Comments to FDA on Draft “Endocrine Disruption Potential of Drugs: Nonclinical Evaluation.”

Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852


Re: Draft guidance for industry entitled
“Endocrine Disruption Potential of Drugs: Nonclinical Evaluation.”
Docket ID: FDA-2013-D-1039


We welcome the opportunity to comment on the FDA’s guidance to industry on preclinical detection of endocrine disruption potential in drug and biologics applications.

There is increasing awareness in the medical community that the human endocrine system is very vulnerable to disruption, whether from pharmaceutical or other environmental sources.  In 2009, the American Medical Association adopted the recommendations of The Endocrine Society, calling for increased action on this issue by FDA.1

Between 1982 and 1995, infertility rates almost doubled in American women ages 18-25,2 and in 2002 alone, Americans spent 2.9 billion dollars on fertility treatments.3  While these are complex medical issues likely stemming from multiple factors, it is clear that FDA could be doing more to address this public health concern.

Several well-documented pharmacological features of endocrine disruptors are disregarded in FDA’s proposed preclinical study guidelines.  These policies would unfortunately set the stage for unintended endocrine-disrupting function to be obfuscated in preclinical studies, with potentially disastrous consequences.

Our specific areas of concern include:

  1. Many studies have shown that endocrine disruptors display non-traditional, non-monotonic dose-response curves in toxicology studies, consistent with historical work in hormone receptor biology.4 This issue has been clearly described by the Director of the National Institute of Environmental Health Sciences, Dr. Linda Birnbaum, who is a leading expert on this issue.5  The FDA’s draft guidance ignores this issue, citing only the need for toxicology studies over “a wide range of doses,” when the weight of evidence clearly indicates that higher doses would be expected to have different, if not opposite effects, when compared to lower doses.   The weight of evidence strongly challenges the FDA’s statement that “endocrine activities that only occur in animals at exposures substantially above the human exposure usually do not warrant additional investigation. Additional assessment likely would be appropriate for endocrine-active drugs for which human exposure is comparable to or exceeds the exposure level at which activity on endocrine-sensitive tissues is observed in standard nonclinical studies.” Toxicology studies must be done at the doses that humans are likely to experience in order to be acceptable.
  2. The use of inappropriate laboratory animal strains and uncontrolled experimental design is a notorious problem in toxicology studies of endocrine disruptors.  Several studies have demonstrated that certain rodent strains do not respond to endocrine disrupting chemicals, likely due to inherent genetic differences.6  Without rationally chosen animal models combined with relevant positive controls, these studies are useless and do not meet the basic requirements of responsible science.  Standardization of animal models and positive controls in these studies would do much to improve scientific quality, and would also prevent the waste of resources which comes from performing studies only to repeat them due to inconclusive findings.
  3. Many scientific studies have shown that endocrine disrupting agents exert their strongest effects during developmental windows when delicate hormone balance is required for biological events to properly occur, such as during prepregnancy (i.e. before and including the time when pregnancy is possible for all women of reproductive age),  prenatal and prepubescent stages.6   FDA is aware of this fact, stating that “Some developmental stages (e.g., gestational, neonatal, peripubertal) are particularly sensitive to endocrine disruption effects” while at the same time acknowledging insufficiency in their guidance on this issue.   For example, FDA states that “Standard developmental and reproductive toxicity (DART) studies generally capture gestational developmental time points effectively, but might not be adequate for evaluation of effects on postnatal development unless the neonates are dosed directly during the lactation period.”   And yet, in this guidance, such studies are inappropriately left to the discretion of the sponsor, rather than required by the FDA.  The FDA needs to take a stronger stand regarding the need for these studies, since otherwise such studies may never be conducted.  Direct dosing during these developmental stages could be included in preclinical studies without requiring the initiation of new studies with additional animals, while generating critical information about endocrine disrupting function when it would be most obvious.
  4. “Inactive” ingredients and delivery agents, such as enteric coating, in pharmaceuticals have been shown to possess endocrine disrupting function.7 Toxicology studies must be conducted using the same formulation intended for human use in order to be relevant.  Similarly, the route of exposure, such as through vaginal delivery, can significantly alter the dose-response behavior of hormonally active agents.8  Drug administration in preclinical studies must mirror the route of administration intended for human use.
  5. Gross anatomical assays described here, such as preputial separation and anogenital distance, may not be as sensitive or quantitative as direct measurement of hormones levels, which are mentioned only as a suggested alternative or addition to these standard tests.  As such assays are not laborious or expensive and could be performed simultaneously with preclinical studies already being done, why should they be held in reserve for only special cases?  Similarly, FDA acknowledges that other animal models, such as castration studies, are more sensitive than standard ones.  What is the scientific rationale for not performing the most sensitive assays available?  Logic suggests that starting with the most sensitive assays, rather than the least, to detect endocrine disrupting function is the most judicious use of resources, and most likely to ensure that critical safety information is not overlooked.

We strongly urge that the FDA modify the guidance to better reflect the concerns above as well as the scientific issues that have been raised by a sister PHS agency, NIEHS.  We also urge the FDA to make it clear to sponsors that these important preclinical studies are not mere theoretical suggestion, but are essential for approval.


The National Research Center for Women & Families

For more information, contact Anna Mazzucco at (202) 223-4000 or


  1. Press Release of The Endocrine Society, November 10, 2009.  
  2. Chandra, et al., Impaired Fecundity in the United States: 1982-1995. Family Planning Perspectives. 1998; 30(1): 34-42.  
  3. Vallombrosa Consensus Statement on Environmental Contaminants and Human Fertility Compromise. Bolinas: The Collaborative on Health and the Environment. 2005  
  4. Schug, et al., Endocrine disrupting chemicals and disease susceptibility. Journal of Steroid Biochemistry & Molecular Biology. 2011. 127: 204– 215.  
  5. Statement of Linda Birnbaum, Ph.D., D.A.B.T., A.T.S. before the Subcommittee on Energy and Environment, Committee on Energy and Commerce, United States House of Representatives. February 25, 2010.  
  6. Stokes, et al., Selecting Appropriate Animal Models and Experimental Designs for Endocrine id=”__mceDel”>Disruptor Research and Testing Studies. Institute for Laboratory Animal Research. 2004; 45(4): 387-393.  
  7. Kelly, et al., Identification of Phthalates in Medications and Dietary Supplement Formulations in the United States and Canada. Environ Health Perspect. 2012; 120(3): 379–384.  
  8. Alexander, et al., Why Consider Vaginal Drug Administration? Fertility and Sterility. 2004. 82(1): 1-12.