By Riëtte van Laack –
In 2002, FDA issued regulations providing for a process, the Time and Extent Application (TEA), to create a new Over-the-Counter (OTC) drug monograph or amend an existing monograph to recognize that an active ingredient or condition (e.g., dosage form) is Generally Recognized as Safe and Effective (GRASE). The TEA review is a two-step process: first, the drug must be determined eligible, in which case FDA will publish a notice of eligibility (NOE); and, second, the drug must be determined GRASE.
The Sunscreen Innovation Act (SIA), enacted in 2014 (see our previous post here), amended the FDC Act to provide specific deadlines for FDA’s review of TEAs for sunscreen active ingredients. Among other things, the SIA sets deadlines for FDA’s determination of eligibility, review of safety and efficacy data, publication of a proposed order, and publication of a final order. The SIA applies to sunscreen TEAs that were pending before its enactment and to new sunscreen TEAs. (The SIA also applies to non-sunscreen ingredients with separate but similar procedures).
The SIA also required that FDA, within one year of the enactment of the SIA, publish draft guidance on the implementation of, and compliance with, the requirements of the SIA with respect to sunscreens. A few days before this one-year deadline, FDA issued the required draft guidance, in the form of four draft guidance documents on:
- format of submissions by the sponsor to support GRASE status;
- withdrawal of a sunscreen TEA;
- requesting an advisory committee review; and
- safety and effectiveness data to determine whether a sunscreen active ingredient is GRASE.
In light of FDA’s determination that all pending sunscreen TEAs were lacking sufficient information to determine that the active ingredients are GRASE, the draft guidance on required data to support GRASE status of the sunscreen ingredient undoubtedly will get the most attention. Nevertheless, the other draft guidance’s should not be ignored as they provide information relevant to pending as well as new TEAs as well.
For example, FDA’s draft guidance on content and format of the sponsor’s submission in support of the GRASE status of the sunscreen active ingredient reminds sponsors that they “should not submit . . . evidence of safety and efficacy that the sponsor has marked as confidential.” Not surprisingly, the data to support a GRASE determination must be publicly available.
The draft guidance on withdrawal of sunscreen TEAs describes the consequences of withdrawal at various stages in the SIA process. Notably, FDA intends to consider a sunscreen TEA withdrawn if a sponsor fails to respond within 90 days for a request for data or update by FDA. Although, FDA generally will stop the review process upon receipt of a request for withdrawal, the request for withdrawal may not affect the process if the withdrawal occurs after a proposed order has been published. In that case, FDA may proceed and issue a final order.
The draft guidance on requesting advisory committee review clarifies what conditions, according to FDA, may merit an advisory committee review and the process that FDA will use when it determines an advisory committee meeting is warranted. The SIA limits the number of advisory committee meetings FDA must convene per sunscreen TEA and per year. The combination of FDA’s limits on what conditions merit a committee review, the costs of organizing an advisory committee meeting and FDA’s limited resources, suggests that the likelihood of FDA's granting an advisory meeting request is low.
Safety and effectiveness data for GRASE sunscreens
As mentioned above, what data are required to support a determination that a sunscreen active ingredient is GRASE has been an issue of discussion. In 2014, FDA held a 2-day meeting of the Nonprescription Drugs Advisory Committee to discuss the data requirement. Thus far, FDA has determined that the data for the eight pre-SIA sunscreen TEAs were insufficient to support that any of these ingredients are GRASE.
FDA's draft guidance describes the various studies that may be needed. According to FDA, “the proposed studies are not novel and are consistent with [FDA’s] standard data requirements for approved topical drug products for chronic use.”
Safety issues that FDA wants addressed include: dermal tests to determine irritation, rashes, reaction to exposure to the sun (photo safety studies), available adverse event data, and absorption through the skin (maximal usage trial). If the ingredient is absorbed, additional data (in animals) regarding carcinogenicity, reproductive harm, and possible endocrine effects due to systemic exposure (in addition to dermal exposure studies) may be required. Whether pediatric studies are required will depend on the characteristic of the ingredient.
Efficacy testing on the ingredient should be done in accordance with the procedures described in FDA’s regulation for SPF testing of monograph products, 21 C.F.R. 201.327(i).
One novel issue is FDA’s discussion on possible requirement for final formulation testing. Apparently, “FDA has not yet determined whether final formulation testing as described in [its draft guidance]” will be required. FDA “is particularly interested in . . . a scientifically persuasive rationale as to why” such testing would not be necessary or alternative approaches to the one described in the draft guidance.
FDA opened separate dockets for the four draft guidances. Comments must be submitted by January 22, 2016.