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Pink Sheet – Accelerated Approval: US FDA Review Of Expedited Program Could Bring More Withdrawals

Pink Sheet – Accelerated Approval: US FDA Review Of Expedited Program Could Bring More Withdrawals

Executive Summary

Oncology Center of Excellence’s ‘industry-wide evaluation’ of accelerated approvals leads to removal of indications for two PD-1/L-1 inhibitors, AstraZeneca’s Imfinzi and Bristol-Myers Squibb’s Opdivo, both of which had failed confirmatory trials.

The recent withdrawal of accelerated approval indications for two cancer immunotherapies is part of a broader US Food and Drug Evaluation review of the expedited pathway and could portend more oncology drug and indication removals for failure to confirm clinical benefit.

On 22 February, AstraZeneca PLC announced the withdrawal of its PD-L1 inhibitor Imfinzi (durvalumab) for use in previously treated adults with locally advanced or metastatic bladder cancer. The withdrawal announcement came almost a year after the company announced the failure of a required confirmatory study, the Phase III DANUBE trial in first-line metastatic bladder cancer, on an overall survival endpoint.

The Imfinzi and Opdivo accelerated approval withdrawal decisions “were made in consultation with the FDA and as part of a broader industry-wide evaluation by the FDA Oncology Center of Excellence,” the agency said.

The regulatory action follows the 29 December removal of an indication for third-line metastatic small cell lung cancer (SCLC) from the label of Bristol Myers Squibb Company’s PD-1 inhibitor Opdivo (nivolumab) because confirmatory studies completed in 2018 did not meet their overall survival primary endpoints. (Also see “Keeping Track: Submissions Galore Start The New Year; US FDA Clears New Indications For Enhertu, Xalkori” – Pink Sheet, 18 Jan, 2021.)

In both cases, the sponsors said the withdrawal decision was made “in consultation” with the FDA and in accordance with agency guidelines for evaluating accelerated approval indications that do not meet their postmarketing requirements and “as part of a broader industry-wide evaluation.”

Neither the companies nor the FDA would say why the withdrawals took so long following the failed confirmatory studies. The agency took less than six weeks to review BMS’ labeling supplement for the Opdivo indication’s removal, and a mere two weeks to review AstraZeneca’s labeling supplement for Imfinzi.

“Both withdrawal decisions were made in consultation with the FDA and as part of a broader industry-wide evaluation by the FDA Oncology Center of Excellence,” the agency told the Pink Sheet, adding that further details regarding this evaluation would be announced at a later date.

Accelerated Approval ‘Working As It Was Designed’

While the details of the agency’s “broader industry-wide evaluation” are unclear, there are a number of similarities between the two recent withdrawals that could highlight areas of agency focus.

Both Opdivo and Imfinzi are part of the PD-1/L-1 class of therapeutics that has revolutionized treatment of many cancer types. Drugs in the class carry a long list of indications, some of which remain under accelerated approval. Since the accelerated approval of the Imfinzi and Opdivo indications at issue, the treatment landscape has changed, with other therapies in the class gaining either full or accelerated approval for the same uses.

For Imfinzi and Opdivo, the indications in question received accelerated approval on the basis of overall response and durability of response data, while the confirmatory trials used an overall survival endpoint. In addition, both immunotherapies are labeled for other indications and will remain on the market, so the question of complete product withdrawal was never an issue.

The now-withdrawn indications for Imfinzi and Opdivo “were sort of the classical working of accelerated approval, where the early indication was approved based on an intermediate endpoint” but the confirmatory trials did not pan out, Friends of Cancer Research president and CEO Jeff Allen told the Pink Sheet. “This is accelerated approval working as it was designed.”

Rethinking Accelerated Approval

Frustrated with inefficiencies in the accelerated approval process, Center for Drug Evaluation and Research leaders have expressed interesting in taking a hard look at the expedited pathway. Of particular concern is the need to complete confirmatory trials in a timely fashion, and the ability to swiftly and easily remove a drug or indication if clinical benefit is not confirmed postapproval. (Also see “Accelerated Approval Under Review By US FDA: Completing Confirmatory Trials A Focus” – Pink Sheet, 4 Nov, 2020.)

