Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-26T07:58:39.317Z Has data issue: false hasContentIssue false

Harms of excluding Pregnant Women from Clinical Research: The Case of HIV-Infected Pregnant Women

Published online by Cambridge University Press:  01 January 2021

Extract

Since the beginning of the AIDS epidemic, the proportion of AIDS cases among women has continued to rise. Women constituted 23 percent of the AIDS cases reported to the Centers for Disease Control and Prevention (CDC) in 1995, and 81 percent of these women were of childbearing age (13 to 44 years). It was not until 1991, however, that epidemiological studies of women were initiated. By comparison, the representation of HIV-infected women in clinical trials gradually has grown. Undoubtedly, a consequence of the increased numbers of women in clinical and epidemiological research is the earlier identification of and more appropriate treatments for HIV-related syndromes when women present in the clinical setting. Despite this expanded focus on women, however, clear information to guide the treatment of HIV-infected women who are pregnant is still lagging behind.

Type
Article
Copyright
Copyright © American Society of Law, Medicine and Ethics 1996

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report, 6, no. 2 (1995): 139; and U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report, 7, no. 2 (1996): 1–39.Google Scholar
In this paper, we use the terms clinical trials or clinical research to mean randomized clinical trials of therapeutic interventions to address specific medical conditions. We do not consider here research with no possibility of therapeutic benefit, such as observational clinical research.Google Scholar
Cotton, D.J. et al. , AIDS Clinical Trials Group, “Determinants of Accrual of Women to a Large, Multicenter Clinical Trials Program of Human Immunodeficiency Virus Infection,” Journal of Acquired Immune Deficiency Syndromes, 6 (1993): 1322–28.Google Scholar
Cotton, D.J. et al. , “Guidelines for the Design and Conduct of AIDS Clinical Trials,” Clinical Infectious Diseases, 16 (1993): 816–22.CrossRefGoogle Scholar
Levine, C., “Women and HIV/AIDS Research: The Barriers to Equity,” IRB: A Review of Human Subjects Research, 13, no. 1–2 (1991): 1822; and Korvick, J., “Trends in Federally Sponsored Clinical Trials,” in Kurth, A., ed., Until the Cure Caring for Women with HIV (New Haven: Yale University Press, 1993): 94–103.CrossRefGoogle Scholar
Levine, C., “Ethical Issues,” in Kurth, A., ed., Until the Cure Caring for Women with HIV (New Haven: Yale University Press, 1993): 105–24.Google Scholar
Thomas, S.B. Quinn, S.C., “The Tuskegee Syphilis Study, 1932 to 1972: Implications for HIV Education and AIDS Risk Education Programs in the Black Community,” American Journal of Public Health, 81 (1991): 1498–504.CrossRefGoogle Scholar
Johnson, T. Fee, E., “Women's Participation in Clinical Research: From Protectionism to Access,” in Mastroianni, A. Faden, R. Federman, D., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume II (Washington, D.C.: National Academy Press, 1994): 8490; and Bush, J.K., “The Industry Perspective on the Inclusion of Women in Clinical Trials,” Academic Medicine, 69 (1994): 708–15.Google Scholar
Cotton, et al. , supra note 3.Google Scholar
Caschetta, M.B. Chavkin, W. McGovern, T., correspondence, “FDA Policy on Women in Drug Trials,” N. Engl. J. Med., 329 (1993): 1815.Google Scholar
Minkoff, H. Moreno, J., “Drug Prophylaxis for Human Immunodeficiency Virus–Infected Pregnant Women: Ethical Considerations,” American Journal of Obstetrics and Gynecology, 163 (1990): 1111–14.CrossRefGoogle Scholar
Cotton, et al. , supra note 3.Google Scholar
Greg Folkers, Office of Communication, National Institute of Allergy and Infectious Diseases, National Institutes of Health, personal communication, July 21, 1995.Google Scholar
