AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 October 21, 1994 Women and HIV Infection (Part XI) NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Biomedical and Behavioral Research [Editor's Note: The following summary is taken from the Notice published in the NIH GUIDE, Volume 23, Number 11, March 18, 1994, and in the Federal Register of March 9, 1994 (59 FR 11146-11151), Part IV. SCOPE OF POLICY: This document sets forth guidelines on the inclusion of women and members of minority groups and their subpopulations in clinical research, including clinical trials, supported by the National Institutes of Health (NIH). For the purposes of this document, clinical research is defined as NIH-supported biomedical and behavioral research involving human subjects. IMPLEMENTATION: A. Date of Implementation This policy applies to all applications/proposals to be submitted on and after June 1, 1994 (the date of full implementation) seeking Fiscal Year 1995 support. Projects funded prior to June 10, 1993, must still comply with the 1990 policy and report annually on enrollment of subjects using gender and racial/ethnic categories as required in the Application for Continuation of a Public Health Service Grant (PHS Form 2590), and in contracts. B. Transition Policy NIH-supported biomedical and behavioral research projects involving human subjects, with the exception of Phase III clinical trial projects as discussed below, that are awarded between June 10, 1993, the date of enactment, and September 30, 1994, the end of Fiscal Year 1994, shall be subject to the requirements of the 1990 policy and the annual reporting requirements on enrollment using gender and racial/ethnic categories. For all Phase III clinical trial projects proposed between June 10, 1993 and June 1, 1994, and those awarded between June 10, 1993 and September 30, 1994, Institute/Center staff will examine the applications/proposals, pending awards, awards and intramural projects to determine if the study was developed in a manner consistent with the new guidelines. If it is deemed inconsistent, NIH staff will contact investigators to discuss approaches to accommodate the new policy. POLICY A. Research Involving Human Subjects It is the policy of NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification establishes to the satisfaction of the relevant Institute/Center Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances may be made by the Director, NIH, upon the recommendation of an Institute/Center Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research. All NIH-supported biomedical and behavioral research involving human subjects is defined as clinical research. This policy applies to research subjects of all ages. B. Clinical Trials Under the statute, when a Phase III clinical trial is proposed, evidence must be reviewed to show whether or not clinically important gender or race/ethnicity differences in the intervention effect are to be expected. C. Roles and Responsibilities (Partial List) Certain individuals and groups have special roles and responsibilities with regard to the adoption and implementation of these guidelines. 1. Principal Investigators Principal investigators should assess the theoretical and/or scientific linkages between gender, race/ethnicity, and their topic of study. Following this assessment, the principal investigator and the applicant institution will address the policy in each application and proposal, providing the required information on inclusion of women and minorities and their subpopulations in research projects, and any required justifications for exceptions to the policy. Depending on the purpose of the study, NIH recognizes that a single study may not include all minority groups. 2. Institutional Review Boards (IRBs) As the IRBs implement the guidelines, described herein, for the inclusion of women and minorities and their subpopulations, they must also implement the regulations for the protection of human subjects as described in Title 45 CFR Part 46, "Protection of Human Subjects." They should take into account the Food and Drug Administration's "Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," Vol. 58 Federal Register 39406. 3. Peer Review Groups In conducting peer review for scientific and technical merit, appropriately constituted initial review groups (including study sections), technical evaluation groups, and intramural review panels will be instructed, as follows: -- to evaluate the proposed plan for the inclusion of minorities and both genders for appropriate representation or to evaluate the proposed justification when representation is limited or absent, -- to evaluate the proposed exclusion of minorities and women on the basis that a requirement for inclusion is inappropriate with respect to the health of the subjects, -- to evaluate the proposed exclusion of minorities and women on the basis that a requirement for inclusion is inappropriate with respect to the purpose of the research, -- to determine whether the design of clinical trials is adequate to measure differences when warranted, -- to evaluate the plans for recruitment/outreach for study participants, and -- to include these criteria as part of the scientific assessment and assigned score. 