The FDA’s Accelerated Approval (AA) Program was created in 1992 and was provided statutory support by the FDA Safety and Innovation Act (FDASIA) in 2012.¹ Although the article in this issue by Janssen Scientific Affairs authors Benedict et al² makes a number of questionable assumptions in its modeling, of greater concern is the authors’ foundation for their policy recommendations. In our opinion, the policy impact of the AA Program on life years gained (LYG) for patients with cancer is far less than that suggested by Benedict et al.

The FDASIA required the FDA to “help expedite the development and availability to patients of treatments for serious or life-threatening diseases or conditions.”¹ The AA Program, however, does not expedite availability of drugs to the vast majority of American patients when the AA is part of a supplemental New Drug Application and the off-label use has been previously listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Because CMS must cover all compendia-listed uses such as those in the NCCN Guidelines,³ NCCN and its expert guideline committees, not the AA Program, should be credited with expediting availability for new indications of approved agents.

Of the 69 drug indication combinations highlighted by Benedict et al,² only 33 (48%) of them are for drugs receiving their first approval through the AA Program. Of these 33 first AA drug indications, 6 (18%) later withdrew the AA indication. Thus, only 27 (39% of the total dataset) AA drug indications potentially provided patients early access to a drug with clinical benefit. This is consistent with prior analysis of AA for antineoplastic drugs.⁴

In considering the authors’ dataset, we focused on the drugs with the highest patient uptake, such as pertuzumab, which accounted for 17% of the total uptake. Pertuzumab was first approved on June 8, 2012, for the treatment of metastatic breast cancer, and it subsequently received AA on September 30, 2013, for neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. More than 2 months before this AA, NCCN revised its breast cancer guidelines to support this new indication.⁵ Thus, the LYG attributed to the AA Program for the 155,000 patients with breast cancer on neoadjuvant pertuzumab should primarily be attributed to NCCN.

As another example, panitumumab received AA on September 27, 2006, for EGFR-expressing metastatic colorectal cancer after progression on standard regimens, with an increase in median progression-free survival of only 5 days and no difference in overall survival.⁶ Although Benedict et al² cite a study conducted entirely outside the United States as the regular approval confirmatory trial,⁷ this study does not appear in the revised prescribing information associated with the May 23, 2014, regular approval but first appears in the June 2017 label. Instead, the primary support for the regular approval of panitumumab in 2014 appears to be a study demonstrating noninferiority but absolutely no survival advantage compared with cetuximab.⁸ Because cetuximab had been available since February 12, 2004, for refractory metastatic colorectal cancer, the AA for panitumumab in 2006 did not provide any incremental LYG or other benefits for patients. This level of scrutiny is necessary in interpreting inaccurate attributions of survival benefit to AA drug indications by Benedict et al.

There are some success stories from the AA Program, such as trastuzumab deruxtecan. This antibody–drug conjugate received AA on December 20, 2019, for its first indication, and thus was brought to market early per the FDASIA. Trastuzumab deruxtecan was subsequently granted regular approval on May 4, 2022, for the same indication with updated data from a phase III confirmatory trial demonstrating increases in both progression-free survival (median, 28.8 vs 6.8 months) and overall survival (hazard ratio, 0.64) compared with trastuzumab emtansine.⁹ Furthermore, trastuzumab deruxtecan is relatively cost-effective when compared with trastuzumab emtansine, with a gain of 0.73 quality-adjusted life-years (QALYs) and an incremental cost-effectiveness ratio (ICER) of roughly $82,000 per QALY.¹⁰

The AA Program also has the potential to expedite availability of ineffective drugs, thereby harming patients. Of the 69 drug indication combinations in Benedict et al,² 15 (22%) have had that indication subsequently withdrawn.¹¹ On average, these withdrawals are occurring almost 5 years after the AA date, although more recent withdrawals have been within 3 years of AA.

One concern is that prior AA indications persist in NCCN Guidelines despite unsuccessful confirmatory trials.¹² For example, bevacizumab received AA on February 22, 2008, for the treatment of metastatic breast cancer, and this indication was later revoked by the FDA on November 18, 2011. Despite the lack of clinical benefit in confirmatory trials and increased risk of serious adverse events leading to the withdrawal of the indication, the NCCN Guidelines for Breast Cancer¹³ continue to recommend bevacizumab in combination with paclitaxel in certain circumstances.

We also note that the time to regular approval has been progressively decreasing since 2006, with recent intervals measuring less than 2 years. This may be limited by selection bias, however, given that 61 AA drug indications were omitted due to lack of available overall survival data. Even when overall survival data are available, they may be immature and often result in questionable regular approvals.^4,14

From our perspective, the impact of the AA Program is overstated by Benedict et al. Sponsors and regulators should focus more on premarket randomized dose-ranging studies, which is the goal of FDA’s Project Optimus, to provide a more rigorous dataset for consideration of AA.¹⁵ The cost of the AA Program on payers is not calculated, but the cost-effectiveness for a maximum gain in survival of roughly 3.5 months per patient, per Benedict et al’s tabulations, is unlikely to be cost-effective even at generous thresholds. The current AA Program has been largely exploited for approvals of secondary indications that do not change allowable prescribing patterns and thus do not provide direct benefit for patients. Such secondary indications may also delay availability of cost-effective generic and biosimilar drugs due to new patents issued in conjunction with label changes. Because many of these newer indications had previously been included in compendia, these approvals are not responsive to the FDASIA statutory language regarding the “Sense of Congress” detailed in Section 901 of that Act.¹ Although the AA Program clearly benefits the pharmaceutical industry, the true benefit for patients needs further evaluation.⁴