Guest Column | April 21, 2023

New FDA Guidance: Clinical Trial Considerations To Support Accelerated Approval Of Oncology Therapeutics

By Marjorie Zettler, Ph.D., MPH, senior director, clinical science, Accutar Biotech

On April 6, AbbVie announced that it was voluntarily withdrawing ibrutinib from the U.S. market for two indications: mantle cell lymphoma (MCL, for patients who have received at least one prior therapy) and marginal zone lymphoma (MZL, for patients who require systemic therapy and have received at least one prior anti-CD20-based therapy).1 Ibrutinib was granted accelerated approval for MCL in 20132 based on results from 111 patients in the single-arm Phase 2 PCYC-1104-CA trial (NCT01236391)3 and for MZL in 20174 based on results from 63 patients in the single-arm Phase 2 PCYC-1121-CA trial (NCT01980628).5 Both studies relied on the surrogate endpoint of overall response rate (as assessed by the investigator for the PCYC-1104-CA trial and by independent review committee for the PCYC-1121-CA trial). For each of the approvals, post-marketing requirements for Phase 3 confirmatory clinical trials were issued (with final reports for both confirmatory trials due to be submitted to FDA by 2019).2,4 The randomized, double-blind, placebo-controlled Phase 3 SHINE study (NCT01776840) study evaluated ibrutinib in patients with newly diagnosed MCL.6 Although this study, published in 2022, demonstrated that the trial met its primary efficacy endpoint of progression-free survival, treatment with ibrutinib was associated with increased adverse events.7 The randomized, double-blind, placebo-controlled Phase 3 SELENE study (NCT01974440) evaluated ibrutinib in patients with relapsed or refractory MZL.8 The complete results of this study have not been disclosed; however, the April 6 AbbVie press release indicated that the trial did not meet its primary endpoint of progression-free survival.1 Based on the safety signal in the MCL confirmatory trial, and the lack of efficacy in the MZL confirmatory trial, the sponsor elected to withdraw ibrutinib from the U.S. market for the two indications.

Shortcomings And Criticisms Abound For The Accelerated Approval Pathway

The ibrutinib example highlights some of the limitations that have been identified with the accelerated approval pathway since its inception and provides insight into the rationale for new legislation and new FDA draft guidance for industry aimed at improving the program.

The accelerated approval pathway is an expedited program that was created in 1992 to help patients with serious or life-threatening conditions and unmet medical needs gain quicker access to new therapies.9 The program allows for approval of drug products for these conditions based on earlier assessment of surrogate endpoints that are “reasonably likely” to predict clinical benefit. However, the approval comes with post-marketing requirements for the sponsor to conduct confirmatory clinical trials to verify the clinical benefit. If the confirmatory trials fail, the approval may be withdrawn.

While the accelerated approval program was originally established to help address the HIV-AIDS epidemic, in recent years, the majority of accelerated approvals have been for therapies to treat cancer.10 Use of surrogate endpoints in clinical trials supporting oncology drug approvals also has increased over time,11 with response rate most frequently chosen as the endpoint in trials supporting accelerated approvals.12 A single-arm design has been employed predominantly in the trials supporting accelerated approvals of cancer therapeutics.12 Withdrawals of accelerated approvals in oncology are rare: an FDA review published in 2018 found that only 5% of accelerated approvals for oncology or malignant hematology therapies had been withdrawn over a 25-year period.12

Despite some notable success stories over the years and the approvals of some practice-changing oncology drugs, the accelerated approval program has faced considerable criticism. Concerns raised about delayed confirmatory trials13 and “dangling” accelerated approvals (cases where confirmatory trials did not verify clinical benefit, but the drug had yet to be withdrawn from the market for the indication)14,15 led to a reevaluation of the program by FDA’s Oncology Center of Excellence. In 2021, four sponsors elected to voluntarily withdraw oncology drug products from the market for indications with failed confirmatory trials. Six other accelerated approvals were the subject of an Oncologic Drugs Advisory Committee meeting, and the committee voted to rescind two of the six approvals.16 The FDA’s Oncology Center of Excellence launched Project Confirm the same year, providing publicly accessible trackers for all oncology drug accelerated approvals to clearly indicate which approvals have confirmatory trials underway, which have completed trials with verified clinical benefit, and which have been withdrawn.17

New FDA Recommendations Reduce Risk, Require Stronger Evidence Of Safety And Efficacy

New legislation was enacted in December 2022 to “modernize” the accelerated approval program. The Food and Drug Omnibus Reform Act of 2022 (“FDORA,” part of the Consolidated Appropriations Act) gives the FDA more power to define the details of post-marketing confirmatory clinical trials, to require that they be underway at the time of accelerated approval, to impose fines if the trials are unduly delayed or not completed, and to expedite withdrawal of the drug from the market for the indication in the event that confirmatory trials fail.18

In March 2023, the FDA continued the accelerated approval reforms by issuing a new draft guidance document on clinical trial considerations to support accelerated approval of oncology therapeutics.19 This guidance document reiterates the points stipulated in the FDORA legislation and provides additional advice with respect to trial design and conduct.