At most academic institutions, any research conducted by affiliated faculty, regardless of the source of funding, must follow the DHHS regulations.Google Scholar
21 C.F.R. §§ 50, 56 (1991); 21 C.F.R. § 312 (1987); and 21 C.F.R. §314(1985).CrossRefGoogle Scholar
The most recent comprehensive revision was propose in 1983. 48 Fed Reg. 26,720 (1983), adopted in 1987, 52 Fed. Reg. 8,798 (1987) (to be codified at 21 C.F.R. § 312 (1987)).Google Scholar
Phase I only involves a small number of normal, healthy volunteers, and is designed to determine how a drug is metabolized and to identify side-effects. Once a drug is determined to be safe, it can go on to Phase II. Phase II usually involves no more than a few hundred participants, and is designed to monitor safety and the effectiveness of the drug. If the drug is determined to be effective, it is allowed to move on to a Phase III trial. Phase III trials can involve thousands of participants, can last for several years, and are designed to determine safety, effectiveness, and optimal dosing of the drug. 21 C.F.R. § 312.21 (1987).Google Scholar
21 C.F.R. § 312.80 (1987).Google Scholar
The most recent comprehensive revision was proposed in 1982. 47 Fed. Reg. 46,622 (1982), adopted in 1985, 50 Fed. Reg. 7,462 (1985) (to be codified at 21 C.F.R. § 314 (1985)).Google Scholar
21 C.F.R. § 314.510 (1985).Google Scholar
One regulation was originally proposed in 1979. 44 Fed. Reg. 47,713 (1979), adopted in 1981, 46 Fed. Reg. 8,942 (1981). It was most recently revised in 1991. 56 Fed. Reg. 28,025 (1991) (to be codified at 21 C.F.R. § 50 (1991)). The other was originally proposed in 1978. 43 Fed. Reg. 35,186 (1978), adopted in 1981, 46 Fed. Reg. 8,958 (1981). It was most recently revised in 1991. 56 Fed. Reg. 28,025 (1991) (to be codified at 21 C.F.R. § 56 (1991)).Google Scholar
FDA regulations are similar but not identical to the Federal Policy, given that FDA is a regulatory agency and it does not regularly conduct or support clinical investigations. 56 Fed. Reg. 28,025 (1991).Google Scholar
U.S. Department of Health, Education, and Welfare, Public Health Service, Food and Drug Administration, General Considerations for the Clinical Evaluation of Drugs (Washington, D.C.: U.S. Government Printing Office, 1977).Google Scholar
Id. at 11.Google Scholar
U.S. Department of Health and Human Services, Public Health Services, Food and Drug Administration, Guideline for the Format and Content of the Clinical and Statistical Sections of the New Drug Applications (Rockville: Department of Health and Human Services, 1988).Google Scholar
Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs; Notice, 58 Fed. Reg. 39,406 (1993).Google Scholar
Id. at 39,408.Google Scholar
Id. at 39,409.Google Scholar
U.S. Department of Health and Human Services, Public Health Service, “Evaluation and Management of Early HIV Infection,” Clinical Practice Guidelines (Rockville: Agency for Health Care Policy and Research, No. 7, 1994): 7273.Google Scholar
Sibai, B.M. et al. , National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units, “Risk Factors for Preeclampsia in Healthy Nulliparous Women: A Prospective Multicenter Study,” American Journal of Obstetrics and Gynecology, 172, no. 2, pt. 1 (1995): 542–48; and De Swiet, M., “Pre-Eclampsia, III, the Role of Aspirin in Prevention,” Modern Midwife, 4, no. 12 (1994): 20–22.CrossRefGoogle Scholar
Merkatz, R.B. Temple, R. Sobel, S., “Women in Clinical Trials of New Drugs, A Change in Food and Drug Administration Policy,” N. Engl. J. Med., 329 (1993): 292–96.CrossRefGoogle Scholar
Transcript from U.S. Food and Drug Administration Meeting on Regulated Products and Pregnant Women, Nov. 7–8, 1994; and Merkatz, R.B. Temple, R., “From the FDA: Women in Clinical Trials,” Oncology, 8, no. 6 (1994): 5257.Google Scholar
In 1953, guidelines were passed that required peer review of all research conducted at the National Institutes of Health Clinical Center for the purpose of determining if there was unreasonable risk to participants; but the guidelines did not apply to research conducted outside NIH. Levine, R.J., Ethics and Regulation of Clinical Research (New Haven: Yale University Press, 2nd ed., 1986).Google Scholar
