Accelerated Approval of Cancer Drugs: Benefit or Burden?

Background

In 1992, the FDA started the accelerated approval program (AAP) for medications. The idea was to allow for the rapid approval of drugs for serious conditions that had unmet medical needs by using a surrogate end point or other intermediate clinical end point that is reasonably likely to predict clinical benefit.¹ In addition, confirmatory trials are required post approval to verify the drug’s actual clinical benefit.¹ The basis of this program was rooted in getting potentially lifesaving treatments to patients faster than the traditional new drug application (NDA) pathway. Originally designed to focus on HIV medications, the AAP was later broadened to include other serious conditions such as cancer. In the case of cancer specifically, the expansion aimed to address the need for new treatments, particularly those demonstrating “unprecedented activity,” which would be measured by surrogate end points.^2,3

The surrogate end points the FDA evaluates for oncology medications for AA are overall response rate, progression-free survival, complete response rate, or patient-reported outcomes. Overall, response rate has been the primary end point used for AA in oncology indications⁴. In contrast, for full FDA approval, the end points utilized for evaluation are overall survival, health-related quality of life, tumor-related symptoms, and/or physical functioning⁵. Surrogate end points allow for flexibility in the overall FDA regulatory framework because they are considered to be reasonably likely to predict clinical benefit.¹ The balance between validating clinical benefit with improving access is meant to be bridged with the AAP, which is structured to provide increased access while requiring manufacturers to conduct confirmatory trials that demonstrate the predicted clinical benefits after initial market entry.⁶

The AAP has seen a rapid increase in the number of AAs over the past 10 years (FIGURE 1)⁷, with most occurring in oncology. However, this coincides with an increase in the number of indications or products withdrawn (FIGURE 2)⁷. Between 1992 and 2024, 328 indications were approved through AAP, with 205 (62.5%) approved since 2014. Overall, 185 (56.4%) of the approvals have been converted to full approval, 27 (8.2%) drug applications have been withdrawn, 22 (6.7%) indications have been withdrawn, and 94 (28.7%) indications have yet to be reviewed because the confirmatory trials have not been completed (TABLE 1). Many of the indications waiting for confirmatory trials were for drugs that received AA after 2017 (FIGURE 2). In oncology specifically, 226 indications have been approved since 1992, of which 122 (54.0%) have been converted to full approval. Additionally, 34 (15.0%) indications have been withdrawn, and 70 indications (31.0%) are still awaiting confirmatory data (TABLE 2).⁷

The AAP was developed to address the delay between a promising drug showing initial signs of effectiveness and the time-consuming process required to demonstrate full clinical benefit through traditional randomized clinical trials (RCTs) necessary for an NDA. The idea was a good one—the time for approval was shortened with AA reaching the market several years faster than traditional routes.^8,9 And overall, the program is considered a success in that 76.5% of drugs have received full approval.^8,9 However, although well intentioned, there is continued debate over the AAP due to the withdrawal of drugs and drugs staying on the market despite a delay in confirmatory studies. Therefore, the overall program must be judged as a balance between the benefits of prompt access and the cost and uncertainty of final approval of these medications.

AAP Advantages

One of the most significant advantages of the AAP is its ability to speed up access to lifesaving or life-extending therapies, particularly in oncology, rare diseases, and infectious diseases. Patients with limited life expectancy or few therapeutic options can access treatments years earlier than they would under the traditional approval timeline, thus improving access to critical, potentially lifesaving treatments. For example, the Institute for Clinical and Economic Review found that oncology drugs receiving AA were made available a median of 3.4 years earlier than if full clinical outcome data (eg, overall survival) had been required at the time of FDA review.⁹

The use of surrogate end points, such as tumor response rate, biomarker changes, or radiographic findings, enables shorter and smaller clinical trials. This is particularly beneficial in rare or molecularly defined populations where recruitment for large-scale RCTs is infeasible. For these populations, the AA mechanism offers not only a regulatory pathway but often the only practical route to study new therapies promptly. This flexibility has catalyzed innovation in precision oncology because drugs targeting rare mutations or biomarkers can be approved rapidly based on biomarker response.^1,2,4,5,8

