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FDA GENDER GUIDELINES: FETAL EXPOSURE JUSTIFICATION COULD REDUCE LIABILITY

Executive Summary

FDA GENDER GUIDELINES: FETAL EXPOSURE JUSTIFICATION COULD REDUCE LIABILITY concerns by describing conditions in which therapeutic benefit might outweigh risk to fetus, the Pharmaceutical Manufacturers Association said in Nov. 19 comments on FDA's "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs." PMA maintained: "No matter how well a woman understands the risks, legal liability either as a result of inadvertent fetal exposure or possibly from an undetected long-term adverse effect on a future pregnancy, remains a very substantial concern. These concerns would be lessened if the guideline stated explicitly the circumstances in which FDA considered potential fetal exposure, justified." FDA acknowledged the potential for increased liability to pharmaceutical manufacturers adhering to the new guidelines in a July New England Journal of Medicine article co-authored by FDA Special Assistant to the Commissioner on Women's Health Issues Ruth Merkatz, MD, and Commissioner Kessler ("The Pink Sheet" July 26, T&G-4). The guidelines, published in the July 22 Federal Register, lift FDA's long-standing ban on the inclusion of women of childbearing potential in early clinical trials, encourage increased enrollment of women in all studies, and request studies on the pharmacokinetic effects of gender differences and gender- based analyses of data. In Nov. 12 comments, Merck said that "including women of childbearing potential in earlier clinical trials [does not] increase product liability in and of itself," but the "wording in the guidelines, as proposed, we feel does increase sponsor liability unnecessarily." Merck recommended that FDA could reduce liability concerns by altering the wording of several sections of the guidelines. The company advised the agency to replace a reference to "adequate counseling" of women on the importance of preventing pregnancy during clinical trials with a cautionary statement to the effect that "it should be understood that careful attention by the subject/patient must be placed on contraception use, as well as pregnancy testing by the sponsor during the clinical trial in women of childbearing potential enrolled in early clinical trials." Another change recommended by Merck would be the removal of the statement that "appropriate precautions" should be taken in clinical studies to guard against fetal exposure to potentially toxic agents, and, instead of a more general statement, the insertion that "the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable." With regard to pharmacokinetics, Merck emphasized that few PK effects translate into pharmacodynamic differences. Therefore, the firm suggested that qualifying statements be included in the guidelines to the effect that "the need and timing of investigation for gender-related differences be decided in the context of the clinical program and what is known about the drug, rather than simply trying to document pharmacokinetic differences which have limited clinical meaning." Both Merck and PMA expressed concerns about FDA's recommendation that, in addition to conjugated estrogens and oral contraceptives, sponsors consider the influence of menstrual status on a drug's pharmacokinetics. "With no available evidence of changes in drug pharmacokinetics/pharmacodynamics over the menstrual cycle, and the influence of menstrual status on disease states being poorly understood, there seems to be little justification for giving this issue the same emphasis as other drug/hormone interactions during drug development." Bristol-Myers Squibb maintained in Nov. 12 comments that animal reproductive toxicity studies should not be required to be completed before Phase II testing as stated in the guidelines. The company proposed that completion of reproductive toxicity studies should be required by the start of Phase III, arguing that sponsors may not choose to start or complete those studies until after a Phase II decision and that for some patients with life- threatening diseases, "a benefit-to-risk assessment might support enrolling [women of childbearing potential] prior to the completion of any animal reproductive toxicity studies." BMS also suggested that FDA amend the statement "Long-term follow-up will usually be needed to evaluate the effects of [reproductively toxic] drugs in humans" to state that long-term follow-up "'may be needed' to allow for greater flexibility in making this decision on a drug-by-drug basis." The manufacturers and PMA projected the effect of the guidelines on the costs of drug development. "The need for larger trials, additional pharmacokinetic studies, conduct of animal studies earlier, and conduct of animal studies in drugs that ultimately are not developed, all contribute to higher drug development costs at a time when Congress and the current Administration are searching for cost containment and reduction in healthcare spending," PMA contended.
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