Women Living with HIV/AIDS: Towards New Ethical National Research Policies

Speech by Maxine Wolfe

National Conference on Women & HIV
Pasadena 5/97


Chart 1: Faulty Foundations of Current Research Programs and Policies
Chart 2: Towards an Ethical National Research Policy For Women Living with HIV/AIDS

When I was asked to speak about future national research policies, my first thought was, "That's easy. Given the current state of knowledge, I will say there has been no coherent policy and then I will propose one." Then, I reconsidered my thought. Let me tell you why.

Women account for about 11.9% of participants ever to have been in government-sponsored AIDS Clinical Trials Groups (ACTG) research testing the outcomes of anti-HIV treatments or treatments for opportunistic infections. With the exception of one study, even when there have been enough women in research, comparison of outcomes for men and women have not been done. Most studies don't have enough women to do comparisons. In drug company research the percent is lower. And, while there have been about 1,000 pregnant women in government-sponsored trials to study perinatal transmission and 13 more are planned or just completed which will include about 5,000 more pregnant women, studies of anti-HIV or opportunistic infection treatments exclude pregnant women.

We don't know dosing or dose intervals for women, though some data exist for pregnant women. Drug labels do not state whether a drug has been tested in women; they give this information about pregnant women, children and the "elderly." We know how pregnancy influences disease progression, but not how anti-HIV treatments affect infections women get, like cervical cancer or bacterial pneumonia or how they affect women's renal functioning, liver functioning, or viral load. Measures of drug effectiveness are based on men. We don't know how viral load relates to disease progression in women; we do have some data relating viral load to perinatal transmission. We don't know how treatments for infections like lymphoma or MAC affect women. We know that using fluconazole prevents vaginal yeast infections in women with HIV but not whether eating yogurt will do the same thing. We don't know about viral concentrations in women's lymph nodes or about long term non-progressing women.

We do know that in 1996, AIDS deaths for women rose while for men they decreased and that survival times are shorter for women than for men.

The first cases of women with HIV/AIDS were reported in 1981. After 16 years, I asked myself, why do we know so little? This question led me to consider my first thought.

I believe there is a national research policy, but much of it is unspoken. It reflects ideas about women in general, and about women living with HIV/AIDS in particular, which seem so natural that, even when spoken, they are accepted as true without thinking. Changing them is not going to be easy. But if we want an ethical national research policy which might extend or save women's lives, we are going to have to create it based a whole different set of ideas.

I call the ideas which now exist "the faulty foundations" of current research policies (See Chart 1 left column). As I talk about them, you can contrast them to those on the right -- what I call the "building blocks" for an ethical research policy, that is, what a different set of basic ideas would be. After I go over these, I will propose some first steps towards a new policy.

Numbers 1-5 are explanations given for why women were and are not included in clinical or basic research, why so little women-focused research exists, and why we know so little. Numbers 1-3 were spoken until about 1990. We have disproved them, but they still influence, in unspoken ways, what is being done now.

The MAC study, following 6,000 infected men, but no women, was federally funded and began in 1983. Almost everything we know about disease progression and immune system functioning is based on it. But researchers were denied federal funding to study women. The government, the medical research establishment, and drug companies acted like (#1) WOMEN WITH HIV/AIDS DID NOT EXIST. Around 1987 these institutions had to admit that women with HIV/AIDS existed, but said (#2) THERE WERE TOO FEW TO BE INCLUDED IN RESEARCH. But women are almost totally absent from the phase of pharmacokinetics -- how drugs are absorbed and cleared by the body -- which influences toxicity, dosing, safety and effectiveness. Another reason suddenly appeared: (#3) MOST WOMEN ARE IN THE EARLY STAGES OF DISEASE. However, we don't know if the women were really asymptomatic. They simply did not have male-defined symptoms. And, the data were not analyzed by gender anyway.

So, women AIDS activists did the research and produced the first Women's Treatment and Research Agenda in 1990, in which we discussed TB, vaginal candidiasis, cervical cancer, MAC, bacterial pneumonia, and more. We pressured the government to form a Women's Health Committee at the ACTGs, which happened in 1990, and to do a natural history study of women, comparable to the MAC study. The WIHS (Women's Interagency HIV Study) was finally funded in 1991; it began in 1993. We also pressured the Centers for Disease Control to add women's infections to the definition of AIDS and as HIV symptoms because numbers of cases based on those definitions were used to decide what should be studied and because almost all clinical research required a CDC definition of AIDS or an HIV symptom as an entry criterion. The CDC capitulated in 1993, also adding <200 CD4s as an AIDS definer, In the half-year following, over 9,000 cases in women were reported, an increase of 34% over cumulative total. In 1996, of 13,820 cases in women, 64.5% fit only the 1993 definition.

