FDA’s MUsT Draft Guidance Extends Challenge To Wider OTC Drug Industry

It’s known that challenges posed by FDA-advised maximal usage trials have been the bane of OTC sunscreen and antimicrobial drug ingredient sponsors of late, but new draft guidance from the agency signals that MUsTs will be expected generally from companies looking to add topical ingredients to OTC drug monographs.

Newly released draft guidance from FDA underscores the agency’s increasing reliance on maximal usage trials (MUsTs) to support topical ingredients’ inclusion in OTC drug monographs.

The document could have more companies contemplating new drug approval pathways as an alternative to generally recognized as safe and effective (GRASE) review, a process in which stakeholder confidence has eroded significantly since its implementation in the early 1970s.

For companies committed to adding ingredients to OTC monographs, the guidance makes clear that FDA consultation regarding planned MUsTs is an option that firms should exercise to avoid unpleasant surprises.

“The MUsT paradigm is now a recommended assessment for topical drug products developed under an NDA,” FDA says.

Slated for publication in the Federal Register May 23, the draft guidance – “Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an Over-The-Counter Monograph” – details FDA’s expectations for studies exploring ingredients’ absorption potential to inform systemic exposure and overall safety and efficacy conclusions.

MUsT discussions have arisen most conspicuously of late in the context of firms’ frustrated efforts to add next-generation UV filters to the OTC sunscreen drug monograph.

FDA may be doing its own sunscreen MUsT behind the scenes to gain insight into the undertaking first-hand.  (Also see "FDA To Try Its Hand At Sunscreen Absorption Study, A MUsT For TEA Sponsors" - HBW Insight, 16 Mar, 2018.)

The agency also has requested MUsTs from antimicrobial ingredient sponsors seeking GRASE findings for substances that remain viable for monograph inclusion, following FDA rules in recent years that eliminated numerous ingredients from GRASE contention across germ-killing product categories due to lack of supporting data.  (Also see "More GRASE Time For 6 OTC Antiseptic Ingredients But 24 Flushed In Final Rule" - HBW Insight, 16 Feb, 2018.)

Industry generally maintains that MUsTs have a limited history of use, providing scant visibility into how studies should be designed and what FDA’s response to them will be. Such questions have weighed on companies’ MUsT investment considerations.  (Also see "FDA’s ‘Exploratory’ MUsT Won't Affect OTC Sunscreen Rulemaking Schedule" - HBW Insight, 29 Mar, 2018.)

FDA’s new guidance doesn’t so much dispel these concerns as provide insight into FDA’s growing insistence on MUsTs as part of the systemic safety evaluation for topical drug products.

“Historically, topical treatments were commonly believed not to result in clinically relevant systemic drug absorption,” the agency explains. “Even when the potential for systemic absorption of topically applied OTC products was recognized, the in vivo bioavailability of such products could not always be measured because of limitations in analytical methods.”

Scientific advances have driven corresponding refinements to FDA’s drug testing requirements. The agency highlights a pair of previous draft guidances – regarding acne and head-lice treatments, published in 2005 and 2015, respectively – that included discussion of MUsTs.

“The MUsT paradigm is now a recommended assessment for topical drug products developed under an NDA,” it says.

FDA also furnished a relatively condensed set of MUsT principles, compared with the new, broader guidance, in its November 2016 recommendations for safety and effectiveness data needed to support nonprescription sunscreen drug products.  (Also see "FDA's Sunscreen Data Guidance Lacks Risk/Benefit Balance – Stakeholders" - HBW Insight, 24 Feb, 2016.)

In its exchanges with sunscreen ingredient sponsors, the agency has made no bones about the fact that GRASE can be a higher bar to clear than new drug approval.

FDA’s MUsT guidance reflects this reality. “An NDA review focuses on the safety and effectiveness of a single drug product, i.e., a specified formulation of active and inactive ingredients, while the review to establish an OTC monograph necessitates determining the conditions under which any of multiple drug products would be recognized as [GRASE].”

Further, the agency notes that inactive ingredients in a finished drug product can bear on active ingredients’ absorption.

For these reasons, MUsTs conducted for the purposes of listing active ingredients in OTC monographs should evaluate those ingredients in a range of formulations, including formulations designed for optimal absorption, in accordance with use instructions on existing or anticipated labeling, FDA says.

The agency intends to leverage data derived from MUsT sponsors’ blood sample analysis, together with relevant animal study data, to estimate margins of safety for systemic exposure to active ingredients within OTC monograph categories and set conditions for GRASE use.

Pilot Study Recommended To Inform MUsT Design

The guidance delves into specific MUsT study elements and considerations, many of which are intuitive if short on concrete specifics, given the need to adapt trials to product types and usage particulars.

For example, the amount of test article applied to MUsT subjects, and the amount of surface area treated, should be consistent with intended monograph directions for use, FDA says.

When it comes to number of subjects, FDA notes that sample sizes in MUsTs likely will exceed those in pharmacokinetic studies performed to support approval of single drug formulations, again due to the diversity of formulations in which a monographed active ingredient can be used.

According to the agency, sponsors should consider conducting pilot studies first to determine an appropriate sample size if information is not available – “such as the expected intersubject and intrasubject variability” – to dictate this decision.

Pilot studies should selectively focus on a formulation with the greatest potential for absorption – for example, one containing known permeation enhancers, it says.

“A pilot study can also be used to validate the analytical methodology, assess the PK variability, evaluate the time intervals for sample collection, and provide other information that can inform the design of the MUsT,” FDA says, adding, “While useful in optimizing the study design of a MUsT, a pilot PK study is unlikely to provide sufficient data to substitute for a full-scale MUsT.”

FDA notes that additional MUsT studies may be needed to assure the safety of pediatric populations owing to differences in the skin of young children compared with adults and their larger ratio of skin surface-to-body volume.

Consistent with previous communications on the subject, FDA advises MUsT sponsors to test at least four “market image” formulations, guided by information obtained via in vitro skin permeation testing.

“Justification for the formulations chosen, including results of the in vitro testing, should be included in the MUsT protocol,” the agency states.

Generally, FDA urges companies to err on the side of testing formulations expected to yield the highest absorption levels.

FDA notes that additional MUsT studies may be needed to assure the safety of pediatric populations owing to differences in the skin of young children compared with adults and their larger ratio of skin surface-to-body volume.

“If the calculated safety margin for a proposed monograph active ingredient (based on nonclinical results and human MUsT) is relatively small for an adult population, the FDA will determine if an additional MUsT in young children or other studies are warranted for any specific pediatric age range,” the agency says.

FDA concludes by urging companies to meet with the agency in advance of initiating MUsTs to discuss their specific ingredients and indications, among other factors. It also provides some assurance that confidential business information will be protected in private meetings leading up to a MUsT, a concern that’s been cited before by industry.

Companies that are put off by FDA’s MUsT guidelines in the context of OTC monograph proposals – or the unpredictability of the GRASE review process in general – have the option of pursuing an NDA, though many firms tend to balk at the costs.

Further, legislation is advancing in Congress to reform the OTC monograph system, aimed at speeding the review process and potentially providing exclusivity periods for approved products under certain conditions, including sponsors’ investment in clinical studies.  (Also see "OTC Monograph Legislation Clears Another Hurdle Despite Exclusivity Concerns" - HBW Insight, 11 May, 2018.)