Accelerated Approval Pathway Part 1

Aditya Kelkar

Implications of the upcoming FDA Oncology Advisory Meeting and the Future of Oncology Drug Development

The FDA has scheduled a three-day advisory committee meeting (April 27 – 29) to review supplemental BLAs for three biologics; Keytruda, Opdivo, and Tecentriq – across four oncology indications; triple negative breast cancer, urothelial cancer, Gastric / GEJ cancer, and liver cancer. The discussion and outcomes of these meetings will not only impact approvals for these drugs but could also impact Oncology drug development in general.

This first article, part of a three-post series, focusses on need for such a meeting and underlines the impact of accelerated approvals in the field of Oncology.

History of Accelerated Approvals

The accelerated approval pathway was introduced in 1992 and modified in 2012 to allow the FDA to expedite the approval of drugs for serious conditions with unmet medical need, based on whether the drug had an effect on a surrogate or an intermediate clinical endpoint. In the context of oncology, it meant that drugs could be approved based on response rates / percentage of tumor shrinkage. Next, a confirmatory trial would be required post-approval to demonstrate the impact on overall survival.

Accelerated Approvals in Oncology

Given the unmet needs in cancer indications, adoption of accelerated approvals has been highest in oncology with roughly 67% (169/253) of all accelerated approvals being granted in the therapy area since 1992 [Data as of Dec 31,2020]. Over the last few years, the number of accelerated approvals in oncology has jumped from an average of 6 approvals (between 2010 – 2016), to 15 approvals (between 2017 – 2019), and in 2020 there were 42 accelerated approvals in oncology, which represents 93% of all accelerated approvals in 2020.

Keytruda (pembrolizumab, Merck) leads with way with 33 accelerated approvals (20% of all oncology accelerated approvals to date), followed by Opdivo (nivolumab, BMS) with 11 accelerated approvals (6.5% of all oncology accelerated approvals.) An independent analysis showed that accelerated approvals have allowed for drugs to be available a median of 3.4 years earlier than what would be achievable if approval was based on an endpoint such as overall survival.

Issues with Accelerated Approvals

While this has been a very positive outcome of the pathway, as of Dec 31, 2020, only 44% of all oncology accelerated approvals had been converted into full approvals – which means that more than half of all accelerated oncology approvals have yet to show a statistically significant improvement in overall survival. For the oncology drugs that received accelerated approval between 2014 – 2017, the average time for getting full approval by demonstrating survival benefit in a confirmatory trial was 27 months. To date, only 8% of all accelerated approvals (20/253) have been withdrawn due to lack of confirmed survival benefit in the confirmatory trials. Within oncology, this number is even lower with only 6% (10/169) of accelerated approvals withdrawn.

For these reasons, accelerated approvals remain an area of active discussion within the pharma industry, key stakeholders, physicians, and the payor community. Questions are being raised on merit of the pathway and if any changes need to be made to make this regulatory incentive more meaningful from a scientific and medical perspective.

Catalysts Leading to FDA Oncology Advisory Meeting

Recently four pharma companies voluntarily withdrew their accelerated approvals for their drugs in oncology indications.

  • Bristol Myers Squib withdrew approval for Opdivo (nivolumab) in SCLC following failure in the confirmatory CheckMate 451 and CheckMate 331 trials.
  • AstraZeneca withdrew approval for Imfinzi (durvalumab) in bladder cancer following failure in the confirmatory DANUBE trial.
  • Merck withdrew approval for Keytruda (pembrolizumab) in SCLC following failure in the confirmatory Keynote 604 trial.
  • Roche withdrew approval for Tecentriq (atezolizumab) in urothelial cancer following failure in the confirmatory IMvigor 211 and IMvigor 130 trials.

These withdrawals coupled with the FDA’s continued assessment of the Accelerated Approval Pathway led to the FDA convening this Oncologic Advisory meeting, where the FDA will ask the committee to opine on whether the following drugs should continue to have approvals, given the lack of survival benefit in their confirmatory trials.

Structure for the FDA Oncology Advisory Meeting

The 3-day long FDA advisory meeting will provide external experts along with cancer patients to share their inputs and perspective with the FDA. After the meeting, the FDA staff will consider the committee’s comments and will make final decisions regarding continuing of each indication. The indications that will be discussed on each day are as follows. The meeting will be open to public and meeting materials will be made public at least two days before the meeting.

April 27

Tecentriq + paclitaxel

  • Atezolizumab in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic triple-negative breast cancer (TNBC).

April 28


  • Pembrolizumab as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy.


  • Atezolizumab as monotherapy for patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.

April 29


  • Pembrolizumab for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy.
  • Pembrolizumab for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.


  • Nivolumab as a single agent for patients with HCC who previously received sorafenib.

Pharma, Patient, & Physician Impact

Pharma Impact:

Discussions from the meetings will be critical for these drugs, as each of the indications is associated with significant revenues for the respective companies. (e.g Tecentriq along with paclitaxel has been the market leader for TNBC indication [ IQVIA Feb 2021] and was anticipated to bring in peak revenues of anywhere between $500M – $1B for the TNBC indication, whereas peak revenues for Opdivo in the liver cancer indication were being pegged at $1B.) With Keytruda leading in terms of having the highest number of accelerated approvals and bringing in one-third of Merck’s annual revenues, continued approval in the majority of its accelerated approvals is going to be key for the company.

Patient and Physician Impact:

There are not many effective treatment options available for indications such as TNBC and liver cancer and although the confirmatory trials of these drugs did not demonstrate benefit in terms of overall survival, they did provide a treatment alternative for patients who would otherwise have to rely on chemotherapy. The Friends of Cancer research, a non-profit cancer research organization based in Washington, D.C., published a white paper in December 2020 which discusses optimizing the use of accelerated approval in oncology programs and provides suggestions on how survival endpoints could be re-defined and made more realistic in order to address challenges in demonstrating an overall survival benefit in cancer patients.

A recent article published in the JAMA Oncology Journal (March 2021) indicates that in a cohort of 298 randomized controlled trials conducted between 2010 – 2020, a majority of the trials were measuring surrogate endpoints as primary endpoints and were almost exclusively being funded by the pharma industry. It is therefore very evident that any major changes to the accelerated approval pathway will not only impact the pharma companies developing the drugs but could also lead to a lack of approved treatment options for conditions with unmet medical needs.

The Advisory Committee and the FDA therefore have a very important task ahead of them – balancing the agency’s commitment of providing early access of drugs to patients, but at the same time, ensuring that these drugs have a favorable benefit-risk ratio. Prudent modifications to the accelerated approval pathway will be critical to incentivize future drug development.

Sedulo Group is a full-service competitive strategy consultancy specializing in the Pharma and Biotech space, offering competitive intelligence (CI), market intelligence (MI), and strategy consulting. Through 15 years of providing competitive intelligence research and consulting to the life sciences community, Sedulo has developed a network of > 20,000 sources across the globe and a suite of competitive strategy services which support all stages of the drug development and commercialization life cycle.

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Aditya Kelkar

Director of Strategic Insights

Aditya Kelkar
Director of Strategic Insights