Two important recommendations from the new guidance are summarized below:

  1. Randomized controlled trials (RCTs) are the preferred approach, both for studies to support accelerated approvals and for studies to confirm clinical benefit. This is a significant departure from the historical precedent, as single-arm trials have supported the majority of oncology drug accelerated approvals to date. The sponsor may choose to conduct two RCTs (one trial to support the accelerated approval and a separate trial to verify clinical benefit) or a single RCT (to support both the accelerated approval and to verify clinical benefit). If the one-trial approach is pursued, sponsors should ensure the trial is adequately powered to detect significant differences for both the endpoint to support the accelerated approval and the endpoint to verify clinical benefit. An adaptive trial design may be appropriate. If the investigational treatment regimen is a combination, the sponsor should design the study to assess the contribution of each component of the combination.
  2. The guidance acknowledges that in some cases an RCT may not be feasible; therefore, single-arm trials are still an option. This is a critical point, since many cancers are rare diseases and clinical trials are challenging. When single-arm trials are employed and the primary endpoint selected is response rate (defined as the sum of partial responses + complete responses), blinded independent central review of response (BICR) assessment should be performed. Assessment of response by investigators has been shown to overestimate treatment effect relative to BICR, yet a recent study showed that for 20% of trials supporting approval of drugs to treat solid tumors, investigator assessment was the only method used to evaluate response rate. 20 Consistent use of BICR to evaluate tumor response in all single-arm registrational trials going forward will help to reduce variability and the potential for overinflation of treatment effect.

Ibrutinib was on the U.S. market for more than nine years for MCL and more than six years for MZL before being voluntarily withdrawn for these indications. If the clinical development of ibrutinib was beginning today, would this story be different? It’s certainly possible: the regulatory environment has evolved, and many elements of the ibrutinib story for these indications (single-arm trial designs to support the accelerated approvals, with response rate as a surrogate endpoint [investigator-assessed for one of the trials]; late confirmatory trials; a failed confirmatory trial) are covered in the new guidance. While there will always be some risk involved when it comes to accelerated approvals, the measures outlined in this guidance will serve to reduce those risks by requiring stronger evidence of clinical safety and efficacy.


  1. AbbVie press release. Update on IMBRUVICA (ibrutinib) U.S. Accelerated Approvals for Mantle Cell Lymphoma and Marginal Zone Lymphoma Indications. Accessed at:
  2. Food and Drug Administration. Ibrutinib ORIG-1 approval letter. November 13, 2013. Accessed at:
  3. Safety and Efficacy of PCI-32765 in Participants With Relapsed/Refractory Mantle Cell Lymphoma (MCL) (PCYC-1104-CA). Accessed at:
  4. Food and Drug Administration. Ibrutinib S-016 approval letter. January 18, 2017. Accessed at:
  5. Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed/Refractory Marginal Zone Lymphoma. Accessed at:
  6. A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma. Accessed at:
  7. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. doi: 10.1056/NEJMoa2201817. Accessed at:
  8. A Study of PCI-32765 (Ibrutinib) in Combination With Either Bendamustine and Rituximab or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Participants With Previously Treated Indolent Non-Hodgkin Lymphoma (SELENE). Accessed at:
  9. Food and Drug Administration. Expedited Programs for Serious Conditions – Drugs and Biologics. Guidance for Industry. May 2014. Accessed at: 
  10. Monge AN, Sigelman DW, Temple RJ, et al. Use of U.S. Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021. JAMA Netw Open. 2022 Nov 1;5(11):e2239336. Accessed at:
  11. Zettler M, Basch E, Nabhan C. Surrogate End Points and Patient-Reported Outcomes for Novel Oncology Drugs Approved Between 2011 and 2017. JAMA Oncol. 2019 Sep 1;5(9):1358-1359. doi: 10.1001/jamaoncol.2019.1760. Accessed at:
  12. Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of U.S. Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018 Jun 1;4(6):849-856. doi: 10.1001/jamaoncol.2017.5618. Accessed at:
  13. US Government Accountability Office. DRUG SAFETY: FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement (GAO-16-192). December 15, 2015. Accessed at:
  14. Zettler ME, Nabhan C. Fulfillment of post-marketing requirements to the FDA for novel oncology products approved between 2011-2016. JAMA Oncology, 2018:4(7):993-994. Accessed at:
  15. Beaver JA, Pazdur R. "Dangling" Accelerated Approvals in Oncology. N Engl J Med. 2021 May 6;384(18):e68. Accessed at:
  16. Food and Drug Administration. FDA in brief: FDA oncologic drugs advisory committee to review status of six indications granted accelerated approval. March 11, 2021. Accessed at:  
  17. Food and Drug Administration. Project Confirm. Accessed at:
  18. H.R.2617 - Consolidated Appropriations Act, 2023. 117th Congress (2021-2022) Accessed at:
  19. Food and Drug Administration. Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics. Guidance for Industry. March 2023. Accessed at:
  20. Zettler ME, Lee CH, Gajra A, et al. Assessment of objective response rate (ORR) by investigator versus blinded independent central review in pivotal trials of drugs approved for solid tumor indications. Journal of Clinical Oncology 39 (15_suppl), e13570-e13570. Accessed at:

About the Author:

Marjorie Zettler, Ph.D., MPH is executive director of clinical science at Regor Pharmaceuticals, Inc. and a 2022 Woman Worth Watching in STEM. An award-winning industry veteran with two decades' experience in clinical research, drug development, and regulatory strategy, she has published over 100 abstracts, manuscripts, book chapters, and patents.