Interchangeability Guidances for TDS, Need for Harmonization

Miguel Fortuny – Clinical Research Manager

 

Introduction:

Since 2016, both FDA and EMA keep on updating centralized guidances to define the requirements and recommendations to assess Adhesion and Skin irritation/Sensitization for transdermal delivery systems, both for ANDA and NDA purposes.

In the same line, both COFEPRIS (Mexico) and ANVISA (Brazil) become pioneers in launching their guidances for interchangeability of patches since 2015, following several rounds of discussions with the pharmaceutical industry to bring the current regulations in force. Particularly, Brazil has recently published a product specific guidance for the submission of generic patches containing an antiparkinsonian, in line with the product specific guidances regularly updated by FDA.

If a comparison is made among them, several differences are evident, which could prevent the set of studies submitted to support a marketing application to be approved in a specific country.

This article intends to bring a summarized comparison highlighting the main differences on the requirements for clinical studies stated in said guidances.

 

Differences detected among Guidances’ clinical requirements for a Generic TDS:
  • Studies required for an ANDA submission

 

Topic

FDA

EMA

COFEPRIS

ANVISA

Type of studies

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 study.

(2): For ANVISA, the term Bioequivalence comprises 3 studies: Pharmacokinetics, Adhesion and Skin irritation/sensitization.

(3): COFEPRIS requires test adhesion robustness of the patch to showers, moisturizers and physical exercise.

(4): Agency could ask for other specific studies

  • For Bioequivalence

 

Topic

FDA

EMA

COFEPRIS

ANVISA

Analysis of Variance, Effects to be considered 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 (Area under the curve)

It depends on the considered API

It depends on the degree of drug accumulation, when a multiple dose study is not required

Not required

Required (same criteria as EMA)

 

 

  • For Patch Adhesion

 

Reviewed Topic

FDA

EMA

COFEPRIS

ANVISA

Assessment Criteria

Mean adhesion score

Percentage of patch adhesion at the end of the dosing interval

Cumulative adhesion score

Same as EMA

Adhesion under normal activities

Recommended

Not mentioned (only required for TDS under an NDA) 

Required

Nor required

Statistics for secondary variables

Descriptive

Descriptive

Descriptive

Descriptive and Inferential

 

 

  • For Irritation/Sensitization

 

Reviewed Topic

FDA

EMA

COFEPRIS

ANVISA

Design

One group, induction phase, resting and challenge phase.

Two groups (differ in patch usage time), induction phase, resting and challenge phase

Same as FDA

Same as FDA

 

(Formerly, it 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 for Other Effects

 Letters and numerical equivalents: A(0), B(1), C(2), F(3), G(3) and H(3). The higher the number, the higher the 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+, and different assignation of dermal responses than FDA and EMA)

Adhesion evaluation during induction phase (assigning scores)

Not required

Not required

Not mentioned

Required*

 

Sensitization analysis

Descriptive statistics only

Tabulations of dermal response scores ≥2.

No further stats required.

Mean response of Test between 80%-125% of that of RLD

Degree of sensitization: Test ≤ RLD.

Occurrence time: Test ≥ RLD.

*: It allows the use of tape to reinforce patch detachments.

 

Conclusions

Although the target remains the same, i.e., to yield and interchangeable TDS, the clinical topics required by the guidances of agencies like Brazil and Mexico to approve a generic TDS are different from EMA and/or FDA.

This scenario obligates the Sponsors to be highly tuned with the respective agency to agree the expected set of studies to be included in the clinical package submission.

Moreover, experience says that even regulatory evaluators are approached during clinical plan development, their opinions are not necessarily binding to agencies’ thinking and/or final decision, so some risks are pre-assumed when running the agreed clinical trials.

Consequently, the challenge would be to advance to more harmonized guidances and opinion-binding definitions by regulatory evaluators so that the submissions of generic patches can be reviewed in a more reasonable and equalized scenario.

 

References

  • Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs. Guidance for Industry, Draft, CDER/FDA, Oct 2018.
  • Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms, EMA/CHMP/EWP/280/96 Rev1, 20-Nov-14. Last access: Nov 11, 2024.

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

 

Subscribe to
#AmarinNews




    Partner with us!

    We offer expertise and experience, together with flexibility and the ability to adapt to your needs.

    Facebook Twitter Linkedin
    Explore

    Copyright ©2021 Amarin Technologies Todos los derechos reservados - Desarrollo by Cuervo estudio