatments being tested. According to Freedman et al: As a normative matter, it defines ethical trial design as prohibiting any compromise of a patient’s right to medical treatment by enrolling in a study…these principles allow for testing new agents…. At the same time they foreclose the use of placebos in the face of established treatment. (32: 244-5) If the phrase “studies where no current proven intervention exists” is interpreted to mean the location of the trial where no treatment exists, then by conducting PCTs, the indeterminacy of treatment options is lost; that is, equipoise does not exist because when one compares the test drug with ‘no treatment’ (placebo) then the advantages of the former over the latter are already established: placebos cannot treat a disease. Furthermore, randomised controlled trials are phase 3 trials (phase 1 being primarily for safety and phase 2 for safety and efficacy on small numbers of participants) by which time preliminary data from earlier phases provides some information about the potential benefits of the test drug (43) that would suggest that the new therapy is better than placebo (44). We argue that conducting a PCT in the light of such evidence -- where equipoise is lost -- is ethically tenuous. Since science and ethics are not separate, it is necessary that in conducting research on human participants the scientific merit of the research must be matched by the ethical merit of the work (45-46).

III. Placebo control and “standard of care” This argument in favour of PCTs depends on ambiguities in the DoH. In the past the “current proven method” was interpreted as standard of care (in its narrow interpretation) which was again subjected to varied interpretations. Depending on the

[ 15 ]


frame of reference, it meant either standard medical practice in the host country or the universal standard of care if the frame of reference was a practice with widespread acceptance among the medical profession worldwide. In other words, it was a normative standard set by the judgement of experts in the medical community, and not a description of the local practice (47). Similarly, if the phrase “studies where no current proven intervention exists” is interpreted by sponsors as: “studies conducted at locations where no treatment exists”; by deduction, placebo control is acceptable. This argument resonates with the claims that in Sub-Saharan Africa, the local standard of care was “no treatment” and hence use of placebo was justified (37) and left no woman “worse off”; on the contrary at least some benefited from the test drug (23, 48). An argument like this would be unacceptable to ethics committees in a developed country which do not allow PCTs when effective treatment exists, even though these treatments are not accessible to a substantial number of their people (49). If antibiotics are not available in a community, it does not mean that the standard care for infections in this community is “no treatment”; since the standard care for infections is antibiotics. All it means is that the drugs are not available in that community, and this non-availability is determined by vested interests driven by economic considerations (50). No standard can be set in circumstances of deprivation and fiscal constraint, and the argument that “no treatment” is “standard care” at a certain locale is a misinterpretation of Paragraph 32 of DoH, used to substantiate the use of placebos in the control group. The phrase “studies where no current proven intervention exists” could be misinterpreted to strengthen the arguments for conducting PCTs in developing countries (as did the standard of care debate) but this would contravene the DoH’s more unambiguous paragraph: “it is the duty of the physician in medical research to protect the life, health and dignity of the subject”(18: para.11). The guidelines have been formulated so that the subjects’ welfare is not subordinated to the objectives of the research and came into being as a consequence of (some) scientists’ misadventures. Now, the moral obligation is to avoid acts that would contravene the deontological imperative of the medical profession to “do no harm”. Although Ellenberg and Temple make exceptions to the use of placebo controls in conditions where “temporary discomfort” may occur; omitting proven therapy is not an option where morbidity and mortality may result (51). A trial which places the trial participant’s life and health in jeopardy by using less than the effective standard treatment would not be permitted in the sponsoring country; because the “local standard of care is the same as the universal standard of care so anything less would not have sufficient social value to justify its risks”(48:926). Arguably, there are marginalised people in sponsoring countries who do not have access to standard healthcare (52). Even so, the use of a placebo (in the presence of a proven intervention) would not be approved by their ethics review

boards. Therefore, if conducting placebo-controlled trials in the sponsoring country is unethical, then exporting them to developing countries is also unethical (53); in other words, the researchers and sponsors are guilty of double standards. Sponsors of collaborative trials, interpreting the phrase “studies where no current proven intervention exists” as the locale of the study where no treatment exists and buttressing it on “scientifically sound methodological reasons” could then conduct a PCT(6). As established earlier, this claim is not based on scientifically sound reasoning, nor is it ethically valid, hence its removal brings to the surface other reasons for misinterpreting Paragraph 32 and conducting PCTs in the developing world. These are exclusively based on expediency: financial advantage and ease in enrolling patients (7, 9, 30,50,54). In developing countries, research participants’ lack of knowledge regarding disease and their rights places them in a position where the interests of science and the “common good” can take precedence over the research participants’ own well being (55-56). However “all research subjects are entitled to minimum guarantees that are transnational and non-negotiable” (57:545). Concerns have been raised that some sponsors and researchers, by conducting unethical research, denigrate the integrity of those who perform ethical research (58). In the HIV/AIDS trials conducted in Sub-Saharan Africa, of the 12,000 women participating, 6,000 received the test drug and benefited. The other 6,000 received placebos -- in others words they received nothing. Thus, the researchers knowingly failed to minimise harm to those research participants (53). When the reason for conducting PCTs in a developing country is financial, it is necessary to remember that healthcare provision in developing countries is minimal and sparse. In such circumstances, it has been argued, high standards should be set by bringing in new resources to deal with old problems (59). The wide disparities in the healthcare systems of the developed and developing countries require a commitment so that people in the latter also benefit from scientific and economic progress and not just peripheral benefits (60). A step forward would be if each successive research project were to leave the host community benefitted; over a period of time a cumulative effect would help reduce this inequity (30).

Conclusion Pursuing the path of least resistance in order to expedite trials jeopardises the lives (and liberty) of patients living in developing countries; it is morally (and ethically) commendable to design trials (and policies) that help reduce inequities between developed and developing countries and do not promote double standards. The purpose of revising the Declaration of Helsinki is to remove ambiguities and prevent the conduct of unethical trials. Members of the scientific community and ethics review committees ought to be sensitive to the health needs (and rights) of their fellow citizens. They should enter into deliberations so that each successive trial reduces health inequities between the developed and the developing worlds. It is a normative requirement that universal

[ 16 ]


standards ought to be applied universally. References 1. Wagstaff A. Poverty and health sector inequalities. Bull World Health Organ. 2002;80(2):97-105. 2. Rosenfeld R, Tongia R, Sherwani J. HealthLine offers speech-based access to health information [Internet]. Microsoft Research. 2007 [cited 2011 Nov 28]. Available from: http://research.microsoft.com/en-us/ collaboration/papers/carnegie_mellon.pdf 3. Population reference bureau. Improving the health of the world’s poorest people [Internet]. Population reference bureau. 2004 [cited 2011 Nov 28]. Available from: http://www.prb.org/pdf04/ImprovingtheHealthbrief_ Eng.pdf 4. Anyanwu J, Erhijakpor AO. Health expenditures and health outcomes in Africa. Economic research working paper no 91[Internet]. African Development Bank; Tunisia:2007 Dec[cited 2011 Nov 28]. Available from: http://www.afdb.org/fileadmin/uploads/afdb/Documents/ Publications/26820442-EN-ERWP-91.PDF 5. Kahn J. A nation of guinea pigs [Internet]. Wired: [place unknown]; 2006 [cited 2011 Nov 28]. Available from: http://www.wired.com/wired/ archive/14.03/indiadrug.html 6. Rowland C. Clinical trials seen shifting overseas. Int J Health Serv. 2004;34(3):555-6. 7. Glickman SW, McHutchison JG, Peterson ED, Cairns CB, Harrington RA, Califf RM, Schulman KA. Ethical and scientific implications the globalization of clinical research. N Engl J Med[Internet].2009 Feb 19[cited 2011 Dec 13];360(8):816-23. Available from: http://www.nejm. org/doi/full/10.1056/NEJMsb0803929 8. Hundley K. The latest industry being outsourced to India: clinical drug trials. Tampa Bay Times [Internet]. 2008 Dec 14[cited 2011 Nov 25]. Available from: http://www.tampabay.com/news/business/ article934677.ece 9. Bailey W, Cruickshank C, Sharma N. Make your move: taking clinical trials to the best location [Internet]. 2009[cited 2011 Nov 28];56-62. Available from: http://graphics.eiu.com/upload/gtf/1571871942.PDF 10. Angell M. The ethics of clinical research in the Third World. N Engl J Med. 1997 Sep 18;337(12):847-9. 11. Lurie P, Wolfe S. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med. 1997 Sep 18;337(12):853-6. 12. Kimmelman J, Weijer C, Meslin EM. Helsinki discords: FDA, ethics, and international drug trials. Lancet. 2009 Jan 3;373(9657):13-4. 13. Rennie S, Sturmer T. Strengthening Howick’s argument against the methodological superiority of placebo-controlled trials. Am J Bioeth.2009 Sep;9(9):62-4. 14. Mudur G. Indian study sparks debate on the use of placebo in psychiatry trials. BMJ. 2006 Mar 11;332(7541):566. 15. Polman C, Reingold S, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O’Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ,Weinshenker BG, Wolinsky JS. Ethics of placebo controlled clinical trials in multiple sclerosis: a reassessment. Neurology. 2008 Mar 25;70(13Pt 2):1134-40. 16. Valeo T. Trialists Debate: Are randomised placebo-controlled trials always ethical. Neurology Today. 2010 Jul 15;10(14):20-1. 17. Michels K B, Rothman KJ. Update on unethical use of placebos in randomised trials. Bioethics.2003 Apr;17(2):188-204. 18. World Medical Association. Declaration of Helsinki. Ethical principles for medical research including human subjects [Internet]. France: WMA;2008 [cited 2011 Nov 28]. Available from: http://www.wma.net/ en/30publications/10policies/b3/index.html 19. Varmus H, Satcher D. Ethical complexities of conducting research in the developing countries. New Engl J Med. 1997 Oct 2;337(14):1003-5. 20. ICH expert working group. ICH harmonized tripartite guidelinechoice of control group and related issues in clinical trials- current step 4 version [Internet]. ICH; 2000 [cited 2011 Nov 28]. 35p. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Efficacy/E10/Step4/E10_Guideline.pdf 21. Temple R, Ellenberg S. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments. Part I: ethical and scientific issues. Ann Intern Med. 2000 Sep 19;133(6):455-63.