However, although we have proven that lots of women with HIV/AIDS are in various stages of illness, we still have not seen large numbers of women in clinical or basic research; we have not seen gender analyses, women-specific studies, or women-specific measures of drug effectiveness. No government-funded research team is required to have a women's health specialist. On the Women's Health Committee, obstetricians and pediatricians dominate. The ACTG Oncology Committee does not do studies of the cancers women get. At conferences, as we have seen at this one, information is presented about treatment outcomes or relating immune function to progression based on studies with men, although this is hardly ever stated. When we ask "Is this data based on women?", the presenters panic. Why can't they even give us this information? Clearly, ideas 1-3 still influence the research agenda.

When we raise these issues, we are told (#4) WOMEN DON'T WANT TO PARTICIPATE IN RESEARCH. Women are suspicious about medical research -- based on experience and information. The Tuskeegee syphilis studies are often cited as a reason African-American women don't want to participate. But we rarely hear about the experiences poor women, especially Puerto Rican and other Latina women, have had with doctors coercing them into sterilizations in exchange for abortions or about how FDA approved research also produced DES and the Dalkon Shield.

But, still, most of women's lack of participation is not of their own choosing. There are lots of ways women are excluded from drug research, for example, trials exclude former or present drug users. But even if women enter research they are likely to drop out because they are treated as "subjects" not as participants -- not given either information about data being collected from them nor receiving state-of-the-art primary care -- when these may be why they agreed to participate since this may be their only way to obtain either.

Miraculously, there have been women who met study criteria and were desperate to enter a trial to access experimental therapy, only to be told they would have to be surgically sterilized in order to participate. This points to a major reason for women's exclusion from drug research -- the Food and Drug Administration guidelines and regulations for clinical research. These are based on several other ideas about women, ideas shared by researchers and used by drug companies to continue business-as-usual. One idea is (#5) WOMEN LIVING WITH HIV/AIDS ARE NOT CAPABLE OF MAKING DECISION ABOUT THEIR OWN LIVES AND ARE IN NEED OF PROTECTION.

The 1977 FDA guidelines excluded women of "child-bearing potential" from Phase I studies and from later studies as well unless animal fetal toxicity and reproductive studies were completed. A woman of "child-bearing potential" was defined as a menstruating woman capable of becoming pregnant (even if she used birth control) -- the major age group of women with HIV/AIDS Entry criteria for AIDS research trials still can and do exclude "women of child-bearing potential."

Researchers, drug companies, and the FDA claimed they were and are protecting women and "potential" fetuses. But they were and are willing to put women and "real" fetuses at risk in perinatal transmission studies, while excluding pregnant women from studies of treatments for themselves. And, more women are at risk, taking drugs tested on men and not labeled as such. Lack of concern for the fetus and the sexist bias are clear because men of child-bearing potential are not excluded or required to be sterilized even when there are known effects on fetuses if a man's sperm have been exposed to toxic substances.

After more demonstrations by women AIDS activists, and the filing of a Citizen's Petition charging the FDA with sex-discrimination, in 1993 the FDA issued a detailed set of new guidelines about how and why to do gender analyses in clinical trials. Admitting that the 1977 guidelines were paternalistic, unnecessary, and put women's lives at risk, all these did was "lift and the strict limitation" on "women of child-bearing potential" and "encourage" drug companies to include them. But they did not require the inclusion of women in research nor did they require the presentation of data about women for the approval of a new drug. The FDA admitted these guidelines would not increase the number of women in trials. And, these guidelines contained other ideas about women which signaled a continuation of business-as-usual, #6, 7, and 8.

The first (#6) is that WOMEN ARE ONLY A SUB-GROUP OF THE POPULATION. In practice this statistical term means that sometimes the subgroup is put into trials but only in small numbers unless you have reason to believe you will find differences. Small numbers mean no meaningful or statistical analyses of data. So, you never find differences; then you have no reason to believe you will and the circle continues. For example, Viracept from Aguron was approved about one month ago, under these guidelines, based on a study of 33 women and 1,000 men. They claimed there were no differences.

