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Oct-Dec2001-9(4)
DISCUSSION
Research on
hire
Amit Sen
Gupta
I recollect one of the first lectures in my first
year of medical college where my venerable professor thundered: "... the first
thing that a doctor should have is confidence. If you kill a patient, kill him
with confidence." This is a classic expression of the necessity felt by the
medical profession to maintain a veneer of confidence, even in the face of
relative uncertainty.
In such a setting, medical technology is often
used, not as a legitimate tool for diagnosis and treatment, but as a prop to
hide inadequacies regarding knowledge about what constitutes the best course of
action. In order to protect themselves from the anxieties which would otherwise
accompany their relative ignorance, the profession seeks succour by immersing
itself in the mindless pursuit of 'advanced' technology. The use of technology
becomes an end in itself rather than a means to relieving human suffering. The
last century has given us X-rays, ECGs, sonography, computerised scanning and
much more. Yet, instead of clearing the prevailing chaos in medical practice,
many of these tools have compounded the chaos. Not because it was inevitable,
but because control over these technologies has been the driving force behind
the immensely profitable health care industry. Patients are over-investigated,
over diagnosed, over treated and under cared for because the practice of
medicine has to play second fiddle to large corporate interests.
Contract research
Medical research is often organised, paid for,
commissioned or subsidised by the drug industry. The companies commissioning
such research are only looking for conclusions which will enable them to market
their product and reap profits. Nowhere is this more apparent than in the manner
in which medical research is conducted in the 'seat' of the pharmaceutical
industry, the United States.
An estimated 2 million Americans got hooked on to
Redux (dexfenfluramine), a new anti-obesity drug marketed in the US by
Wyeth-Ayerst, after it was approved by the US FDA in April 1996. At its peak
popularity, doctors were writing 85,000 new prescriptions a week. But a little
more than a year after the drug's introduction, this craze collapsed, as
patients began to exhibit symptoms of damage to their hearts and lungs. Fearing
an epidemic, the FDA banned the drug in September 1997. (1) The manner in which
'scientific' evidence was created in favour of Redux is a shocking indictment of
the system of medical research. In 1994, Wyeth had signed a $180,000 contract
with a medical publishing company called Excerpta Medica that offered
pharmaceutical companies an invaluable tool: ready-made scientific articles,
placed in leading medical journals, and carrying the signature of influential
academic leaders. Excerpta laid out for Wyeth a schedule of nine articles, each
with a carefully crafted message aimed at a targeted audience, from primary care
physicians to cardiologists to nurse practitioners to pharmacists. The articles
had a 'writer' and an 'author' - but they weren't the same person. The writer
was a free-lancer who was paid $5,000 to actually write the articles. The
'author' was often a top university scientist who was paid $1,500 to review the
work and assign his or her name to it for publication.
The Redux story clearly focuses on the growing
reliance of university scientists on corporate funding. Clinical research is now
a multi-billion-dollar industry, with hundreds of testing and drug companies
working with thousands of private doctors. Patients have become commodities,
bought and traded by testing companies and doctors. The number of private
doctors in research in the US since 1990 has almost tripled, and top recruiters
can earn as much as $500,000 to $1 million a year. Reports of fraud in drug
trials are pouring in. Such abuses point to weaknesses in the new system that
has developed in recent years for testing experimental drugs. No longer does the
pharmaceutical industry rely on career researchers at academic medical centres,
whose professional reputations are forged on the quality of their data. Rather,
the industry has turned to thousands of private-practice doctors for whom
testing drugs is a sideline for making money.
Research in developing countries
Medical research in the developing world suffers
from the problems of underdevelopment, on which are superimposed the ills of a
neo-colonial approach assumed by external research funding. In the developing
world, research is poorly funded, monitored and prioritised. The situation is
compounded by foreign domination in setting research priorities. While,
globally, medical research is fuelled by corporate interests; the market for
medical technology and pharmaceuticals in the developing world is very small.