22. Crouch R, Arras JD. AZT trials and tribulations. Hastings Cent Rep. 1998 Nov-Dec;28(6):26-34. 23. Grady C. Science in the service of healing. Hastings Cent Rep. 1998 NovDec; 28(6):34-8. 24. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. CONSORT Group. Reporting of non inferiority and equivalence randomised trials: an extension of the CONSORT statement. JAMA. 2006 Mar 8;295(10):115260. 25. Testing equivalence of two binomial proportions. In: Machin D, Campbell MJ. Statistical tables for the design of clinical trials. Oxford, England: Blackwell Scientific.1987.35-53. 26. Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, O’Sullivan MJ, Van Dyke RB, Jimenez E, Rouzioux C, Flynn PM, Sullivan JL. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996 Nov 28;335(22):1621-9. 27. Weijer C. The ethical analysis of risk. J Law Med Ethics. 2000 Winter;28(4):344-61. 28. Weijer C. Anderson JA. The ethics wars. Disputes over international research. Hastings Cent Rep. 2001 May-Jun;31(3):18-20. 29. Resnik DB. The ethics of HIV research in developing nations. Bioethics. 1998 Oct;12(4):286-306. 30. Benatar SR, Fleischer T. Ethical and policy implications of clinical drug trials conducted in developing countries. Harvard Health Pol Rev. 2005;6(1):97-105. 31. Howick J. Questioning the methodologic superiority of ‘placebo’ over ‘active’ controlled trials. Am J Bioeth. 2009 Sep;9(9):34-48. 32. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I: Empirical and methodological myths. J Law Med Ethics. 1996 Fall:24(3):243-51. 33. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005 Nov 9;25(45):10390-402. 34. Oken BS. Placebo effects: clinical aspects and neurobiology. Brain. 2008 Nov; 131(Pt11): 2812-23. Epub 2008 Jun 21. 35. Friedman JH, Dubinsky R. Patient page. The placebo effect. Neurology, 2008 Aug 26;71(9):e25-6. 36. Annas GJ, Grodin MA.Human rights and maternal- foetal HIV transmission prevention trials in Africa. Am J Public Health. 1998 April;88(4):560-3. 37. Levine RJ. The “best proven therapeutic method” standard in clinical trials in technologically developing countries. IRB.1998 Jan-Feb; 20(1):5-9. 38. Landes M. Can context justify an ethical double standard for clinical research in developing countries? Global Health. 2005 Jul 26;1(1):11. 39. French HW. AIDS research in Africa: juggling risks and hopes. New York Times[Internet]. 1997 Oct 9][cited 2011 Nov 27]. Available from: http:// www.nytimes.com/1997/10/09/world/aids-research-in-africa-jugglingrisks-and-hopes.html?pagewanted=all&src=pm 40. Edejer TT. North-south research partnership: the ethics of carrying out research in developing countries. BMJ. 1999 Aug 14;319(7207):438-41. 41. Lemmens T, Miller PB. Avoiding a Jekyll and Hyde approach to the ethics of clinical research. Am J Bioeth. 2002 Spring;2(2):14-7. 42. Miller FG, Brody H. What makes placebo-controlled trials unethical? Am J Bioeth. 2002 Spring;2(2):3-9. 43. Malik AY. Physician-researchers’ experiences of the consent process in the asociocultural context of a developing country. AJOB Prim Res[Internet].2011[ cited 2011 Dec 11];2(3):38-46. Available from: http:// dx.doi.org/10.1080/21507716.2011.616183 44. Levine C, Dubler NN, Levine RJ. Building a new consensus; ethical principles and policies for clinical research on HIV/ AIDS. IRB. 1991 JanApr;13(1-2):1-17. 45. Koski G, Nightingale SL. Research involving human subjects in developing countries. N Engl J Med. 2001 Jul 12;345(2):136-8. 46. Benatar SR. Reflections and recommendations on research ethics in developing countries. Soc Sc Med. 2002Apr;54(7):1131-41. 47. Macklin R. Double standard in medical research in developing countries. Cambridge: Cambridge University Press;2004 Jun 21.263p. 48. Wendler D, Emanuel EJ, Lie RK. The standard of care debate: can research in developing countries be both ethical and responsive to those countries’ health needs? Am J Public Health. 2004; 94(6):923-8.

[ 17 ]


49. Kottow MH. Who is my brother’s keeper? J Med Ethics. 2002 Feb;28(1):247. 50. Schuklenk U. The standard of care debate: against the myth of an “international consensus opinion”. J Med Ethics. 2004 Apr;30(2):194-7. 51. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases. Ann Intern Med. 2000 Sep 19;133(6):464-70. 52. Shapiro K, Benatar SR., HIV prevention research and global inequality: steps towards improved standards of care. J Med Ethics.2005 Jan;31(1):3947. 53. Levine C. Placebos and HIV. Lessons learned. Hastings Cent Rep. 1998 Nov-Dec;28(6):43-8. 54. Malik AY. Research ethics in the context of a developing country perspectives from Pakistan. 2011. Unpublished data. 55. Abbas EE. Industry-sponsored research in developing countries. Contemp Clin Trials.2007 Nov;28(6):667-83. 56. Clark PA. The ethics of placebo controlled trials for perinatal trials of HIV

in developing countries. J Clin Ethics.1998 Summer;9(2):156-66. 57. Studdert DM, Brennan TA. Clinical trials in developing countries: scientific and ethical issues. Med J Aust. 1998 Nov 16;169(10):545-8. 58. Glickman SW, Cairns CB, Schulman KA. Ethical and scientific implications of the globalisation of clinical research. Correspondence: The authors reply. N Engl J Med [Internet]. 2009 June 25[cited 2011 Dec 13];360(26): 2793.[C1] Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMc090588 59. Farmer P, Frenk J, Knaul FM, Shulman LN, Alleyne G, Armstrong L, Atun R, Blayney D, Chen L, Feachem R, Gospodarowicz M, Gralow J, Gupta S, Langer A, Lob-Levyt J, Neal C, Mbewu A, Mired D, Piot P, Reddy KS, Sachs JD, Sarhan M, Seffrin JR. Expansion of cancer care and control in countries of low and middle income: a call to action. Lancet. 2010 Oct 2;376(9747):1186-93. 60. Farmer P, Campos NG. New malaise: bioethics and human rights in the global era. J Law Med Ethics. 2004 Summer;32(2):243-51.

