Equality in Clinical Trials
Drugs and Gender
Women woke up almost twice as fast from anesthesia as men in a study reported at the annual meeting of the American Society of Anesthesiologists, in October 1996. In another recent study, the class of painkillers called kappa opoioids seemed to work about twice as well for women as for men. These are but two of a growing number of clinical studies providing new information about possible differences in ways women and men respond to drugs.
Reporting on the anesthesia study, one of the researchers, Peter S. Glass of Duke University Medical Center, said the gender finding emerged unexpectedly during a study of how management of anesthetic drugs during surgery influences recovery time from general anesthesia. The study included 300 people. Women took an average of seven minutes to emerge from anesthesia, while men took 13. The difference occurred independently of differences in body weight.
In the painkiller study, according to a report published in the November 1996 issue of Nature Medicine, women having wisdom teeth removed had a better and longer response to these drugs than men, even when factors such as body size and menstrual cycle were considered.
Until recently, women were not routinely included in many human trials to determine whether drugs are safe and effective. The reason usually given was that excluding women protected them, since there was often no way to be sure that a woman was not pregnant or that the drug might not cause some problem that might interfere with future pregnancies. In addition, it was thought that women's hormonal cycling or other factors peculiar to being female might constitute variables that could skew trial results.
However, over the last several years, research has accumulated indicating that drug results from male-only trials may not apply equally to women, or may not give data on effects important to women. At one time, researchers thought most of the differences between the way men and women reacted to drugs might be attributed to differences in height, weight and hormones. This meant, for example, that simply because most men weigh more than most women, most men would be able to tolerate higher doses of medications without side effects.
Today many scientists think it's far more complicated. For example, the liver may be different enough in men and women to account for at lease part of why most women seem to metabolize drugs differently than men. And in the case of pain relief, there may be gender differences in pain tolerance and differences in the way each gender responds to various pain medications.
The rising recognition of these and other gender factors has brought changes in the way the Food and Drug Administration asks firms to test drugs and in the data the agency asks them to provide.
For example, in September 1995 FDA proposed to amend its investigational and new drug regulations to require drug sponsors to include data about gender, as well as age and race. The proposal does not require manufacturers to conduct additional studies. Rather, the manufacturers would simply provide information previously gathered in a new, more useful, format.
FDA suggested changes of this nature in 1993 as a revision to a 1977 Guideline, "General Considerations for Clinical Evaluation of Drugs, " after the agency found that few women were included in the earliest stages of drug clinical trials. In addition, the agency found that there had been little study of the effects on drug action of such factors as the menstrual cycle, menopause, and hormone use. The 1993 guideline left gender analysis voluntary; it was not a requirement.
Subsequent studies by FDA and the General Accounting Office have shown that women are often included in later phases of clinical trials, and are included in proportions similar to the proportion of women who have the condition the drug is being tested for. But FDA believes that inclusion alone is not enough. What is needed, in addition, is an effort to use data from the trials to discover potential gender differences.
Impact of HIV
Rachel Behrman, M.D., supervisory medical officer in FDA's division of antiviral drug products, says the issues surrounding these changes were brought to the forefront by efforts to treat HIV (the virus that causes AIDS) in women.
"The guidelines always provided that women with serious or life-threatening diseases could obtain an experimental drug in early phases of testing," say Behrman. "What's new is that now we're saying to drug manufacturers, 'Not only do we recommend that you study it in women, we may insist that you do so, if it's going to be used by women who have serious and life-threatening diseases.'"
She explains that because of the urgent need, drug testing for HIV is on a fast track, with condensed stages of controlled studies and, frequently, fewer people in them.
"Since the process moves so quickly, extensive clinical data collected over a long period of time often are not available," she says. "You need to know as soon as possible, for example, what adverse effects occur that might be dose-dependent, and work up those differences early in the drug development program. You don't want to wait for later stages of testing to begin to define dosage adjustments for men and women."
Many researchers feel the reason for including women in any phase 1 drug trial -- regardless of the seriousness of the disease -- should be to provide important data about the drug. This data includes whether women in general absorb, metabolize or excrete the drug differently from men, or have different reactions to the drug.
Early in the AIDS epidemic, very few women with HIV were included in studies. But their numbers are increasing. According to the National Institute of Allergy and Infectious Diseases (NIAID), in 1995 women accounted for 16.2 percent of adult participants in the AIDS Clinical Trials Group, the institute's largest clinical trials network. That percentage is up from 7 percent in 1988 and 8.4 percent in 1991.
In a study by FDA's Behrman, Kimberly Struble, Theresa Toigo and Debra Birnkrant, 136 of 156 clinical studies of HIV treatment conducted between 1988 and 1994 enrolled women. And, even in the 20 trials that did not include women, enrollment of women -- including those of childbearing ages -- was permitted. Enrollment of women in the other trials ranged up to 64 percent, with a mean of 11.6 percent.
Some HIV studies include only women. Better information on the length of survival and quality of life in HIV-infected women are research goals of the Women's Interagency HIV Study, conducted by the Centers for Disease Control and Prevention and NIAID. This large-scale study is designed to identify clinical signs of HIV infection in women, describe how the immune system declines, and look for factors that can affect the progression of the disease. It will also examine factors influencing women's access to health care.
Other NIAID-sponsored studies center on pregnancy and HIV. They are designed to examine the effect of antiviral drug treatment on both the mother and fetus, the influence of HIV on pregnancy, and the effects of pregnancy on the course of HIV infection. In addition, two experimental vaccines are being tested in pregnant women who are infected with HIV but are otherwise healthy. Phase 1 studies focus primarily on safety, but will also evaluate the vaccines' potential to reduce the amount of virus in the mother and to stimulate antibodies that will prevent infection of the fetus.
In August 1994, FDA approved the antiviral Retrovir (zidovudine, or AZT) to help prevent maternal-fetal transmission of HIV. A study of the drug for this use was halted early when preliminary data showed extremely encouraging results; that 8.3 percent of babies born to HIV-infected pregnant women treated with the drug became infected, compared with 25.5 percent of babies born to women on placebo.
Breast Cancer Trials
FDA has also been involved in a project to determine what resources are available for women seeking information about clinical trials of breast cancer treatments.
A 1995 study by FDA's Office of Special Health Issues and the agency's Office of Women's Health determined that there was no central source of clinical trials information that included both federally and privately sponsored clinical trials of breast cancer therapies.
The FDA researchers found that, in most cases, women seeking information about investigational drug studies directly from most university centers or other clinics were referred back to their doctors. Generally, only the Cancer Information Service (1-800-422-6237) of the National Cancer Institute (NCI) provided information on trials being conducted both at NCI and elsewhere. However, NCI, which relies mostly on its Physician Data Query (PDQ) database, did not usually have information about privately funded cancer research.
As a result, after consulting with NCI officials, FDA asked the Pharmaceutical Research and Manufacturers Association to encourage its members to submit information about their non-federally funded clinical trials to NCI's PDQ database. FDA and NCI also sent a letter to industry sponsors of drug trials informing them that they may submit information about active cancer clinical trials to NCI for possible inclusion in the PDQ database.
The days of routinely excluding women from clinical trials seem to be over. In fact, gender difference in drug effect is a growing area of research. In 1997, studies focusing on women included those on HIV, heart disease, various cancers, weight and eating disorders, menopause, and psychiatric disorders. It is hoped that information from such studies will improve the lives of women in the years to come.
Your Guide to Women's Health, Third Edition, an FDA Consumer Special Report, September 1997
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