The size of the Indian pharmaceutical market, for example, is less than
one-tenth of the market in the US or Japan. As a consequence, donor-driven
research in developing countries (largely, corporate sponsored research) focuses
on areas of interest in their home countries. Tropical medicine (itself a
colonial construct) has a long history of descriptive studies that benefit
researchers but have no direct implications for participants. For example, a
bibliography of research up to 1977 in Papua New Guinea identifies 135
publications that describe Melanesian blood groups but only 25 concerned with
treating malaria (2). Different 'styles' of foreign donor driven research are
prevalent. (3). 'Postal research' - where western researchers request colleagues
in developing countries to courier to them biological samples. 'Parachute
research' - where researchers travel to developing countries for short periods
and take back biological samples. The most prevalent is the practice of
maintaining 'annexed sites' for field research, led and managed by expatriate
staff. These 'annexed sites' attract promising academics away from national
institutions, and their research findings are infrequently translated into
policy and practice. Research fellows in 'annexed sites' may receive good
training there, but few return to national institutions. In a welcome
development, India has recently forbidden 'annexed site' research and outsiders
are now obliged to work through Indian institutions. However the long-term
advantages of this move will, in all probability, be frittered away given the
encouragement being provided to public sector R&D institutions to undertake
contract research for corporate entities.
Drug companies have been known to perform research
in developing countries that do not conform to the Declaration of Helsinki and
could not be conducted in the developed world. Reasons quoted for conducting
research in these countries, rather than developed countries, are lower costs,
lower risk of litigation, less stringent ethical review, the availability of
populations prepared to give unquestioning consent, anticipated under-reporting
of side effects because of lower consumer awareness, the desire for personal
advancement by participants, and the desire to create new markets for drugs. The
commercial secrecy that surrounds early clinical research, and safety and dose
ranging in phase I trials in paid normal volunteers (that is, poor volunteers),
means that much preliminary research is unpublished, particularly when adverse
effects are high and further development is abandoned. (3).
Medical research in India
There is, however, no denying that India (as a
consequence of its size and ability to pledge greater funds) is different from
most developing countries. Real science and research is done mostly with public
money and mostly in non-profit institutions. But such indigenous research
funding is still too small and too badly organised to address local priorities.
A report published in 1997 in Current Science, a journal of the Indian Academy
of Sciences, suggested that most medical research in India is unrelated to the
country's major health problems. The report, based on an analysis of research
publications from India indexed in the Medline database, said that achievements
in research have 'little influence' on healthcare delivery. It lamented that
research seemed to be concentrated in the fields of tertiary health care and new
biology. (4)
There also exists a problem in defining local
priorities. For long the two thrust areas for medical research in India have
been vaccine research and research on contraceptive technologies (and recently,
reproductive health). Both priorities can be contested on the ground that they
emanate from a view of public health that is technocentric - vaccines as
'quick-fix' remedies for communicable diseases and contraception to control
population growth. Given the hype surrounding both these concerns,
government-funded research in these areas has scant regard for standard ethical
guidelines.
Unethical and dubious
The decades of the 1980s and '90s have thrown up
numerous instances of unethical and dubious research in the country. Research on
long acting hormonal contraceptives like Net-En, Depo Provera and Norplant have
been conducted without observing ethical requirements like informed consent and
the need to follow up participants.
A team headed by Dr G PTalwar at the National
Institute of Immunology (NII) persisted for years with trials to develop a
contraceptive vaccine despite criticisms that these trials were being run
unethically. The vaccine passed through phase II clinical trials in the late
1980s. Only 80% of the women who received the vaccine showed adequate response
necessary for contraception. More importantly, according to published reports on
the trial, only 94 out of 162 women in the trial 'volunteered' for long-term
follow-up. The Indian government did not give approval for phase III clinical
trials of the vaccine but continued to fund the research on contraceptive
vaccines. The trials were put on 'cold storage' only when Dr GP Talwar retired
from the NII. In 1998 it was revealed that the Institute for Cytology and
Preventive Oncology, had left cervical dysplasia (a pre-cancerous condition)
untreated in 1,100 women to study the progress of the disease, without warning
them or taking their consent. In at least nine women the lesions progressed to
invasive cancer, and 62 women developed localised carcinoma of the cervix before
they were treated. The study had been sponsored by the Indian Council for
Medical Research, whose function is to lay down the ethical guidelines for
medical research. The investigators said, in their defence, that they did not
obtain written consent because most of the women in the study were illiterate
and also because written consent was not mandatory when the study was launched!
