Women and Health Research Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1 (1994) / Chapter Skim
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7 Risks to Reproduction and offspring
7 Risks to Reproduction and offspring
Pages 175-202
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From page 175... ...
These risks give added importance to informed consent and contraceptive options. Risk assessment for reproductive and developmental toxicity is complicated by the high background rates of infertility and birth defects, as well as the difficulty of identifying the specific effects of the drug under investigation.
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From page 176... ...
Nevertheless, concerns about reproductive and developmental toxicity do not override the need to improve the medical management of these populations. Our understanding of treatment options for all of these groups will only be advanced by their inclusion in clinical studies and by more systematic collection of empirical data on reproductive and developmental outcomes.
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From page 177... ...
Hazard Characterization If a drug represents a potential hazard for reproduction or development, it is necessary to determine the dose-response relationship, site of action, and mechanisms through which the adverse effects are produced. Some drugs that appear to be reproductive or developmental toxicants in animals may not produce adverse effects in humans during a clinical trial.
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From page 178... ...
The risk characterization should also include the assessment of the background incidence of adverse reproductive or developmental outcomes. Challenges to Identification of Reproductive and Developmental Toxicants In order to isolate and evaluate observed drug effects, it is also necessary to consider the background incidence of adverse reproductive or developmental outcomes.
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From page 179... ...
Listed in Table 7-1 are some adverse reproductive and developmental outcomes of interest, the background rate of these adverse outcomes, and the sample size needed to determine a doubling of that outcome in a clinical trial. Male-Mediated Developmental Toxicity Although traditional concerns about developmental toxicity have focused on exposures (or treatment)
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From page 180... ...
+ live births Children to age 15 0.4 3,300 Men 230 Couples 286 Live births 174 Pregnancies 25 Miscarriages 1,068 Late fetal deaths + live births 1,068 Live births 5,533 Live births 66,936 Late fetal deaths + live births 8,324 Children to age 15 aWhere a range is given, the background rate used in the determination of sample size is shown in parentheses. bThe sample size indicated is the size required of each population (i.e., both the study population and the control population will need to be at least as large as the sample size indicated)
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From page 181... ...
Although evidence is inconclusive concerning the role of the male in developmental toxicity, the possibility that he has a role provides reason enough for investigators to consider including discussion of developmental toxicity in the informed consent process for male subjects who may be exposed to developmental toxicants in the course of a clinical study. As discussed below, the provision of advice about contraceptive options may also be wise.
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From page 182... ...
As discussed in earlier chapters, federal policies and practices designed to protect women of reproductive potential from risks associated with experimental treatment have hindered the collection of information about drug effects in this subpopulation. Investigators designing clinical studies need to be particularly concerned about the potential reproductive and developmental toxicity of the compounds they wish to study in this population.
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From page 183... ...
RISKS TO REPRODUCTION AND OFFSPRING Chemical structure and properties Reproductive or develop- i' mental effects of similar drugs Animal studies of effects on reproduction and development \ 1 / WEIGHT OF EVIDENCE it__ I Reproductive or develop mental effects of similar drugs Develop data on: · Dose-response relationship · Site of toxicity · Mechanism of toxicity 183 Mechanism of therapeutic action Mechanisms of other forms of toxicity No evidence of reproduc tive or developmental toxicity Conservative (average or worst case) risk calculation Inform study subjects t Monitor participants for reproductive and/or developmental toxicity FIGURE 7-1 Considerations in the protection of reproductive and developmental health of research subjects.
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From page 184... ...
For example, data from in vitro testing or structure-activity relationships may provide useful information for counseling subjects in a clinical trial. Recent data using expert systems to explore the relationship between chemical structure and developmental toxicity suggest that a substantial amount of useful information could be extracted from existing developmental toxicity data sets (Takihi et al., in press)
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From page 185... ...
Contraception in Clinical Trials When considering participation in clinical trials of agents with potential reproductive or developmental toxicity, men and women of reproductive age need to be made aware of the contraceptive options available to them as study participants and of what is known about the effectiveness of each method. Table 7-3 lists low and high reported failure rates for the range of contraceptive methods currently available in this country.
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From page 186... ...
186 TABLE 7-3 Methods of Contraception WOMEN AND HEALTH RESEARCH Failure Ratea Category Method Mechanism of Action Low High Nonhormonal No method 85.0 85.0 Spermicide alone Inactivation of sperm 21.6 25.6 Sponge with spermicide Mechanical barrier 16.0 51.9 to sperm; inactivation of sperm Withdrawal 14.7 27.8 Periodic abstinence Avoidance of coitus 13.8 19.2 during presumed fertile days Diaphragm or cervical Mechanical barrier to 12.0 38.9 cap with spermicide sperm; inactivation of sperm Condom Mechanical barrier to sperm 9.8 18.5 Intrauterine device, Inhibition of sperm 2.5 4.5 Copper T-380A migration, fertilization, or ovum transport Hormonal Oral contraceptives Combined 3.8 Suppression of ovulation, changes in cervical mucus and endometrium Changes in cervical mucus and endometrium, possibly suppression of ovulation 8.7 Intrauterine device Inhibition of sperm 2.5 4.5 Progesterone T migration, fertilization, or ovum transport Medroxyprogesterone Changes in cervical mucus
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From page 187... ...
