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Oct-Dec2001-9(4)
DISCUSSI0N
Research on public health
interventions in poor countries
Sandhya
Srinivasan
In countries like India the researcher's
responsibilities to research participants may sometimes come into conflict with
the search for affordable drugs and therapies for problems of the poor. An
on-going trial in Mumbai illustrates this situation, and is being presented here
for discussion.
The trial evaluates the use of clinical breast
examination (CBE) by trained health workers for breast cancer and visual
screening of the cervix for cervical cancer. The control arm receives only
health education messages - effectively a placebo. Both the Helsinki Declaration
and the Indian Council of Medical Research's ethical guidelines state that
placebos cannot be used when an effective intervention is available.
Dr Indraneel Mittra, surgeon at the Tata Memorial
Hospital, Mumbai, is overseeing this trial. In October 2000, he was kind enough
to describe the purpose of this study and its details. As the subject may
deserve public discussion the following note has been prepared based primarily
on notes from the interview with Dr Mittra. Detailed references supporting Dr
Mittra's statements are not given here. The note is followed by some questions,
and readers are invited to comment.
Screening
The purpose of screening - going out into the
community and inviting people to come in for testing - is to detect the problem
early and thus to reduce mortality from the condition. A screening technique's
value is based not only on whether it catches the problem early, or finds more
cases through screening; it should also result in a reduction in the mortality
rate from that condition.
However, mammogram screening for breast cancer has
various problems. Because of false positives, false negatives (true for all
screening techniques), over-diagnosis and unnecessary treatment of more
relatively benign tumours identified by screening, many women would be subjected
to psychological trauma and unnecessary treatment.
There is also the question of whether mammograms
are cost-effective. It is believed that mammogram screening would be
cost-effective only if it resulted in a 20 per cent drop in mortality from
breast cancer. However, Dr Mittra stated, the results of various studies suggest
that it can contribute to not more than a 10 per cent drop.
Even with this limited value, mammography cannot be
considered for use as a screening tool in India. In addition to the problems
posed by an anticipated increase in false positives given the lower estimated
incidence of breast cancer here, mammogram screening would entail training
radiologists, quality control, and a learning curve of 10 years before it could
possibly become an effective tool.
Dr Mittra also implied that unlike in the West,
mammograms are too expensive to be offered as part of a public health
intervention. In India, he said, we need simpler screening methods. Elsewhere he
has been quoted as saying about his trial of a cheaper screening method: "The
studies are investigating appropriate diagnostic technologies that can be used
on a mass scale in India… We're trying to show that low cost does not mean bad
science." (1)
He also referred to a recent randomised clinical
trial in Canada, comparing clinical breast examination (CBE) by nurses, with CBE
plus mammograms. Researchers found no difference in death rate in the two
groups. In other words, mammograms provided no additional benefit.
(2)
The trial
An ongoing trial conducted by Dr Mittra and funded
by the US National Institutes of Health is evaluating the value of CBE as a
screening tool. It is described in the press as one of 'the world's largest
randomised control studies on early detection of common cancers among women.'
(1) The participants are 150,000 women in 10 slum areas of Mumbai. Every 18
months over a period of six years, 75,000 women in the experimental group
undergo CBE by trained health workers. They also receive health messages on the
value of early detection, and dangers of tobacco. To make the trial more
cost-effective, another component has been added: visual examination of the
cervix with 4% acetic acid for early detection of changes in the form of white
patches. The 75,000 women in the control group get only the health awareness
messages.
One assumption behind this study design is that
comparing CBE with mammograms would not permit effective evaluation of the
cheaper and affordable screening techniques. It would not provide information on
whether the cheaper screening technique would bring down the mortality rate due
to the disease in question. Dr Mittra has stated, "We wish to validate
low-cost, low-technology and simple preventive and diagnostic techniques for
women's cancers in the most scientifically stringent way." (1)
Ethical guidelines
International and national ethical guidelines on
medical research do not permit the use of placebos in trials if an effective
treatment exists. The earlier Helsinki Declaration already stated this.
Following the controversy on placebo control trials to prevent the vertical
transmission of HIV (3), revisions in October 2000 were even more explicit:
experimental interventions were to be compared with the 'best proven'
prophylactic, diagnostic or therapeutic interventions. (4) The Indian Council of
Medical Research recently finalised ethical guidelines on biomedical research.
These guidelines do not address trials of such public health interventions.
However, the section on drug trials does state that placebos cannot be used when
an effective treatment is available. (5)
Some questions
It is true that 75,000 poor Indian women get some
form of care. The other 75,000 are no worse off than they would have been
otherwise. Perhaps they are better off, since they are educated on the dangers
of tobacco and the importance of early detection. Does the fact that the
participants would not otherwise have access to care justify such a study? The
control group will be part of a research project but will be offered no
diagnosis or treatment, though they are not prevented from seeking such services
on their own. Is this justified? Mammography is accepted as the current standard
of care, despite its many limitations. Even if it cannot be implemented as a
screening technique in India, it can be provided to the control group. On the
other hand, the results of the Indian trial could enable the medical community
in India to decide whether CBE is an effective, affordable intervention.