Furthermore, the AAP has proven to be an effective channel for therapeutic innovation. Most indications in the AAP converted to full approval following confirmatory trials. When focusing on the drugs granted approval between 1992 and 2016, 76.5% of approvals were converted to full approval, indicating that many drugs do ultimately reach their trial end points and demonstrate clinical benefit.⁹ Although many of the indications waiting for data to convert to full approval were approved in the past few years, many of the withdrawals have occurred since 2017 (Figure 2).⁷

The program also creates strong incentives for manufacturers to develop treatments in high-need areas^1,3. This is particularly clear in the proliferation of immune checkpoint inhibitors and other targeted therapies in oncology^1,8. Additionally, the ability to commercialize therapies earlier generates revenue that can be reinvested into confirmatory trials or other research and development pipelines, creating a virtuous cycle of innovation¹.

From a public health perspective, prompt access to effective therapies can shift standards of care and improve long-term outcomes.¹⁰ Notable example is imatinib (Gleevec; Novartis Pharmaceuticals Corporation) for chronic myelogenous leukemia (CML) and underscores the lifesaving potential of therapies initially granted AA.¹⁰ For example, the clinical trial data that supported the AA for imatinib showed a 98% rate of complete hematologic response—highlighting the agent’s potential as well as the critical need to bring these types of treatments to patients.¹⁰ This drug became the cornerstone of treatment for CML before full approval was granted, transforming prognoses for patients and confirming the utility of well-chosen surrogate end points.¹¹

The AA program has also provided a substantial benefit to patients, which can be demonstrated through evaluations of life-years gained by drugs approved through the program. When looking at cancer treatments that were approved between 2006 and 2021 through the AA pathway, the estimated life-years gained by patients is more than 250,000.¹² But to truly assess the value of these treatments and make meaningful comparisons, we need to consider the patient population, specific malignancy type, and life-years gained.¹³ The number of life-years gained by patients is a critical point of consideration for drugs that receive approval through the AA program.

Finally, the program has engendered robust patient and advocacy support. For communities affected by devastating or rare diseases, the promise of early access—even with some degree of evidentiary uncertainty—is a tangible demonstration of the system’s responsiveness. In these scenarios, patients and caregivers often weigh the risks of uncertainty against the opportunity for benefit, with the AA framework empowering shared decision-making between patients and providers.

The AA program provides a critical regulatory bridge that aligns patient needs, scientific innovation, and public health impact. Although the program is not without controversy or challenges, its core strength lies in its responsiveness to unmet needs and delivering earlier access to transformative therapies. The program has the potential to shape the future of evidence generation by embracing real-world data and adaptive trial designs. These approaches may help refine the use of surrogate end points, enhance post-marketing evidence generation, and ensure continued alignment between early approval and long-term clinical value.

AAP Disadvantages

One disadvantage of the AAP is the lack of cost controls and more rigorous time limits to complete confirmatory trials. Of the 328 drugs approved through the AA between 1992 and 2024, 49 (14.9%) applications were subsequently withdrawn or the medication’s use for that indication was removed from the market ¹⁴Focusing only on the 226 oncology agents granted AA since 1992, 34 (15.0%) of those approvals were later withdrawn ¹⁴For medications that were removed from the market, the average time in months from AA to application withdrawal was 95.6 months regardless of drug type and 62.4 months for oncology agents ¹⁴The Office of Inspector General of the US Department of Health and Human Services expressed concerns with the FDA AA program after the approval of aducanumab (Aduhelm; Biogen Inc) and the subsequent questions raised about the approval.¹⁴