(5)
In 1997 the scandal surrounding trials on
quinacrine sterilisation forced the Supreme Court of India to step in.
Quinacrine was used in the treatment of malaria till it was replaced by better
drugs. Some time back there was renewed interest in its use in a method of
'chemical' sterilisation. In June 1994, the WHO Consultation on Female
Sterilisation Methods categorically stated that human trials with quinacrine
should be stopped forthwith pending the outcome of toxicological studies. In
India, quinacrine sterilisation was carried out in the '90s with 'hundreds of
doctors involved' according to an early convert to the cause, Dr.Biral Mullick.
Coordinating the supply of drugs and equipment in the country was Dr.J.K.Jain,
former MP. There were widespread protests against these trials. The Government
of India denied granting approval. Finally, bowing to the public outcry,
quinacrine sterilisations were banned by the Drug Technical Advisory Board in
1997. (6)
There is a discernible pattern in all the above
instances. All of them pertain to research on contraceptive technologies,
reproductive health and vaccine research. More importantly, all of them (except
in the case of quinacrine sterilisation) have been conducted in public funded
institutions using public money. They point to the extreme laxity in existing
regulatory institutions and mechanisms and also to the tendency of such
institutions to submit themselves to pressures when faced with so called
'national priorities'. Government sponsored (or approved) research in India,
seems to have been fraught with equally potent dangers as corporate funded
research is globally.
The anarchy in medical research in the country is
typified in three recent examples, only one of which has received some
publicity. The last pertains to a clinical trial conducted on human subjects in
the Regional Cancer Centre (RCC) in Kerala, with an experimental drug in
advanced oral and cervical malignancies. The trials were conducted in
collaboration with the John Hopkins University in the US. The drug used, M4N, is
an active principle of 'chaparral tea' made from leaves of the creosote bush, a
common American desert plant. Although chaparral tea has been used over the
years as an herbal remedy for cancer, it is also known for its toxic effect on
the liver. While the trial was conducted in 1999 and 2000, the application for
permission to conduct the trials was forwarded to the Drug Controller of India
only in February 2001! Further, the Ministry of Health and Welfare states that
the RCC was granted permission to import M4N from Johns Hopkins only in February
2, 2001. Apart from these procedural problems it now appears that the trials
ignored basic norms regarding informed consent. Further, a preliminary enquiry
indicates that subjects enrolled in the trial were given the experimental drug
in preference to established treatment regimes, a clear violation of the
Declaration of Helsinki on research on human subjects. The trials had not been
approved or reviewed by any of Johns Hopkins' institutional review boards
concerned with the protection of human subjects, in spite of the Centre's claims
that the permission for the trials were granted on the basis of 'pre-clinical
and other relevant data'.
Even more bizarre is the report of a trial of
another 'anti-cancer' cure conducted in Calcutta in 2000. The trial was
conducted on 24 patients by a team comprising a private medical practitioner and
a group of non-medical scientists at the Indian Association for the Cultivation
of Science, (IACS), a non-clinical organisation. The results of the clinical
trial have been published, of all places, in the Indian Journal of Physics! (7).
The journal, coincidentally, is run by the IACS. The paper acknowledges that the
trial was conducted through funding from the CSIR and DST and had the approval
of the Institutional Ethics Committee of the IACS. Clearly approval was not
obtained from any body that is authorised to give such approval. The paper goes
on to exhort that, "We (authors) sincerely hope that researchers and clinicians
with open minds will immediately make a concerted effort to use and to further
improve the present formulation and treatment." Worse still, the main ingredient
of the drug formulation is a chemical (methylglyoxal) purchased from the
American warehouse supplier, Sigma Chemical Company, whose chemicals are
laboratory grade, not intended to be used as drugs, i.e. not biological
grade.
