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EVIDENCE-BASED-HEALTH  December 2005

EVIDENCE-BASED-HEALTH December 2005

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Subject:

Re: Can clinical trials ever be truly ethical?

From:

Paul Glasziou <[log in to unmask]>

Reply-To:

Paul Glasziou <[log in to unmask]>

Date:

Tue, 6 Dec 2005 07:20:34 +0000

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Dear Edwin,
Thanks for passing on. Its odd that the central example of an 
"experiment" used was Tuskegee which was *not* a randomised  trial. 
I'll assume that is ignorance rather than malicious misuse. But it 
does raise the interesting question of whether participation in 
trials is harmful (or beneficial) to your health. The best current 
review of this says its neutral (see abstract below).
Cheers
Paul Glasziou

Vist GE, Hagen KB, Devereaux PJ, Bryant D, Kristoffersen DT, Oxman 
AD. Systematic review to determine whether participation in a trial 
influences outcome. BMJ. 2005 May 21;330(7501):1175.
OBJECTIVE: To systematically compare the outcomes of participants in 
randomised controlled trials (RCTs) with those in comparable 
non-participants who received the same or similar treatment.
DATA SOURCES: Bibliographic databases, reference lists from eligible 
articles, medical journals, and study authors.
REVIEW METHODS: RCTs and cohort studies that evaluated the clinical 
outcomes of participants in RCTs and comparable non-participants who 
received the same or similar treatment.
RESULTS: Five RCTs (six comparisons) and 50 cohort studies (85 
comparisons) provided data on 31,140 patients treated in RCTs and 
20,380 comparable patients treated outside RCTs. In the five RCTs, in 
which patients were given the option of participating or not, the 
comparisons provided limited information because of small sample 
sizes (a total of 412 patients) and the nature of the questions 
considered. 73 dichotomous outcomes were compared, of which 59 
reported no statistically significant differences. For patients 
treated within RCTs, 10 comparisons reported significantly better 
outcomes and four reported significantly worse outcomes. 
Significantly heterogeneity was found (I2 = 89%) among the 
comparisons of 73 dichotomous outcomes; none of our a priori 
explanatory factors helped explain this heterogeneity. The 18 
comparisons of continuous outcomes showed no significant differences 
in heterogeneity (I2 = 0%). The overall pooled estimate for 
continuous outcomes of the effect of participating in an RCT was not 
significant (standardised mean difference 0.01, 95% confidence 
interval -0.10 to 0.12).
CONCLUSION: No strong evidence was found of a harmful or beneficial 
effect of participating in RCTs compared with receiving the same or 
similar treatment outside such trials.


