FDA updates generic transdermal and topical delivery systems guidances

The US Food and Drug Administration (FDA) on Wednesday issued two revised draft guidances for generic drug submissions that use transdermal and topical delivery systems (TDS). The revised guidances make numerous technical clarifications that abbreviated new drug application (ANDA) sponsors should consider when filing their premarket application.

The revised documents update previous draft versions issued in 2018 and shed light on the agency’s evolved thinking on how generic drug TDS products should be evaluated. (RELATED: Latest Batch of FDA Product Specific Guidances Focus on Topical, Transdermal Drugs, Regulatory Focus, 9 October 2018)

In the first guidance, which addresses assessing adhesion for TDS products, FDA said it is updating the document to clarify the appropriate methods sponsors should consider when measuring the surface area of the TDS product that is expected to adhere to a patient’s skin and how to statistically analyze that data.

“The amount of drug delivered by a TDS into and through the patient’s skin is dependent, in part, on the surface area dosed,” said FDA. “The entire contact surface area of a TDS should remain consistently and uniformly adhered to the patient’s skin throughout the duration of wear under the conditions of use included in the [reference listed drug] RLD labeling. When a TDS loses its adhesion during wear, the amount of drug delivered to the patient may be reduced.”

Typically, FDA has used trained visual assessment and/or dot matrix templates and a five-point adhesion scale to estimate the adhesion of TDS to the skin. But in the updated draft guidance, the agency is encouraging sponsors to explore alternative scales and to discuss them with reviewers during their pre-ANDA meeting.

“If applicants use a scale different from the five-point adhesion scale described below to record TDS adhesion measurements, they should report each TDS adhesion measurement as both the score according to the selected scale, as well as the corresponding score according to the five-point adhesion scale,” said FDA.

The guidance also clarifies that while photographic evidence is not currently intended for automated or photometric analysis, it can be used by sponsors to support visual observations of the TDS adhesion capability over time.

The second draft guidance makes recommendations on designing and conducting studies to evaluate in vivo skin irritation and sensitization (I/S) of TDS products. Compared to the 2018 draft guidance, the new guidance clarifies recommendations for designing and conducting studies that evaluate in vivo skin I/S potential of a proposed TDS product.

“The components and composition of a TDS formulation, including the nature of the drug substance and/or the degree to which the TDS materials occlude the transmission of water vapor from the skin, in conjunction with other factors such as the environmental humidity or the condition of the skin, may have the potential to irritate the skin or lead to a sensitization reaction,” FDA noted. “Such reactions can be unpleasant to the patient and may affect patient compliance, skin permeability, and/or adhesion of the TDS to the skin.”

As a result, the agency said sponsors should conduct comparative assessments studies of the TDS product with its reference product. That includes skin I/S studies with human subjects to show it is not worse than the reference product.

“Skin I/S studies are designed to compare the similarity between the [test] and [reference] TDS products for the potential to cause irritation and/or sensitization reactions,” said FDA. “A TDS may elicit these reactions in only some of the patients using the product, but even if the frequency of this occurrence were low, the adverse reactions could affect thousands of individuals.”

To evaluate the I/S potential, FDA said sponsors should compare the test and reference products in at least 200 subjects and they should be conducted under “provocative conditions” where the products are repeatedly removed and reapplied on the same part of the skin to maximize the potential for I/S reactions.

The guidance also clarifies when an in vivo study to assess the sensitization potential of a TDS product may not be needed and details how sponsors can use alternative scoring scales or alternative approaches to compare I/S between the test and reference TDS products.

FDA updates generic transdermal and topical delivery systems guidances

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