Evaluating Drugs for Use in Lactating Women Investigators must be especially concerned about developmental toxicity when testing drugs in the subset of the population of reproductive age that is composed of lactating women. Exposure to drugs and chemicals can lead to the presence of these agents in their breast milk, creating concern for: (1)
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From page 188... ...
Medications used most commonly during pregnancy include analgesics, antipyretics, antimicrobials, antiemetics, diuretics, cough medications, and psychoactive agents (Quirk, 1986~. Yet despite their frequent need for medical treatment, few clinical trials of new drugs include pregnant women.
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From page 189... ...
Therefore, systematic surveillance for developmental effects is essential to any plan to include pregnant women in clinical trials. Together, both methods will further our understanding of the medical management of the ill pregnant woman.
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From page 190... ...
While surveillance cannot guarantee detection of developmental toxicants, systematic collection of information about pregnancy outcomes in a wide range of situations, complemented with information gained through clinical trials that include pregnant women, provides an important element of protection for pregnant women and their offspring. The committee recommends that a review be undertaken of existing birth defects monitoring programs to critically define what they are capable of doing and suggest improvements and reasonable expectations for their use.
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From page 191... ...
A committee member who is a member of one IRB reports that heated disputes have arisen over how to characterize the level of risk of lumbar punctures in infants or demented elderly patients, insertion of urethral catheters in six-year-old boys, right-heart catheterization in cardiac patients, withdrawing medication from patients with mild-to-moderate hypertension, and withholding antipsychotic medication from patients with severe emotional disorders. Those who agree on the scientific facts concerning the magnitude and probability of side effects will bring different personal values and experiences to the question of whether the risks are acceptable.
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From page 192... ...
For men and women of reproductive age, reproductive issues affect the type of information included in the informed consent process. It will be the IRBs' obligation, as with all research involving presumptively competent adults, to continue to ensure that: (1)
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From page 193... ...
It is the responsibility of investigators and IRBs to assure that the informed consent process include an adequate discussion of risks to reproduction and potential offspring, including, where appropriate, an adequate discussion of relevant considerations of birth control. The committee recommends that the participant be permitted to select voluntarily the contraceptive method of his or her choice where there are no relevant study-dependent, scientific reasons to require
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From page 194... ...
The committee recommends that investigators and IRBs not exclude women who are lactating from participation in clinical studies. It is the responsibility of investigators and IRBs to ensure that the informed consent process includes, wherever appropriate, an advisory to potential participants that there may be special risks to their children if nursing mothers participate.
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From page 195... ...
In this context, "vulnerable" suggests that pregnant women are less autonomous or more easily exploited than other personsan inference that the committee has found no evidence to support. The labeling of pregnant women as a vulnerable population also might be viewed as suggesting that they cannot weigh the risks to a fetus or potential child in deciding whether to enroll in a clinical study; that pregnant women do not care sufficiently about the health or well-being of their future children to make sound decisions; and that the prevention of all potentially harmful outcomes of pregnancy is a goal that warrants governmental, regulatory, or other official intervention into the lives and free choices of women.
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From page 196... ...
Adequate Information With respect to the obligation to ensure that pregnant women are provided with adequate information about the risks and benefits to their pregnancy and potential offspring, the committee recommends the following strengthened informed consent procedure. The disclosure statement of consent forms for all studies that pose a risk to pregnancy or potential offspring should include, highlighted in bold type, a statement such as: If you are pregnant or contemplating pregnancy, we urge you to consult your obstetrical care provider before deciding about participation in this study.
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From page 197... ...
Paternal Consent It is appropriate for investigators to encourage a potential participant who is pregnant to discuss her participation in clinical studies and risks to potential offspring with the potential baby's father, but the committee rejects any requirement that the consent of the potential baby's father be a condition of the participation of a pregnant woman in research. The committee recognizes that the husbands of pregnant women, as well as future fathers who are not husbands, have an interest in the health of their children and that these men may have a deep emotional attachment toward their offspring prior to birth.
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From page 198... ...
A finding that a risk of significant harm to potential offspring is "known or can be plausibly inferred" may be based on evidence from animal studies, in vitro studies, structure-activity relationship data, or previous clinical experience. Under this standard, IRBs may exclude pregnant women from the earliest phases of many drug trials, but most clinical studies would remain open to pregnant women.
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From page 199... ...
a role for conscience and an individual investigator's moral commitments. It was agreed that, at a minimum, such a mechanism would require that the investigator provide the IRB with a written explanation of his or her concerns of conscience and that the IRB review any such requests in light of a presumption that favors the inclusion of pregnant women in clinical studies.
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From page 200... ...
Although the committee is not indifferent to the risk of harm to even one potential child, the committee felt compelled to consider as primary the interests of all women in being treated justly and with dignity. The committee recommends that OPRR revise and reissue Subpart B of the DHHS regulations for the Protection of Human Subjects, titled "Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In-vitro Fertilization [45 C.F.R.
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From page 201... ...
1989. Prediction of risk for human developmental toxicity: How important are animal studies for hazard identification?
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From page 202... ...
1994. Ethical issues related to the inclusion of women of childbearing potential in clinical trials.
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