Generic drugmakers submitting clinical studies on the adhesive performance of a transdermal delivery system (TDS) or topical patch will want to take note of new draft guidance released Tuesday from the US Food and Drug Administration (FDA).
This guidance describes the recommended approach to an adhesion clinical study design used to support an abbreviated new drug application (ANDA) and, once finalized, the guidance will supersede FDA’s prior recommendations related to adhesion studies in individual product-specific guidance documents.
The amount of drug delivered into and through the skin from a TDS is dependent, in part, on the surface area where the patch is applied.
“It is expected that the entire surface area of a TDS should remain consistently and uniformly adhered to the skin throughout the duration of wear under the conditions of use included in the product label,” FDA says.
But because a TDS is expected to encounter strains arising from movements, or be impacted by changes in temperature or humidity, such as the daily exposure to water (e.g., during showers), and contact with clothing, bedding or other surfaces, FDA raises some concerns with TDS products that “do not maintain consistent and uniform adhesion with the skin under the range of conditions experienced during the labeled wear period for the TDS.”
The guidance will be particularly important for designing such patches where a TDS may partially detach, meaning there may be uncertainty about the resulting drug delivery profile and about the rate and extent of drug absorption, the agency notes.
Clinical Study Design
ANDA applicants should consider adhesion as part of the drug's Quality Target Product Profile, FDA says, noting that sponsors should develop a strategy for assessing the adhesive attributes.
“For example, the characterization of the adhesive properties of a TDS should demonstrate that any conditions of labeled use for the R product relevant to TDS adhesion are substantiated for the T product (e.g., demonstrating that incidental exposure of the TDS to water, such as while bathing or showering, is acceptable). Applicants should also ensure that the TDS can be removed from the packaging and peeled off the release liner without difficulty. In addition, the TDS is expected not to cause undue irritation when worn, and not to damage the skin when the TDS is removed after the duration of wear,” according to the guidance.
To evaluate adhesion in a study, FDA recommends “assessing the adhesion of T and R TDS products at a series of time points throughout the study to determine whether the entire surface area of the TDS remains adhered for the duration of wear under labeled conditions of use.”
The recommended study design is a single-dose, randomized, two-treatment, two-period crossover study where all subjects are dosed with the same strength of T and R TDS. The study population should typically be the same as enrolled or as recommended for enrollment in the pharmacokinetic bioequivalence study, FDA adds, and it should include healthy males and non-pregnant females, unless there are product-specific considerations associated with the labeled conditions of use.
In terms of when adhesion should be evaluated, FDA calls for its evaluation at multiple times following application to adequately compare the adhesion characteristics throughout the system’s duration of wear.
“For example, adhesion of a TDS with a 7-day wear period should be assessed at least daily, and at equally spaced time points (e.g., 24 hr, 48 hr, 72 hr, 96 hr, 120 hr, 144 hr, and 168 hr); adhesion of TDS with 72-hour wear period should be assessed at least every 12 hours (e.g., 12 hr, 24 hr, 36 hr, 48 hr, 60 hr, and 72 hr); adhesion of TDS with a wear period between 12 and 24 hours should be assessed at least every 4 hours; adhesion of a TDS with a 9-hour wear period should be assessed at least hourly,” FDA says.
For each assessment, applicants should use a 5-point numerical scale in which each score corresponds to a specified range of adhered surface area of the TDS, such as:
- 0 = ≥ 90% adhered (essentially no lift off the skin).
- 1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin).
- 2 = ≥ 50% to < 75% adhered (less than half of the TDS lifting off the skin).
- 3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the skin without falling off).
- 4 = 0% adhered (TDS detached; completely off the skin).
The guidance also offers information on study conduct, considerations for statistical analysis, studies evaluating adhesion and bioequivalence with pharmacokinetic endpoints and recommendations on formatting data submissions.
Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs: Draft Guidance for Industry