US FDA’s Rising First-Cycle Complete Response Rate Draws Congress’ Attention

The House Appropriations Committee wants the US Food and Drug Administration to explain the recent rise in complete response letters.

The committee also wants the agency to halt the availability of counterfeit GLP-1 agonist products and supports the planned re-examination of the safety and efficacy of the abortion drug mifepristone, according to report language attached to the committee’s fiscal year 2026 FDA funding bill.

The committee began marking up the 2026 Agriculture, Rural Development, FDA and Related Agencies appropriations bill on 11 June. However, the markup recessed in late afternoon for the annual congressional baseball game. The markup was expected to continue after press time.

The funding bill, which an appropriations subcommittee cleared a week earlier on a party-line vote, would give the FDA $6.68bn.

The agency would receive $3.2bn in budget authority, a decline of $375.7m, or 10.5%, from the current funding level, but $33.1m more than requested by the Trump Administration. User fees would total $3.48bn.

Before adjourning, the committee rejected an amendment from Rep. Steny Hoyer, D-MD, that would have required the FDA and other agencies to demonstrate before initiating any reductions-in-force or deferred resignation programs that the moves would not reduce revenue or increase costs, and the affected employees were no longer necessary to carrying out the agencies’ mission.

Congressional Directives

The directives in the bill’s report language reflect committee members’ policy priorities and seek FDA action on several drug and biologic issues, many of which are repeated from year to year.

Among the report’s directives not included in the FY 2025 funding bill was a demand for more details underlying the rise in first-cycle CRLs.

The committee is aware of a recent decrease in FDA first-cycle approval rates with an increasing number of CRLs issued to drug manufacturers, the report states.

“This decline is observed across all human drug review programs, including novel drug approvals,” the committee wrote. “In keeping with the PDUFA performance goals to increase the first-cycle approval rate for medicines that are ultimately approved, the committee directs FDA to provide a report with an analysis of how issues that led to CRLs for medicines over the past five years could have been resolved within the first review cycle.”

In 2024, the FDA issued 16 CRLs for novel drug and biologic agents, a 21% CRL rate. At least two of every 10 agency decisions on novel agents resulted in a CRL for the fourth straight year, according to a Pink Sheet analysis.

The 2015 CRL rate was 5% in 2015.

Quality topics were reported in nine CRLs, while seven included clinical issues. One-third of the quality CRLs involved a third-party manufacturer.

Counterfeit GLP-1s

The report also raises concern about the “production of counterfeit and untested GLP-1 and GIP/GLP-1 medications” and encourages the FDA to exercise its existing authority to combat illegal distribution of the products.

The committee wants an agency briefing within 60 days of enactment and a report within 120 days outlining a plan to stop the distribution of counterfeit GLP-1 and GIP/GLP-1 medications.

The committee also raised “deep concern over the health risks posed by illegal importation of unapproved and misbranded drugs, particularly through third-party brokers facilitating access via employer-sponsored health plans,” the report states.

The drugs lack FDA oversight, potentially containing incorrect dosages, unknown ingredients or contaminants, which can have serious health consequences for vulnerable populations such as patients with HIV, cancer or hepatitis.

The committee directed the FDA within 180 days of enactment to provide a comprehensive report addressing the issue, “including safety risks, verification challenges, enforcement actions and recommendations for strengthening oversight.”

Cell/Gene Therapy Modernization

The report states the FDA should continue its work modernizing regulatory pathways for cell and gene therapies, including incorporating innovative clinical trial designs and establishing pathways that embrace novel endpoints for safety and efficacy.

“Given the transformative potential of these therapies, the committee encourages enhanced alignment between FDA centers and the patient community regarding risk tolerance,” the report states. “The FDA should consider that for conditions where cell and gene therapies offer significant clinical outcomes, including type 1 diabetes, a broader risk-benefit assessment may be warranted beyond viewing these as rescue therapies.”

“The committee also recommends utilizing accelerated development pathways for therapies demonstrating significant clinical evidence and/or in instances of significant patient unmet need, such as when no other therapeutic alternative exists,” the committee wrote.

The committee also stressed the need “for clear communication and proactive engagement with sponsors to address regulatory concerns efficiently, ensuring that clinical holds are applied judiciously and with transparent rationale.”

Center for Biologics Evaluation and Research Director Vinay Prasad recently said he is committed to expediting drug approvals for life-threatening conditions using surrogate endpoints.

At a recent roundtable on cell and gene therapies, he also appeared open to loosening regulatory oversight of early clinical trials for bespoke gene therapies.

Mifepristone Review

The committee also wants a briefing after the FDA’s review of new data on the safety and efficacy of mifepristone.

At his confirmation hearing in March, FDA Commissioner Martin Makary said he wanted to review the data on mifepristone, but would not commit to maintaining the drug’s current prescribing requirements.

In May, Health and Human Services Secretary Robert F. Kennedy Jr. said the agency would review a conservative think tank’s study of serious adverse events from mifepristone.

“The committee supports the FDA conducting an internal review in light of new findings and data and directs the FDA to provide a briefing to the committee within 30 days upon the completion of any internal reviews undertaken at the agency,” the report states. “This briefing shall include an overview of the review process, findings, and any subsequent regulatory actions or guidance considerations the agency may pursue.”

Rep. Lauren Underwood, D-IL, objected to the mifepristone review language, calling it a waste of taxpayer resources and an attack on women’s bodily autonomy.

The report includes numerous directives that were part of the FY 2025 funding bill, but never enacted, including a request for FDA clarification that survival data can be used to support accelerated approval for neurological diseases like amyotrophic lateral sclerosis.

The committee wants the agency to ensure its application review practices are consistent across the drug and biologics centers and to consider a single, shared system Risk Evaluation and Mitigation Strategy for biosimilars and their reference products.

A manager’s amendment to the bill adopted by the committee states that within 30 days of enactment, the FDA commissioner must submit to the House and Senate appropriations committees a “detailed obligation plan delineated by program, project, and activity, as defined in the report” for all amounts made available under the bill and appropriations acts that remain available for obligation, including appropriated user fees.

The plan should include the estimated obligations for each program, project or activity by fiscal quarter, source appropriation, and number of full-time equivalent positions supported.