On May 10, 2019, FDA published a notice of availability for a final guidance document on Maximal Usage Trials (MUsT studies) for topically applied active ingredients being considered for OTC drug monographs, including sunscreens. As FDA has previously explained, the guidance states that MUsT studies can identify the potential for the systemic exposure for a topically-applied active ingredient. FDA believes that this information is necessary to determine whether additional safety studies are needed to support a finding that the ingredient is generally recognized as safe and effective (GRASE) for its intended use.
FDA’s reliance on MUsT studies has been a subject of controversy with the sunscreens industry. Industry has argued that MUsT studies are unreasonably expensive and sunscreen products have been marketed in the U.S. and around the world for decades without adverse events or data identifying safety concerns related to absorption. To support an OTC drug monograph, FDA has said that a MUsT study should evaluate the ingredient in a range of formulations, which further adds to the cost and time needed for such a study.
FDA: Absorption Is Not Just a Theoretical Concern
However, just a few days before the issuance of the MUsT guidance, on May 6, 2019, FDA released a statement reaffirming the agency’s reliance on MUsT studies for evaluating sunscreens. The FDA statement highlights an FDA-funded study published on the same day in the Journal of the American Medical Association (JAMA), evaluating the absorption of four sunscreen ingredients: avobenzone, oxybenzone, octocrylene, and ecamsule. The FDA statement was intended to emphasize that “that absorption of sunscreens is not just a theoretical concern.” According to the JAMA article, all four ingredients were absorbed such that systemic concentrations greater than 0.5 ng/mL (nanograms per milliliter) were reached after four applications on day 1. FDA’s statement reflects the agency’s position that sunscreen active ingredients absorbed above this threshold “would generally need to undergo further testing to help determine if they increase the risk for cancer, birth defects or other adverse effects.”
Private Meetings in Support of Developing MusT Studies
Highlights of the MUsT guidance include the following:
- FDA encourages MUsT study sponsors to seek FDA’s advice before initiating a MUsT study to support OTC monograph status for a particular ingredient.
- Although the results of MUsT study would ultimately need to be included in the public docket to support inclusion of a particular active ingredient in the OTC drug monograph, FDA is willing to hold private meetings with sponsors to discuss MUsT protocol details that are not yet part of the public record. This would give sponsors the opportunity to privately discuss and receive input from FDA about their preliminary plans to generate MUsT data.
- However, minutes from the private meetings, including a summary of general concepts discussed, would subsequently be submitted to the public docket. But information that sponsors would not routinely publicly disclose, such as chemistry data and detailed protocols, would not be disclosed to the extent that they constitute confidential commercial or trade secret information.
Rulemaking Deferral Requests
The issuance of the guidance follows FDA’s decision published on April 18, 2019, to extend both the comment period on the proposed sunscreens rule and the period to request a rulemaking deferral for certain active ingredients. FDA granted a 30-day extension, until June 27, 2019. The extension is of particular importance for the manufacturers of the 12 sunscreen ingredients that were identified in the proposed rule as requiring additional data and information, in particular relating to absorption, to determine whether the ingredients could be established as GRASE. To provide the absorption data, the proposed rule stated that FDA expects that data from a MUsT study “will be needed to support an adequate assessment of safety for most sunscreen active ingredients.” 84 FR 6204, 6213 (Feb. 26, 2019).
FDA invited requests for the agency to defer rulemaking for certain ingredients, to allow for the submission of the necessary data. But the language of the proposed rule appeared to signal that FDA would not grant such deferrals unless it appeared that the “sum of the data … would be adequate” to provide all the data necessary to establish GRASE. 84 FR 6204 at 6249.
We believe that FDA is not likely to grant a deferral request for a sunscreen ingredient without a commitment to conduct a MUsT study. And additional safety studies are likely to be expected for at least the four ingredients identified in the JAMA article as exceeding FDA’s absorption threshold. However, FDA’s May 6 statement described above adopted a softer tone for sunscreen manufacturers willing to commit to MUsT studies, stating that “we understand that manufacturers may need additional time to generate new data and information” and will consider deferral requests for this purpose.
In a previous post, we explained that FDA is facing a statutory deadline to finalize the sunscreens monograph by November 26, 2019. Now that FDA has granted an extension for comments, it will be even more difficult for FDA to meet with this deadline. It is possible that FDA will miss the deadline and take its chances on being sued. But it is also possible that FDA will grant deferrals for any of the 12 ingredients for which there is a credible commitment to conduct the necessary MUsT and related studies. The studies could be conducted over an extended period of time, which would allow for continued marketing during the interim period, as long as FDA continues to renew the deferrals. Taking a generous approach to deferrals could ease the path for FDA to finalize the remainder of the rule in accordance with the statutory deadline.