After more protests, critiques, letter writing campaigns, and in 1994 a protest at the FDA and the National Drug Development Task Force Meetings, in September 1995 the FDA put out, for public comment, proposed amendments to the Investigational New Drug (IND) and New Drug Approval (NDA) regulations. These have still not been issued -- one and one-half years later. But, even if they were, they will hardly change the situation.

They use the word "require" and they are "regulations" instead of guidelines, but they all they "require" is_ 1) a drug sponsor who gets approval to investigate a new drug has to provide a yearly report, giving the number of people entered in the research by age, race and gender. But dosing studies last far less than one year, so all we will get is more proof that women are excluded, after the fact; and_ 2) for NDAs, which for life-threatening illnesses like AIDS can be submitted during the second of three phases of testing, sponsors must provide "evidence" to support the dosing recommendations on labels, as well as "effectiveness data" by gender, age and racial subgroups. But this regulation also specifically states that it does not require the inclusion of particular numbers of individuals from (you guessed it) "subgroups". Simply by having a few women or people of color in a study and stating either that there do not seem to be differences or they could not be sure, a new drug could still be approved. This may change labeling so it might say the drug has not been tested adequately on women. But there is no requirement to label drugs previously approved.

As long as women are considered only a subgroup of the population, the lack of information will continue. Comparative trials require enough numbers of each group to enable analyses. To scare us, we are told that putting enough women in research will delay drug approval. This is not a problem about women. If having enough people to do comparisons will delay things (and I don't believe it will), and since the last 150 years of research have been based on male bodies, perhaps we need women-only studies for the next 150 years and men can take the drugs tested in our bodies. The response of the researchers and male AIDS activists to this suggestion is horror, and I myself, believe this would be unethical. But so is the opposite.

Women as a subgroup reflects two other faulty ideas (#7 & 8): that THERE ARE NO DIFFERENCES BETWEEN MEN AND WOMEN and, if there are, THEY ARE ONLY IN AREAS OF REPRODUCTIVE ORGANS AND FUNCTIONING. Women do get cervical cancer, men don't, but they are also more likely to get bacterial pneumonia and to have renal problems. Estrogen affects drug absorption and clearance. Trials with post-menopausal women or pregnant women eliminate exactly the thing that makes a difference. Some small studies point to the outcomes for infected women. Here are two: 10 a recent Dutch study (Burger, D.M. et al. Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions. J. of AIDS, 1994, 8(12), 1683-1689) found that AZT cleared women's bodies 42% slower than men's and this wasn't due to body weight. Another study, to be a late-breaker at this conference, found that women taking the same dose of delavirdine as men were getting more absorbed into their bodies. What does this mean for toxicity, for combination therapies, for compliance, for effectiveness? We don't know.

The studies with women enrolled which do exist are based on idea #9: WOMEN ARE MORE LIKELY TO TRANSMIT HIV TO OTHERS (BABIES AND MEN, BUT NOT OTHER WOMEN) THAN TO HAVE HIV TRANSMITTED TO THEM -- even though the opposite is true. Search the medical indexes under "women and AIDS." In 1989 most papers were about pregnancy and prostitution. This remains true today. We have studies of viral load in cervicovaginal fluid but not in a women's lymph nodes. No one really takes woman-to-woman transmission seriously. Yet, we have one perinatal transmission study after another, even though the numbers of children with AIDS was very low before the use of AZT during pregnancy -- about 1/10 the number of women with AIDS. And, if you dare to say this you risk being called a baby-hater.

But, the absence of research on treatments addressing women's own health, and the exclusion of pregnant women from research for treatment for themselves, indicates that the focus on perinatal transmission trials, as well as the way in which the research is done, reflects idea #10: ALL WOMEN WITH HIV/AIDS WANT TO BECOME PREGNANT OR ARE PREGNANT AND SHOULD BE WILLING TO GIVE UP THEIR HEALTH IN ORDER TO HAVE AN UN INFECTED CHILD. The ideas of the innocent child and the guilty women are alive and well in the AIDS research establishment. Pregnant women who do not want to take AZT or other drugs are considered criminal by some and ignorant by others. And, their health comes last in these studies. Recently, women AIDS activists pointed out that AZT monotherapy is no longer the standard of care for any infected person and that the perinatal guidelines could be considered bad medical practice. There are now new draft guidelines but they also give women unacceptable choices based on no information, suggesting that due to lack of data from animal fetal toxicity and reproductive studies, and because of possible genetic damage to the fetus, women "might" consider stopping combo therapy for the first 14 weeks of pregnancy. The whole world is telling PWAs not to miss a dose and pregnant women are being given this advice. Why didn't the FDA require these studies before approving the drugs?