4. Recruitment Outreach by Extramural and Intramural Investigators Investigators and their staff(s) are urged to develop appropriate and culturally sensitive outreach programs and activities commensurate with the goals of the study. The objective should be to actively recruit the most diverse study population consistent with the purposes of the research project. Indeed, the purpose should be to establish a relationship between the investigator(s) and staff(s) and populations and community(ies) of interest such that mutual benefit is derived for participants in the study. Investigator(s) and staff(s) should take precautionary measures to ensure that ethical concerns are clearly noted, such that there is minimal possibility of coercion or undue influence in the incentives or rewards offered in recruiting into or retaining participants in studies. It is also the responsibility of the IRBs to address these ethical concerns. Furthermore, while the statute focuses on recruitment outreach, NIH staff underscore the need to appropriately retain participants in clinical studies, and thus, the outreach programs and activities should address both recruitment and retention. DEFINITIONS: See full text for definitions of "clinical trial," "research involving human subjects," "valid analysis," "significant difference," "racial and ethnic categories," "outreach stragegies," and "research portfolio." OPPORTUNITY TO COMMENT: Although these guidelines are effective on the date of publication, written comments can be sent to either the Office of Research on Women's Health, National Institutes of Health, Building 1, Room 203, Bethesda, MD 20892, or to the Office of Research on Minority Health, National Institutes of Health, Building 1, Room 255, Bethesda, MD 20892. During the first year of implementation, NIH will review the comments and experience with the guidelines in order to determine whether modifications to the guidelines are warranted. NIH CONTACTS FOR MORE INFORMATION: Addresses and phone numbers are listed for each of the NIH Institutes and Centers at the end of the full text. NIAID Begins Clinical Trials of Therapeutic AIDS Vaccine Candidates in Pregnant Women Who Are HIV-Infected HHS Secretary Donna E. Shalala announced [on May 6, 1993] that the National Institute of Allergy and Infectious Diseases has begun the first clinical trials of therapeutic AIDS vaccine candidates in pregnant women who are HIV-infected but otherwise healthy. In these separate Phase I trials, two experimental vaccines are being evaluated primarily for safety but also for their potential to stimulate anti-HIV immune responses in expectant mothers and to prevent their passing HIV infection to their babies. Secretary Shalala said, "Although three-fourths of infants born to HIV-infected mothers in the United States escape HIV infection, nearly all children who become infected acquire the virus from their mothers. We need therapies that not only improve the health of pregnant women infected with HIV but that also prevent this tragic mode of HIV transmission." No one knows exactly when HIV passes to the fetus, or why some babies get infected and others do not. Evidence suggests that HIV frequently is transmitted either late in pregnancy or during birth. "By vaccinating HIV-infected pregnant women, we hope to induce immune responses that will reduce the amount of virus present, thus helping the women, while simultaneously stimulating antibody responses that can cross the placenta and protect their babies from HIV infection," said NIAID Director Anthony S. Fauci, M.D. One precedent for using maternal immunization to prevent the transmission of infectious diseases from a mother to her newborn is tetanus immunization. Vaccinating pregnant women in non- industrialized countries has proved to be the most cost-effective way to prevent neonatal tetanus, a significant cause of newborn deaths in these countries. With the development of the technologies to make vaccines safer, concerns about the risks associated with vaccinating pregnant women have lessened, and interest in maternal immunization has grown. The Centers for Disease Control and Prevention predicts that women will continue to be a growing share of new U.S. AIDS cases through the decade's end. HIV/AIDS is now the sixth leading cause of death after cancer, unintentional injuries, heart disease, suicide and homicide for women of childbearing age (15 to 44 years old) nationwide. HIV/AIDS is the leading cause of death for women in this age group in New York and New Jersey. Moreover, as a greater percentage of women of childbearing age become infected with HIV, experts expect a concurrent rise in the number of infected children. Already, HIV/AIDS is the fifth leading cause of death for children in the United States between the ages of 1 and 14. The two new trials in pregnant