- The U.S. Food and Drug Administration (FDA) recently issued two new guidance documents governing details of the Accelerated Approval Program, including a focus on product withdrawal and requirements for ongoing confirmatory trials.
- Accelerated Approval continues to be controversial, with benefits and drawbacks being debated by stakeholders.
- The intersection between the FDA’s Accelerated Approval Program and drug pricing issues, including proposals on Accelerated Approval drugs by the Medicare Payment Advisory Commission (MedPAC), the Centers for Medicare and Medicaid Services’ (CMS’s) drug pricing models under the Center for Medicare and Medicaid Innovation (CMMI) and CMS’s implementation of the Inflation Reduction Act (IRA), is still developing.
- The incoming Trump administration’s position on Accelerated Approval and related drug pricing issues has yet to be clarified.
On Dec. 6, 2024, the FDA released draft guidance, marking a significant development in the regulatory framework for therapies approved under the Accelerated Approval Program. The 22-page guidance document, “Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics,” (Accelerated Approval Guidance), offers insights into qualifications for accelerated drug approvals and provides a framework for withdrawing approvals when confirmatory trials fail.
On Jan. 7, 2025, the FDA introduced an additional draft guidance, “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway” (Confirmatory Trial Guidance). This guidance focuses on confirmatory trials required for drugs approved under the Accelerated Approval Program. The guidance emphasizes the importance of timely completion of confirmatory trials to verify clinical benefit and provides clarity on FDA expectations around trial design and data requirements.
The FDA is soliciting public comment on the Accelerated Approval Guidance until March 6, 2025, and on the Confirmatory Trial Guidance document until March 10, 2025.
Background on Accelerated Approval Controversies
These updates come amid ongoing developments related to drugs approved under the Accelerated Approval Program. For example, on the same day the FDA released its draft guidance, CMS intervened to ensure Medicare Advantage plans cover Qalsody (tofersen), an Accelerated Approval drug for amyotrophic lateral sclerosis (ALS), after it found insurers incorrectly classifying the drug as experimental.[1] On Dec. 17, 2024, the FDA rejected full approval of the only currently available drug that reverses the anticoagulant effect of blood thinners, due to safety concerns pursuant to a complete response letter (CRL) from the agency. The drug was marked under an Accelerated Approval granted by the FDA in 2018, and the company reports that it plans to keep the product on the market despite the CRL and lack of full approval.[2]
The Accelerated Approval Program
The FDA introduced the Accelerated Approval Program in regulations in 1992, later codified under the Food & Drug Administration Safety Innovations Act of 2012, to expedite therapies for serious or life-threatening conditions that address unmet medical needs.[3] Drugs that qualify for the Accelerated Approval Program must meet specific criteria including therapies for conditions that:
- Are life threatening or serious (e.g., cancer, certain chronic diseases and rare conditions)
- Address unmet medical needs, meaning no available therapies or limited effective treatments exist
- Show evidence of effectiveness through surrogate endpoints or early clinical data, such as evidence that a drug shrinks tumors.
By allowing approval based on certain surrogate or intermediate clinical endpoints, the program grants early access to patients for promising treatments while requiring manufacturers to confirm clinical benefits through post-approval trials. The pathway continues to play a critical role in providing access to treatments for patients with serious or life-threatening conditions.
Key Concerns With and Benefits of Accelerated Approval
While the Accelerated Approval Program has led to breakthroughs in oncology, rare diseases and infectious diseases, it has also raised concerns about high drug prices, delayed confirmatory trials and uncertain clinical benefits in certain cases. The FDA’s new draft guidance documents aim to address these concerns, providing clearer expectations for drug approval and post-approval requirements to ensure the continued efficacy and safety of treatments approved under the pathway.
Key concerns include:
- High Drug Prices. Accelerated Approval drugs often enter the market at premium prices because of their value to overall patient care. A 2022 pricing analysis found that, on average, drugs granted Accelerated Approval have 26% more price increases over 10 years than other medicines.[4] One example of the impact of high prices is the Alzheimer’s treatment Aduhelm (aducanumab), which was initially listed for $56,000 per person, per year and was approved based on surrogate endpoints.[5] Following approval, CMS announced a 14% increase in Medicare Part B premiums for 2022, with approximately half of the increase attributed to the need to generate revenue to pay for Medicare patients taking Aduhelm. At the time, Aduhelm raised broader concerns about Accelerated Approvals, leading to Office of Inspector General evaluations of the pathway.[6]
In response to the high costs and uncertain clinical benefits of Aduhelm, CMS issued a national coverage determination in 2022 that limited coverage of any monoclonal antibodies, including Aduhelm, to clinical trials. This policy effectively curtailed the availability of Aduhelm, limited its commercial prospects and led to Biogen discontinuing the drug.[7] - Delayed Confirmatory Trials. Sponsors may delay post-approval trials or the FDA may approve drugs without meeting all efficacy endpoints. While these measures are sometimes necessary to provide patients with urgent medical needs access to potentially life-saving therapies, they can also lead to prolonged uncertainty about a drug’s clinical effectiveness. In June 2023, the FDA approved a muscular dystrophy drug through the Accelerated Approval pathway, despite the drug missing a key functional endpoint.[8] A review of the Accelerated Approval pathway for nononcology drug indications between 1992 and 2018 analyzed 57 nononcology indications approved through the Accelerated Approval pathway.[9] The review found that approximately 20% of confirmatory trials failed to meet FDA requirements and, in certain cases, clinical efficacy was unconfirmed.
