History is replete with cautionary tales about the dangers of acting on insufficient evidence in pursuit of urgent goals. The 2003 invasion of Iraq, justified by unproven claims that Iraq possessed weapons of mass destruction, can be seen as a form of “accelerated approval” for a war that led to geopolitical instability and mass casualties. The Challenger space shuttle disaster in 1986 reflected a “go” decision, where pressure to maintain schedules overrode expressed safety concerns and led to tragic consequences. Similarly, the Flint water crisis of 2014 stemmed from a rushed decision to switch the city’s water supply without adequate safety review or corrosion control, leading to widespread lead poisoning and long-term damage to public health and trust.
In drug regulation, the stakes of acting prematurely are no less consequential. The FDA established an accelerated approval pathway in 1992 during the HIV/AIDS crisis to allow earlier market access for drugs treating serious or life-threatening conditions. This mechanism permits drugs to be approved on the basis of surrogate endpoints — indirect measures such as increases in CD4 cell counts (which reflect immune function in HIV patients), tumor shrinkage, or biomarker changes — rather than waiting for direct evidence of clinical benefit like improved survival. The goal is noble: to provide hope and potentially life-saving treatments to patients with urgent needs. However, this expedited path raises critical questions about the balance between speed and certainty.
Motivations and benefits of accelerated approvals
Accelerated approval serves the interests of multiple stakeholders, each motivated by distinct, sometimes overlapping, concerns.
For drug manufacturers, the benefits are clear: earlier market entry leads to quicker revenue streams, extended effective patent life, and heightened investor confidence. FDA approval, even if provisional, permits full-scale marketing and significantly increases the likelihood of payer coverage.
Patient advocates often champion accelerated approvals as a lifeline, especially for rare or life-threatening diseases with no existing treatments. These designations provide early access to potentially transformative therapies and instill hope among patients facing otherwise bleak prognoses.
For providers, accelerated approvals can offer new treatment options where none previously existed, allowing them to address urgent patient needs more effectively.
For regulators, accelerated approval offers flexibility — a mechanism for addressing public demand for innovation while maintaining a structured oversight process. Regulators often face political pressure from lawmakers seeking faster access to treatments, as well as public pressure from advocacy groups demanding urgent action.
Yet payers are often less enthusiastic. They face the financial burden of covering high-cost drugs with uncertain benefits, leading to difficult coverage decisions.
The risks of accelerated approvals
Despite the benefits, accelerated approval carries at least seven significant risks.
1. Safety and efficacy concerns
Drugs granted accelerated approval often enter the market with limited clinical data. For instance, Elevidys (delandistrogene moxeparvovec), approved in 2023 for Duchenne muscular dystrophy, was linked to the death of a patient last March due to acute liver injury. The FDA had approved the therapy despite internal concerns about its effectiveness.
Similarly, Aduhelm (aducanumab) was approved in 2021 for Alzheimer’s disease based on amyloid plaque reduction, despite inconclusive evidence of cognitive benefit and concerns over serious safety issues like amyloid-related imaging abnormalities (ARIA), or brain swelling. Medicare restricted coverage because of these uncertainties.
2. Economic waste and opportunity cost
Accelerated approvals often apply to high-cost specialty drugs. When such treatments fail to deliver, the economic impact can be staggering. Lartruvo (olaratumab), approved for soft tissue sarcoma in October 2016, was withdrawn in 2019 after confirmatory trials showed no survival benefit. Substantial resources were allocated to a drug ultimately proven ineffective, with approximately $300 million in global sales — paid by plan sponsors and patients — before its withdrawal.
3. Delayed or undermined confirmatory trials
Post-approval trials intended to confirm benefit are frequently delayed or underenrolled. Patients and physicians may prefer the marketed treatment over participation in clinical studies, and sponsors may deprioritize costly confirmatory studies when financial returns are already being realized. Although the FDA has the authority to withdraw approval to enforce timely completion of confirmatory trials, this and other enforcement mechanisms are rarely used promptly — allowing drugs to remain on the market without validated benefits. Enrollment challenges delayed confirmatory trials for Mylotarg (gemtuzumab ozogamicin), which was approved under accelerated approval in 2000 for acute myeloid leukemia and remained available for nearly a decade before its withdrawal in 2010.
