Since 2016, both FDA and EMA have been periodically updating their centralized guidelines to define the requirements for assessing adhesion and skin irritation/sensitization in transdermal delivery systems (TDS), both for ANDA and NDA submissions. In parallel, COFEPRIS (Mexico) and ANVISA (Brazil) have developed their own regulatory frameworks, becoming regional pioneers in establishing patch-specific interchangeability guidelines since 2015.
The problem: when these guidelines are compared against each other, the differences are substantial. The same set of clinical studies can be approved by one agency and rejected by another. For any company developing a generic patch with multi-market registration ambitions, this scenario represents a concrete regulatory risk that must be anticipated from the clinical plan design stage.
This article summarizes the main differences in the clinical requirements of each guideline, focusing on the four parameters that concentrate the greatest divergence: type of studies, bioequivalence, adhesion, and irritation/sensitization.
Studies Required for a Generic TDS ANDA Submission
Tema / Topic | FDA | EMA | COFEPRIS | ANVISA |
|---|---|---|---|---|
Type of studies required | Bioequivalence, Adhesion (1), Sensitization and/or Irritation | Bioequivalence, Adhesion (1,4), Sensitization and Irritation, Phototoxicity | Bioequivalence, Adhesion (1), Adhesion under normal activities (3), Sensitization and/or Irritation | Pharmacokinetics (2) + Adhesion (must be done in the same study), Sensitization/Irritation |
(1) Adhesion can be evaluated in a combined BE+Adhesion study or in a specific independent study.
(2) For ANVISA, the term Bioequivalence comprises 3 studies: Pharmacokinetics, Adhesion, and Skin Irritation/Sensitization.
(3) COFEPRIS requires testing adhesion robustness against showers, moisturizers, and physical exercise.
(4) The agency may request other additional specific studies.
Differences in Bioequivalence Requirements
Topic | FDA | EMA | COFEPRIS | ANVISA |
|---|---|---|---|---|
Analysis of variance, effects in the model | Treatment, Period, Sequence and Subject nested in sequence | Treatment, Period, Sequence and Subject nested in sequence | Treatment, Period, Sequence and Subject nested in sequence | Treatment, Period, Sequence, Site of Application and Subject nested in sequence |
Requirement of Partial AUCs | Depends on the API considered | Depends on degree of drug accumulation when multiple dose study is not required | Not required | Required (same criteria as EMA) |
Differences in Adhesion Criteria
Topic | FDA | EMA | COFEPRIS | ANVISA |
|---|---|---|---|---|
Assessment criteria | Mean adhesion score | Percentage of patch adhesion at end of dosing interval | Cumulative adhesion score | Same as EMA |
Adhesion under normal activities | Recommended | Not mentioned (only required for TDS under NDA) | Required | Not required |
Statistics for secondary variables | Descriptive | Descriptive | Descriptive | Descriptive and Inferential |
Differences in Irritation and Sensitization Criteria
Topic | FDA | EMA | COFEPRIS | ANVISA |
|---|---|---|---|---|
Design | One group: induction phase, resting and challenge phase | Two groups (differ in patch usage time): induction, resting and challenge phase | Same as FDA | Same as FDA (formerly resembled EMA design) |
Definition of excessive skin irritation | Combined score ≥ 3 | Combined score ≥ 4 | Dermal response score 3–7 or any dermal response combined with other effect | Same as FDA |
Dermal response scale | Letters and numerical equivalents: A(0), B(1), C(2), F(3), G(3), H(3). Higher number = higher response. | Numbers from 0 to 4, different assignation of dermal responses than FDA | Same as FDA, without numerical equivalents for letters (A to H) | Numbers from 0 to 4 (including 0+, different assignation than FDA and EMA) |
Adhesion evaluation during induction phase | Not required | Not required | Not mentioned | Required* (allows tape to reinforce patch detachments) |
Sensitization analysis | Descriptive statistics only | Tabulations of dermal response scores ≥2. No further stats required. | Mean response of Test between 80%-125% of RLD | Degree of sensitization: Test ≤ RLD. Occurrence time: Test ≥ RLD. |
(*) ANVISA allows the use of tape to reinforce patch detachments during the induction phase.
Conclusions: Why Regulatory Harmonization Is the Segment’s Next Priority
Although the ultimate goal of all agencies is the same — ensuring the generic TDS is interchangeable with the reference product — the regulatory pathways to reach that result are divergent. Differences in study design, statistical criteria, and acceptance thresholds between FDA, EMA, COFEPRIS, and ANVISA force sponsors to liaise with regulatory agencies and calibrate their clinical plan according to each target market, assuming risks that in many cases only materialize at the final evaluation stage.
Accumulated experience in the sector shows that even when regulatory reviewers are consulted during clinical plan development, their opinions are not binding on the Agency’s final decision. This uncertainty margin is structural and translates into increased development costs and time.
The harmonization of guidelines and the generation of binding opinions by regulatory reviewers are the challenges to be addressed. Moving in that direction would allow generic patch submissions to be reviewed in a more predictable and equitable scenario for all stakeholders.
References
FDA. Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs. Guidance for Industry, Draft, CDER/FDA, Oct 2018.
EMA. Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms, EMA/CHMP/EWP/280/96 Rev1, 20-Nov-14. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf
FDA. Product-Specific Guidances for Generic Drug Development. https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm
ANVISA. Diário Oficial da União, Instrucão Normativa IN No 328, de 9 de Outubro de 2024. https://www.in.gov.br/en/web/dou/-/instrucao-normativa-in-n-328-de-9-de-outubro-de-2024-589783953
Consulta Pública No 760, 27/Dezembro 2019. Criteria for conduction of BA/BE studies. ANVISA.
Amarin Technologies. Assessment of the requirements for the submission of generic transdermal systems in Latin America. https://amarintech.com/es/assessment-of-the-requirements-for-the-submission-of-generic-transdermal-systems-in-latin-america/
