The Food and Drug Administration’s (FDA) accelerated approval (AA) program is a regulatory pathway allowing for early approval of drugs based on endpoints that are reasonably likely to predict clinical benefit (Figure 1). The majority (60%) of these approvals have been granted for oncology indications, leading to patient access an estimated median 3.1 years prior to approval through the traditional pathway. After AA, FDA requires successful completion of confirmatory trials to verify clinical benefit, otherwise the AA indication may be withdrawn. These issues have been publicly scrutinized and addressed by recent legislation in the Consolidated Appropriations Act, which allows FDA to require that confirmatory trials are underway at the time of AA and specifies new, streamlined processes for withdrawal of an AA.1
Figure 1:
The accelerated approval program and confirmatory trials.
A confirmatory trial is usually considered to have “failed” to verify clinical benefit if it does not achieve its statistically pre-specified primary endpoint, if it demonstrates a potential detriment in overall survival (OS) even if achieving its primary endpoint, or if on review an observed benefit is outweighed by toxicity. To date, 15% (30 of 198) of oncology AAs have been withdrawn due to “failed” or incomplete confirmatory trials (Table 1); however, the regulatory decision to withdraw after a “failed” trial should consider possible reasons for this “failure” as well as therapies available to patients at the time the withdrawal is contemplated.2
Table 1.
Withdrawn Oncology Accelerated Approvals
| Drug Name | Accelerated Approval Indication | Accelerated Approval Date | Withdrawal Date |
|---|---|---|---|
| Celebrex (celecoxib) | To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis patients, as an adjunct to usual care | 12/23/1999 | 6/8/2012 |
| Mylotarg (gemtuzumab ozogamicin) | For patients with CD33+ AML in first relapse 60 years of age or older and not candidates for cytotoxic chemotherapy | 5/17/2000 | 11/28/2011 |
| Iressa (gefitinib) | As monotherapy for locally advanced or metastatic NSCLC after failure of platinum-based and docetaxel chemotherapy | 5/5/2003 | 4/25/2012 |
| Bexxar (tositumomab and iodine i 131 tositumomab) | For patients with relapsed or refractory low-grade follicular or transformed CD20+ NHL who have not received rituximab | 12/22/2004 | 10/23/2013 |
| Avastin (bevacizumab) | In combination with paclitaxel for patients who have not received chemotherapy for metastatic HER2 negative breast cancer | 2/22/2008 | 11/18/2011 |
| Oforta (fludarabine phosphate) | For adults with B-cell CLL that has not responded to or progressed during or after treatment with at least one standard alkylating agent containing regimen | 12/18/2008 | 12/31/2011 |
| Istodax (romidepsin) | Peripheral T-cell lymphoma in patients who have received at least one prior therapy | 6/16/2011 | 7/30/2021 |
| Marqibo (vincristine sulfate liposomal) | Adults with Philadelphia (PH) chromosome negative (-) ALL in second relapse or greater relapsed or whose disease has progressed following 2 or greater treatment lines of anti-leukemia therapies | 8/9/2012 | 5/2/2022 |
| Imbruvica (ibrutinib) | Adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy | 11/13/2013 | 5/18/2023 |
| Zydelig (idelalisib) | For the treatment of relapsed follicular B-cell Non-Hodgkin Lymphoma (FL) in patients who have received at least 2 prior systemic therapies and relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies | 7/23/2014 | 2/18/2022 |
| Farydak (panobinostat) | In combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior regimens, including BTZ and an immunomodulatory agent. | 2/23/2015 | 3/24/2022 |
| Tecentriq (atezolizumab) | Locally advanced or metastatic urothelial carcinoma that progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | 5/18/2016 | 4/13/2021 |
| Lartruvo (olaratumab) | In combination with doxorubicin for adults with soft tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery | 10/19/2016 | 2/25/2020 |
| Imbruvica (ibrutinib) | Adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy | 1/18/2017 | 5/18/2023 |
| Tecentriq (atezolizumab) | Patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 as determined by an FDA approved test or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status | 4/17/2017 | 12/2/2022 |
| Imfinzi (durvalumab) | Locally advanced or metastatic urothelial carcinoma that progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | 5/1/2017 | 2/19/2021 |
| Aliqopa (copanlisib) | Treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies | 09/14/2017 | 03/18/2024 |
| Keytruda (pembrolizumab) | For patients with recurrent or locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 [CPS ≥1] as determined by an FDA-approved test, with disease progression on/after two or more prior lines of therapy including fluoropyrimidine and platinum containing chemotherapy and if appropriate, HER2/NEU targeted therapy | 9/22/2017 | 2/4/2022 |
| Opdivo (nivolumab) | Hepatocellular carcinoma previously treated with sorafenib | 9/22/2017 | 7/23/2021 |
| Opdivo (nivolumab) | Metastatic SCLC with progression after platinum-based chemotherapy and at least one other line of therapy | 8/16/2018 | 12/29/2020 |