Less equal than others? Experiences of AYUSH medical officers in primary health centres in Andhra Pradesh JK Lakshmi Indian Institute of Public Health, Hyderabad (Public Health Foundation of India), Plot # 1, A N V Arcade, Amar Co-operative Society, Kavuri Hills, Madhapur, Hyderabad 500 081 INDIA e-mail: [email protected]

Abstract The National Rural Health Mission (NRHM) includes, inter alia, the establishment of an AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy) component (practitioner, trained assistants, drugs and equipment) in every primary health centre (PHC). However, five years following the launch of the NRHM, the AYUSH mainstreaming scenario is below expectations, riddled with ethical and governance issues. Accounts from AYUSH practitioners at PHCs in various regions of the state of Andhra Pradesh reveal enormous lacunae in implementation: unfilled positions, inequitable emoluments, inadequate or absent infrastructure, assistance and supplies, unethical interpersonal arrangements, and limited support from non-AYUSH personnel. The widespread negative impact of these conditions undermines the value of AYUSH, demotivating both practitioners and patients, and failing to provide the intended support to the public health system. .

Introduction Traditional, complementary and alternative medicine (TCAM) are therapeutic systems distinct from the dominant allopathic system followed in mainstream medical practice. They are classified as “complementary” when employed in tandem with the dominant system, and “alternative” when employed instead of it. The World Health Organisation defines traditional, complementary and alternative medicine (TCAM) as follows (1): Traditional medicine: Traditional medicine is the sum total of the knowledge, skills, and practices based on the theories, beliefs, and experiences

indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness. Complementary/alternative medicine (CAM): The terms “complementary medicine” or “alternative medicine” are used inter-changeably with traditional medicine in some countries. They refer to a broad set of health care practices that are not part of that country’s own tradition and are not integrated into the dominant health care system. Based on its provenance, context and employment, a system may be traditional, complementary or alternative, or a combination of these. For example, ayurveda used concurrently with allopathy in India is “traditional” and “complementary”; homoeopathy used instead of allopathy in India is “alternative”.

TCAM in the Indian health system Allopathy is the dominant health care system in India.Nonallopathic therapeutic systems find a place in the formal health system in the country under a department of the ministry of health and family welfare (MoHFW). This department was established as the department of Indian systems of medicine and homoeopathy (ISMandH) in 1995, and renamed the department of ayurveda, yoga and naturopathy, unani, siddha and homoeopathy (AYUSH) in 2003 (2). It governs the education, research, practice and quality of all the systems

[ 18 ]


represented in the acronym “AYUSH”, and in addition, a therapeutic system known as sowa-rigpa, or amchi, practised in the Himalayan regions and some parts of north east India. The years since the establishment of the department of AYUSH have witnessed considerable growth in AYUSH educational institutions (undergraduate and post graduate), hospitals, dispensaries and drug manufacturing units (3). The rational use of TCAM is increasingly recognised as a vital public health need. Some of the reasons are: escalation in noncommunicable and chronic diseases; resurgence of certain communicable diseases and emergence of new diseases; drug resistance; and a growing consciousness of the need to incorporate healthy behaviours into our daily lives. This awareness is expressed in international and national policies to mainstream TCAM(4), including promoting research, education, licensing, drug-standardisation and regulation, and awarenessraising. The NRHM in India is a case in point. It incorporates policies and strategies for the mainstreaming of AYUSH, with special emphasis on skill development and infrastructural support for AYUSH personnel.

AYUSH in the NRHM The NRHM, launched in 2005 to fortify public health in India, sought to revitalise and mainstream AYUSH, specifically to strengthen human resources, infrastructure and drug quality and standardisation, supported by advocacy for AYUSH, and the establishment of inter-sectoral linkages to facilitate AYUSH practice. Activities under this initiative include facilitation of specialised AYUSH practice, integration of AYUSH practitioners in national health programmes, integration of AYUSH modalities in primary health care, strengthening the governance of AYUSH practice, supporting AYUSH education, establishing laboratories and research facilities for AYUSH, and providing infrastructural support (5). Actions pertaining to human resources and practice include contractual appointment of AYUSH doctors in community health centres (CHCs) and PHCs; appointment of paramedics, compounders, data assistants, and managers to support AYUSH practice; establishment of specialised therapy centres; involvement of AYUSH doctors in national disease control programmes; and incorporation of AYUSH drugs into community health workers’ primary healthcare kits.

Experiences of AYUSH practitioners under the NRHM The observations made here were generated from interactions with a cross-section of AYUSH doctors contracted to medical officer posts in PHCs in Andhra Pradesh. This was supplemented by a visit to a PHC staffed by an AYUSH doctor, and the perusal of the limited formal literature on the evaluation of the integration of AYUSH into mainstream public health in India. AYUSH medical officers were contacted informally over several weeks, from March to June 2010, during training programmes that they attended, in batches drawn from all the districts of the state, and asked about their experiences in their PHCs. Medical officers practising ayurveda, yoga and

naturopathy, homoeopathy, and unani were approached and communicated with. No siddha practitioner could be accessed as there are none appointed in PHCs in Andhra Pradesh at present. Responses were gathered from discussions in dyads, or in small groups of three to six doctors, yielding rich accounts of the experiences of AYUSH doctors in the NRHM. Thirty AYUSH doctors in all participated in 10 of these discussions, each of which lasted between 10 and 30 minutes. The narratives, besides highlighting a few good practices in certain PHCs, point to numerous lacunae in the implementation of the mainstreaming initiatives in the NRHM. Data gathered on these shortcomings were interpreted, and grouped into five major categories: recruitment, remuneration, facilities, technical support, and interpersonal relationships.

Recruitment The 1,525 PHCs in Andhra Pradesh entail the appointment of an equal number of AYUSH medical officers. The positions were mandated to be filled in three phases by the year 2009. However, over 50 percent of the AYUSH medical officer positions in Andhra Pradesh were unfilled in the year 2010, the majority through never having been filled, and a few through the dismissal of the serving AYUSH medical officer. A recent review of the NRHM (6) reports that only 29 percent of PHCs across India have integrated AYUSH staff into their personnel. The low proportion of filled AYUSH medical officer positions in Andhra Pradesh, (approximately 43 percent according to a 2010 report (7)) though not as bleak as the national average, is nevertheless a cause for concern. But, although the quantum of recruitment is well below the target, the process of recruitment is commended by AYUSH doctors as transparent and in accordance with stated policy, beginning with advertising in leading newspapers, and guided by merit, and the government’s categories of reservations. The contracts, under which AYUSH doctors are recruited to PHCs under the NRHM initiative, which are meant to be renewed annually, are often not renewed in a timely manner. Many doctors report their continuing to work for months, despite the lapse of their contracts, with the implicit understanding that the delay in renewal is an expression of administrative inertia, rather than a herald of dismissal. The delay, sometimes over six months, in the renewal of contracts is observed to be a feature only of the AYUSH personnel appointments, and not of other contractual executives of the NRHM. The contractual AYUSH medical officers report to the regional deputy director of their respective zone, under the commissioner of AYUSH of the state. Despatches include the regular attendance report (attested by the allopathic medical officer at the PHC), and the out-patient report of the consultations performed. The regional deputy director is also the official who disburses the AYUSH medical officers’ salaries.

Remuneration AYUSH medical officers unvaryingly lament their meagre salaries, as being well below the emoluments of allopathic

[ 19 ]


colleagues. The current consolidated monthly salary of Rs 9,300 (8) is reported to be based on a previous calculation of the basic pay of allopathic medical officers, and precludes both the increments in said basic pay over the years, as well as all the substantial allowances which are added to the basic pay to form the allopathic medical officer’s salary. AYUSH medical officers in PHCs in Andhra Pradesh cite the comparatively higher emoluments of certain unskilled support staff in allopathic hospitals to underscore their frustration at the low salaries that they receive. The insufficiency of the salary is acknowledged in several submissions to the government, by AYUSH medical officer associations as well as their administrative superiors, for enhancement of pay, and an approach to parity with AYUSH medical officers’ salaries in other states, as well as the basic (unconsolidated) pay of allopathic medical officers, which is Rs. 15,600 at present (8,9). There are very few contractual allopathic medical officer positions for comparison: These positions come with a salary equal to the basic pay of regular allopathic medical officers, which, as detailed above, is considerably higher than the contractual AYUSH medical officer’s salary. Other (nonAYUSH) contractual employees’ salaries are regularly revised in accordance with Pay Commission recommendations, unlike contractual AYUSH doctors’ salaries. The contractual position does not offer any perquisites, such as benefits or allowances for family, health, housing, education, and geographic location. The working hours of AYUSH medical officers are the same as those of allopathic medical officers. The range of responsibilities is different however: AYUSH personnel are not assigned emergency duties and obstetric duties. AYUSH doctors are justifiably exempt from the ‘emergency allowance’ over their basic pay, but the denial of a ‘rural allowance’ for geographic location is not defensible. There is no overlap or express sharing of responsibilities between the AYUSH and non-AYUSH departments of the PHC. In addition to the salary, each AYUSH medical officer is allocated a contingency fund to cover expenses not already accounted for. This contingency fund, ostensibly usable for some equipment, stationery, repairs etc, is not conveyed in a timely manner to all the AYUSH medical officers. Some report not receiving the fund at all, and going to the extent of using their personal funds to institute minor repairs, and installation of equipment, such as signboards, in the PHC.