These guidelines are not about reproductive choices. Neither are perinatal trials planned in Thailand, the Ivory Coast and Uganda, for several thousand pregnant women, all of which compare AZT monotherapy to placebo. Even if we don't deal with the AZT monotherapy part of these studies, how could the NIH and the CDC knowingly fund research which allows women to transmit HIV to their children when they could prevent 2/3 of these cases according to their own research? And, given the high cost of these drugs, who is the research really for? Are WOMEN LIVING WITH HIV/AIDS IN OTHER COUNTRIES EXPENDABLE? (#11).

This question leads to #12. When asked why these perinatal trials were using placebos and not comparing AZT to combos, one response was that they need to have a group of high transmitters to show the differences statistically. When researchers do not see women living with HIV/AIDS as human beings, but merely "research subjects", SCIENCE BECOMES MORE IMPORTANT THAN LIFE. But good science does not have to sacrifice lives.

Even if federal agencies, researchers and others agree that what we know about women is little and yes, "they hear our anger", and yes, there is room for improvement, they tell us (#13) there is no money and (#14) it will take time. There is money for perinatal trials, for the WITS (Women and Infants Transmission Study), for the MAC. There is separate pediatric ACTG -- though I do not think their research is any better. The quality of research is an issue. One researcher at an ACTG meeting, seeing my frustration, said: "You want cutting edge research, but what we do here is mediocre research." We are told that our complaints about the WIHS study, as it is designed to run, is also mediocre research. It is quickly becoming another transmission study -- never one of its goals. It has no state of the art immunology or virology.

If you believe that the lives of all people living with HIV/AIDS are equally valuable, put expertise and money into women's lives too because women living with HIV/AIDS don't have any more time to wait than anyone else. Women can't wait another ten years for useless or anachronistic information or for people to care about keeping them alive or about why they died.

We must completely refocus our research policy, programs, and funding. Each of you had, on your seat when you came in, a paper with an initial set of recommendations for an ethical national research policy for women living with HIV/AIDS (See second chart). I will summarize them and you can read them when you have the time.

Right now, with no acts of Congress, no changes in regulations, in fact with only a telephone call or e-mail, everything on the first page could be implemented and move us incredibly far ahead. Donna Shalala and Sandy Thurmond should put their political will and control of money where their mouths are -- give priority to funding AIDS research for women and get all Public Health Service Agency heads who control any research money to have a plan for implementing this priority within the next month. They are asked to do this sort of thing all the time. The NIH has the power, right now, to require that all of their funded research include enough women to do gender analysis, use women-specific measures in all studies and study women's infections, as well as to mandate women's health specialists on all research teams. If we can't wait for the FDA to force the drug companies to do fetal toxicity and reproductive studies for drugs already approved, the NIH can contract them out and we can have the information within a few months. If the WIHS study cannot quickly produce state-of-the-art immunological and virological data and relate it to disease progression and treatment, give that part of the study to the MAC, add a women's health specialist to their teams, and pay them to do it. And, put knowledgeable women living with HIV/AIDS on all grant review panels.

The second set of recommendations are for the FDA: Above all they should create regulations requiring the inclusion of enough women in clinical trials to allow meaningful analyses and requiring meaningful gender analyses for drug approval. They must find a way to force drug sponsors to do animal studies before they can test the drug in humans and let women and men decide what they want to do based on the information. All drugs previously approved must be immediately labeled stating they were not tested in women. And, women living with HIV/AIDS, who are knowledgeable, must be placed on all FDA, IND and NDA approval panels.

It is past due time for research about and for women living with HIV/AIDS, research of the highest quality, which speaks to women's bodies and needs and designed around women's lives. Women living with HIV/AIDS need research which allows real reproductive choice but they must not be viewed as only reproductive machines or transmitters to babies and men.

If the answer to the question -- "Who is "The Cure" for?" is truly to be "It's for everyone", we must not simply ask for, but must demand research to save women's lives.


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