Choosing the Appropriate Reference Item in Diverse Regulatory Jurisdictions

Choosing the Appropriate Reference Item in Diverse Regulatory Jurisdictions

The process of selecting a reference product for generic drug development varies significantly across different regions due to distinct regulatory frameworks and requirements.

United States (USFDA): In the United States, the US Food and Drug Administration (USFDA) defines the reference product as the Reference Listed Drug (RLD), listed in the Orange Book. To gain approval, a generic must demonstrate bioequivalence to the RLD, meaning it delivers the same amount of active ingredient in the same time frame. The Active Pharmaceutical Ingredient (API) must be identical to the RLD, and while inactive ingredients (excipients) can differ, they must not affect safety, performance, or effectiveness. The generic product must also be therapeutically equivalent but physically distinct in appearance due to trademark laws.

European Union (EMA and Member States): In the European Union, the reference product is typically the innovator drug nationally authorized in an EU member state. The approval process can occur through the Centralized Procedure, Decentralized Procedure (DCP), or Mutual Recognition Procedure (MRP). The EU emphasizes bioequivalence to the reference medicinal product without repeating clinical safety/efficacy trials. However, post-approval, Health Technology Assessment (HTA) and reimbursement decisions are national, adding variability.

United Kingdom (UK MHRA): Post-Brexit, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) follows procedures similar to the EMA but operates independently with national approvals. Generics require demonstration of bioequivalence to the UK authorized reference product. The UK may also require additional clinical or pharmacodynamic studies if bioequivalence via plasma concentration cannot be established.

Rest of World (ROW): Criteria vary widely but generally require demonstration of bioequivalence to the local innovator or approved product, comprehensive Chemistry, Manufacturing and Controls (CMC) documentation, and stability data supporting shelf life. Some regions may require additional clinical or local bridging studies if reference products differ or local populations have specific characteristics.

Australia (TGA): In Australia, the Therapeutic Goods Administration (TGA) requires demonstration of bioequivalence to an Australian registered reference product. The reference product is typically the innovator drug registered and approved in Australia, and guidelines require extensive CMC data, bioequivalence studies, and may require additional supportive studies depending on drug class.

Middle East and North Africa (MENA): In the MENA region, regulatory requirements are evolving but commonly rely on international standards with local registration and sometimes clinical data. Often, approval is based on bioequivalence to a reference product approved by a stringent regulatory authority (e.g., USFDA, EMA). Local agencies may require documentation of comparability to the reference product marketed in their territory.

Summary Table of Key Reference Product Selection Criteria

| Region/Agency | Reference Product Requirement | Bioequivalence Evidence | Additional Notes | |-------------------|------------------------------------------------|-------------------------------------------|-------------------------------------------------------| | USFDA | US-approved RLD, identical API | Pharmacokinetic bioequivalence studies | Inactive ingredient differences allowed if justified | | EU (EMA + MRP/DCP)| Innovator approved in RMS or centralized EU approval | PK bioequivalence; may require clinical endpoints for some drugs | HTA separate at national level | | UK (MHRA) | UK authorized innovator product | Bioequivalence; possible PD or clinical studies | Regulatory independence post-Brexit | | ROW | Local innovator or internationally recognized reference | Bioequivalence; additional local studies possible | Varies by country | | Australia (TGA) | Australian approved innovator product | Bioequivalence studies required | Full CMC and stability dossier | | MENA | Reference product approved by SRA or local agency | Typically bioequivalence; local registration needed | Regulatory frameworks evolving |

This reflects a general framework based on publicly available regulations and industry practice as of 2025. Specific product guidances, such as FDA’s Product-Specific Guidances (PSGs), provide detailed recommendations tailored to each drug product. It is essential for developers to review country-specific guidelines before selecting a reference product for generic drug development.

1. In the United States, such as the US Food and Drug Administration (USFDA) guidelines, the drug development process requires a generic product to demonstrate bioequivalence to the Reference Listed Drug (RLD), with the Active Pharmaceutical Ingredient (API) being identical to the RLD, and differences in inactive ingredients permitted only if they do not affect safety, performance, or effectiveness.
2. As per the European Union's regulations, the approval process for generic drugs hinges upon bioequivalence to the reference medicinal product, and may waive repeating clinical safety/efficacy trials, but post-approval, Health Technology Assessment (HTA) and reimbursement decisions are national, adding variability.
3. Post-Brexit, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) requires generics to demonstrate bioequivalence to the UK authorized reference product, and may require additional clinical or pharmacodynamic studies if bioequivalence via plasma concentration cannot be established.
4. In the rest of the world, criteria for generic drug development vary widely, but generally necessitate demonstration of bioequivalence to the local innovator or approved product, comprehensive Chemistry, Manufacturing and Controls (CMC) documentation, and stability data supporting shelf life.
5. In Australia, the Therapeutic Goods Administration (TGA) mandates demonstration of bioequivalence to an Australian registered reference product, requiring extensive CMC data, bioequivalence studies, and potential additional supportive studies depending on the drug class.

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