Curran, W.J., “Government Regulation of the Use of Human Subjects on Medical Research: The Approaches of Two Federal Agencies,” in Freund, P.A., ed., Experimentation with Human Subjects (New York: George Braziller, 1970): 402–54.Google Scholar
Levine, , supra note 34.Google Scholar
Also referred to as the Common Rule.Google Scholar
45 C.F.R. § 46.102(I) (1978).Google Scholar
There are four exceptions to the requirement of paternal consent: “(1) the purpose of the activity is to meet the health needs of the mother; (2) his identity or whereabouts cannot be reasonably ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape.” 45 C.F.R. § 46.207 (1987).Google Scholar
45 C.F.R. § 46.206 (1987).Google Scholar
Mastroianni, A. Faden, R. Federman, D., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume I (Washington, D.C.: National Academy Press, 1994): At 198.Google Scholar
Gary Ellis, Director, Office of Protection from Research Risks, National Institutes of Health, personal communication, Apr. 30, 1996. The proposed revision was drafted by the PHS Human Subject Regulations Drafting Committee. If approved by the secretary, the proposed revision will appear as a Federal Register notice for public comment.Google Scholar
Merton, V., “The Exclusion of Pregnant, Pregnable, and Once Pregnable People (a.k.a. Women) from Biomedical Research,” American Journal of Law & Medicine, XIX (1993): 369451.CrossRefGoogle Scholar
U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Guide for Grants and Contract, 20, no. 32 (1991): 13.Google Scholar
59 Fed. Reg. 14,508 (1994).Google Scholar
This mandate is specific to Phase III trials of clinical or public health interventions. When Phase III trials are proposed, investigators must review evidence from prior studies to determine whether existing evidence indicates of significant differences by gender. If the data strongly indicate a gender difference, investigators are required to include enough women in Phase III studies to be able to perform “valid analyses” of differences, but they are not required to include enough women to “provide high statistical power.” If data strongly support no difference, investigators are strongly encouraged to include women, but they are not required to do so. If data are inconclusive, investigators are required to include women. 59 Fed. Reg. 14,508, 14,509 (1994).Google Scholar
59 Fed. Reg. 14,508, 14,510 (1994).Google Scholar
Merton, , supra note 42; Charo, R.A., “Protecting Us to Death: Women, Pregnancy, and Clinical Research Trials,” St. Louis University Law Journal, 38 (1993): 135–67; and Mastroianni, Faden, Federman, , supra note 40.Google Scholar
Areen, J. King, P. Ulshen, Z., “Clinical Research Involving Women as Subjects: Legal Considerations,” monograph commissioned by the Office for the Protection from Research Risks and the Office of Extramural Research of the National Institutes of Health, Apr. 15, 1992.Google Scholar
Wetherill v. University of Chicago, 565 F. Supp. 1553 (N.D. Ill. 1983).Google Scholar
Mastroianni, Faden, Federman, , supra note 40.Google Scholar
Mink v. University of Chicago, 460 F. Supp. 713, 718 (N.D. Ill. 1978).Google Scholar
Roberts v. Patel, 620 F. Supp. 323, 325 (N.D. Ill. 1985).Google Scholar
Grodin v. Grodin, 301 N.W.2d 869 (Mich. Ct. App. 1980); and Bonte v. Bonte, 616 A.2d 464 (N.H. 1992).Google Scholar
Stallman v. Youngquist, 531 N.E.2d 355 (Ill. 1988).Google Scholar
International Union, UAW v. Johnson Controls, 499 U.S. 187, 208 (1991); and 620 F. Supp. 323, at 326.Google Scholar
