FDA issues draft guidance for transdermal adhesion systems

Regulatory NewsRegulatory News | 01 July 2021 |  By 

The US Food and Drug Administration has issued new draft guidance for clinical trials examining the adhesion performance of transdermal and topical delivery systems (collectively, TDS) for new drug applications.
Surface area is an important variable in determining the amount of drug delivered through a TDS; adhesion performance can affect both safety and effectiveness of TDS products because adhesion failures can result in reduced effectiveness caused by suboptimal dosing or potentially increased exposure when a new TDS needs to be applied sooner than the scheduled dose,” notes FDA in the introduction to the guidance.
A TDS must maintain adherence despite body movement, perspiration, humidity from activities such as showering, as well as contact with clothing and bedding fabrics and other surfaces. Also, complete detachment of a TDS may pose a risk to children or other household members who might inadvertently be exposed to the drug.
“TDS development has evolved over the years, especially with respect to expected adhesion performance. TDS products developed today may use technologies that were not available when the first TDS products were approved,” according to the guidance, which takes these factors into consideration.
An in vivo clinical adhesion trial should be part of the new drug application or supplemental new drug application process (NDA or sNDA) for a drug to be delivered via TDS. Circumstances where such a trial is required include when a new TDS is submitted in an NDA, or when an sNDA is submitted for a previously approved TDS but seeking approval for a new patient population, application site, wear time or strength. A postapproval change to a TDS involving changes that might affect adhesion will ordinarily also warrant another trial.  
The proposed commercial product, rather than a placebo, should be used for the clinical trial since the active pharmaceutical ingredient (API) “can influence the adhesive properties of a TDS,” notes FDA. Also, the largest TDS size proposed should be used for the trial, since increased size may increase the risk for detachment because of torsional strains and flexion. The site or sites of greatest torsional strain or contact with clothing or bedding should be used for testing.
Sponsors should plan for an inpatient clinical wear trial and, in some cases, an outpatient clinical wear trial with use of data from patient diaries. The inpatient trial may be a standalone trial or conducted with a pharmacokinetics trial.
The TDS should be applied to clean, bare skin free of topical products; hair should be clipped but not shaved before application. Participant movement should be unrestricted, they should bathe and shower as usual, recording these and other activities that might impact adhesion.  In no case should applicants use a binding or overlay to blind participants and assessors because of the risk of affecting how the product performs.
The draft guidance lays out the time points at which adhesion should be evaluated in both the reference and tested TDS. A TDS with a 7-day wear period should be evaluated at least daily, with more frequent evaluation recommended for a TDS with a shorter wear period. In general, evaluations should be evenly distributed across time.
The draft guidance advises that adhesion should be assessed by “a trained observer” who estimates the percentage of the total surface area of the TDS that is still adhered to the skin at each assessment point. A grid or dot matrix can be used as an aid, but pressure must not be applied to the TDS. Photographs should accompany assessments at each time point.
The draft guidance sets out statistical considerations, including the sample size needed for statistical power.
“Although the inpatient setting of a clinical wear trial informs the adhering capability of the TDS, the actual user experience may differ,” FDA notes in the guidance. Using patient diaries will help sponsors collect this information, which are particularly important when a novel TDS is being evaluated, when a high-risk drug substance such as an opioid is being evaluated, or “when the clinical wear trial may not adequately capture use in the intended population.”
The draft guidance lists information to be included in patient experience diaries, including application site, multiple assessments space equally across time and an estimate of percent surface area of the TDS that remains adherent. Diaries should also seek information about their removal, smoothing, or pressing of the TDS, any unscheduled replacement, and daily activities involving exposure to water or generating perspiration. Also, any localized issues should be recorded and an electronic case report form should be designated by the sponsor.
FDA is seeking commentary on the draft guidance over the next 60 days.
Draft guidance


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