- Uncertain Clinical Benefits. In some instances, Accelerated Approvals are withdrawn when post-market data fails to support continued use and safety concerns arise. In 2024, a sickle cell disease therapy was withdrawn from worldwide markets after data showed a higher risk of deaths and complications in treated patients.[10] In February 2023, the FDA withdrew approval for a drug for multiple myeloma after confirmatory trials failed to demonstrate clinical benefit. The FDA further determined that the drug was not safe or effective under its conditions of use.[11] In 2022, the FDA pulled approval for a cancer drug based on ongoing safety concerns, including possible increased risk of death.[12]
A study evaluating cancer drugs approved through the FDA’s Accelerated Approval pathway from 2013 to 2017 found that while 63% of these drugs were converted to regular approval, only 43% demonstrated a clinical benefit in confirmatory trials after over five years of follow-up.[13] Cancer drugs Clolar (clofarabine) and Xydelig (idelalisib) exemplify this trend. Clolar received Accelerated Approval in 2002, yet after 18 years, it was withdrawn from the market due to a lack of clear clinical benefit for its target population. Similarly, Xydelig saw an eight-year period of approval before being withdrawn due to ongoing safety concerns, including fatal adverse effects and serious side effects related to immune system function.
Legal and Regulatory Context
In response to some of these concerns, the Consolidated Appropriations Act (CAA) of 2023 granted the FDA additional authorities and imposed additional obligations regarding Accelerated Approvals.[14] It required the FDA to set conditions for confirmatory trials leading to the creation of the Accelerated Approval Guidance and the Confirmatory Trial Guidance. The CAA also established new procedures for withdrawing products if they fail to demonstrate clinical benefit. These changes aimed to improve accountability, but also carry implications for drug pricing and market strategies.
Overview of FDA’s New Draft Guidance Documents
Key updates under the Accelerated Approval Guidance and the Confirmatory Trial Guidance include:
a. Confirmatory Trials. The FDA now has authority to require that a confirmatory study already be underway before granting approval under the Accelerated Approval pathway. The Confirmatory Trial Guidance states: “If FDA determines that a confirmatory trial must be underway prior to Accelerated Approval and the trial is not underway, FDA does not intend to grant Accelerated Approval until this deficiency is addressed.” In some cases, the FDA may even require that trial enrollment be complete at the time of approval.[15]
The Accelerated Approval Guidance states that confirmatory trials must begin early, often by the time of approval, with clearly defined milestones to ensure completion.[16] Trials should efficiently verify clinical benefits and align with the drug’s intended use. Delays or lack of due diligence could result in disciplinary action, including withdrawal of approval.
The FDA acknowledges that in certain cases — such as in the development of drugs for rare diseases for which patient enrollment is challenging — it may not require the confirmatory trial to be “underway” at the time of approval. This will be evaluated on a case-by-case basis. The FDA will generally consider a confirmatory trial to be “underway” if three criteria are met:
- The trial has a target completion date that is consistent with diligent and timely conduct of the trial, considering the nature of the trial’s design and objectives.
- The sponsor’s progress and plans for post-approval conduct of the trial provide sufficient assurance to expect timely completion of the trial.
- Enrollment of the confirmatory trial has been initiated.
The FDA may consider other factors, including patient enrollment accrual rates, the number of actively recruiting sites, projected dates of site activation and relevant benchmarks. The FDA may also consider protocol designs that include, for example, pre-planned assessment of surrogate or intermediate endpoints from an ongoing trial that will continue after the approval date.
b. Endpoint standards. The Accelerated Approval Guidance clarifies the meanings of two types of endpoints that can be used as bases for Accelerated Approval, a surrogate endpoint that is considered reasonably likely to predict clinical benefit and/or a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit.
