In summary therefore, these studies are a priority of Uganda's efforts in controlling the spread of the epidemio. Furthermore they conform to high scientific and ethical standards interpreted in the light of the epidemic and financial resources available to cater for the ever growing need in our country. In approving them we have been guided by our needs, the international accepted ethical principles and at the mme time rejecting "ethical imperiliasa".

Sincerely yours,

Grade

Edward K.Mbidde, MBCHB

Chair,

AIDS Research Committee

It is interesting to have heard and read about the debate that is currently ongoing in the United States about the ethics of conducting AZT interventive studies in developing countries. As a scientist in South Africa involved with research that is supported by international institutions I thought that it is necessary for me to express some opinion on the matter.

In South Africa the HIV epidemic is having a major public health impact. The National
Department of Health has just last week released the results of the 7th national survey of
women attending antenatal clinics. Nationally approximately 14% of women were found
to be HIV positive and in some areas, which are predominantly the most disadvantaged in
the country, the rate in excess of 25% Extrapolating from these figures, estimates are that
that approximately 70000 IIIV infected infants will be born this year.

The result of the 076 trial was extremely heartening. AZT successfully reduced the rate of vertical transmission The major problem for virtually all countries in Africa is that the 076 trial regimen and cost of AZT precludes its routine use. Even in South Africa, given its material wealth, it would probably be impractical. If AZT (or any other anti-retroviral agent) is to be used as a strategy to reduce perinatal transmission then a more cost effective regimen must be developed. The only way to prove the efficacy of such an intervention would be in a placebo controlled clinical trial.

The invert Cm Town commuters to policies of equationoominty and offirmative action
which org csontial to the mission of promoting critical inquiry and scholars-o.

Child Ilearth Unit

Public Citizen has accused American researchers of violating international rules of ethical practice by supporting placebo control clinical trials in developing counties. By implication they are accusing the researchers in these countries of doing likewise. Many of us who (as health activists) have been involved in the struggle for democracy in health under the old apartheid regime in South Africa will be offended by such accusations. In South Africa two clinical trials are currently taking place and is being conducted by scientist from within the country. Onc is evaluating anti-retrovial therapy and the other vitamin A therapy. Many of us do not see these trial as violating ethical norms. My colleagues involved in the trial are responsible scientist and the project has undergone a stringent ethical review process. Many of persons involved in these studies are AJDS activists and are not involved for personal gain or glorification. In addition the Department of Health under the Mandela government has given the studies its full support

The efforts of organisations who speak up for and who are attempting to protect the interest of the oppressed and exploited in developing countries are to be commended In the context of the current debate it would have been more constructive to have obtained the viewpoint of those who are being spoken for and those (the researchers in developing countries) who are being accused of violations of ethical practice. There will always be controversies relating to the conduct of placebo control clinical trials in developing countries. Given the available scientific data and taking into account the problems of delivering health care in developing countries, such studies can help define the most appropriate cost-effective interventive strategy.

The debate on anti-retoviral therapy clinical trials in pregnancy has been raised. Hopefully the matter will be resolved in a constructive manner. This is not the only problem. There are numerous other moral and ethical dilemmas that confront all of us involved in AIDS work. In the context of AIDS treatment should we not be harnessing our energies to get the pharmaceutical companies to reduce the costs of anti-retrovirals and thus make these dnigs accessible to all?

Yours sincerely

Associate Professor Greg Husscy

Senior Specialist and Head of Pacdiatric Infectious Diseases Service

Mr. Towns. Thank you very much.

Mr. SHAYS. Thank you. Mr. Kucinich.

Mr. KUCINICH. I just have a quick question of Dr. Varmus. If NIH believes that only placebo controlled studies can provide answers to the questions most relevant in developing countries, why then is the NIH funding one Harvard study in Thailand in which no women will receive a placebo and all with receive anti-viral drugs?

Dr. VARMUS. Well, we don't believe that that is the only way to achieve results. Thailand, of course, is a somewhat different situation than some of the African countries we're discussing today, because of the more the stronger economy and the ability of the country to provide drugs that are more expensive and would be unaffordable in Africa.

Mr. KUCINICH. And if it's true that using placebo controls reduces the number of subjects needed to demonstrate statistical significance, why does NIH funded non-placebo controlled study in Thailand anticipate in enrolling fewer subjects than the U.N. AIDS program study in Tanzania, Uganda and South Africa? For example, you have, I think, 1,554 subjects in Thailand versus 1,900 in a combined U.N. AIDS study.

Dr. VARMUS. 1,500 subjects being enrolled in Thailand. I'm not quite sure what the question is, Mr. Kucinich.

Mr. KUCINICH. I'm asking why, if you are using placebo controls-if you're saying that reduces the number of subjects that you need to have statistical significance do you agree that you do that?

Dr. VARMUS. Yes.

Mr. KUCINICH. OK. Then why do you-why does this funded nonplacebo controlled study in Thailand anticipate enrolling fewer subjects than the study that's going on with the U.N. AIDS program in Tanzania, Uganda, and South Africa. I'm trying to compare your policies with the other.

Dr. VARMUS. I would have to look at the details of the protocols more closely to give you a direct answer to that question. I'd be happy to do that for the record.

[The information referred to follows:]

Insert for the Record of the May 8, 1997, Hearing before the House Government Reform and Oversight Subcommittee on Human Resources, page 82, lines 1843-1847.

Response to Question Raised by Representative Kucinich to Dr. Harold Varmus, Director, National Institutes of Health:

Before any clinical trial is started, it is essential to estimate as precisely as possible the number of study participants that will be required to answer the question of whether or not the treatment being studied is effective. There are a number of factors that go into a statistically-based estimation of how many study participants will be required. These factors include:

1) how large is the impact of the treatment expected to be? That is, is the treatment expected to be 100 percent effective or 50 percent effective or less effective?

2) how certain do the investigators wish to be that their finding at the end of the study is in fact real and did not occur by chance alone?

3) how common is the occurrence of disease that the investigators are seeking to reduce? For example, if a certain disease outcome happens in 40 percent of people exposed and you wish to reduce this occurrence such that it occurs only to 10 percent of the people exposed, you need a much smaller number of study participants than if a certain disease outcome happened in 10 percent of people exposed and you are trying to reduce it to 2.5 percent of the people exposed with the treatment you are studying. In both of these cases, the reduction you are trying to see is a four-fold reduction, but many more participants will be needed in the latter versus the former case.

Other issues that come into play in determining the number of study participants include how many participants may be lost to follow-up before the end of the study.

The two studies referenced in this question are very different studies. One study (the UNAIDS study which is placebo-controlled) is looking to see whether or not two drugs used together (ZDV and 3TC) can reduce mother-to-infant transmission of HIV. This study is ongoing in several sites in Africa and is comparing three different regimens of the two-drug combination against placebo. In this study, the mothers will be breast-feeding their babies after delivery. In the other study (the NIH-supported Harvard study in Thailand), one drug (ZDV) is being studied in four different types of regimens. The mothers in this study will not breast-feed their babies after delivery.

In putting together their sample size calculations in planning how many women would be needed to participate in their studies, the investigators of the two different studies used the three factors listed above. In addition, they made some estimate of the number of women who might not complete their study. Because some of the factors that go into calculating the needed number of subjects are very different when comparing Thailand to multiple sites in Africa, the investigators reached different estimates concerning the number of study participants needed.