Selecting the appropriate reference product is a key step in generic drug development. It serves as the basis for bioequivalence studies and regulatory submissions. The definition and selection criteria for a reference product vary by region, as outlined below.
1. United States (USFDA) – Reference Listed Drug (RLD)
The USFDA defines the reference product as the Reference Listed Drug (RLD), listed in the Orange Book. The RLD must match in strength and dosage form. If discontinued, FDA may assign a new reference standard for BE studies.
2. European Union (EMA) – Reference Medicinal Product (RMP)
In the EU, the RMP must be an innovator product approved under a full dossier (Article 8(3)). It must be authorized in any EU member state and be fully traceable. The EMA emphasizes complete quality, safety, and efficacy data.
3. United Kingdom (MHRA) – Reference Medicinal Product (RMP)
Post-Brexit, the reference product must be authorized by MHRA via the UK national procedure or legacy MRP/DCP approvals. MHRA provides public data to help sponsors identify suitable RMPs for the UK market.
4. Rest of World (ROW) Markets – Country-Specific Approaches
In ROW countries, the accepted reference may vary. Some regulators accept USFDA or EMA products, while others require locally marketed innovator brands. Country-specific guidelines must be reviewed before selection.
5. Australia (TGA) – ARTG-Registered Reference Product
TGA requires the comparator to be registered in the Australian Register of Therapeutic Goods (ARTG). If using a foreign comparator, strong justification and bridging data are required for acceptance in BE studies.
6. MENA Region (e.g., GCC, Saudi FDA) – Preference for US/EU Products
Regulators in the Middle East and North Africa generally accept USFDA or EU-authorized products. In some countries, local availability of the reference product is mandatory. Ministry of Health guidance must be followed.
Conclusion
While the core principle of using a scientifically validated reference product remains the same, each regulatory authority has specific expectations. Developers must ensure alignment with local regulatory requirements, including strength, dosage form, and product availability. In multi-market strategies, multiple BE studies with different reference products may be necessary.
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