Determining whether an endpoint is reasonably likely to predict clinical benefit involves biological plausibility and empirical evidence.[17] The FDA stresses that while these endpoints do not need to fully prove clinical benefit at the time of approval, they must demonstrate sufficient potential to predict positive patient outcomes. In making the judgment as to whether a drug’s effect on a given endpoint is reasonably likely to predict clinical benefit, the FDA considers all relevant evidence and may consult external experts.
The FDA also recommends early consultation between sponsors and reviewing agencies for surrogate and clinical endpoints and stresses the importance of developing novel endpoints for more efficient drug development.
c. Withdrawal procedures. The Accelerated Approval Guidance clarifies the FDA’s authority to withdraw approvals if confirmatory trials fail to demonstrate benefit or are not conducted diligently. The FDA can withdraw approval if sponsors fail to conduct confirmatory trials on time, trials fail to confirm clinical benefits, safety concerns arise or promotional materials misrepresent the drug.[18] Sponsors receive formal notice and can appeal, request advisory committee reviews or meet with FDA officials. The guidance emphasizes public transparency, with announcements and responses published.
d. Promotional oversight. The FDA heightened oversight of promotional materials for drugs granted Accelerated Approval. Sponsors must align promotional claims with verified benefits, with materials subject to FDA review before dissemination. Claims must be accurate, balanced and consistent with the evidence available at the time of approval. The FDA also highlighted its authority to address misleading or unsubstantiated promotional materials.
Pricing and Economic Considerations
While the FDA’s draft guidance focuses on clinical efficacy, the economic sustainability of Accelerated Approval drugs remains a critical issue. In 2023, the high costs of Accelerated Approval drugs and uncertainty of clinical benefits prompted MedPAC — a quasi-independent body that advises Congress on Medicaid/Medicare issues — to recommend legislative reforms.[19] These recommendations included capping payments for Accelerated Approval drugs until a manufacturer can verify a drug’s clinical benefit. MedPAC also proposed creating a valuation system to assess the initial price of these drugs involving setting a cap based on estimated value while awaiting confirmation of clinical benefit and implementing rebates to refund the difference between the capped price and the average sales price once clinical efficacy is proven. How such a valuation would be determined remains unclear, as there is no standardized formula for measuring the value of an unconfirmed drug.[20] MedPAC recommended using bundled pricing to group drugs with similar health effects, reducing Medicare Part B’s average-sales-price-based add-on payments for high-cost drugs and introducing fixed-dollar caps.
As part of CMS’s response to President Biden’s directive in Executive Order 14087 to take steps to lower drug prices, in addition to the legislative changes mandated under the drug price negotiation program of the IRA,[21] CMMI had proposed the Accelerating Clinical Evidence Model in February 2023. CMMI reported that 104 out of 278 drug applications approved through the Accelerated Approval pathway have incomplete confirmatory trials, 35 (34%) of which have at least one trial past their originally planned completion date. Between 2018 and 2021, Medicare and Medicaid together spent an estimated $18 billion on Accelerated Approval Program therapies that were past their originally scheduled confirmatory trial completion date.[22] The model aims to explore targeted adjustments in Part B fee-for-service payments for drugs approved under the Accelerated Approval Program. It is designed to develop payment methods for Accelerated Approval drugs in a way that incentivizes timely completion of confirmatory trials, reduces Medicare spending and ensures that quality of care is maintained or improved.
CMMI’s model had already faced opposition from members of Congress. In March 2023, a group of Republican senators sent a letter to HHS Secretary Xavier Becerra and CMS Administrator Chiquita Brooks-LaSure, expressing concerns that the proposed model would interfere with the FDA’s role in regulating drugs and the purpose of the Accelerated Approval pathway. They argued that the model could stifle innovation and undermine the FDA’s authority to make independent regulatory decisions.[23] In an October 2023 update, CMMI, in collaboration with the FDA, analyzed trends for Part B drugs approved through the Accelerated Approval pathway. The analysis showed that over 90% of Accelerated Approvals for Part B drugs in the past five years were for oncology indications, where confirmatory trials are generally completed within five years. [24] Outside oncology, some drugs, particularly those approved for orphan diseases, have experienced longer delays in confirmatory trials due to challenges such as limited treatment options and difficulties enrolling participants.
President Trump has now rescinded Executive Order 14087 on his first day of office,[25] seemingly removing CMMI’s executive mandate to execute the Accelerating Clinical Evidence Model specifically, although an executive order isn’t needed for CMMI to undertake demonstration projects. It remains to be seen how the new administration and CMS leadership will address pricing for Accelerated Approval products.
