Executive Summary

The U.S. Food and Drug Administration’s (FDA) Product-Specific Guidances (PSGs) have long served as a strategic foundation for generic drug development. These guidances provide clarity on how to demonstrate bioequivalence (BE) for specific Reference Listed Drugs (RLDs), helping sponsors align clinical trial design with regulatory expectations and accelerate time-to-market.

However, a sharp decline in PSG issuance since late 2024 has disrupted the regulatory landscape. This white paper explores the implications of this slowdown and offers actionable strategies for sponsors navigating this uncertainty.

1. The Role of PSGs in Generic Drug Development

PSGs are critical tools that communicate the FDA’s current thinking on how to demonstrate BE for specific RLDs. They are essential for:

• Aligning clinical trial design with regulatory expectations
• Reducing the risk of ANDA rejection
• Accelerating time-to-market for generic products

Grounded in 21 CFR 320.24, PSGs ensure that BE testing—whether in vivo or in vitro—is accurate, sensitive, and reproducible. For developers, PSGs serve as both a roadmap and a benchmark for regulatory success.

2. GDUFA III Commitments vs. Reality

Under the Generic Drug User Fee Amendments Reauthorization (GDUFA III), effective October 1, 2022, the FDA committed to:

• Issuing PSGs for 50% of complex NDAs within 2 years
• 75% within 3 years
• 90% of non-complex NCEs within 2 years

These targets were designed to enhance transparency and predictability in generic drug development. However, as of May 2025, no new PSGs have been published since November 2024, despite dozens being scheduled. This slowdown is attributed to internal restructuring and staffing reductions at the FDA, including the loss of key policy personnel.

3. Clinical and Regulatory Implications

The PSG slowdown has created significant challenges for generic drug developers:

• Protocol Design: Without PSGs, sponsors face uncertainty in selecting appropriate endpoints, study populations, and analytical methods.
• Safety Monitoring: Ambiguity around RLD labeling requirements, including boxed warnings and contraindications, complicates subject screening and monitoring.
• Data Compliance: Lack of updated guidance on electronic submission formats under Section 745A(a) of the FD&C Act increases the risk of formatting errors and review delays.
• Regulatory Engagement: Sponsors must now rely more heavily on Pre-ANDA meetings and Controlled Correspondences to clarify expectations and reduce development risk.

4. Strategic Recommendations

To mitigate the risks associated with the PSG slowdown, sponsors should:

• Engage early with the FDA through Pre-ANDA meetings to clarify regulatory expectations.
• Monitor the FDA’s guidance pipeline and Upcoming PSGs portal for any new developments.
• Leverage experienced CROs that can adapt trial design and regulatory strategy in the absence of formal guidance.
• Invest in regulatory intelligence to anticipate changes and proactively adjust development plans.

5. Why Partner with Us?

As a trusted clinical trial services provider, we help sponsors navigate regulatory uncertainty with confidence. Our services include:

• Protocol development aligned with evolving FDA expectations
• BE/BA study design and execution
• Seamless support for regulatory application preparation and submission, including expert eCTD publishing, ANDAs, and DMFs
• Real-time pharmacovigilance and safety monitoring
• FDA-compliant data management systems

By combining regulatory foresight with operational agility, we help sponsors accelerate development timelines and enhance submission success—even in uncertain regulatory environments.

Conclusion

The FDA’s PSG slowdown is reshaping the generic drug development paradigm. Sponsors must adapt quickly to maintain momentum and minimize regulatory risk. In this evolving landscape, partnering with a CRO that understands the nuances of FDA policy and clinical trial execution is more critical than ever.

Contact us today to discuss how we can support your regulatory strategy and help bring your generic products to market with confidence.