On Wednesday, June 1st the FDA issued a draft guidance that provides various recommendations concerning studies to evaluate the adhesion performance of a Transdermal Delivery System (TDS) or a topical patch submitted as part of an Abbreviated New Drug Application (ANDA). The guidance, entitled “Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs,” describes the Agency’s recommended approach regarding the design and conduct of adhesion studies.
In its draft guidance, the FDA states that “the amount of drug delivered into and through the skin from a TDS is dependent, in part, on the surface area dosed.” As such, the contact surface area of a TDS should stay consistently and uniformly attached to the skin during the entire duration of wear that is stated on the product’s label under the conditions of use. In situations where a patch does not stay fully attached for the full duration of time that is provided, the amount of drug delivered to the patient may be reduced.
In addition, the Agency states that “as the potential for complete detachment of the TDS increases, so does the risk of unintentional exposure of the drug product to an unintended recipient (e.g., a household member who may potentially be a child).”
Due to the fact that generic products are developed after their branded counterparts, it is possible that generic drug makers may be able to utilize technology that was not available when the branded product was developed. As such, the FDA states that “applicants submitting an ANDA for a TDS product (including supplemental ANDAs relating to reformulations of an approved generic TDS product) are expected to demonstrate that reasonable efforts were made to optimize the adhesive characteristics of the TDS. This optimization is expected to balance properties such as adhesiveness, cohesiveness and stability, to ensure a consistent and uniform adhesion of its entire surface area to the skin for the entire duration of wear.”
FDA advises applicants to consider adhesion as part of the Quality Target Product Profile (QTPP), and notes that a comprehensive strategy should be developed to evaluate the adhesive attributes of a TDS.
Adhesion Scoring System
Sponsors should assess the adhesion of a product at various points throughout the study. This will help determine whether or not the surface area of the TDS stays attached for the entire duration of wear that is provided on the label. “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, as follows:
- 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).”
Furthermore, the highest adhesion score that is assessed at any time “should be used for subsequent time points until a higher score is assessed.”
Study Design, Conduct, & Statistical Analysis
FDA recommends that the adhesion study design is “a single-dose, randomized, two-treatment, two-period crossover study where all subjects are dosed with the same strength” of the generic and reference products. The Agency also recommends blinding the products whenever possible.
Both the generic and reference products should be administered to study subjects as described on the label of the reference product. The study protocol should include provisions to ensure that interventions such as re-application of a detached (or partially detached) TDS, repressing of the TDS, or any reinforcement of TDS adhesion with the skin are avoided throughout the study. “Subjects should not apply make-up, creams, lotions, powders, or other topical products to the skin area where the TDS will be placed, as this could affect adhesive performance. Hair at the application site should be clipped (not shaved) prior to TDS application.”
The protocol should also describe the method of randomization as well as the randomization scheduled (which should be provided as a SAS transport data set in .xpt format). In an attempt to reduce and avoid bias, the Agency advises sponsors to use an independent third party to “generate and hold the randomization code throughout the conduct of the study.”
Applicants should submit a statistical analysis plan (SAP), which provides a detailed description of the planned analysis, as soon as possible “and certainly prior to the unblinding of the data.”
Evaluating Adhesion & Bioequivalence with Pharmacokinetic Endpoints
Applicants may choose conduct a single study that evaluates both the adhesion performance and pharmacokinetic (PK) bioequivalence (BE) of the generic and reference products. “If pursued, such a study should be conducted in a population of sufficient size to adequately power the comparative evaluation of adhesion and to include a subpopulation of subjects of sufficient size to adequately power the evaluation of BE with appropriately selected PK endpoints. The participants for PK BE evaluation should be selected according to a randomization scheme pre-specified in the protocol.”
For additional information on the Agency’s recommendations regarding studies evaluating both adhesion and BE with PK endpoints, view the full draft guidance.
Format of Data Submissions
When submitting data to the Agency, FDA notes that standardized format should be used.
“For the adhesion study analysis, a separate line listing should be provided for each individual test article (i.e., T TDS, R TDS, T overlay, R overlay, etc.) per subject, per adhesion assessment time point (if data exist), using the following headings, if applicable:
- Subject identifier
- Study center (if applicable)
- Treatment: test article (i.e., T TDS, R TDS, T overlay, R overlay, etc.)
- Period (i.e., TDS was applied during Period 1 or Period 2) if applicable
- Application sequence number: number of particular test article application (i.e., 1=first, 2=second)
- Location of dose administration: individual test article application site
- Application date/time
- Number of days/hours since TDS application
- Adhesion assessment /scoring date/time
- Initials of adhesion evaluator
- TDS complete detachment (yes or no)
- Date and time of complete detachment
- Treatment discontinued (yes or no)
- Date and time of treatment discontinuation
- Reasons for treatment discontinuation
- Duration of Treatment: time (hours) from individual test article application to removal or complete detachment
- Included in PP population for adhesion analysis (yes/no)
- Reason for exclusion from PP population for adhesion analysis”