Diving deeper into the indications that were withdrawn, 14 of 27 (52%) drugs withdrawn were approved for a cancer indication and 10 (37%) had Medicare Part B or Part D spending data available from the Centers for Medicare & Medicaid Services database.¹⁶ At the time of this review, the database only provided spend data between 2018 to 2022 for Medicare Part B and Part D. Oral agents with Medicare spend data available through the Part D database included mobocertinib (Exkivity; Takeda Pharmaceuticals USA, Inc), infigratinib (Truseltiq; BridgeBio Pharma, Inc), umbralisib (Ukoniq; TG Therapeutics, Inc), and panobinostat (Farydak; Novartis, Secura Bio, Inc).¹⁷ Olaparib (Lynparza ; AstraZeneca Pharmaceuticals LP) was excluded from the cost analysis because it had other FDA-approved indications beginning in 2017 and there is no mechanism to differentiate spend and use by indication. Injectable agents with Medicare spend data available through the Part B database included melphalan flufenamide (Pepaxto; Oncopeptides AB), belantamab mafodotin (Blenrep; GSK plc), vincristine liposomal (Marqibo; Talon Therapeutics, Inc), and gemtuzumab ozogamicin (Mylotarg; Pfizer Inc).¹⁶ In total, with cost information available for these medications, the cumulative spend by Medicare exceeded $100 million ($100,592,743), a total of 2685 beneficiaries received treatment, and the average spending per beneficiary was $3.6 million.^16,17

From 2021 to 2022, the cost per beneficiary went up by 13% for belantamab mafodotin, 4% for vincristine liposomal, and 7% for gemtuzumab ozogamicin for the years of available spending data.¹⁶ Melphalan flufenamide was the only AA agent in the Medicare Part B cohort that had reduced spend per beneficiary in 2022 compared with 2021—with a 57.5% reduction; however, this was likely influenced by decreased beneficiaries treated, at 24 beneficiaries in 2022 compared with 41 beneficiaries in 2021, aligning with its application withdrawal in October 2021.¹⁶ For Medicare Part D, there were larger changes in spending, with cost per beneficiary increases of 19% for panobinostat, 45% for infigratinib, and 85% for mobocertinib.¹⁷ Contrastingly, umbralisib saw a cost decrease of 27% influenced by decreased claims and beneficiaries observed in 2022 compared with 2023.¹⁶ On average, with spending data available and excluding cost decreases for melphalan flufenamide and umbralisib, the cost increase per year was 8% for Medicare Part B drugs and 50% for Medicare Part D.¹⁶ Given the length of time from approval to market withdrawal, there is a high risk of substantial increase in spend for AA agents.^16,17

There is a trend for payers, including Medicare in the case of aducanumab, to consider AA agents experimental and to not cover the drug.¹⁴ Lack of coverage places higher financial burden on the patient, requiring them to seek alternative sources of funding, such as manufacturer co-pay assistance or grant programs, which hinders drug uptake in the market and may ultimately lead companies to discontinue marketing of the drug. This occurred with aducanumab.¹⁴ Many insurers block newly approved drugs from coverage upon market launch with periods that vary by insurer. For example, Independent Blue Cross does not cover AA drugs and has an 18-month period after approval to allow for confirmatory trials to be completed.¹⁴ Provided that the average time from AA to change in status for oncology agents is 62.4 months, plans like Independent Blue Cross likely will exclude coverage of AA agents beyond the 18-month period.¹⁴ State Medicaid programs must cover all FDA-approved drugs with manufacturer rebate agreements, including AA drugs prescribed for medically accepted uses. This requirement can strain budgets due to the uncertain clinical benefits of some AA drugs at the time of approval. Although access to AA drugs may benefit patients, coverage by Medicaid would increase spending by state and federal programs.¹⁴

Additionally, the number of cancer drugs initially approved through the AA pathway that later converted to full approval continues to be lower than expected, based on the original intent of the program. For example, in a review of 93 cancer drug approvals through the AA pathway from 1992 to 2017, only 20% converted to full approval through confirmatory RCTs, 21% utilized confirmatory studies focusing on different surrogate end points, and 20% reported on the same surrogate end points.¹⁸ In recent years, there have been several oncology medications that have utilized the same surrogate endpoint, overall response rate and/or duration of response, in the confirmatory trial albeit with additional patients and time that ultimately converted to full approval^19-22. Another measure to highlight is that approximately 15% of all oncologic drugs approved through the AA pathway have been withdrawn.⁷ Given the ongoing debate regarding the clinical utility of surrogate end points, the limited number of drugs demonstrating definitive clinical benefit through RCTs, and increasing financial burdens on insurers, government programs, and patients, it is evident that reforms or adjustments to the current AA program structure are warranted.²³

Lastly, although the life-years saved appear impressive, the data are based on the best available surrogate end point data at the time of the AA.¹³ What we do not know is the life-years lost due to patients being placed on a therapy that was later shown to be ineffective rather than on a therapy with proven effectiveness.