| Copiktra (duvelisib) | Treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least 2 prior systemic therapies | 9/24/2018 | 12/17/2021 |
| Tecentriq (atezolizumab) | In combination with paclitaxel protein-bound for unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering = 1% of the tumor area), as determined by an FDA-approved test. | 3/8/2019 | 10/6/2021 |
| Keytruda (pembrolizumab) | Metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy | 6/17/2019 | 3/30/2021 |
| Blenrep (belantamab mafodotin-blmf) | Adults patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent | 8/5/2020 | 2/6/2023 |
| Gavreto (pralsetinib) | Treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy | 12/1/2020 | 7/20/2023 |
| Ukoniq (umbralisib) | Adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20- based regimen | 2/5/2021 | 5/31/2022 |
| Ukoniq (umbralisib) | Adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy | 2/5/2021 | 5/31/2022 |
| Pepaxto (melphalan flufenamide) | In combination with dexamethasone for the treatment of adult patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody | 2/26/2021 | 02/23/2024 |
| Truseltiq (infigratinib) | Treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangement as detected by an FDA approved test | 5/28/2021 | 5/16/2024 |
| Exkivity (mobocertinib) | Treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy | 9/15/2021 | 7/15/2024 |
Most often in oncology, AA has been based on tumor response endpoints indicating reduction in tumor size, with verification of clinical benefit achieved in randomized clinical trials with time-to-event endpoints, such as OS or progression-free survival (PFS), and frequently in earlier lines of therapy. Tumor responses provide evidence of biological activity and demonstrate the potential for individual patient benefit. Given this potential benefit, trials that fail to meet their statistically pre-specified primary endpoint are not always a result of absence of meaningful clinical benefit or direct failure of the drug but could be attributed to methodological issues in designing the confirmatory trial.
These design challenges may be statistical, such as overestimating the drug’s effect size in powering the trial, choosing a primary endpoint that may not reflect drug’s true benefit, or conducting a direct evaluation with the comparator rather than an add-on design. In addition, failure to either select a patient population who may optimally benefit from the drug or adequately characterize the drug’s dosage prior to embarking on the trial may be obstacles in demonstrating clinical benefit. These issues were highlighted by trials of multiple checkpoint inhibitors studied in similar populations, using different study designs, and resulted in conflicting outcomes.3 The first-line trials of atezolizumab and durvalumab for small cell lung cancer (SCLC) demonstrated advantages in OS leading to traditional approvals, whereas, a trial in a similar setting for pembrolizumab did not show an OS advantage, leading to AA withdrawal.4 Differences in biologic effect could not be excluded since direct comparisons of the drugs were not performed, but given the similarities of these drugs, differences in the above design considerations may have accounted for these discrepant results.
As noted above, confirmatory trials may also “fail” because the trial enrolled patients who were not optimally selected to benefit from the drug. This challenge is increasingly observed with targeted drugs that enroll patients irrespective of the drug’s purported mechanism of action. The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor (TKI) gefitinib was initially granted AA in 2003 for patients with refractory locally advanced or metastatic NSCLC. Although five confirmatory trials in this unselected population did not achieve the prespecified threshold for statistical success leading to the AA withdrawal, the drug was eventually granted approval in the appropriate biomarker-selected population in 2015.5
Selecting the wrong dosage for the confirmatory trial may also confound the demonstration of clinical benefit. In 2011, the AA for gemtuzumab ozogamicin for acute myeloid leukemia (AML) was withdrawn after the confirmatory trial demonstrated safety findings including early deaths. After new trials of gemtuzumab ozogamicin at a lower dose, with a different schedule, and in a new AML sub-population demonstrated favorable benefit-risk, the drug was granted traditional approval in 2017 as a single-agent and in combination with chemotherapy.6 To address dose optimization earlier in drug development, the FDA’s Oncology Center of Excellence (OCE) has initiated Project Optimus to promote better characterization of dose and schedule prior to initiation of registrational trials.7
Over three decades experience with AA has provided a framework for regulatory action when oncology confirmatory trials are unsuccessful. FDA considers the unmet medical need that may still exist and the public health implications of AA withdrawal, particularly for drugs with only one approved indication, where withdrawal would completely remove the drug from the market. Since many confirmatory trials demonstrate overall response rates and response durations similar to that observed at the time of AA, responding patients who with few or no therapeutic options may still derive benefit.