Facilities Each medical officer is expected to be furnished with a consultation chamber, a dispensing zone, and a waiting area for patients, adding up to a minimum of 800 square feet of space (10). This includes provision for fresh construction of a building in situations where the existing structure cannot accommodate the AYUSH facility, and the PHC site has enough space. While some AYUSH doctors report satisfactory, and a small minority, excellent, infrastructural provision, numerous doctors describe the premises provided to them as grossly inadequate. Accounts were communicated of verandahs and cramped storerooms

being pressed into service as consulting, drug storage, and drug dispensing spaces. Besides space, furniture and equipment are reported to be in short supply in several PHCs. The supply and replenishment of medications, across systems of AYUSH, leave a lot to be desired at many PHCs. While some doctors complained of the delay of several months, in the initial stocking of medications, others reported prompt primary stocking followed by months without replenishment. Considering that many AYUSH medications, eg certain ayurvedic and unani formulations, are too expensive for PHC patients to afford to procure from private pharmacies, this inadequate supply may mean the difference between receiving AYUSH treatment and being denied it. The inability to obtain stocks of appropriate medication is a common grievance of AYUSH doctors in PHCs across the nation, as revealed by an evaluation of service delivery under the NRHM in four states (11).

Technical support Every PHC is expected to be populated with a trained AYUSH compounder, an assistant to dispense medication and provide therapeutic services on the prescription of the medical officer. Reports reveal that the position of an assistant is not filled in some PHCs, and that assistants appointed at certain PHCs are not appropriately skilled, leaving the doctor to undertake the dispensing in addition to the prescription. For instance, some individuals appointed to assist unani medical officers, are not literate in Urdu, and thereby not competent to decipher prescriptions in Urdu and dispense medications labelled in Urdu. Besides the compounder, every AYUSH medical officer is assigned a sweeper and nursing orderly, to help with the maintenance of the AYUSH facility at the PHC and with patient flow during consultation hours: This post is also unfilled in some cases. It bears mentioning that the emoluments of the AYUSH support staff are low, specifically Rs. 4800 per month for a compounder, and Rs. 3900 per month for a sweeper and nursing orderly (9).

Interpersonal relationships A few AYUSH medical officers enjoy collegial and cordial relationships with their allopathic counterparts, as well as the other personnel working at the PHC. Some report minimal interaction, and no adverse communication, with the allopathic medical officer and other PHC personnel. Several others recount unpleasant interactions with the allopathic medical officer, and several of the other PHC personnel. These range from tacit disapproval and deprecatory references by the nonAYUSH personnel at the PHC, to verbal discouragement of potential patients from visiting the AYUSH doctor, and blatantly unethical interpersonal arrangements between the allopathic and AYUSH doctors. For instance, the allopathic medical officer may fraudulently document the attendance of the absent AYUSH medical officer, in exchange for a financial consideration, or as part of a reciprocal arrangement. Some AYUSH doctors are reported to have been asked to perform case-taking, diagnosis and prescription of allopathic medications on behalf of the

[ 20 ]


absent allopathic medical officer. This is clearly against the law, not to mention unethical, as not all AYUSH students are trained in allopathic pharmacology and licensed to prescribe allopathic medications. In premises shared by allopathic and AYUSH medical officers, it is reported that the sweeper and nursing orderly assigned to the centre, although notionally able to work for the AYUSH facility as well as the allopathic, may not work at the AYUSH facility. AYUSH medical officers cite interpersonal tension and an antagonistic attitude towards AYUSH as reasons for this. The NRHM envisages the participation of AYUSH personnel in national health programmes(5). However, the guidelines for such participation are not elucidated, with the result that the involvement of AYUSH personnel in national programmes is predicated on the interpersonal equation between the allopathic medical officer and the AYUSH doctor. Thus, some PHCs see a high level of involvement of AYUSH personnel in national health programmes, some moderate, eg, participation in the pulse polio programme, and many others see no participation of AYUSH personnel in national health programmes. Clear guidelines on the roles of AYUSH medical officers in national health programmes are urgently needed to resolve this, to harness all health personnel appropriately, and strengthen national health programmes.

Conclusion In summary, few AYUSH doctors report positive experiences of technical and social support in their work at PHCs. The straitened economic situation is universally lamented, by those with positive, as well as those with negative, social and infrastructural circumstances. AYUSH doctors observe that besides the few patients sceptical from the start, numerous patients enthusiastic at first get discouraged with time from using AYUSH treatments, under the conditions prevalent at several PHCs. The procedures to “mainstream AYUSH” in PHCs have placed AYUSH and allopathic systems in a largely parallel configuration – with separate reporting channels, fiscal and logistical structures, and distinct duties – not providing optimal scope for the deployment and development of AYUSH. The negative impact of the circumstances of AYUSH in PHCs is widespread, affecting practitioners, patients, and eventually the nation at large. The effects range from minor delays in treatment, to job-dissatisfaction, interpersonal tension and the calling into question of the professional integrity of medical practitioners. The value and practice of AYUSH are undermined, demotivating both practitioners and patients. The injury to public health lies in the denial of proper AYUSH treatment to the many who may desire, and benefit from, it; the denial of a platform to AYUSH practitioners to contribute to public health; and the denial to the nation of the public health gains to be made from the optimal application of AYUSH to public health challenges, including health promotion and disease prevention.

The dissonance between the stated goals of revitalising and mainstreaming AYUSH and the reality of inequitable implementation is patent. The injustice to AYUSH practitioners, and patients, and by extension to the national community, calls for a systematic evaluation of the integration (particularly the underlying structural and social issues) of AYUSH into the public health mainstream in India, and the implementation of prompt remedial measures. Acknowledgement The author is grateful to the AYUSH medical officers who articulated their experiences in PHCs, raised her consciousness of the technical, administrative and ethical issues encountered in the mainstreaming of AYUSH in PHCs in Andhra Pradesh, and present an inspiration in perseverance and dedication to their systems of medicine. Competing interests: none Funding support: The author was supported by the Indian Institute of Public Health, Hyderabad, during the process of gathering information and writing. No other funds were received or expended for this work. References 1. World Health Organisation. Traditional medicines: definitions [Internet]. Geneva: WHO;2011[cited 2011 Nov 8]. Available from: http://www.who. int/medicines/areas/traditional/definitions/en/index.html 2. Department of AYUSH,Ministry of Health and Family Welfare,Government of India. Welcome to AYUSH [Internet]. New Delhi: Government of India; 2011[cited 2011 Nov 8]. Available from: http://indianmedicine.nic.in/ index.asp?lang=1 3. Department of AYUSH, Ministry of Health and Family Welfare, Government of India. AYUSH in 2008 [Internet]. New Delhi; Government of India;2010[cited 2011 Nov 8]. Available from: http://indianmedicine. nic.in/index3.asp?sslid=388&subsublinkid=136&lang=1 4. World Health Organisation. WHO traditional medicine strategy 2002 - 2005[Internet]. Geneva:WHO;2005[cited 2011 Nov 8]. Available from: http://whqlibdoc.who.int/hq/2002/who_edm_trm_2002.1.pdf 5. National Rural Health Mission. Department of Health & Family Welfare, Government of Orissa. Mainstreaming AYUSH under NRHM [Internet]. New Delhi: Government of India; [cited 2011 Nov 25]. Available from: http://203.193.146.66/hfw/PDF/ayus.pdf 6. Husain Z. Health of the National Rural Health Mission. Econ Pol Wkly. 2011 Jan 22;46(4):53-60. 7. Planning and Evaluation Cell, Department of AYUSH, Ministry of Health and Family Welfare. Government of India. AYUSH Report 2010 [Internet]. New Delhi: Government of India 2010; [cited 2011 Nov 15]. Available from: http://www.similima.com/pdf/ayush-complete-report-2010.pdf 8. AYUSH Medical Officers Association, a. 2010 [Internet]. AYUSH Medical Officers Association: 2010[cited 2011 Jul 20]. Available from: http://apayushmosassnnrhm.com/pages/Pogroms_7.html 9. AYUSH Medical Officers Association, b. 2010 [Internet]. AYUSH Medical Officers Association: 2010[cited 2011 Jul 20]. Available from: http://apayushmosassnnrhm.com/pages/Pogroms_2.html 10. AYUSH Medical Officers Association, c. 2010 [Internet]. AYUSH Medical Officers Association: 2010[cited 2011 Jul 20]. Available from: http:// apayushmosassnnrhm.com/pages/Pogroms_5.html 11. Gill KA. Primary evaluation of service delivery under the National Rural Health Mission: findings from a study in Andhra Pradesh, Uttar Pradesh, Bihar and Rajasthan. Working Paper 1/2009, Planning Commission[Internet]. 2009[cited 2011 Nov 11]. Available from: http://planningcommission.nic.in/reports/wrkpapers/wrkp_1_09.pdf