women and a similar one expected to begin by early summer will test genetically engineered candidate HIV vaccines. Completed and ongoing trials of these experimental vaccines in healthy individuals with and without HIV infection have shown them to be well-tolerated. Because each candidate contains no live HIV and only a piece of the virus, these so-called subunit vaccines cannot transmit HIV infection. Although testing different candidate HIV vaccines, the trials are designed similarly. Both enroll women between ages 16 and 40 who are free of AIDS-defining symptoms and have 400 or more CD4+ T cells, a primary cell of the Immune system. Volunteers must not have any other medical conditions, such as insulin-dependent diabetes or moderate to sever hypertension, that would make their pregnancy high-risk. Therapy with zidovudine(AZT) can be continued during the trial. The multicenter trial will enroll 24 women. Sixteen will receive the experimental vaccine, the rest a non-active dummy vaccine, or placebo. The smaller trial will enroll 12 women, nine assigned to receive vaccine and the others a placebo. Assignments will be made randomly, and throughout the trial, neither the investigators nor the participants will know if the women are receiving the active or placebo vaccine. Each trial volunteer will receive at least four or five immunizations: the first between the 16th and 24th week of pregnancy and thereafter monthly booster doses until the end of her pregnancy. The health of the women will be monitored with regular blood and urine tests, and the health of their fetuses with ultrasound. The mothers may opt for a second series of booster immunizations at three, six, nine and 12 months after delivery. Both trials will last about two years, including an 18-mouth follow-up period after delivery. Newborns will be examined at birth and six weeks later, and then every three months during follow-up. The investigators will periodically sample the babies' blood to monitor their health and determine any vaccine effects. "By intentionally altering the HIV immune status of pregnant women through active immunization, eventually we hope to discover the critical factors that prevent mothers from passing the infection to their babies," says Patricia Fast, M.D., Ph.D., who leads the Phase I/II HIV vaccine trials program for NIAID's Division of AIDS. The trials are being conducted through two of NIAID's national clinical trials networks, the AIDS Vaccine Evaluation Group and the AIDS Clinical Trials Group. Study co-chairs and AVEG investigators Peter Wright, M.D., of Vanderbilt University, and John Lambert, M.D., of the University of Rochester in New York, will coordinate the trial. Dr. Gast, along with James McNamara, M.D., and Evelyn Rodriguez, M.D., both medical officers in NIAID's Division of AIDS who specialize in perinatal and pediatric clinical trials, will help facilitate the studies. One trial, known as AVEG 104/ACTG 235, will be conducted at seven sites located in Rochester, Seattle, St. Louis (two sites), Nashville, Baltimore and San Francisco. Women in this trial will receive an experimental vaccine made by Genentech Inc. of South San Francisco. The vaccine contains a genetically engineered surface protein of HIV, gp120 (MN), and the adjuvant alum. An adjuvant is a substance formulated with a vaccine to boost specific immune responses. Alum is the only adjuvant now in human vaccines licensed by the Food and Drug Administration. The second trial, known as AVEG 102/ACTG 234, will be carried out at one site in New Haven. This trail uses a vaccine made by MicroGeneSys Inc. of Meriden, Conn., containing gp 160 (LAV), the parent protein of gp120, and alum. Alum will be used in both trials as the placebo vaccine. These studies are part of a comprehensive effort by NIAID to improve the health of HIV-infected pregnant women and their offspring. NIAID, a component of the National Institutes of Health, supports research on AIDS and other infectious diseases, allergy and immunology. NIH, CDC, and FDA are agencies of the U.S. Public Health Service within HHS. For more information about the trial sites or eligibility criteria, call the AIDS Clinical Trials Information Service, 1-800-TRIALS-A, from 9am to 7pm ET weekdays. Spanish-speaking information specialists are available. Women interested in participating also may speak directly to trial recruiters at the site telephone numbers listed below. Trial Sites for AVEG 104/ACTG 235 Johns Hopkins University, Baltimore, MD (410-955-2149) St. Louis Univ. School of Medicine, St. Louis, MO (314-577-8649) Washington University, St. Louis, MO (314-362-2418) Univ. of Rochester Medical Center, Rochester, N.Y.(716-275-0526) Univ. of Cal. at San Francisco, San Francisco, CA (415-206-8919) University of Washington, Seattle, Wash. (206-526-2535) Vanderbilt University, Nashville, TN (615-343-2437) Trial Site for AVEG 102/ACTG 234 Yale Univ. School of Medicine, New Have, Conn. (203-737-4040) (Press Release, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, May 6, 1993.)