The third instance is the permission granted by the
Ministry of Health and Family Welfare to conduct trials of the long-acting
hormonal contraceptive, Netethisterone Enanthoate (NetEn), in 12 medical college
hospitals across the country in 2001. The Ministry has not released any other
details regarding the purpose of the trial or the protocols to be followed. It
is being presumed that the trials are a prelude to introduction of NetEn in the
country's population control programme. Various health and women's groups have
represented to the National Human Rights Commission (NHRC) against conduct of
the trials on the grounds that the introduction of NetEn in the mass population
control programme is unacceptable given the drug's potential toxicity and the
absence of a monitoring mechanism.
What informs medical practice?
There is possibly an even more fundamental
conundrum that faces medical research in a country like India. Research output
is, as yet, too insignificant and too unfocused to inform the practice of
medicine in the country. The latter continues to be largely determined by
medical research conducted in the West. This situation has been given a novel
twist recently by Dr Samiran Nundy in a letter to the British Medical Journal.
He argued that given the state of medical research in the country it made more
sense to first attempt to regulate medical practice in the country rather than
regulate medical research (8): "That medical research in developing countries is
meagre and of generally poor quality is well known, and it has not improved in
the past 20 years. Should one therefore discuss research ethics in developing
countries when they barely exist? In my view the ethics of medical practice is
more important. To see how the public can be safeguarded from an inefficient and
often corrupt medical system and receive comprehensive health care of a
reasonable quality is paramount."
Such issues arise today because the research
institutions in the country have singularly failed to provide any cogent
direction to the practice of medicine. It would almost appear as though the two
work in entirely different paradigms. Unless there is, at the least, an attempt
to marry research with practice, public perception of medical research will
continue to range from suspicion to derision.
References:
1. US Department of Health and Human Services. Statement by the Food and Drug Administration. September 15, 1997.http://www.fda.gov/bbs/topics/NEWS/NEW00591.html
2.Hornabrook RW, Skeldon GHF. A bibliography of medicine and human biology of Papua New Guinea. Goroka: Papua New Guinea Institute of Medical Research , 1977 (Monograph series No 5.). Cited in: Garner Paul et al. Implementing research findings in developing countries. BMJ 1998;317:531-535.
3. Garner Paul et al. Implementing research findings in developing countries. BMJ 1998;317:531-535.
4. Arunachalam S: How relevant is medical research done in India? A study based on Medline. Current Science 1997; 72: 912-22.
5. Mudur G: Indian study of women with cervical lesions called unethical. BMJ 1997; 314: 1065.
6. Mudur G: India to ban female sterilisation with malaria drug. BMJ 1998; 316: 955.
7. Ray Manju et al. Implication of the bioelectronic principle in cancer therapy : treatment of cancer patients by methylglyoxal-based formulation, IJP, 2001; 75B (2): 73-77.
8. Nundy Samiran. Let's consider ethics of medical practice first. Letters BMJ 2000;321:830.
1. US Department of Health and Human Services. Statement by the Food and Drug Administration. September 15, 1997.http://www.fda.gov/bbs/topics/NEWS/NEW00591.html
2.Hornabrook RW, Skeldon GHF. A bibliography of medicine and human biology of Papua New Guinea. Goroka: Papua New Guinea Institute of Medical Research , 1977 (Monograph series No 5.). Cited in: Garner Paul et al. Implementing research findings in developing countries. BMJ 1998;317:531-535.
3. Garner Paul et al. Implementing research findings in developing countries. BMJ 1998;317:531-535.
4. Arunachalam S: How relevant is medical research done in India? A study based on Medline. Current Science 1997; 72: 912-22.
5. Mudur G: Indian study of women with cervical lesions called unethical. BMJ 1997; 314: 1065.
6. Mudur G: India to ban female sterilisation with malaria drug. BMJ 1998; 316: 955.
7. Ray Manju et al. Implication of the bioelectronic principle in cancer therapy : treatment of cancer patients by methylglyoxal-based formulation, IJP, 2001; 75B (2): 73-77.
8. Nundy Samiran. Let's consider ethics of medical practice first. Letters BMJ 2000;321:830.
Dr Amit Sen Gupta, Delhi Science Forum, D-158, Lower Ground Floor, Saket, New Delhi - 110 017. Email:ctddsf@vsnl.com