[ 21 ]


Continuing oversight through site monitoring: experiences of an institutional ethics committee in an Indian tertiary-care hospital Yashashri C Shetty1, Padmaja Marathe 2, Sandhya Kamat3, Urmila Thatte4 Assistant Professor, 2 Associate Professor,3 Professor, Department of Pharmacology and Therapeutics, 4 Professor and head, Department of Clinical Pharmacology, Seth G S Medical College and K E M Hospital, Parel, Mumbai 400 012 INDIA Author for correspondence: Yashashri C Shetty e-mail: [email protected]

1

Abstract WHO-TDR and the Indian Council of Medical Research recommend site visits by institutional ethics committees (IECs) for continued oversight, to ensure the ethical conduct of research. Our IEC conducted seven site visits in 2008-2009 using a standardised format to monitor adherence to protocol and the informed consent process. The study identified issues related to informed consent (6/7), deviation from protocol (5/7), reporting of study progress to the IEC (3/7), recruiting additional participants without IEC approval (2/7), reporting of serious adverse events (1/7), investigator’s lack of awareness of protocol and the informed consent document (2/7) and other findings. Investigators were informed about the findings and were asked to submit an explanation. The IEC issued warnings about not repeating such lapses in the future(5/7), restricted enrollment of new participants(2/7), recommended continued good clinical practice training to the study team (4/7), advised the recruitment of additional study coordinators(2/7), and requested the submission of adverse event reports(2/7) or sponsors’ audit reports(2/7). Our study showed that the ethical conduct of studies can be ensured by conducting routine site monitoring.

Introduction The continuing review of approved research by institutional ethics committees (IECs) is essential to ensure the ethical conduct of clinical research. IECs perform this duty primarily by reviewing data submitted to them during the conduct of a trial at pre-specified regular intervals. This data includes serious adverse event (SAE) reports, progress reports, reviews of protocol violations, and of amendments of protocol, and related documents submitted by the investigators etc, as recommended under national and international guidelines and legislation (1-3). This is generally a form of “passive monitoring”. In order to ensure the safety and well being of participants ,as well as to ascertain that potential risks have not altered, these same guidelines also recommend site visits as one of the methods for continuing review by IECs (1-3). Site monitoring is a routine activity in the United Kingdom and research ECs carry out proactive monitoring through questionnaires and/or by visiting research sites for pharmaceutical industry-sponsored trials (4). However, IECs in India have neither the mechanisms in place nor the manpower or resources to meet this requirement, and therefore cannot fulfil this obligation (5). Consequently, they rely upon passive

monitoring. Additionally, and perhaps as relevant, is the fact that all medical institutions take up investigator-initiated studies where sponsor-driven routine monitoring may not be carried out, emphasising the greater need for continued monitoring by IECs (6). As a strategy to address this issue, our IEC (located in a tertiary care hospital in India) conducted site monitoring visits according to pre-drafted standard operating procedures (SOPs) (7). Visits to different study sites were organised to monitor the conduct of the ongoing studies. The objectives of these visits were to check compliance of investigators with the protocol and the informed consent process approved by the IEC as well as to assess the level of understanding of the research participants. This paper discusses the observations made during site visits and the subsequent recommendations made to the investigators as also action taken by the IEC.

Methodology Seven sites were monitored by members of the IEC between January 2008 and December 2010, using a standardised predecided format based on the SOPs (Appendix 1). The sites were selected for monitoring either ‘for cause’ (n=5) including incomplete communication from the principal investigator (PI) regarding study progress, a large number of SAEs (deaths) reported from a site, large numbers of protocol deviations, recruitment of additional participants without approval of the IEC and a large number of studies undertaken by the PI at one site or routine (n=2) for investigator-initiated studies. The site visits were conducted according to the IEC’s SOP number 15 (7). The PIs were informed in writing two weeks in advance about the schedule of site visits, and their acceptance and availability were confirmed before conducting the visits. A team of two IEC members conducted the visits and noted down the observations in the site monitoring report (Appendix 1).The approval of the IEC was obtained to compile and analyse the site visit reports. The reports were analysed for violations and categorised under seven themes: (1) informed consent; (2) deviation from investigational plan , (3) non-reporting of study progress to IEC, (4) IEC approval (5) lack of investigator understanding of protocol and informed consent documents (ICD), (6) SAE reporting, and (7) other findings.

Results Of the seven studies selected for monitoring, five were pharmaceutical industry-sponsored and two were investigator-

[ 22 ]


initiated studies. All seven were drug trials. The most common findings in these audits were related to the informed consent process (6/7). Others included deviations from the investigational plan (5/7), non-reporting of the study’s progress to the IEC (3/7), recruiting additional participants without IEC approval (2/7), lack of investigator awareness regarding the protocol and informed consent document (3/7), and serious adverse event reporting (1/7). In addition to the above, some other findings were also noted, all of which have been summarised in Table 1. Table 1: Violation themes observed during site monitoring by IEC Monitoring sites Violation theme (n=7) Informed consent issues

6/7

Deviation from investigational plan

5/7

Non-reporting of study progress to IEC

3/7

Deficiencies in study supervision

2/7

IEC approval

2/7

Lack of investigator’s understanding about protocol and informed consent document

3/7

Serious adverse event reporting

1/7

in Marathi (local language) and had signed the English consent form in Marathi. The explanation given by the investigator was that the patients’ signatures were obtained only after explaining everything to them. In one case, the ICD was signed 10 days after obtaining the participant’s signature by the PI and co-investigator (Co-I). In one ICD, a nurse of the Institute was used as an impartial witness. In one study, names of all the 30 participants and dates had been filled in by the PI. Without documenting the participant’s consent on the ICD, all the data had been filled in into the case record forms. In one study, informed consent was re-obtained from participants with an amended (approved by IRB) version of the ICD containing information on important new side effects after a delay of 1-3 months. The informed consent addendum was signed by the PI and the Co-I 10 days later, and in the case of 30 participants, a copy of the ICD had not been given to any of them. In order to assess the participants’ understanding of the study, one participant of each of three studies (a total of three participants) was interviewed. Since the participants were not familiar with the English language, they were interviewed in the local language. It was observed that the participants had a good understanding of the study and the drugs given. They could explain the risks and discomforts of participation in the study. One of the participant’s relatives confided that they were participating in the study as they received free treatment.

Deviations from the investigational plan At one of the sites, investigators were using an older version of the study protocol. For the investigator-initiated study, participants were not randomised as required in the protocol.

Other findings No source documents found; No coded drugs used; Documents not kept under lock and key; Auditors’ monitoring report missing; PI reported SAE late;

Failure to report study progress to IEC

1/7

As per the SOP, our IECs grant approval for a period of one year and then extension of approval after reviewing the annual status report of the study. There was a lapse in submitting the annual status report and taking extension of approval by one of the PIs and 85/125 patients were recruited during the period not covered by valid approval of the IEC.

[ one observation was noted in each of the 7 studies monitored]

Biodata of investigators in the project file not signed

Recruitment of additional participants without IEC approval

The informed consent process Six of the seven sites monitored had issues concerning the process of documenting informed consent. Copies of the informed consent documents (ICD) were not available at the site. The explanation given by the investigator was that as it was a collaborative study, the ICDs were archived with the other institution, in spite of the fact that the patients had been recruited from our institution. Other findings included missing signatures of patients (n=1) and principal investigator (n=2). The consent of four participants had been obtained using the vernacular (Hindi) consent form which had not been approved by the IEC, while only the English version had approval. In one study, we found that six participants had been administered the English version of the ICD when they were actually literate

In one of the sponsored studies, the IEC had given permission for recruiting 25 patients while the PI had recruited 30 patients.

