Patch adhesion and local tolerability of Transdermal Delivery Systems Requirements according to the new draft EMA Guidelines

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1 Patch adhesion and local tolerability of Transdermal Delivery Systems Requirements according to the new draft EMA Guidelines Dr. Janet Schriever Federal Institute for Drugs (BfArM), Germany

2 Transdermal drug delivery systems (TDDS) Designed to deliver a therapeutically effective amount of drug across a skin into the systemic circulation. Examples: Nicotine patches Fentanyl and Buprenorphine patches Hormonal patches

3 NEW Draft Guideline on quality of transdermal patches Deadline for comments March 2013 Annex 2: In vivo skin adhesion Draft Guideline on the pharmacokinetic and clinical evaluation of modified-release dosage forms Deadline for comments September 2013 Appendix I: Sensitisation and irritation test for transdermal products

4 Generic application Equivalence testing should comprise bioequivalence, non-inferiority in terms of adhesion, and demonstration of satisfactory clinical safety and local tolerance.

5 The adhesive of the TDDS is critical to the safety, efficacy and quality of the product. Dr. J. Schriever International Symposium on Past Successes, Future Challenges in Paediatric Oncology, May 16, 2008

6 Skin adhesion study Ensure adhesion equivalence prior to bioequivalence investigations in volunteers. May be included as a component part of human clinical pharmacokinetic and efficacy studies, or May be an independent study with either patients or volunteers.

7 Skin adhesion study As a minimum, the smallest and the largest patch sizes should be tested in vivo.

8 Assessment of patch area adherence using a 7-point score Smaller increments allow improved differentiation

9 Assessment of patch area adherence The frequency of assessment should be more than daily, e.g. 0.0 hours (immediately after application), 6.0 hours, 12.0 hours and 24.0 hours (immediately prior to patch removal) after patch application. The adherent area may be photo-technically recorded (i.e. digital photographs) at each assessment time point.

10 Requirements Mean adherence > 90% should be expected Poor adherence events should be investigated and possible causes and risk factors determined. The results should be reported in explanatory tabular and graphical formats.

11 Under discussion: How to assess the adhesion score? Hold a transparent overlay (pre-printed with a box grid) over the patch. Mark the area of detachment directly on the overlay. Avoid re-attachment of the patch to the skin during the assessment.

12 Under discussion: How to perform such a study when the proposed to be marketed product includes a non-transparent integrated cover patch?

13 The condition of the skin may influence the absorption of an active substance from a TDDS and affect the efficacy or safety of the product. Dr. J. Schriever International Symposium on Past Successes, Future Challenges in Paediatric Oncology, May 16, 2008

14 Sensitisation and irritation test Similarity has to be shown for skin irritation and sensitization unless otherwise justified by e.g. very similar quantitative and qualitative composition. Draft Guideline on the pharmacokinetic and clinical evaluation of modified-release dosage forms (Appendix I) recommends study design and scoring systems

15 Overall Study Design for a generic application Active- and placebo-controlled, multiple-dose, three-phase, parallel-group design. Evaluation of both cumulative dermal irritation and contact sensitization. Test, reference and placebo transdermal patches should be applied to randomly assigned test areas on the backs of subjects in two groups (Group 1 and Group 2). Trained blinded observer.

16 Federal Institute for Drugs

17 Assessment of dermal response using a 8-point scale Dermal response scores require that at least 25% or more of the patch area demonstrate an observable response. "Strong" reaction to the test patch

18 Assessment of other effects using a 5-point score Dermal response scores require that at least 25% or more of the patch area demonstrate an observable response. "Strong" reaction to the test patch

19 Results Skin irritation: Compare the test and reference treatments for the mean irritation scores (average numeric dermal response over the observations) and the total cumulative irritation scores (sum of the numeric dermal response scores over the observations). Skin sensitization: Tabulate dermal response scores 2 during the Challenge Phase.

20 Thank you for your attention, and now questions!