FDA must evaluate benefit-risk for the AA at the time the results of the confirmatory trial become available. AA is reserved for drugs demonstrating the potential for meaningful advantage in efficacy or safety over available therapies (other drugs that have been granted traditional approval) and changes in available therapies since the AA was granted can influence decision-making. If the available therapies have not changed and an unmet medical need still exists, FDA may maintain the AA and allow the sponsor to pursue alternative confirmatory trials, provided such trials are feasible and can be conducted in a timely manner. The confirmatory trial for the 2020 AA of lurbinectedin for refractory metastatic SCLC did not meet its primary endpoint of OS; however, no detriment in survival was observed. At the time this confirmatory trial completed, high unmet medical need still existed for this population. As alternative, ongoing trials of lurbinectedin could be leveraged to verify the drug’s clinical benefit, the AA for lurbinectedin was maintained.8
When confirmatory trials do not meet their primary endpoint for superiority and also demonstrate a negative benefit-risk profile or a potential OS detriment, the AA indication should be withdrawn. Eight AAs were withdrawn for these reasons, including the 2016 AA of olaratumab for soft tissue sarcoma, the 2021 AA of melphalan flufenamide for multiple myeloma and multiple AAs of PI3 kinase inhibitors for indolent non-Hodgkin lymphomas (idelalisib, duvelisib, copanlisib, and umbralisib).2
When new available therapies for the indication have been subsequently approved, the AA should generally be withdrawn if the confirmatory trials fail to demonstrate benefit. Eleven AAs were withdrawn under these circumstances, including the 2018 AA of nivolumab and the previously-described 2019 AA of pembrolizumab for third-line SCLC indications. The confirmatory trials in first- and second-line settings did not meet statistical significance for OS. During the conduct of these trials, other checkpoint inhibitors were granted traditional approval in the first-line setting for SCLC, altering the standard of care and advancing immunotherapy as initial SCLC treatment. Given the failed confirmatory trials and new available therapies, these nivolumab and pembrolizumab AAs were withdrawn.4 FDA will also consider an advantage in safety of an AA drug in determining whether to withdraw the indication.
AAs in oncology balance early access to potentially life-saving drugs against uncertainty regarding the clinical benefit of the endpoints used to support approval. The risk of this uncertainty can be mitigated by timely completion of confirmatory trials, which allows earlier verification of clinical benefit and is supported by legislative changes in the Consolidated Appropriations Act.1,9 FDA may now require that confirmatory trials be underway before granting AA, providing incentive for sponsors to more rapidly identify study sites and begin enrollment, and reducing the potential impact of marketing of the drug post-approval on the confirmatory trial’s progress. Sponsors are also required to submit biannual progress reports on their confirmatory trials, which will allow FDA to identify delays in trial progress earlier.
A “failed” confirmatory trial after AA in oncology does not always equate to a “failed” drug. In some cases, a drug may have inherent characteristics that lead it to be unsuccessful, including a lack of efficacy or unacceptable toxicity. However, oncology drugs granted AA often have demonstrated tumor responses and response durations that may be meaningful, especially to patients with life-threatening diseases and few or no therapeutic options. These responses are not due to chance and reflect the drug’s direct anti-tumor activity. Inability to verify clinical benefit may be due to issues with confirmatory trial methodology, dosage selection, and population. When an AA confirmatory trial “fails,” FDA must consider the potential reasons and the current available therapies to balance the public health outcomes for patients who may benefit against the public health risks of continued marketing of an unverified drug while additional trials are conducted.
Footnotes
Disclaimers:
None
Contributor Information
Gautam U. Mehta, Oncology Center of Excellence, Food and Drug Administration, Silver Spring, MD
Richard Pazdur, Oncology Center of Excellence, Food and Drug Administration, Silver Spring, MD
References
- 1.H.R.2617 - Consolidated Appropriations Act, 2023. https://www.congress.gov/bill/117th-congress/house-bill/2617, accessed 2/1/2024.
- 2.Withdrawn | Cancer Accelerated Approvals. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals, accessed 7/18/2024.
- 3.Beaver JA, Pazdur R. “Dangling” Accelerated Approvals in Oncology. N Engl J Med. 2021;384(18):e68. doi: 10.1056/NEJMp2104846 [DOI] [PubMed] [Google Scholar]
- 4.Singh H, Beaver JA, Pazdur R. Immunotherapy for Patients With Small-Cell Lung Cancer-2 Gains, 2 Losses. JAMA Oncol. 2022;8(1):37–38. doi: 10.1001/jamaoncol.2021.4956 [DOI] [PubMed] [Google Scholar]
- 5.Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer. Clin Cancer Res. 2016;22(6):1307–1312. doi: 10.1158/1078-0432.CCR-15-2266 [DOI] [PubMed] [Google Scholar]
- 6.FDA approves Mylotarg for treatment of acute myeloid leukemia. https://www.fda.gov/news-events/press-announcements/fda-approves-mylotarg-treatment-acute-myeloid-leukemia, accessed 5/1/2024.
- 7.Shah M, Rahman A, Theoret MR, Pazdur R. The Drug-Dosing Conundrum in Oncology - When Less Is More. N Engl J Med. 2021;385(16):1445–1447. doi: 10.1056/NEJMp2109826 [DOI] [PubMed] [Google Scholar]
- 8.Postmarket Requirements and Commitments (fda.gov). https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm, accessed 2/1/2024.
- 9.Fashoyin-Aje LA, Mehta GU, Beaver JA, Pazdur R. The On- and Off-Ramps of Oncology Accelerated Approval. N Engl J Med. 2022;387(16):1439–1442. doi: 10.1056/NEJMp2208954 [DOI] [PubMed] [Google Scholar]