Oncology Center of Excellence director Richard Pazdur has called for a re-examination of the accelerated approval program’s strengths and weakness, and consideration for potential changes, in conjunction with potential  21st Century Cures 2.0 legislation. (Also see “Cures II Wish List: Reconsidering Accelerated Approval?” – Pink Sheet, 17 Jun, 2020.)

Project Accelerate

  • “OCE launched Project Accelerate in February 2020 to track the oncology approvals using the accelerated approval pathway. The team created a tracking database with the accelerated approval application information and corresponding postmarketing requirement(s) to verify clinical benefit. The team also met with international regulatory authorities to discuss experience with equivalent programs such as conditional marketing authorisation program (European Union), notice of compliance with conditions (Canada), and provisional approval (Australia).”


FDA Oncology Center of Excellence 2020 Annual Report

In February 2020, OCE launched Project Accelerate, which is described as a framework for reviewing the US regulatory experience with accelerated approvals. (Also see “US FDA ‘Project Post COVIDity’ Will Track Infection Impact On Cancer Patients Using Real-World Data” – Pink Sheet, 15 Feb, 2021.) The initiative also involves analyzing comparable programs in other parts of the globe, and determining areas for improvement by reviewing similarities and differences in the global experience. (See box.)

Pazdur’s desire for a “fresh look” at the accelerated approval program led an FOCR multi-stakeholder working group to suggest changes. The recommendations included reframing the focus of accelerated approval on a drug’s risk/benefit profile rather than the effect on a surrogate endpoint, and having sponsors submit for continued approval instead of putting the burden on the FDA to get the drug or indication pulled. (Also see “Accelerated Approvals Could Be Improved By Focusing On Benefit/Risk, Making Withdrawal Easier” – Pink Sheet, 9 Feb, 2021.)

Pazdur previously has said that a change in the available therapies for an indication could inform a re-examination of whether an accelerated approval drug’s benefit/risk profile is still appropriate. Only drugs that hold regular approval for a given indication are considered “available therapy.”

Drugs Linger On Market

The quandary created by confirmatory trials that take years to complete and yet fail to confirm clinical benefit is of particular concern.

Withdrawals under the accelerated approval program have been few and far between. Prior to the recent Opdivo and Imfinzi indication withdrawals, 10 drugs or indications had been withdrawn for failure to complete a postmarketing trial or to confirm clinical benefit, according to a Pink Sheet analysis, with withdrawals sometimes occurring more than a decade following accelerated approval. (Also see “Accelerated Approval Withdrawals Through The Years” – Pink Sheet, 25 Apr, 2019.)

Genentech, Inc. ’s Avastin (bevacizumab) is the only withdrawal that has gone through the public hearing process under the accelerated approval regulations. However, AMAG Pharmaceuticals Inc. is challenging CDER’s proposal to withdraw accelerated approval of the preterm birth prevention drug Makena (hydroxyprogesterone caproate) and has requested a public hearing. (Also see “Keep Makena Under Accelerated Approval Pending More Studies, AMAG Tells US FDA” – Pink Sheet, 19 Jan, 2021.)

Makena has been on the market since 2011; its confirmatory trial, which took nine years to conduct, failed to meet its coprimary endpoints. In proposing to withdraw the drug, CDER cited the failed confirmatory trial as well as the “integrity” of the accelerated approval process. (Also see “Accelerated Approval: US FDA Request For Makena’s Withdrawal Goes Beyond Failed Confirmatory Trial” – Pink Sheet, 5 Oct, 2020.)

Opdivo Holds New Record For Time To Removal

Opdivo and Imfinzi typify the challenges inherent in quickly removing accelerated approval indications from the label when confirmatory trials fail to verify clinical benefit.

At the time of Eli Lilly and Company’s withdrawal of Lartruvo (olaratumab) in April 2019, the sarcoma drug represented the shortest interval (2.5 years) between an accelerated approval and removal. (Also see “A Successful Failure? Lartruvo’s Speedy Withdrawal Sets New Bar For Accelerated Approval Drugs” – Pink Sheet, 25 Apr, 2019.)

