Ex-US Approaches to Drug Accelerated Approval

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Summary

International methods of expedited approval offer approaches that policymakers may adopt to reform the US system, as signaled in recent legislative proposals.

The Accelerated Approval Pathway (AAP) used by the Food & Drug Administration (FDA) is designed to bring priority therapies to the market quickly and support patient access for conditions with unmet medical need. Following increased scrutiny of the program, some policymakers have expressed interest in reforming parameters of the AAP, such as requiring time-limited approvals based on confirmatory trials in line with international approaches. As policymakers consider potential reforms to the program, there may be additional comparisons of US and ex-US programs in comparable markets. Product sponsors should understand international approaches to expedited approval as reforms may move quickly through user fee amendment (UFA) negotiations later this year.  

Background on the Accelerated Approval Pathway

The AAP was initiated in the early 1990s by the FDA to provide early access to priority drugs and biologics and has since granted more than 230 approvals for therapeutics and preventive products. The approval of aducanumab for the treatment of Alzheimer’s disease in 2021 renewed conversations on the program’s use of surrogate endpoints and single-arm trials, total costs to US healthcare systems, and FDA oversight. Recent congressional proposals have introduced options for AAP reform that appear to draw on international practices. And in January, the FDA’s director of the Oncology Center of Excellence highlighted the successes of the AAP to deliver treatments to patients but also noted the agency’s limited authority to enforce completion of confirmatory trials. He suggested that policymakers may look to global counterparts for potential reforms. In light of recent commentary and congressional policy proposals, Avalere examined publicly available information on international expedited approval pathways in the European Union (EU), United Kingdom (UK), and Australia to compare similarities and differences to the AAP in the US.

Requirements and Timelines for Similar Programs in Other Countries

Examples of analogue programs include the European Medical Agency’s (EMA) “conditional market authorization” program, the UK Early Access to Medicines Scheme for products that address unmet medical needs and have promising early clinical trial data, and Australia’s provisional pathway for products with preliminary data with benefits that outweigh the potential risks. In contrast to the US, the EMA places time limits on early approvals for certain drugs (also called conditional market authorizations), do not rely on surrogate endpoints to estimate clinical benefits, and use accelerated approval primarily for new molecular entities (NMEs). Each program has requirements for post-approval evidence generation and time limits on the designation (e.g., up to 5 years) as well as distinct eligibility criteria based on the scope of each program. For example, the AAP has been in existence since 1992, and at least 236 products have gone through this pathway, compared to the European conditional market authorization program, which began in 2004 and approved 30 products over a 10-year period, according to public reports.

Table 1. Comparison of US and Ex-US Programs
US Accelerated Approval Pathway​ Expedited Approval in Comparable Organization for Economic Development Countries​
History​
  • Pathway was established in 1992​
  • 236 products received accelerated approval, 111 of which were converted to standard approvals between 1992 and 2021​
  • Programs were established mid-2000s to late-2010s​
  • Typically fewer applications are submitted and approved per year based on eligibility as compared to the US​
Application Requirements
  • Post-marketing studies are required to confirm clinical benefits for full approval​
  • Designation does not expire but may be voluntarily withdrawn​
  • Assessment requires data demonstrating a likely benefit using surrogate endpoints​
  • Post-marketing studies are required as part of the application process​
  • Designation may last for a short period of time but may be renewed​
  • Designation expires after 5–6 years if clinical benefits have not been confirmed, or may be voluntarily withdrawn​
  • Assessment relies on less comprehensive clinical evidence than normally required based on the immediate benefit/risk profile​
Eligibility Criteria​
  • Eligible products must:​
    • Address serious conditions​
    • Demonstrate meaningful advantage over available therapies​
    • Supplemental applications are permitted​
  • Products must address seriously debilitating or life-threatening diseases with unmet medical need​
  • Eligibility may include products for emergency use​
  • Generally only new molecular entities are permitted​

Policy Interest in International Approaches

Congressional proposals have introduced options for AAP reform that appear to draw on international practices and may be combined with upcoming FDA reforms via UFA negotiations later this year. H.R.6963, the Accelerated Approval Integrity Act of 2022, would codify the FDA’s authority for expedited withdrawal of approval if post-market study requirements are not met and—similar to expedited approval in the EU—would mandate an expiration of the designation 1 year after the target date for clinical trial completion or 5 years after the product is first approved. H.R.6963 would place significant limits on the approvals of AAP drugs and has notable parallels with the approach taken in Europe, despite inherent programmatic differences between the AAP and similar expedited approval programs in other high-income countries.

Future Outlook

As Congress looks to update the US’s drug development paradigm and increase program efficiency through UFA reauthorization later this year, it may consider the parameters of comparable programs in other countries. Reforming the AAP could impact patient access to breakthrough therapies that is a result of the program’s unique eligibility criteria and emphasis on surrogate endpoints rather than standard clinical data. Stakeholders should consider the long-term impacts, strengths, and weaknesses of different programs in their approach to policy advocacy.

Avalere can help you examine approaches to international health policy and how potential reforms may impact drug coverage and ongoing clinical development programs. To learn more about how Avalere can support you, connect with us.

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