Conclusions

The success of the AAP to date must be seen as mixed. Lifesaving drugs, such as imatinib and trastuzumab, are made available more rapidly, which has resulted in a substantial number of life-years saved. However, the program still faces problems and concerns, as evidenced by 2 Office of Inspector General reports on the topic.^15,24 Although the AAP bridges the gap between patient access to therapies and ensuring their safety and efficacy, there continues to be discussion about how to guarantee timely completion of the confirmatory trials post approval. With the number of trial delays, withdrawals, and drugs converting using surrogate end points as opposed to rigorous RCT end points such as OS, improvement is necessary for the program to continue to meet its original purpose.

From a cost perspective, there are ways to implement cost constraints into the AA pathway that would help payers as well as patients while these drugs pursue full approval. A solution to improve the AAP and cut costs in the United States would be price caps implemented for these drugs until confirmatory trials are finished. This includes setting a list price cap at launch (ie, an agreed upon cost-per-clinical-benefit measure) and an inflation cap limiting annual price increases for Part B and Part D drugs. As of late 2022, the FDA has the authority to require that confirmatory trials be underway prior to approval and to expedite withdrawal of approvals if the manufacturer is not meeting required milestones.¹³ The FDA must require these measures to be in place at the time of market launch to hold manufacturers accountable. Lastly, the FDA needs to focus on defining surrogate end points that predict the ultimate end point needed for full approval and that are transparent and readily available for review. These measures would reduce high spending risks, encourage commercial payers to cover AAP agents, motivate companies to complete trials promptly, and provide prompt access to crucial drugs.

The AAP aims to strike a balance between expediting the availability of therapies for serious or life-threatening conditions with unmet medical needs and ensuring the safety and efficacy of those treatments. The program has experienced both successes and failures since inception. Clear highlights include rapid access to drugs that have made a significant impacts on patient lives; however, one concern is the failure of some drugs to demonstrate clinical benefit in confirmatory trials and at a significant cost. To this end, implementing cost constraints, having confirmatory trials in place at market launch, and improving surrogate end point definitions with relevance to end points needed for full approval would greatly enhance the AAP and create ingrained, structural incentives for manufacturers.

REFERENCES

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15. How FDA Used Its Accelerated Approval Pathway Raised Concerns in 3 of 24 Drugs Reviewed. US Department of Health and Human Services Office of Inspector General; January 2025. Accessed August 12, 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf

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19. Food and Drug Administration. FDA approves pralsetinib for non-small cell lung cancer with RET gene fusions. FDA. Published August 9, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions

20. Food and Drug Administration. FDA approves capmatinib for metastatic non-small cell lung cancer. FDA. Published August 10, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capmatinib-metastatic-non-small-cell-lung-cancer

21. Food and Drug Administration. FDA approves tepotinib for metastatic non-small cell lung cancer. FDA. Published February 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tepotinib-metastatic-non-small-cell-lung-cancer

22. Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Published November 26, 2018. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0

23. Kanapuru B, Carioti T, Gormley N, Pazdur R. Autopsy of a drug withdrawal - the case of melphalan flufenamide. N Engl J Med. 2024;391(23):2177-2179. doi:10.1056/NEJMp2412068

24. Delays in confirmatory trials for drug applications granted FDA's accelerated approval raise concerns. US Department of Health and Human Services Office of Inspector General data snapshot. September 2022. Accessed August 12, 2025. https://oig.hhs.gov/documents/evaluation/2622/OEI-01-21-00401-Complete%20Report.pdf