Lack of investigator awareness regarding the protocol and informed consent document At six sites, investigators were interviewed to verify their awareness of the protocol. In one study, the PI did not know the inclusion criteria. At another study site, a ready-reckoner of selection criteria prepared by investigators to facilitate recruitment of participants was found incomplete. This could have led to protocol violations in recruitment. At three sites, when Co-Is were interviewed in the absence of PIs, it was observed that answers given by Co-Is to questions

[ 23 ]


on inclusion criteria were inappropriate. One Co-I commented that an elaborate consent process would deter patients from participating in the study. In two investigator-initiated studies, the investigators (post-graduate students) were not aware that source documents had to be maintained; patients were not being randomised according to the charts; ICDs that were administered to the participant were not in the language that the patient understood; and participants had not been given a copy of the ICD.

training of resident doctors in clinical research. PIs who did not keep their documents securely under lock and key were asked to make arrangements to do so. Table 2: Action taken by IEC against monitoring sites.

A total of 20 SAEs from the 1/7 sites were reported to the IEC after seven working days.

Other findings

Action taken by IEC After monitoring the sites, the teams presented their reports at the next IEC meeting. After the presentation of each report, the findings of monitoring visits were conveyed in writing to the PIs with a request to demonstrate compliance within a specified time. The compliance report was again presented to the IEC and recommendations were given to the PIs. If the PI was found to have deviated from the investigational plan frequently, the IEC put temporary (till PIs gave evidence of taking recommended corrective actions like training of staff ) restrictions on further recruitment. In case of protocol violation and lack of reporting of study progress, the IEC asked for an explanation, with a clear warning not to repeat the violation in future and ensured that corrective actions were implemented. Additional AE reports were asked for from investigators who had failed to submit them in time. For the SAEs not reported earlier, follow-up reports and outcome were called for from the PIs and reviewed. Continued GCP training of all investigators was made compulsory and PIs were asked to submit a copy of the certificate at the time of submission of a new project. Moreover, in certain studies where it was felt that patients’ safety and wellbeing were compromised, IECs asked for monitoring reports from the sponsors and the recommendations of the data safety monitoring board, if relevant. At sites with inadequate study supervision, the IEC advised recruitment of additional GCP trained members in the study team. It was recommended that at least one study coordinator per trial be appointed. In many investigator-initiated studies, resident doctors were the PIs, so the IEC recommended the

Action taken by IEC

Protocol deviation

Explanation asked for with a clear warning against future repetition

Deviation from Restriction on future recruitment, investigational plan submission of audit reports from sponsor

SAE reporting

All the case record forms were found to be incompletely filled in with pencil [25/25] at one site. One of the sites had been monitored by the sponsor, but the monitoring report was missing. The bio-data of the investigators in the project file had not been signed. No source documents were found at two study sites. Documents were not kept under lock and key. A single study co-ordinator was handling multiple studies. At one site, the study had been initiated without having received the approval of the directorate general of foreign trade, India, for shipping of samples abroad.

Violation theme

Non-reporting of study progress to IEC Deficiencies in study supervision

Explanation asked for with a clear warning against future repetition Recruitment of additional members in the study team advised

SAE reporting

Submission of AE reports

Lack of investigator Continued GCP training of study awareness (protocol recommended and ICD)

Discussion The site monitoring visits carried out by the IECs of a tertiary care hospital in India revealed innumerable protocol violations, which would not otherwise have been identified. The findings relating to violations of the informed consent process were particularly disturbing as they violated the basic principle of autonomy, a fact that needs to be viewed seriously. There were discrepancies between the consent forms approved by the IEC and the forms used at the site; in some cases, ICDs, or the signatures of patients and /or PIs were missing. These violations were similar to those observed in the studies carried out by McCusker et al(8), in which an audit of 188 consent forms of 33 protocols revealed that consent forms were missing from the site, non-approved consent forms had been used, and the signatures of participants, witnesses and investigator were found missing in many forms. Another study by Smith et al (9) in 1997 showed that, of the 39 projects reviewed; a quarter had protocol deviations in relation to the consent process. The same study had found that, though adverse events had been reported, projects which were abandoned or late to start were vastly underreported to the IEC (9). In our study, delayed reporting of serious adverse events was a common finding.

Qualitative interviews with investigators for 16 research projects conducted by Douglass et al (10) concluded that an active monitoring programme can detect deviations from the approved protocol not disclosed in the annual report. The same was observed in our study during the interviews with the PIs. An encouraging finding in our study was that the

[ 24 ]


patients’ understanding of the research study, including the benefits and risks involved, was adequate. It was therefore felt that most of the protocol violations, including those related to the ICD, were due to an overload of clinical work rather than the unethical behaviour of the PI. The results of this study reveal that there is an urgent need for an active monitoring programme by IECs for the continuing review of ongoing projects. Currently, lack of infrastructure, manpower, funds and time is a major hurdle for conducting active site monitoring. Most IECs spend a substantial amount of time in reviewing and approving protocols and reserve some

time for passive monitoring, ie, reviewing SAE reports, periodic status reports, etc. There is very little time left to carry out site monitoring. Another aspect is the lack of training. IEC members are not trained to conduct monitoring. In India, there is no central body which offers accreditation, trains IEC members to monitor studies, and monitors IECs for their compliance. In the studies by Demets and Weijer (5, 11) the authors have discussed the problems involved in carrying out continuing review by IECs. Smith et al (9) have reported that each detailed review takes six person hours at a cost of £120.

Appendix1: Site monitoring visit report

Comment:

Is it approved by the IEC?

°

No. of participants approved at site by IEC: ______

°

Total participants recruited since protocol began: ______

°

New participants recruited since last year:

o Yes

ü No. of patients screened: ____ ü No. of patients enrolled: ____

o No

Any adverse event found?

Comment:

o Yes o No Any SAEs found?

Comment:

o Yes o No Was the IEC informed about SAEs within 7 Comment: working days?

ü No. of patients completed: ____ ü No. of patients ongoing: ____

o Yes o No Has any death occurred?

ü No. of patient drop-outs: ____

Comment:

ü No. of patients who withdrew consent: ____ (State reasons)

o Yes o No Was the IEC informed about this death within 24 Comment: hrs?

ü

o Yes o No Any protocol non-compliance /violation?

Comment:

o Yes o No Are all case record forms up to date?

Comment:

No. of patients withdrawn by PI: ____ (State reasons)

Are site facilities appropriate?

Comment:

o Yes o No Are storage of data and investigating products Comment: locked?

o Yes o No Are informed consents of recent version Comment: used? o Yes o No Is it approved by the IEC? o Yes o No Whether consent has been taken

Comment:

o Yes o No Are necessary life-saving present at the site?

Comment:

o Yes o No Are the site personnel adequate?

Comment:

o Yes o No How well are participants protected?

Comment:

from all patients? o Yes o No Whether appropriate vernacular consent Comment: has been taken? o Yes o No Are protocols of recent version used? o Yes

equipments/drugs Comment:

o Good o Fair o Not good Any other relative observations : Comments of the monitor

Comment:

o No [ 25 ]

Duration of visit: …….hours Starting from: Name of IEC/ Independent Monitor

Finish:

Completed by:

Date:


The need for recognition and affiliation of IRBs is currently not mandatory in India and depends, not only on the enthusiasm and motivation of an IEC, but also on the funds that it receives. Many IECs in India do not receive sufficient funding and the institutes in which they are situated are not keen to provide funding on a priority basis. IECs therefore continue to struggle to meet the responsibility of accreditation, continued training, and staffing. Active on-site monitoring helped our IEC to identify problems related to the implementation of GCP which could not have been detected by the passive ongoing review of study-related documents carried out routinely by our IECs. Thus IECs need to have mechanisms for site monitoring in place so as to ensure that GCP is followed in letter as well as spirit. Declaration: No competing interests nor funding from any external agency to be declared. References 1. Indian Council of Medical Research. Ethical guidelines for biomedical research in human participants[Internet]. New Delhi:ICMR;2006 [cited 2011 Nov 9].p.111. Available from: http://www.icmr.nic.in/ethical_ guidelines.pdf