At 06/12/2005, edwin amalraj wrote:
>My Dear Friends,
>
>     This Column appeared in the Daily News paper. I am sending it 
> for your  information. I hope Content is not new to the Scientific 
> community. However, Scientific matters are made available to the 
> public now a days.
>
><http://www.hindu.com/2005/12/06/stories/2005120603081000.htm>http://www.hindu.com/2005/12/06/stories/2005120603081000.htm
>
>Can clinical trials ever be truly ethical?
>
>Unless the rights of those who participate in clinical trials and 
>their ability to get the best treatment in case of injury or 
>infection are guaranteed, the trials will not be fair even if they 
>yield useful scientific results.
>FOR THE benefit of the many, is it all right to endanger the health 
>of a few? This question lies at the heart of bioethics. It was 
>central to the discussions held over three days at the First 
>National Bioethics Conference organised by the Indian Journal of 
>Medical Ethics in Mumbai last week. The timing could not have been 
>more appropriate coming as it did on the eve of World AIDS Day, 
>December 1. For India is now poised to undertake several important 
>clinical trials on the AIDS vaccine.
>In a country where the poor and the most vulnerable have minimal 
>access to health care, ensuring "informed consent" for clinical drug 
>trials is an issue with many dimensions but above all ethical 
>aspects. How do you check that the person who is being used as a 
>guinea pig for a new drug actually knows what is happening? For 
>decades, women's groups have been in the forefront exposing how poor 
>women have been used for clinical trials of various contraceptives 
>without them fully understanding the consequences.
>The issue of ethics has taken on greater urgency in the face of the 
>growing private sector interest in conducting clinical drug trials 
>in India. According to T.V. Padma writing in Nature (July 28, 2005), 
>while the average cost of a clinical trial in the U.S. is $180 
>million, in India it would cost $100 million. Not surprisingly, 
>Contract Research Organisations (CRO) are setting up shop in India 
>and recruiting people to conduct such trials. Indian companies stand 
>to gain from their being held in India. According to one estimate, 
>U.S. and European pharmaceutical companies could spend as much as 
>$1.5 billion per year on clinical trials in India once the system is in place.
>Although "bioethics" as an issue was first raised in the context of 
>Nazi medical experiments in the concentration camps, there have been 
>several more recent incidents of medical experimentation ! where the 
>health of the participant was sacrificed for a so-called "larger 
>cause." The most scandalous of these was the Tuskegee Syphilis Trial 
>in which between 1932 and 1972, the U.S. Public Health Service 
>experimented on 399 black men from Tuskegee, Alabama, one of the 
>poorest areas of the United States. The men, all poor illiterate 
>sharecroppers, were in late stages of syphilis. They were told 
>nothing except that they were being treated for "bad blood," the 
>term used locally for syphilis. Although in the course of these 40 
>years an effective treatment for syphilis had been discovered in the 
>form of penicillin, these men were denied the treatment. They were 
>turned away from public health facilities and their families had to 
>surrender the body after death for an autopsy. This was described as 
>"the longest non-therapeutic experiment on human beings in medical history".
>The lid was finally blown off this experiment when one of the 
>doctors involved in it went publi! c and the details appeared in the 
>media. As a result, the experiment had to be stopped. But by this 
>time, immense damage had already been done. Many of the men died or 
>passed on the syphilis to their partners and their children in utero.
>The Nazi experiments and thereafter trials like the Tuskegee 
>experiment have compelled the formulation of international and 
>national ethical guidelines for clinical trials. Despite such 
>guidelines, incidents of unethical trials, with elements of the 
>scandalous Tuskegee experiment, continue to be reported, 
>particularly in poor countries and amongst vulnerable populations.
>In India, one of the most shocking recent examples is the illegal 
>use of quinacrine, an anti-malarial drug, to sterilise women. This 
>was done by private American researchers with the help of local 
>doctors in West Bengal. By the time this story became known, more 
>than 30,000 women in India, including almost 10,000 in West Bengal, 
>had been ster! ilised through this brutal method that consisted of 
>inserting the drug into the woman's uterus. This led to scarring of 
>the fallopian tubes and in effect ensured that the woman could not 
>conceive. The procedure was stopped only after health and women 
>activists took the matter to the Supreme Court. As a result, 
>sterilisations by using quinacrine have been banned in India. Yet, 
>despite the ban, the drug is still available and continues to be 
>prescribed illegally.
>There has also been at least one instance in India where, as in 
>Tuskegee, the progress of a disease in humans was studied without 
>ensuring that the participants in the trial were treated. The 
>Institute for Cytology and Preventive Oncology in New Delhi studied 
>1,158 women from 1976 to 1988 and monitored the progression of 
>cervical dysplasia or precancerous lesions of the cervix. The object 
>of the study was to see how many of these women, who had mild, 
>moderate and severe dysplasias, would develop cancer ! if left 
>untreated. The Indian Council for Medical Research (ICMR) sponsored the study.
>By 1988, 71 women had developed malignancies, at least nine had 
>invasive cancer and 62 developed localised cancer that was treated. 
>Ten women could not be followed up. When the researchers were asked 
>whether they had informed the women about what was being done, they 
>said they had taken verbal consent as the women were illiterate. 
>Only when the study became public in 1997 and the question was 
>raised about the ethics of a study where you allow people to develop 
>a disease even though a cure is available did the ICMR begin the 
>process of formulating ethical guidelines for biomedical research on 
>human beings. These were finalised in the year 2000.
>As far as the AIDS vaccine is concerned, the trials are only at a 
>very preliminary stage conducted by the National AIDS Research 
>Institute in Pune. These began in February 2005 and are being 
>implemented with great c! aution. Similar trials will also be 
>conducted at a later stage in Chennai. These trials are essentially 
>for a preventive vaccine. That itself has been the centre of 
>considerable debate as there is a school of thought that suggests 
>that work on a therapeutic vaccine should be the priority given the 
>spread of the disease in India and the need to treat those already 
>infected with HIV.
>Informed consent
>Whatever the nature of the vaccine, the issue of ethics and consent 
>continue to be of primary importance. Health activists ask how real 
>"informed consent" can be guaranteed in such clinical trials and 
>whether the participants in the trials will be assured the best 
>treatment in the event of any of them becoming infected with HIV, in 
>the case of AIDS vaccine trials. The counter argument often put 
>forward is that participants are promised the best "available" 
>treatment in such an eventuality. But in a poor country, with an 
>inadequate health infrastructure, what is available is neither 
>"best" nor even adequate to deal with such diseases. Is it fair then 
>to put people through such a trial if at the end of it they might 
>end up worse off than if they had never agreed to participate in it?
>Also, although the ICMR has issued guidelines and there are 
>bioethics committees that are supposed to apply them before 
>biomedical research involving human subjects, there are several 
>loopholes. There is also an absence of a legal framework that 
>prescribes punishment for those violating the guidelines. 
>Furthermore, in India we do not have the kind of independent 
>monitoring boards that exist in most industrialised countries that 
>keep a watch on such trials. Such boards have the power to insist 
>that drug trials be modified or even abandoned if they are perceived 
>to be violating bioethics codes. In the absence of such a regulatory 
>system, there is a r! eal reason for concern about clinical drug 
>trials. The Mumbai Bioethics conference took many of these concerns 
>on board and identified HIV/AIDS as "an arena where massive 
>bioethics, human rights and public health battles will be fought."
>Few will argue for a ban on all human clinical trials as it is 
>evident that they are essential to test the safety and efficacy of 
>drugs and medical interventions. ICMR guidelines have also laid out 
>the basic framework within which trials can be conducted. But unless 
>the rights of the individuals who participate in the trials and 
>their ability to get the best and most effective treatment in case 
>of injury or infection are guaranteed, the trials will not be fair 
>even if they yield useful scientific results. Ultimately, as Dr. T. 
>Jacob John of the Christian Medical College, Vellore, said in his 
>keynote address at the conference on "Bioethics and Public Health", 
>"What is not in the best interests of the individual cannot be in ! 
>the best interest of the community."

Paul Glasziou
Department of Primary Health Care &
Director, Centre for Evidence-Based Practice, Oxford
ph: 44-1865-227055  www.cebm.net  

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