Introduction

The clinical studies required for the approval of a generic transdermal system (patch) differ in kind and quantity from those required for other pharmaceutical forms.

Being the patch a formulation that needs to be adhered to the skin during the entire wearing period (which ranges from few hours up to 7 days), this parameter needs to be studied in depth.

The same occurs with skin response (i.e., irritation and sensitization), because its condition can determine drug delivery and because the skin under the application site remains occluded during patch use and this could cause some disturbances (e.g.: erythema, edema, itching, etc.).

So, the submission of a register for a generic transdermal product currently requires not only bioequivalence be demonstrated (under single and multiple dose) but also statistical non-inferiority in adhesion as well as in skin irritation regarding a reference product.

In this article some aspects of said studies are discussed, to bring a quick perspective of the challenges and complexity they pose.

Bioequivalence, Single Dose, Multiple Dose

According current paradigm, one requirement is that a generic patch needs to be bioequivalent to a comparator product under single and multiple dose schemes.

1. Single Dose studies:

The present tendency of sponsors is to run, in the same study, both bioequivalence (BE) and non-inferiority in adhesion in healthy volunteers. 

Some pros and cons under this scenario are:

To select this approach and to minimize risks it is absolutely necessary to collect some previous data on patch adhesion. This can be reached, for instance, by running exploratory pilot studies testing placebo prototypes of the generic patch (wearing tests, to adjust the formulation), and/or including a placebo patch evaluation when testing the verum patch in an initial pharmacokinetic study.

Always remembering the golden rule that “a single study can not answer all possible questions”, those initial studies should be specifically designed, under an appropriate risk analysis, to obtain the data of interest (patch adhesion, adhesive residue, skin response, water contact resistance, etc.).

Then, once enough confidence has been gained on patch adhesion & performance, a pilot pharmacokinetic study including patch adhesion evaluations can demonstrate the potential of the generic patch prototype. It is important to abide by the recommendations of the available guidelines (FDA, EU) in the design of the protocol before running such pilot studies, to simulate the pivotal study scenario the maximum extent possible. 

In this way, the pivotal BE + Adhesion study will be mostly a “scale-up” of the pilot study, involving an adequate number of healthy subjects to simultaneously satisfy power requirements for adhesion as well as for BE.

It is important to establish in the pivotal single dose study whether there is or not drug accumulation (see below), because it defines the need of the multiple dose study, at least in EU.

1. Multiple Dose Studies:

Commonly, the multiple dose study is run once the pivotal single dose study yields the primary endpoints (BE and non-inferiority in adhesion).

Here, the design takes into account patch duration, pharmacokinetic and active ingredient characteristics, etc. For instance, a multiple dose study for a patch of 24h duration could involve up to 11 consecutive patch applications, whereas for a 4-day or 7-day patch usually 3 patch applications are needed to reach steady state conditions.

Current EMA guidelines state criteria based in the possibility of drug accumulation to establish whether a multiple dose study is required (when the accumulation index is below 90%) or else a single dose study will suffice (accumulation index above 90%). 

However, this last approach adds additional BE criteria to such single dose study, by requiring the analysis of partial areas under the time-concentration plasmatic curves (early pAUC and terminal pAUC), with a cut-off limit normally set at the middle of the pharmacokinetic profile.

For a generic patch to be approved, it must be bioequivalent to the reference product under single dose and multiple dose conditions (if this last one applies, as per the EU regulations).

Patch Adhesion: Non-Inferiority

For a generic patch to be approved, in addition to result BE, its adhesion must be non-inferior to that of the reference product.

Currently, the 2 approaches regulatory accepted to analyze this parameter are the comparison of adhesion scores (FDA criteria) or the comparison of adhesion percentages (EMA).

FDA relies on a mean adhesion score that considers all adhesion evaluations performed throughout the study (there are different instances in which adhesion should be assessed, depending on patch duration) whereas EMA takes into account the adhesion percentage showed by the patches at the end of the wearing period. Other parameters/analysis are also required as a complement (e.g.: percentage of patches showing unacceptable adhesion, histograms, etc.), where the generic patch shall perform equal or better than the comparator.

Nonetheless, even after demonstrating that the generic patch is non-inferior in adhesion to the reference product in a pivotal and adequately powered study in healthy volunteers, regulatory agencies could possibly ask for additional adhesion data collected on the target population (e.g.: products for Parkinson disease, because of skin changes associated to such pathology), adding an additional task (and challenge) for the product registration.

Irritation/Sensitization Studies: non-inferiority

The condition of the skin may influence the absorption of an active substance from a transdermal system and affect the efficacy or safety of the product. In line with this, skin irritation and sensitization should be assessed.

The design of this study comprises an induction phase of 21 days, a rest phase of 14-17 days and a challenge phase of 5 days (which can be repeated to confirm results), involving a considerable number of subjects (aprox. 200).

For a generic patch to be approved, in addition to result BE as well as non-inferior in adhesion respect to the reference product, the dermal response (irritation) must be non-inferior to that of the reference product and the sensitization description obtained with both patches should be similar.

To declare non-inferiority in irritation, both FDA and EMA compare the mean irritation scores obtained throughout the study for the generic patch and the reference product, complemented with other clinically relevant data (e.g.: No. of subjects discontinuing due to excessive irritation).

Some differences between FDA and EMA concepts:

• FDA allows for the use of placebo and positive control when the active substance can be detrimental to the subject well-being (under the administration scheme demanded by the study), whereas EMA allows for the use of a lower dose in such cases.
• FDA guidelines state that if the active pharmaceutical ingredient is known to be a skin sensitizer, it is accepted to run only the irritation phase (thus involving less subjects and exposure times) to satisfy the requirement. EU guidelines does not consider such approach.

Conclusions

The quantity and kind of clinical studies requested for the filing of an application for a generic patch are higher and more complex than for other pharmaceutical forms. 

In consequence, they require extra planning, efforts and resources and -ideally- close liaison with agencies, to accomplish current regulatory requirements, and result approved.

References

1. Product-Specific Guidances for Generic Drug Development, FDA. Last access: Oct 17, 2022. (https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm?event=Home.Letter&searchLetter=B#letterSearchBar) 
2. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application, FDA. Last access: Oct 17, 2022. (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioequivalence-studies-pharmacokinetic-endpoints-drugs-submitted-under-abbreviated-new-drug)
3. Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms, EMA/CHMP/EWP/280/96 Rev1, 20-Nov-14. Last access: Oct 14, 2022.

(https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf)

1. Withdrawal assessment report, Rotigotine Mylan. London, 21 April 2017, EMA/29245/2018, Committee for Medicinal Products for Human Use (CHMP).
2. Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs. Guidance for Industry, Draft, CDER/FDA, Oct 2018.
3. Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs. Draft Guidance for Industry. CDER/FDA, 2018.