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Jul-Sep2003-11(3)
CASE STUDY
A clinical trial in a
developing country: many questions, few answers
SOMBOON KIETINUN*, M D GUPTE**, AMIT
SENGUPTA
I [SK] am the chairperson of the review board of medical ethics research involving human subjects at the Faculty of Medicine, Thammasat University, Thailand. On a number of occasions our committee found it difficult to make a decision, so I would like to put forward a case study for discussion to have opinions of other experts to help us make better decisions.
The study is proposed as part of a multicentre
study of a new antihypertensive drug already licensed in a western country. The
sample size would be 140 cases. The study would be carried out in up to 20
centres in Asia with each centre studying seven cases. The drug company would
provide a protocol for every country to follow, which contains instructions in
English but very little translation in our language. The company would provide
some money for the researcher. The review board is informed that other centres
have already approved the proposal. Researchers would not be permitted to
analyse the data but would have to send it all to the drug company who would
analyse the data. There would be no meeting of researchers nor would there be
instrument standardisation, etc.
Our concerns are as follows:
1. What could our young researchers learn from
these kinds of projects as the protocol will be prepared, analysed and
interpreted by the donor agency?
2. Does the drug company really intend to
learn about the efficacy and side-effects of the drug in Asian people and
whether it is different from that in westerners? Or is it some sort of an
advertisement?
3. Could seven cases in each centre be enough
to eradicate human bias, instrument bias, time of measurement bias, position of
the patient, age, sex, individual, lifestyle and many other biological biases?
Any response would be most appreciated as we have
had many protocols like this coming through our committee.
Response 1: Unscientific and therefore
unethical
I cannot offer any comments on the scientific
nature of the proposed study since protocol details are not available. If a
study is technically not sound, it is also unethical. I hope the ethics
committee has access to the full protocol. However, it is difficult to
understand the logic of having seven cases each in 20 centres, particularly for
a common condition like hypertension. Second, it is not clear why money should
be given to researchers. Is it for their time and expertise or is it an
inducement? What type of analysis do the researchers want to do? Is it a
double-blind study? Informing the ethics committee that other centres have
already approved the study would amount to pressure tactics. In any multicentric
study, standardisation is obligatory. I have raised several questions for
clarification. However, based on the available information given by Professor
Kietinun, such practices followed by drug companies are deplorable and deserve
to be condemned.
M D Gupte
Response 2: Caution is required
The proposed trial raises two important issues and
is typical of the kind of clinical research that is done in developing
countries. Many countries (including India) have a provision that requires the
drug controller to ask for data on clinical trials in the country even if the
drug has been approved in other countries. The rationale for such a provision is
obvious: to look for data that would factor in local conditions such as dietary
habits, lifestyle, etc. This is of particular importance in the case of drugs
for chronic illnesses as these have often to be taken lifelong. Unfortunately,
such trials are often seen as mere formalities to satisfy regulatory
requirements.
Traditionally, the pharmaceutical industry needed
the academic community to do clinical trials, and the latter was the key partner
in such trials and took decisions regarding protocols, sampling, design, etc.
Contrary to this, in the last decade, we have seen a shift where the industry
employs or enrols physicians to do drug trials that are controlled by the
industry. Along with this role reversal, we also see a growth of
contract-research organisations (CROs) that undertake research on behalf of the
industry (1). As multicentre trials involve a large number of sites and
investigators, pharmaceutical companies now prefer to contract out research to
such CROs.
The second issue is the design of the trial, a
rough idea of which we can get from the sample size proposed-140 subjects in 20
centres. Phase III clinical trials are designed to evaluate the effect of a new
drug on clinical outcomes that are of relevance to the patient such as death,
disability, etc.-which may be called 'disease end-points'. Such trials require
many participants and need to be followed-up for a long time. For example, the
Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT) involved 40,000 hypertensive patients followed-up for 6 years (2).
Thus, it may take up to a decade or more to get reliable data about the effect
of drugs on disease end-points. There is an attempt to design trials that 'short
circuit' this lengthy process by using what are called 'surrogate end-points'.
These trials evaluate the effect of a drug not on the eventual outcome, but on
specific markers such as blood pressure, cell count, laboratory results, etc.
Such trials, typically, may involve around 100 patients and could be concluded
in a few months. The logic for doing so is that these markers are fair
indicators of the final outcome.
Unfortunately, this is often not true. Such
short-term studies indicate that the level of certain risk factor(s) are reduced
but do not throw enough light on the eventual outcome. For example, it has been
estimated that to prevent one cardiovascular event in a year, 120 elderly
patients have to be treated for that same period. Most treated patients will
actually receive no benefit. If there are unanticipated adverse effects, even
relatively uncommon ones may minimise or eliminate the average health benefits
from drug therapy. But such adverse effects will not be picked up by trials that
only look at, say the effect of a drug in lowering blood pressure.
For example, a large trial showed that low-dose
diuretic therapy was associated with a reduced risk of coronary heart disease,
but this was not true for high-dose diuretic therapy or beta-blocker therapy(3).
But all three regimens lowered blood pressure. Thus, there is the possibilty of
achieving an incomplete or misleading evaluation of a therapy when
surrogate end-points are used to assess therapies.
This does not mean that short trials using
surrogate end-points are of no value. When combined with observational data
about disease end-points they can be of value. If a drug has already been
evaluated adequately, such trials can be used to generate additional data in
different locales. However, given the relatively uncertain significance of the
outcomes of such trials, results should be treated with extreme caution if they
are sponsored by pharmaceutical companies and the data are not available for
independent evaluation.
Amit Sengupta
References
1. Bodenheimer T. Uneasy alliance-clinical investigators and the pharmaceutical industry. 2000;342:1539-1544.
2. Davis BR, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9:342-360.
3. Psaty BM, Weiss NS, Furberg CD, Koepsell TD, Siscovick DS, Rosendaal FR, et al. Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease. JAMA 1999;282:786-790.
1. Bodenheimer T. Uneasy alliance-clinical investigators and the pharmaceutical industry. 2000;342:1539-1544.
2. Davis BR, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9:342-360.
3. Psaty BM, Weiss NS, Furberg CD, Koepsell TD, Siscovick DS, Rosendaal FR, et al. Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease. JAMA 1999;282:786-790.
*Faculty of Medicine, Thammasat University, Klong
Loung, Pathumtani, Thailand. e-mail:sbk@tu.ac.th; **National
Institute of Epidemiology (ICMR), Post Box 2577, Mayor VR Ramanathan Road,
Chetput, Chennai 600031, India. e-mail:nieicmr@vsnl.com; ***Delhi Science
Forum, D-158 Lower Ground Floor, Saket, New Delhi 110017, India. e-mail:
ctddsf@vsnl.com