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

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): 1–39; 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.

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.

Cotton D.J. , 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.

Cotton D.J. , “Guidelines for the Design and Conduct of AIDS Clinical Trials,” Clinical Infectious Diseases, 16 (1993): 816–22.

Levine C. , “Women and HIV/AIDS Research: The Barriers to Equity,” IRB: A Review of Human Subjects Research, 13, no. 1–2 (1991): 18–22; 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.

Levine C. , “Ethical Issues,” in Kurth A. , ed., Until the Cure Caring for Women with HIV (New Haven: Yale University Press, 1993): 105–24.

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.

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): 84–90; and Bush J.K. , “The Industry Perspective on the Inclusion of Women in Clinical Trials,” Academic Medicine, 69 (1994): 708–15.

Cotton , supra note 3.

Caschetta M.B. Chavkin W. McGovern T. , correspondence, “FDA Policy on Women in Drug Trials,” N. Engl. J. Med., 329 (1993): 1815.

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.

Cotton , supra note 3.

Greg Folkers, Office of Communication, National Institute of Allergy and Infectious Diseases, National Institutes of Health, personal communication, July 21, 1995.

At most academic institutions, any research conducted by affiliated faculty, regardless of the source of funding, must follow the DHHS regulations.

21 C.F.R. §§ 50, 56 (1991); 21 C.F.R. § 312 (1987); and 21 C.F.R. §314(1985).

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)).

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).

21 C.F.R. § 312.80 (1987).

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)).

21 C.F.R. § 314.510 (1985).

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)).

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).

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).

Id. at 11.

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).

Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs; Notice, 58 Fed. Reg. 39,406 (1993).

Id. at 39,408.

Id. at 39,409.

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): 72–73.

Sibai B.M. , 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.

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.

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): 52–57.

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).

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.

Levine , supra note 34.

Also referred to as the Common Rule.

45 C.F.R. § 46.102(I) (1978).

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).

45 C.F.R. § 46.206 (1987).

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.

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.

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): 369–451.

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): 1–3.

Id. at 1.

Id. at 2.

59 Fed. Reg. 14,508 (1994).

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).

59 Fed. Reg. 14,508, 14,510 (1994).

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.

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.

Wetherill v. University of Chicago, 565 F. Supp. 1553 (N.D. Ill. 1983).

Mastroianni Faden Federman , supra note 40.

Mink v. University of Chicago, 460 F. Supp. 713, 718 (N.D. Ill. 1978).

Roberts v. Patel, 620 F. Supp. 323, 325 (N.D. Ill. 1985).

Grodin v. Grodin, 301 N.W.2d 869 (Mich. Ct. App. 1980); and Bonte v. Bonte, 616 A.2d 464 (N.H. 1992).

Stallman v. Youngquist, 531 N.E.2d 355 (Ill. 1988).

International Union, UAW v. Johnson Controls, 499 U.S. 187, 208 (1991); and 620 F. Supp. 323, at 326.

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.

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): 84–90.

Charo , supra note 49; and Charo , supra note 59.

499 U.S. 187, at 208.

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.

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): 91–102.

Merton , supra note 42.

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. , “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.

Merkatz R. , “Overview,” U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, Nov. 7–8, 1994.

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.

Zamula E. , Drugs and Pregnancy: Often the Two Don't Mix (Washington, D.C.: Department of Health and Human Services, FDA 90–3174, 1989).

Chaudhuri G. , “Pharmacokinetics in Pregnancy,” U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, Nov. 7–8, 1994.

Common examples of drugs whose dosing must be changed during pregnancy include antibiotics, anticonvulsants, and antihypertensives. Id.

Merton , supra note 42.

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).

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): 1–34.

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.