Providing mammogram screening to the control group will lower the quality of
information from the study. Does the researcher's belief that the question is
best answered only if one group receives no care justify the trial?
This study could not have been done in the West.
Researchers in the Canadian study state that it was 'deemed unethical to have an
unscreened control group'. (6) In the BMJ, Dr Mittra and his colleagues suggest
that a trial in the West compare the two screening techniques against each
other. "Proper information on which to base decisions, either about
participating in a trial comparing CBE and mammography or for informing the
development of a trial protocol, is essential for both the public and the
profession. This could be achieved through a national questionnaire survey
involving the eligible women." (7) Is it justified to conduct a study that could
not have been conducted in the funding country (or others like it)?
It is unlikely that the cheaper technique will be
implemented in a country where the public health system already deprives people
of the most basic life-saving care. On the other hand, information gathered in
India will certainly benefit screening programmes in the West. Should the fact
that the results will not be implemented in the local community stop the
researcher from undertaking what could be a very useful study?
If the intention is to provide services to the
local community, once evidence emerged that the cheaper technique would work,
could the researchers have focused on training health workers to do the
screening well? Could they do this knowing that they cannot quantify the gains
of such a technique?
A study of such complexity only underlines the need
for voluntary informed consent, and this doesn't mean just signed forms. The
participants are poor, already deprived of their right to accessible, affordable
care, and any contact with a health worker is welcomed as providing some form of
care. In such circumstances, how voluntary can their consent be? Second,
how well could the concept of screening be explained to this particular group of
women? Did they understand that some of them would get screening and others
would get just health messages? Dr Mittra mentioned that about 20 per cent of
the women approached refused to participate. However, it is possible that their
refusal has nothing to do with their understanding of the trial. It would be
interesting to learn whether and how the NIH ethics committee and the TMC ethics
committee addressed such questions. Institutions conducting research would do
well to make the deliberations of their ethics committees public.
Why ask these
questions?
An earlier version of this note was circulated to
the IME editorial group. The responses indicated that some of the questions
raised were worth discussing. However, there was also some debate on the value
of raising such questions. There may be more pressing concerns for groups such
as ours than dissecting a study in which women are not actively harmed; they are
only not offered care as part of the study. Does such questioning divert our
energies from addressing blatant malpractice and corruption in the medical
profession?
However, it was also felt that surely we must call
upon medical researchers to reflect on the aspects of their work which go beyond
its scientific elements, to explain it to the public, and to take active part in
the debates on ethics.
References:
1.Khan Sameera. Studies on to detect, prevent cancer among women. The Times of India.www.indiatimes.com/health/mednews/mednew42htmdownloaded 22/9/01, 11.11 p.m.
2. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000; 92: 1490-9.
3. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the Human Immune Deficiency Virus in developing countries. New England Journal of Medicine 1997; 337: 853-55
4. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. Edinburgh, Scotland, October 2000.
5.Indian Council of Medical Research. Ethical guidelines for biomedical research on human subjects. New Delhi, 2000.
6. Miller Antony B, Baines Cornelia J, Wall Claus. Canadian National Breast Screening Study-2: 13-year results of a randomised trial in women aged 50-59 years. Journal of the National Cancer Institute 2001; 93: 396-397.
7.Mittra I, Baum M, Thornton H, Houghton J. Is clinical breast examination an acceptable alternative to mammographic screening? BMJ 2000; 321: 1071-3.
1.Khan Sameera. Studies on to detect, prevent cancer among women. The Times of India.www.indiatimes.com/health/mednews/mednew42htmdownloaded 22/9/01, 11.11 p.m.
2. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000; 92: 1490-9.
3. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the Human Immune Deficiency Virus in developing countries. New England Journal of Medicine 1997; 337: 853-55
4. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. Edinburgh, Scotland, October 2000.
5.Indian Council of Medical Research. Ethical guidelines for biomedical research on human subjects. New Delhi, 2000.
6. Miller Antony B, Baines Cornelia J, Wall Claus. Canadian National Breast Screening Study-2: 13-year results of a randomised trial in women aged 50-59 years. Journal of the National Cancer Institute 2001; 93: 396-397.
7.Mittra I, Baum M, Thornton H, Houghton J. Is clinical breast examination an acceptable alternative to mammographic screening? BMJ 2000; 321: 1071-3.
Many thanks to Dr Mittra for discussing the
details of his study, and for encouraging further discussion. Many thanks, as
well, to Dr Meenal Mamdani, Dr Bashir Mamdani, Dr Sanjay Nagral, and Dr Aasim
Ahmad for their comments on an earlier draft.
Sandhya Srinivasan, 8 Seadoll, 54 Chimbai Road,
Bandra (W), Mumbai 400 050. Email:sandhya@medicalethicsindia.org.