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Optimizing Your Global Drug Development Program: Strategy for Regional Variations of the 505(b)(2) Pathway

At Premier Consulting, we are often asked for strategic advice on drug development programs seeking approval in not only the United States (US), but also approval from other regulatory agencies, including the hybrid application in the European Union (EU).

It is useful at the beginning of a drug development journey to know what the goals are. If a company’s goal is to gain approval in the US and EU, it may be possible to create a plan to maximize potential efficiencies and reduce redundant efforts to support each regional approval. But to enable an effective strategy to fulfill the requirements of each regulatory authority, the plan and choices must be made early.

By evaluating the complete development program in the context of both US and EU requirements early in development, Sponsors can identify and develop strategies to create the most efficient development program while still addressing the unique requirements of each regional regulatory authority.

The US FDA 505(b)(2) and EU EMA Hybrid Regulatory Pathways

The United States (US) FDA’s 505(b)(2) submissions pathway is considered roughly equivalent to the hybrid application pathway in the European Union (EU). As such, several parallels exist between these pathways that can be used to support a more efficient global development program. Understanding the similarities and differences between the two can allow sponsors to optimize their approach to product development.

Approval of prospective medicinal products via either the US or the EU requires that all requirements of a full marketing application be fulfilled, potentially requiring full reports (or reference to full reports) of investigations of safety and effectiveness of a drug, where some of the information required for approval comes from studies that are not conducted by the applicant and for which the applicant has not obtained a right of reference. The supportive information for such applications can come from either published literature or findings of safety and effectiveness from the relevant regulatory authority for an approved product (“listed drug” or “LD” in the US or “reference medicinal product” or “RMP” in the EU). A 505(b)(2) application can reference EU RMP information, but an EU application must be based on EU-approved RMP.

While the two pathways appear similar, there are key differences that Sponsors should take into account if the goal is to market a product in both regions. The requirements for 505(b)(2) NDA – as well as issues and pitfalls of this submissions approach—have been discussed extensively by Premier Consulting’s 505(b)(2) experts.

In this discussion, we highlight key considerations for when an approval is sought using both the 505(b)(2) procedure in the US and the hybrid procedure in the EU, adding to previous discussion here on the Premier Consulting Blog. Further details on the EU hybrid applications can be found on the European Medicines Agency’s (EMA) website here.

Key Considerations in the US 505(b)(2) and EU Hybrid (or Alternative) Application Pathways:

  • Reference Drug: In general, the LD and RMP are similar, though some differences exist that may alter the requirements for approval between regions. In both the US and EU, the Sponsor can only rely on the finding of efficacy and safety from a relevant authority for a product that has been approved via a complete marketing application (NDA or MAA). However, methods of justifying such reliance often differ by region.
    • A 505(b)(2) does not require a reference drug, so a New Molecular Entity is possible for 505(b)(2). The EU requires a RMP approved in the EU. Thus, a 505(b)(2) can reference an EU RMP, as well.
    • In the US, the FDA’s regulations (21 C.F.R. § 314.3) See Premier Consulting’s blog on referencing a listed drug for a 505(b)(2) application. The use of a listed drug is affected by exclusivity timing and relevant patents.
    • In the EU, the reference medicinal product (RMP) can be for a different strength, pharmaceutical form, administration route or indication than the proposed product and must be identified in the application (product name, strength, pharmaceutical form, Marketing Authorisation Holder, Member State of source). Additionally, the data protection period for the RMP should have expired at the time of the application filing.
  • LD and RMP Source: In the US, sponsors relying upon the FDA’s finding of safety or effectiveness for a LD must justify that reliance by bridging to the US-approved product. Similarly, European authorities require that the RMP be the European-approved product. Sponsors are required to establish a bridge to the LD or RMP by comparing against the specific product to be relied upon meaning that separate comparisons to the US- and EU-approved products may be required unless the Sponsor can demonstrate that the US- and EU-approved products are manufactured by the same facility.
  • Prodrugs may be covered under 505(b)(2) with reliance on the FDA’s previous findings of safety and efficacy for the active moieties (additional requirements will almost certainly apply). In the EU, prodrugs are likely to require a full MAA comprising sponsor-conducted clinical and nonclinical studies.
  • Literature-only NDAs, discussed previously, that can be approved under 505(b)(2) may not qualify for an EU hybrid application under Article 10(3). However, these applications may be covered under Article 10(a) of Directive 2001/83/EC, as amended, and Annex I, Part II(1) (as Bibliographic Application). Bibliographic applications include pharmacological and toxicological tests or clinical trials results with detailed references to published scientific literature if the medicinal product’s constituent has a well-established medicinal use (in EU for at least 10 years), and safety and efficacy for a specific therapeutic indication.
  • Pediatric development plan: In the US, most 505(b)(2) applications are subject to the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c) which requires an assessment of safety and efficacy of the drug product in pediatric patients or justification for a waiver, deferral, or inapplicability of PREA, but pediatric plans differ in the EU.
  • While fixed combination(s) of previously approved drugs can utilize the 505(b)(2) NDA approval process, in the EU, these are covered under Article 10(b) of Directive 2001/83/EC and not Article 10(3) as hybrid medicinal products.


Similar regulations exist in both the US and EU that enable Sponsors to rely on information for which they do not have right of reference to support approval of a given product; however, requirements for approval may not align exactly for a product developed in both regions.

Whether the 505(b)(2) and the EU hybrid procedures can be utilized for parallel/simultaneous drug approvals in the US and the EU is not always clear from the outset of development. Each instance must be evaluated on a case-by-case basis as the requirements are product-specific in both regions.

Overall, both the US 505(b)(2) and the EU hybrid process offer the potential for a time- and cost-effective route to market. It is possible for Sponsors to achieve success in both markets with little to no delay. However, as noted here, the same application in the two regions may have different legal and regulatory bases, require vastly different approaches to regulatory interactions, and may be reviewed differently by regulatory authorities.

The regulatory scene in the EU is further complicated by the recent withdrawal of the United Kingdom (UK) from the EU. Therefore, it is critical to engage experts with ample experience in developing a global drug development strategy for a swift and successful path to market. For more, contact us.