4. Failure to withdraw ineffective drugs
Tecentriq (atezolizumab) was granted accelerated approval in 2016 for bladder cancer. However, confirmatory trials failed to demonstrate a survival benefit, and it was not until 2021 that the FDA and the manufacturer voluntarily withdrew the indication. This delay illustrates how ineffective treatments can remain available for years, despite lacking confirmed benefits.
5. Retreatment barriers in gene therapy
A key concern with gene therapies is that once administered, the body may mount an immune response that prevents future treatment with the same or similar viral vectors. This creates a one-shot opportunity with potentially irreversible consequences if the therapy fails. Elevidys exemplifies this risk: Once given, the patient may be ineligible for treatment with other AAV-based gene therapies.
6. Ongoing uncertainty and erosion of trust
Some drugs granted accelerated approval remain on the market despite growing concerns over their safety or efficacy. For example, Farydak (panobinostat) was granted accelerated approval in 2015 for multiple myeloma and continues to be marketed despite limited uptake and ongoing questions about its clinical benefit relative to toxicity. Similarly, Ocaliva (obeticholic acid), approved in 2016 under the accelerated approval pathway for primary biliary cholangitis, has faced warnings from the FDA about risks of serious liver injury — yet remains available. These ongoing uncertainties highlight a critical risk: When regulators fail to act decisively on emerging evidence, public trust in the FDA’s ability to safeguard patients can erode. Patients and providers may lose confidence in the approval process, and skepticism about new therapies may increase, even when they are truly beneficial.
7. Precedent setting and regulatory standard erosion
Beyond individual product risks, accelerated approvals based on weak evidence can have systemic consequences. Each approval based on limited or uncertain evidence creates a precedent manufacturers can cite to justify similarly weak applications. Over time, this progressive erosion of evidentiary standards can shift the overall regulatory landscape, normalizing approvals that would previously have been considered premature.
For example, Aduhelm’s 2021 accelerated approval, based solely on its ability to reduce amyloid plaques, set a precedent that lowered the evidentiary bar. Subsequently, Leqembi (lecanemab) received traditional approval in 2023, based partly on modest cognitive benefit but also benefiting from the prior acceptance of amyloid plaque reduction as a validated surrogate endpoint. Leqembi’s approval might have been more difficult to secure without the regulatory context created by Aduhelm’s earlier controversial decision.
Over time, what were once intended as an exceptional accommodation risks becoming standard practice. This diminishes the overall quality of evidence supporting new drug approvals and increases patient exposure to ineffective or harmful treatments.
Unfortunately, the perceived need for speed often overrides the critical need for certainty.
Balancing hope and rigor
Randomized controlled trials can be challenging for rare diseases, largely due to small patient populations, the difficulty of recruiting participants, and ethical concerns about placebo use. Some regulatory flexibility would be desirable for patients with rare conditions having no or limited treatment options. However, conditional approvals based solely on a plausible mechanism of action offer little reassurance, even when coupled with rigorous postapproval monitoring to assess safety and efficacy.
Accelerated approval represents a double-edged sword. It has the potential to bring forward transformative treatments, yet it poses a risk of exposing patients to harm and diverts health care resources and dollars away from interventions known to be safe and effective. The FDA’s postmarket surveillance tools, including the Sentinel System and phase IV confirmatory trials, are often criticized as underresourced and too reliant on manufacturer compliance, leading to delayed enforcement actions. The FDA must be empowered not just to approve quickly, but to revoke approvals decisively when drugs fail to meet promised benefits, supported by robust infrastructure and timely oversight.
Recent staffing cuts at the FDA, including a reported 8% reduction in regulatory review personnel over the past year, raise concerns about the agency’s capacity to maintain rigorous oversight. This is especially troubling given FDA Commissioner Marty Makary’s signals of support for even quicker approvals, particularly for rare disease treatments. Speed without safeguards risks harming the very patients these policies intend to protect.
When lives are at stake, urgency must not override evidence. The challenge is to ensure that accelerated approvals remain tools for progress, not shortcuts to dead ends.
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