2. Ministry of Health and Family Welfare, Department of Health. Drugs and Cosmetics (II amendment) rules, 2005 [Internet]. New Delhi: Government of India; 2005 Jan 20 [cited 2011 Nov 23]. Available from: http:// dbtbiosafety.nic.in/act/Schedule_Y.pdf 3. World Health Organisation. Operational guidelines for ethics committees that review biomedical research [Internet]. Geneva:WHO;2000[cited 2011 Mar 26]. Available from: www.who.int/tdr/publications/publications/ 4. Pickworth E. Should local research ethics committees monitor research they have approved? J Med Ethics. 2000 Oct 26; 26(5):330–3. 5. DeMets DL, Fost N, Powers M. An institutional review board dilemma: responsible for safety monitoring but not in control. Clin Trials. 2006;3(2):142-8. 6. Morse MA, Califf RM, Sugarman J. Monitoring and ensuring safety during clinical research. JAMA. 2001 Mar 7;285(9):1201-5. 7. Ethics committee for research on human subjects. Seth GS Medical College and KEM Hospital, Mumbai. Site monitoring visit [Intranet] 2009 Jun 26[cited 2011 Nov 11]. Available from: www.kem.edu/dept/ ethicscommittee/SOP15.PDF 8. McCusker J, Kruszewski Z, Lacey B, Schiff B. Monitoring clinical research: report of one hospital’s experience. CMAJ. 2001 May 1;164(9):1321-5. 9. Smith T, Moore EJH, Tunstall-Pedoe H. Review by a local medical research ethics committee of the conduct of approved research projects, by examination of patients’ case notes, consent forms, and research records and by interview. BMJ. 1997 May 31;314:1588-90. 10. Douglass AJ, Jarvis A, Bloore S. Monitoring of health research by research ethics committees. N Z Med J. 1998 Mar 13;111(1061):79-81. 11. Weijer C, Shapiro S, Fuks A, Glass KC, Skrutkowska M. Monitoring clinical research: an obligation unfulfilled. CMAJ. 1995;152(12):1973-80.

Thank you, reviewers All submissions to the journal undergo extensive review by internal reviewers from within the journal’s editorial boards as well as by external peer reviewers. We would like to thank all our editorial and advisory board reviewers, and also name the following external experts who have reviewed articles for the journal during 2011: Aamir Jafarey, Akash Bang, Akoijam Joy, Amita Dhanda, Amita Pitre, Anant Bhan, Anant Phadke, Anirudh Kala, Anoop Thekkuveetil, Bhushan Shukla, C Adithan, Chinu Srinivasan, David Thambu, Devadasan, Dhanwanti Nayak, Gagandeep Kang, Gopal Dabhade, Indu PS, J Divatia, Joe Varghese, Kajal Bhardwaj, Kalpana Kannabiran, Laxmi Murthy, Leela Visaria, Leigh Turner, MR Hariharan Nair, Nalini Rao, Nandini Kumar, Nithya Gogtay, Prabir Chatterjee, Premila Lee, Rajeev Kumar, Rakesh Aggarwal, Ramakumar, Raman Kutty, Ravi Duggal, Ravindra RP, Renu Addlakha, SP Kalantri, S Srinivasan, Samiran Nundy, Shailaja Tetali, Soumitra Pathare, Sridhar S, Subha Sri, Suneeta Krishnan, Sunita Bandewar, Sunita Simon Kurpad, VR Joshi, Vineesh Mathur.

[ 26 ]


Comments

Finding and using evidence that you can trust Prathap Tharyan Professor of Psychiatry, Director, South Asian Cochrane Network and Centre, Professor BV Moses and ICMR Centre for Advanced Research in Evidence-Informed Healthcare, Christian Medical College, Vellore 632 002, Tamil Nadu INDIA e-mail: [email protected]

Abstract Much of the evidence-base from research is biased. Systematically assembled, quality-appraised, and appropriately summarised reviews of the effects of interventions from all relevant intervention studies are needed, in order to use research evidence to reliably inform health decisions. The Cochrane Library is an online collection of six searchable, up-to-date, evidence-based databases that is available free to access by anyone in India, thanks to a national subscription purchased by the Indian Council of Medical Research. This valuable resource contains the world’s single largest collection of systematic reviews and controlled clinical trials, as well as bibliographic details and records of methodological research, health technology assessments and economic analyses. The robust and transparent methods pioneered and used in Cochrane systematic reviews, and independence from industry funding facilitate the detection of biased, deceptive and fraudulent research, and have earned these reviews the reputation of being trusted sources of evidence to inform health decisions. Cochrane reviews have had considerable impact on academic medicine; have informed health practices, policies and guidelines; improved health outcomes; and saved numerous lives. An editorial in the previous issue of this journal summarised the results of empirical research revealing that much of the evidence from research that is integral to the practice of evidence-based medicine cannot be trusted(1). This does not mean that none of the evidence can be trusted. However, it does require a special effort to identify sources of reliable evidence, to understand how this should be assessed, and the amount of confidence one can place in this evidence.

Finding the right evidence The first step in evidence-informed healthcare is to find relevant evidence that is free of the risk of bias. Randomised controlled trials (RCTs) are considered the type of study design that is least likely to provide biased estimates when assessing the effects of interventions. However, the language of research facilitates deception, through the use of descriptive terms that are widely employed to describe studies that have not necessarily used, or used adequately, the methods required to provide “Gold Standard” evidence that RCTs are assumed to provide (2-4). Moreover, the results of a single RCT are unlikely to be generalisable to all situations where the intervention may be used. The results of different RCTs of the same intervention and control comparison may also differ substantially.

The least biased evidence that addresses these issues regarding the effects of interventions comes from wellconducted systematic reviews and meta-analyses of all RCTs conducted that compare an intervention to no intervention (or placebo), and to other interventions commonly used for that health condition. If RCTs are not ethical, practical, or feasible, then systematic reviews of particular types of well-conducted observational studies could provide alternative sources of evidence. Systematic reviews use explicit and systematic methods to search for, locate, and retrieve; critically appraise for the risk of bias; reliably extract and analyse data from all relevant research studies addressing a focused clinical question, and summarise the overall results. They, therefore, provide information that individual trials cannot. Many systematic reviews, though not all, synthesise their results using meta-analyses. Meta-analysis is the statistical technique that aggregates the numerical data for each relevant outcome from the primary studies that are sufficiently similar in their participants, interventions, methods, and outcomes to combine in a clinically meaningful manner. Systematic reviews in the Cochrane Database of Systematic Reviews (CDSR), one of six evidence-based databases that form part of The Cochrane Library (www.thecochranelibrary.com), are particularly reliable sources of evidence, as are systematic reviews that use the methods pioneered by the Cochrane Collaboration (www.cochrane.org). The resources in The Cochrane Library are free to access by anyone in India with a computer and an internet connection, thanks to a national subscription purchased by the Indian Council of Medical Research (ICMR) since 2007, and renewed for a further three years in 2010. More than half the world’s population also has free access to this valuable resource due to various sponsored initiatives or licensing agreements(5).

The impact of Cochrane systematic reviews Only about 20% of reviews published each year are Cochrane systematic reviews. However, empirical research reveals that Cochrane systematic reviews are scientifically more rigourous, more likely to be up to date, and less biased in their methods and interpretation than non-Cochrane systematic reviews (6, 7). The 2010 impact factor for the CDSR was 6.186. The CDSR is now ranked in the top 10 of the 151 journals in the medicine, general, and internal category, and receives the seventh highest number of citations in its category.

[ 27 ]


Other more important examples of the impact of Cochrane reviews include informing the guidelines of many agencies, including those of the World Health Organisation, and influencing global, national and regional health policies. Cochrane reviews in many topic areas have provided clinicians, patients and their care-givers access to reliable evidence that have improved health outcomes and saved numerous lives.