Opdivo’s SCLC indication has now beaten the Lartruvo record for shortest time on market, clocking in at two years and four months. Nevertheless, the SCLC claim did not come off the label for more than two years after BMS announced top-line results from two failed confirmatory trials.

Opdivo was first approved in the US in 2014; in August 2018 it received accelerated approval in third-line SCLC, making it the first-ever immuno-oncology agent in this cancer type and the first SCLC therapy approved in approximately 20 years. Subsequently, Imfinzi and Genentech’s PD-L1 inhibitor Tecentriq (atezolizumab) received full approval for first-line SCLC, while Merck & Co., Inc.’s PD-1 inhibitor Keytruda (pembrolizumab) holds accelerated approval for third-line SCLC.

Opdivo’s accelerated approval in third-line SCLC was granted on the basis of overall response and duration of response data from an open-label trial of 109 patients. As a condition of approval, BMS was required to conduct and submit the results “of at least one multicenter, randomized clinical trial establishing the superiority of nivolumab over available therapy as determined by an improvement in overall survival” in patients with Stage IV SCLC, according to the approval letter.

In October 2018, BMS reported that in the CHECKMATE-331 study, Opdivo failed to improve overall survival relative to standard of care in relapsed SCLC. One month later, the sponsor announced the combination of Opdivo and Yervoy (ipilimumab), an anti-CTLA4 antibody, missed the primary endpoint of overall survival in second-line SCLC in CHECKMATE-451. The latter trial announcement prompted analyst predictions that the SCLC claim was in jeopardy. (Also see “BMS SCLC Chances Dive After Opdivo, Yervoy Combo Flunks Checkmate-451” – Scrip, 27 Nov, 2018.)

Yet, the claim remained on label until December 2020.

“We respect the FDA’s efforts to evaluate accelerated approvals across the industry to ensure the integrity of this important program.” – BMS’ Abderrahim Oukessou

In announcing the withdrawal, BMS said that since the time of Opdivo’s accelerated approval, the treatment landscape has continued to evolve, leading to the availability of more options for SCLC patients across multiple lines of therapy.”

“Although we are disappointed by the withdrawal, we appreciate that the FDA shared our commitment to bringing an innovative new therapy to patients with high unmet need when the science pointed in that direction,” said Abderrahim Oukessou, VP-thoracic cancers development lead. “Similarly, we respect the FDA’s efforts to evaluate accelerated approvals across the industry to ensure the integrity of this important program.”

Imfinzi Loses Its Original Indication

In the case of Imfinzi, the labeling change means loss of the indication that first enabled the drug to reach the US market in May 2017. (Also see “US FDA Continues Shift From Companion To Complementary PD-L1 Diagnostics With AstraZeneca Imfinzi Approval” – Pink Sheet, 1 May, 2017.) The initial bladder cancer indication was viewed as a relatively small market opportunity that would pave the way for subsequent use in lung cancer, and the drug has since received regular approval for non-small cell lung cancer and SCLC.

When Imfinzi came to market, Opdivo and Tecentriq held accelerated approval in second-line bladder cancer; those indications have not yet converted to full approval. Pfizer Inc.’s PD-L1 inhibitor Bavencio (avelumab) and Keytruda hold regular approval in second-line urothelial cancer.

Imfinzi’s bladder cancer indication, which was on label for more than three-and-a-half years, was granted on the basis of objective response rate and durability of response data in an open-label trial of 182 patients.

In March 2020, AstraZeneca announced that in the Phase III DANUBE trial, neither Imfinzi monotherapy nor Imfinzi plus the anti-CTLA4 antibody tremelimumab met the overall survival endpoints relative to standard of care chemotherapy in unresectable, Stage IV bladder cancer. AstraZeneca is continuing to test Imfinzi in various treatment combinations in several ongoing Phase III trials in bladder cancer.

The company’s withdrawal announcement reflected a tone and language strikingly similar to that of the BMS announcement on Opdivo less than two months earlier.

“The science of immunotherapy has moved swiftly over the past few years, bringing new options to patients at an unprecedented pace,” said Dave Fredrickson, executive VP-oncology business unit. “While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded and remain committed to bringing new and innovative options to patients.”…