FDA releases new draft guidances on topical generic drugs

The US Food and Drug Administration (FDA) recently released several new draft guidances concerning topical generic drug products submitted under abbreviated new drug applications (ANDAs).

FDA’s recent draft guidances for industry on topical generic drugs include a guidance containing recommendations on in vivo bioequivalence studies for topical corticosteroids, a guidance for physicochemical and structural characterizations of topical drug products in ANDAs, a guidance with in vitro release test (IVRT) study recommendations for topical drug products in ANDA and a guidance on in vitro permeation test (IVPT) study recommendations for topical generic drugs.

Topical dermatologic corticosteroids

The agency’s draft guidance on topical dermatologic corticosteroids focuses on recommendations on in vivo bioequivalence studies for ANDAs and is meant to replace the existing guidance on this topic with the same name that was originally issued in June 1995, as the agency’s recommendations have since evolved. The goal of revising the guidance is to “provide clarity for potential ANDA applicants on the appropriate pilot and pivotal studies and other recommendations for pharmacodynamic approach to assess the bioequivalence of topical dermatologic corticosteroids,” FDA said.

The draft guidance makes recommendations about applicants launching a pilot dose-duration vasoconstrictor response study using the reference standard and pivotal vasoconstrictor bioequivalence study comparing the test topical drug with the reference standard to established bioequivalence. It discusses the study design, method qualification, data analysis and data reporting for each of these studies. Also included in the new draft guidance are descriptions of how applicants of ANDA topical corticosteroids can estimate study parameters and sample size in pivotal vasoconstrictor bioequivalence studies.

FDA said prospective applicants should submit a controlled correspondence to discuss issues or questions concerning ANDA complex products or to propose alterative bioequivalence approaches with the agency. “An applicant must submit with their ANDA a complete study report for the bioequivalence study upon which the ANDA relies for approval,” they said.

Guidance

Topical drug product Q3 characterization

FDA’s draft guidance on topical drug product physicochemical and structural (Q3) characterizations, developed as a part of the agency’s Drug Competition Action Plan, contains recommendations on how to identify a proposed ANDA topical product dosage and describe the product’s potentially relevant properties as they relate to performance and support of bioequivalence (BE)—but not product quality control.

“When comparing the Q3 attributes of two topical products (e.g., to support a demonstration of BE), we generally advise that applicants conduct a comparative Q3 characterization of their proposed generic product against the reference standard, which ordinarily is the reference listed drug (RLD),” the agency said.

The Q3 characterization includes “a detailed profile of Q3 attributes that specifically describes the nature of that product” while also describing the arrangement of matter in the product that could impact systemic or local availability of any active ingredients contained in the product. The reference standard (RS) is used to compare the Q3 attributes and identify potential risks of the Q3 attributes in the test product.

“This guidance describes the concepts of sameness, similarity, or difference in Q3 attributes of topical products and describes specific product characterizations that can be used to demonstrate the sameness, similarity, or difference in Q3 attributes between test topical products and reference standards for topical products,” FDA wrote. “These concepts (and relevant product characterizations) can apply to a drug product that is a solution for application to the skin (e.g., characterization of physicochemical properties like pH), and are particularly useful when comparing test topical products and reference standards for topical semisolid products.”

Guidance

IVRT studies for topical drug products

FDA’s draft guidance on in vitro release Test (IVRT) studies for ANDA topical drug products, also developed through the agency’s Drug Competition Action Plan, outlines recommendations for conducting IVRT studies to compare test topical products with the reference list drug (RLD) to show BE.

“An IVRT study may be used to assess the rate of drug release (i.e., release of an active ingredient) from a topical product. Once validated, an IVRT study may also be useful in controlling product quality and/or establishing the acceptability of post-approval manufacturing changes,” FDA wrote.

The agency’s draft guidance outlines the method parameters, receptor solutions and membranes during IVRT method development. It also describes considerations for equipment qualification, membrane qualification, receptor solution qualification and sampling qualification for receptor solutions, environmental control, linearity and range, precision and reproducibility, dose depletion and robustness in IVRT method validation as well as IVRT sensitivity, specificity and selectivity.

The guidance is not intended to be an all-inclusive description of specific topical products, the agency noted.

“FDA recommends that applicants consult this guidance and any relevant product-specific guidances (PSGs) and any other relevant guidances for industry, when considering the design and conduct of IVRT studies that, in conjunction with other studies, as deemed necessary, may be appropriate to support a demonstration that a proposed generic topical product and its RLD are bioequivalent,” they said.

Guidance

IVPT studies for topical drug products

Similarly, FDA released a draft guidance, also part of the agency’s Drug Competition Action Plan, on considerations for in vitro permeation test (IVPT) studies of topical drug products under ANDA.

“This guidance focuses on general considerations and recommendations for the method development, method validation, and conduct of IVPT studies that are submitted in ANDAs and intended to support a demonstration of BE,” the agency said.

FDA said applicants may use IVPT studies to assess “assess the rate and extent to which a drug (i.e., an active ingredient) from a topical product becomes available at or near a site of action in the skin,” and can be used to compare test topical products and reference standards. The agency said that unique IVPT flux profiles are similar to pharmacokinetic profiles, and certain IVPT endpoints can be also considered similar to pharmacokinetic endpoints such as maximum concentration (Cmax) and the area under the concentration-time curve (AUC). However, they noted that what is being measured in IVPT studies is the rate and extent of absorption, rather than in vivo distribution, metabolism and excretion.

“[W]hile it is relevant to characterize the kinetics of topical drug bioavailability monitored by IVPT studies, the use in this guidance of the term ‘cutaneous pharmacokinetics’ should not be construed to embody all aspects of pharmacokinetics—only those related to the absorption component that directly controls the rate and extent to which a topically applied drug becomes available locally at the site of action,” FDA said.

Guidance

FDA releases new draft guidances on topical generic drugs

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