Why are Cochrane systematic reviews and metaanalyses regarded as reliable sources of evidence? The major reasons that contribute to the reliability of Cochrane systematic reviews stem from the rigourous methods used in their preparation. These methods are described in the Cochrane Handbook for Systematic Reviews of Interventions (www.cochrane-handbook.org). They include: 1. Transparent, reproducible methods: Systematic reviews commence with a methods section or protocol that is unusual in traditional review articles. Protocols of Cochrane systematic reviews are peer-reviewed, editorially vetted and published online in the CDSR before the review commences. The protocol outlines in detail the scope and methods planned for undertaking the review. 2. Striving for relevance: The topics selected for Cochrane systematic reviews are agreed in advance by the authors and editorial team as relevant to health care, and are often selected in response to the expressed needs of relevant stakeholders. Cochrane review topics cover not only pharmacological interventions but a variety of nonpharmacological interventions and aspects of health-service delivery. The pre-stated primary outcomes in Cochrane reviews may not be the primary outcomes used in the included trials. Thus, the primary outcome of a systematic review that compared reduced osmolality oral rehydration solution (ORS) versus the WHO-recommended, standard ORS to treat acute dehydration due to diarrhoea in children, was the frequency of unscheduled intravenous saline infusions used. This was considered by the review team as a real-world indicator of the failure of either solution to effectively treat diarrhoea (8). This was not a primary efficacy outcome in most of the 11 included trials and was obtained not from the description of the main results or tables, but from elsewhere in the paper; in three other included trials, it was not reported. In this review, reduced osmolality ORS required significantly fewer unscheduled intravenous saline infusions than standard ORS, and is now the recommended standard. Many other examples exist where Cochrane reviews have challenged the received wisdom and changed established practices and health policy by demonstrating that interventions in common use were ineffective(9-13) or even harmful(14-16). 3. Comprehensive search strategy: Systematic reviews attempt to locate all relevant studies that have addressed the review’s objectives, and not only a biased sub-set of published studies, or ones that were easily available. Empirical research has demonstrated that studies published in journals are

more likely to show statistically significant results; be published in high-impact, mostly English-language journals; be sponsored by the pharmaceutical industry and, be published sooner than unpublished studies (17, 18). If one were to rely only on the results of these published trials, without balancing the evidence from unpublished trials (often smaller and with negative or inconclusive results), one would be seriously misled(19). Hence, apart from searching different online databases, Cochrane reviews routinely search the Cochrane Central Register of Controlled Clinical Trials (CENTRAL), the world’s largest repository of information regarding clinical trials that forms part of The Cochrane Library. It includes details of published articles taken from multiple bibliographic databases, other published resources, and from unpublished sources. Cochrane reviews also routinely search the specialised registers of the respective collaborative review groups supporting the review. Experts in the field and drug manufacturers are contacted for further, often unpublished, information, as well as the authors of identified studies; and the cross references of these studies are searched for further references. Clinical trials registries are also searched for on-going trials. No language restrictions are applied in the search strategy in order to avoid language bias; regional databases are also searched, and retrieved reports are translated, if needed. 4. Minimising biases in the review process: The review teams are assembled to balance the views of all authors and to avoid financial and academic conflicts.Bias in selecting trials is minimised in Cochrane reviews by involving at least two authors who independently apply pre-stated, explicit inclusion and exclusion criteria. They also independently assess quality; extract data and contribute to writing the results and discussion. Disagreements are resolved by discussion or contacting authors of trials. Inputs are provided from two editors, a lay reviewer and peer reviewers. Excluded studies are listed with reasons for exclusion; studies awaiting assessment are also listed, and ongoing trials are described. Any changes between the published protocol and the final review are documented, discussed, and justified. Authors are supported by editorial teams from conception, through development, completion, and publication of the review, and upto updating of the review, ideally every two years, or when new trials are located or published. 5. Minimising conflicts of interest: The Cochrane Collaboration’s polices prohibit industry funding of review teams or collaborative review groups and methods groups earning Cochrane reviews the reputation of being independent sources of reliable evidence. 6. Assessing the risk of bias in included studies: Including studies at high risk of bias that are likely to have erroneous effect estimates, are unpredictable in magnitude and direction (20), will result in systematic reviews with misleading results. Hence, RCTs are preferred in most Cochrane reviews. Quasi-randomised (where allocation to treatments can be predicted) and non-randomised trials are usually not

[ 28 ]


included, if RCTs were thought feasible for the intervention(s) reviewed. In addition, all Cochrane reviews assess each included primary study for the risk of bias across six dimensions empirically shown to influence outcomes. They are: generation of the randomisation sequence; concealment of allocation; blinding (often assessed separately for subjectively reported outcomes, where lack of blinding could introduce bias; and for objectively ascertained outcomes, where lack of blinding usually does not introduce bias); incomplete outcome reporting (again often assessed separately for efficacy measures; and for harms that are less often reported adequately); selective reporting; and other biases such as conflicts of interest. Many non-Cochrane reviews either do not routinely evaluate the risk of bias, or use unreliable quality scales to assess study quality(6).These methods used in Cochrane systematic reviews also facilitate the detection of scientific misconduct, misinformation, and redundant publications (21). 7. Pooling the results of trials instead of “counting votes”: A metaanalysis averages the results of individual trials that provided data for the proportions of participants randomised to the intervention versus the comparison that experience a particular outcome. This is done in order to provide a pooled common estimate of relative effects. The results of the individual trials are commonly expressed as risk ratios (RR) or odds ratios, along with their 95% confidence intervals (CI)(22).For the pooled effect estimate in a meta-analysis, each trial is proportionately weighted so that larger trials, and trials where more people experienced the outcome of interest, particularly with the control intervention or comparison arm (indicating a high baseline risk of developing the outcome), are given more weight in the pooled estimate. The proportionate weight assigned to each trial is the inverse of its variance (a measure that combines the two parameters described above and indicates more precise estimates of the likely range of results). Thus trials that provide more information with more precise results get more weight in the pooled results of all the trials. This is instinctively more appealing than counting the number of trials where the result favoured the intervention over the comparison, versus the number of trials where the reverse occurred, or where the results were inconclusive. In this traditionally used “vote-counting” method, the results of a large trial and a small trial would each be counted as one for and one against the intervention being effective. An example is provided in Figure 1 that displays a (fictitious) meta-analysis (or forest plot) comparing drug A with drug B for the treatment of obesity. The outcome assessed in the figure is the risk of death. In this hypothetical example, the five trials (identified in the rows in column 1 by the last name of the first author and year of publication) included in the meta-analysis randomised 930 adults to anti-obesity drug A, of whom 51 died, (columns two and three), and 928 adults to antiobesity drug B, of whom 72 died (columns three and four). The variance in the trial by Pai 2010 was the least since it

provided the most information (largest sample size and most deaths) and had the most precise results (narrow confidence intervals), and hence is assigned the most weight (66.6%)(column four) in the meta-analysis. Jessani 2005 had the next largest sample size and next highest number of deaths, but gets the least weight (6.9%) since it had the least deaths in the control group (drug B), and the least precise results. The rows in the sixth column display the numerical values of the relative (RR) and 95% CI for the comparisons from each trial (without differential weighting). This is also graphically displayed in the last column as a forest of horizontal lines (hence the name “forest plot”; if there were many more trials, the resemblance to a forest of lines would be even more apparent) scattered around the vertical line that touches the base of the plot at the RR of 1(no significant difference). The rectangular blob in the middle of the horizontal lines represents the RR estimate for each trial. The size of the blob is proportionate to the weight assigned to each trial. The width of the horizontal lines depicts the upper and lower limits of the 95% confidence intervals. The pooled results of the five trials (proportionately weighted in the formula used for the meta-analysis to yield the weighted average) are provided in the last row. The pooled RR is 0.70 [95% CI 0.50 -0.99], and represents the average risk of death with drug A compared to drug B. The diamond at the bottom of the graph in the last column includes the pooled RR and confidence limits of the five trials. The lower limit of the pooled 95% CI in the diamond [RR = 0.99] stops short of touching the vertical line [RR = 1]. 8. Ensuring the results are statistically significant and clinically important: In conventional terms, these results are statistically significant as the p value is < 0.05 (The last row in the forest plot tests the overall effects and reveals the actual p value to be 0.04; indicating that one can be 96% certain that the difference in the effects of the two drugs is not due to chance). From a clinical perspective, an RR of 0.70 means that drug A reduces the risk of death by 30%, and while we think this is the actual estimate of relative risk reduction (RRR), the upper and lower limits of the CI of the estimate suggests that the risk of death could be reduced by as much as 50%, or as little as 1%. If the higher estimate were true, this would be even better than what we think the estimate is, but if it were the lower estimate, then the clinical usefulness of drug A over drug B in averting 1% fewer deaths is less encouraging, given that 51 (6%) of people given drug A in the five trials died versus 72 (8%) with drug B; unacceptably high rates of death with both drugs. If one evaluated the actual number of deaths averted with drug A (51/930) compared to drug B (72/928), the Absolute Risk Difference (ARR) is 0.0227; 95% CI 0.0001-0.0457. This indicates that drug A averted just two deaths out of 1000 people treated compared to 1000 people given drug B; and this could be as few as 1/1000 treated or as many as 5/1000 treated, again not very impressive achievements. This example highlights the importance of evaluating

[ 29 ]


effect sizes such as the RR and 95% CI, rather than only rely on p values