The IRA itself broadly allows CMS to make an assessment of the relevant clinical data supporting a drug’s approval by the FDA into account when setting the “Maximum Fair Price” under the drug negotiation program.[26] This includes data in applications and approvals by the FDA, as well as scientific evidence about alternative treatments including whether the drug is a therapeutic advance, its comparative effectiveness and therapeutic alternatives, and the extent to which the drug addresses unmet medical needs. It remains to be seen whether CMS’s analysis of these factors is influenced if not governed by the FDA’s view of the same or similar issues when it determines the appropriateness of an Accelerated Approval. Given CMMI’s and CMS’s dim view of Accelerated Approval products and proposals to significantly reduce or eliminate federal reimbursement for such products, it will be important to monitor how CMS addresses IRA price negotiation factor for drugs that are marketed under this approval pathway. CMS has already said in its Year 2027 Medicare Drug Price Negotiation Program Draft Guidance memo that it will focus on clinical benefit, productivity and quality of life measures in its assessment,[27] which will, by definition, be absent for most Accelerated Approval pathway drugs that depend on a surrogate marker for approval.
What’s Next?
The FDA has explicitly stated that additional guidance documents may be forthcoming in its ongoing implementation of the CAA. These may include conditions for progress of confirmatory trials and withdrawal of approval if the trial is not conducted “with due diligence.” The FDA may also issue guidance on the precise update reports required for sponsors to submit to FDA on the progress of confirmatory trials every 180 days as provided for under the CAA.[28]
Potential Impacts
Stakeholders in the pharmaceutical and healthcare industries should prepare for potential impacts related to Accelerated Approval drugs. First, regulatory scrutiny may increase, with heightened expectations for timely confirmatory trials and more rigorous endpoint validation. Delays or noncompliance with these requirements could lead to consequences including payment caps, expedited withdrawals of approval or reduced reimbursements. Additionally, economic pressures will likely emerge as payment caps and efforts to reduce drug prices may force companies to rethink their pricing strategies and reconsider the commercial viability of Accelerated Approval therapies.
Additionally, stakeholders may find opportunities to collaborate, particularly during the FDA’s comment period, which allows for input on shaping the final guidance on Accelerated Approval. However, the evolving political landscape also poses uncertainties. While the incoming administration has not yet taken a clearly stated position on the Accelerated Approval pathway, there have been statements regarding the high cost of drugs. Robert F. Kennedy Jr., if confirmed as head of the Department of Health and Human Services, has suggested he would bring the FDA back to “evidence-based science.” Kennedy also has complained that the FDA is preventing important medications from reaching the public due to its conservative approach to drug approvals. This could lead to actions that limit or eliminate the Accelerated Approval pathway, heighten enforcement of Accelerated Approval requirements, or open up the Accelerated Approval pathway even further to allow earlier patient access to important new medicines.
[1] Private Medicare plans must cover Biogen’s ALS drug, US agency says | Reuters
[2] J&J’s subcutaneous Rybrevant, AZ’s Andexxa are rejected by FDA | Fierce Pharma.
[3] Accelerated Approval | FDA.
[5] FDA Accelerated Approval Pathway: Controversies and Reform – National Center for Health Research
[7] Biogen discontinues Alzheimer’s medication Aduhelm | CNN.
[8] Sarepta’s Recent Elevidys Presentations Leave Duchenne Community Wanting – BioSpace.
[10] Pfizer Takes Sickle Cell Drug Oxbryta Off Global Market, Cites Risk of Death – BioSpace; FDA approves novel treatment to target abnormality in sickle cell disease | FDA.
[11] FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide) | FDA.
[12] FDA Pulls Approval for TG Therapeutics’ Cancer Drug – BioSpace.
[13] Fewer Than Half of Accelerated Approval Drugs Showed Clinical Benefit in Confirmatory Trials After Five Years | News Releases | AACR; Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval – PubMed.
[14] Accelerated approval: FDA revises guidance to reflect revised withdrawal procedures | RAPS
[15] Confirmatory Trial Guidance, at 4.
[16] Expedited Program for Serious Conditions—Accelerated Approval of Drugs and Biologics (pg. 12).
[17] Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics (pg. 9).
[18] Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics (pg. 15).
[19] June 2023 Report to the Congress: Medicare and the Health Care Delivery System – MedPAC
[20] Report to the Congress: Medicare and the Health Care Delivery System | June 2023 (Pg. 27).
[22] HHS | A Report in Response to the Executive Order on Lowering Prescription Drug Costs for Americans
[25] Executive Order, January 20, 2025: Initial Rescissions Of Harmful Executive Orders And Actions – The White House.
[26] Inflation Reduction Act, section 1194(e)(2).
[27] See, Memorandum from M. Seshamani, M.D., Ph.D., CMS Deputy Administrator and Director of the Center for Medicare, May 3, 2024, at 85. CMS says it will also “consider” FDA’s guidance on unmet medical needs determinations. Id.
[28] Confirmatory Trial Guidance, at 6, fn. 13.