Restatement (Second) of Torts § 402A (1965). The Restatement of Torts is currently under review, and strict liability standards are being reconsidered. See Henderson, J.A. Jr. Twerski, A.D., “A Proposed Revision of Section 402A of the Restatement (Second) of Torts,” Cornell Law Review, 77 (1992): 1512–57; Shapo, M.S., “In Search of the Law of Products Liability: The ALI Restatement Project,” Vanderbilt Law Review, 48 (1995): 631–98; and symposium, “The ALI's Proposed Restatement (Third) of Torts: Products Liability,” Tennessee Law Review, 61 (1994): 1043–454.Google Scholar
Charo, , supra note 49; and Charo, R.A., “Brief Overview of Constitutional Issues Raised by the Exclusion of Women from Research Trials,” in Mastroianni, A. Faden, R. Federman, D., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume II (Washington, D.C.: National Academy Press, 1994): 8490.Google Scholar
Charo, , supra note 49; and Charo, , supra note 59.Google Scholar
499 U.S. 187, at 208.Google Scholar
The Supreme Court opined that “[d]ecisions about the welfare of future children must be left to the parents who conceive, bear, support, and raise them rather than to employers who hire those parents.” Id. at 206.Google Scholar
Flannery, E. Greenberg, S.N., “Liability Exposure for Exclusion and Inclusion of Women as Subjects in Clinical Studies,” in Mastroianni, A. Faden, R. Federman, D., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume II (Washington, D.C.: National Academy Press, 1994): 91102.Google Scholar
Merton, , supra note 42.Google Scholar
The exception to this rule is the case of Phase I trials of cancer chemotherapy in which the agent is considered to be potentially therapeutic and subjects have failed to respond to standard therapy or have a malignant disease for which there is no standard therapy. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Implementing Human Research Regulations: Second Biennial Report on the Adequacy and Uniformity of Federal Rules and of Their Implementation for the Protection of Human Subjects (Washington, D.C.: U.S. Government Printing Office, 1983): At 41–43. Further, it has been estimated that, in oncology trials, only 5 percent of patients enrolled experienced a “response.” Estey, E. et al. , “Therapeutic Response in Phase I Trials of Antineoplastic Agents,” Cancer Treatment Report, 70 (1986): 1105–55; and Decoster, G. Stein, G. Holdener, E.E., “Responses and Toxic Deaths in Phase I Clinical Trials,” Annals of Oncology, 2 (1990): 175–81. It is not clear whether even this 5 percent “response” corresponds to any change in clinical course for the patient, however.Google Scholar
Merkatz, R., “Overview,” U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, Nov. 7–8, 1994.Google Scholar
Andrews, E., “Use of Observational Methods to Monitor the Safety of Marketed Medications for Risks of Birth Defects,” U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, Nov. 7–8, 1994.Google Scholar
Zamula, E., Drugs and Pregnancy: Often the Two Don't Mix (Washington, D.C.: Department of Health and Human Services, FDA 90–3174, 1989).Google Scholar
Chaudhuri, G., “Pharmacokinetics in Pregnancy,” U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, Nov. 7–8, 1994.Google Scholar
Common examples of drugs whose dosing must be changed during pregnancy include antibiotics, anticonvulsants, and antihypertensives. Id.Google Scholar
Merton, , supra note 42.Google Scholar
U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control “Guidelines for Prophylaxis Against Pneumocystis Carinii Pneumonia for Persons Infected with Human Immunodeficiency Virus,” MMWR, Recommendations and Reports, S-5 (1989).Google Scholar
U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, “USPHS/IDSA Guidelines for Prevention of Opportunistic Infections in Persons with Human Immunodeficiency Virus: A Summary,” MMWR, Recommendations and Reports, 44, no. RR-08 (1995): 134.Google Scholar
Advisory Committee on Human Radiation Experiments, “Subject Interview Study,” in Final Report of the Advisory Committee on Human Radiation Experiments (Washington, D.C.: U.S. Government Printing Office, No. 061-000-00-848-9, 1995): 724–57.Google Scholar