A new draft guidance document issued by the US Food and Drug Administration (FDA) calls on sponsors of estrogenic, androgenic or thyroid activity drugs to interact with regulators early on in the review process to help assess the potential impact of their drugs on aquatic wildlife.

Background

FDA's requirements to conduct environmental testing are the result of the National Environmental Policy Act (NEPA) of 1969. The law required federal agencies to determine the environmental impact of their actions. For FDA, those actions include the approval of new pharmaceutical and biotechnology products.

To comply with the law, FDA requires most pharmaceutical and biotechnology companies to submit what are known as Environmental Assessments (EAs) to FDA when submitting a new drug for approval per 21 CFR 25.40.

The assessments are meant to show how a drug might affect the environment. Many drugs enter the environment as sewage after being excreted by patients. FDA has explained in the past that it's particularly concerned with how drug substances behave once they enter "into the aquatic environment" (i.e. the water supply), whether they can be filtered out by water treatment facilities, and how those drug substances might cause harm to the environment or any wildlife.

The need for environmental assessments is taken seriously by FDA. A company's failure to submit an EA along with a New Drug Application (NDA), Biologic Licensing Application (BLA), Abbreviated New Drug Application (ANDA) or Investigational New Drug Application (IND) can result in a submission being rejected by FDA.

Exclusionary Criteria

But not all drug products are required to be accompanied by an EA. As FDA explains in a new draft guidance document, Environmental Assessment: Questions and Answers Regarding Drugs With Estrogenic, Androgenic, or Thyroid Activity, 21 CFR 25.30-34 contains a list of "categorical exclusions" which, if met, exempt a company from needing to conduct an EA.

For example, under 21 CFR 25.31, a human drug product would be exempt from conducting an EA if it:

• "does not increase the use of the active moiety"
• would only introduce 1 part per billion (PPB) of the active moiety into the aquatic environment
• introduces a substance into the environment which already occurs there naturally

FDA's guidance focuses on the second of these three exclusion criteria:

"Action on an NDA, abbreviated application, or a supplement to such applications, or action on an OTC monograph, if the action increases the use of the active moiety, but the estimated concentration of the substance at the point of entry into the aquatic environment will be below 1 part per billion." – 21 CFR 25.31(b)

FDA notes that while most drugs which meet this exclusion criteria won't have to submit an EA, the agency reserves the right to compel some companies to do so "if extraordinary circumstances indicate that the specific proposed action may significantly affect the quality of the human environment." (21 CFR 25.21) For example, some drugs might significantly harm the environment, even at extremely small levels of exposure.

"If FDA needs more information to determine whether extraordinary circumstances exist, FDA may ask the sponsor to submit additional information concerning the potential environmental effects of approval of the sponsor’s application or supplement," FDA explained.

The Special Case of Hormone Drugs

This "extraordinary circumstances" caveat to the categorical exclusion category is especially applicable to drugs with estrogenic, androgenic or thyroid activity, FDA said in its guidance.

"In light of research indicating that drugs with endocrine-related activity and, more specifically, drugs with estrogenic, androgenic or thyroid activity, have the potential to cause developmental or reproductive effects in the aquatic environment at concentrations below 1 ppb, FDA has, on a case-by-case basis, requested additional information from sponsors to help it determine whether extraordinary circumstances exist," the regulator wrote.

Variousresearch has shown that even low levels of estrogen can potentially decimate aquatic wildlife populations.

Accordingly, the guidance recommends all sponsors of drugs with estrogenic, androgenic or thyroid activity "consult with the Agency early in product development" to determine whether an EA will be required for the application.

FDA says the guidance applies both to drugs that are "based on these hormones" anddrugs that "have the potential to interact with" estrogenic, androgenic or thyroid activity drugs.

Comments on the guidance will be accepted for the next 60 days.

Environmental Assessment: Questions and Answers Regarding Drugs With Estrogenic, Androgenic, or Thyroid Activity (FR)