ICH´s Approach for Harmonization of Standards for Generic Drugs

Recommendation

27-29 February 2024

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On  February 6, 2019, the ICH (International Council for Harmonization) published a new reflection paper on "Further Opportunities for Harmonization of Standards for Generic Drugs". According to ICH, the document outlines a "strategic approach for developing and enhancing ICH Guidelines to support the harmonization of scientific and technical standards for generic drugs". As part of this approach, recommendations are provided to develop a series of ICH Guidelines. These guidelines will include tools for demonstrating equivalence (e.g., bioequivalence) for non-complex dosage forms and more complex dosage forms and products.

Why is harmonization needed?

A generic drug product usually contains a small molecule active pharmaceutical ingredient (API). An applicant can obtain market access by demonstrating equivalence to an already marketed reference product by providing appropriate data to demonstrate safety and efficacy. Individual drug regulatory authorities may differ in the scope of this type of approval and may have different regulatory definitions of a generic drug. Furthermore, legal and regulatory requirements for generic drugs are sometimes not aligned. For example:

• The U.S. Food and Drug Administration (FDA) does not allow a generic drug and its reference product to be different oral dosage forms (e.g., tablets and capsules). In contrast, in the European Union, the competent drug regulatory authorities allow a generic drug and its reference product to be different oral dosage forms if the product meets bioequivalence criteria.
• The U.S. FDA currently requires that the reference product used in testing to support approval (i.e., the “reference standard” for generic drug comparison) has to be registered in the U.S. Not all ICH Members require that the reference product has to be marketed or registered in their country or region, as some permit the use of foreign sourced reference products (for example, Health Canada).
• Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) can limit the granting of biowaivers for specific classes of drugs and additional strengths. Additionally, in Japan, biowaivers for additional strengths may be an issue related to Pharmacopeia standards.

According to ICH, it is therefore proposed to "develop and enhance ICH guidelines in scientific and technical areas that would be valuable and achievable across multiple regulatory pathways and where there is common interest in harmonization". Annex I of the reflection paper identifies existing ICH Guidelines that might be revised to include recommendations for generic drugs.

Possible revision of ICH Efficacy Guidelines

The following ICH Efficacy guidelines might be revised to include recommendations on:

• The conduct of comparative clinical endpoint bioequivalence studies: E3 (Clinical Study Reports), E6 (GCP), E8 (General Considerations for Clinical Trials), E9 (Statistical Principles for Clinical Trials), E10 (Choice of Control Group in Clinical Trials), E17 (Multi-Regional Clinical Trials)
• Pharmacovigilance for generic drugs: E2
• Identification of products with a narrow therapeutic index: E4 (Dose-Response Studies)
• Statistical considerations for bioequivalence: E9 (Statistical Principles for Clinical Trials)

More information can be found in ICH´s new reflection paper on "Further Opportunities for Harmonization of Standards for Generic Drugs".