Between the 27-29 of April 2021, the US Food and Drug Administrations (FDAs) Oncologic Drugs Advisory Committee (ODAC) met to reassess six oncologic immunotherapy indications that had not verified their clinical benefit in confirmatory trials.

In our previous article we looked at the history of the Accelerated Approval pathway. In this piece we explore the implications for development companies of FDA’s handling of these so called ‘dangling’ approvals.

In a confirmatory study a product indication is verified, and its clinical benefit confirmed after it has received an Accelerated Approval. During the three-day ODAC hearing, six indications for immune checkpoint inhibitors granted under the FDA’s Accelerated Approval pathway were reassessed after their confirmatory trials did not confirm the earlier promise of benefit.

The ODAC meeting was organised after four indications of products with Accelerated Approval status were withdrawn from the US market by their manufacturers after confirmatory trials failed to confirm the indication.

Delivering on a promise

Dr. Laurie Smaldone Alsup, CMO and CSO at NDA Group, reflects on the complexity of the process:

“ Accelerated Approval provides earlier patient access, but it also means increased uncertainty of the product’s profile as the data sets are limited. The submitted data is based on surrogate measures that aims to predict meaningful benefits for the patients. This means that the treatment is approved based on the promise of advantages for patients with serious life-threatening diseases, where confirmatory studies must verify the expected clinical benefit. Confirmatory results are critical to substantiate the earlier access.”


The ODAC reviewed six additional ‘dangling’ indications approved under the pathway for breast, urothelial, gastric, and hepatocellular cancers (HCC). During the hearing, the committee gave updates on the status and results of confirmatory clinical studies for the given indications and any ongoing or planned trials.

Predominantly, the unmet need in many disease indications weighed heavily in discussions and voting. Other recurring considerations discussed were the statistics where trends were seen but lacked significance due to a pre-specified hierarchical statistical study plan. Changes in the treatment landscape after the initial Accelerated Approvals was also debated, as new treatment regimens made the product irrelevant for the intended indication. Those indications where confirmatory studies are currently ongoing were discussed by means of relevance and the remaining time to trial fallouts. Trials ending within a year or two had a more favourable outcome.

All six indications were unable to prove clinical benefit in confirmatory studies and two were recommended for withdrawal – Nivolumab (Opdivo) for the treatment of patients with HCC, and Keytruda in third-line gastric cancer.

One of the reasons that Opdivo second-line HCC therapy was voted against was due to the lack of efficacy data of the monotherapy in the population of patients who cannot tolerate first-line bevacizumab as well as those deemed ineligible for other second-line therapies.

For Keytruda in third-line gastric cancer, the landscape has changed. Patients will likely have received immune checkpoint therapy in the frontline setting, making this treatment obsolete. Also, the ongoing clinical trial by the sponsor is not assessing monotherapy as described within the current indication.

Predicting in an evolving landscape

The intense discussion during the meeting illustrates that there is no magic answer for decisions of this complexity. Accelerated Approval provides a quicker pathway for promising treatments when patients lack other options, however delays in the execution of post-marketing requirements are quite common. With the Accelerated Approval, the new drug becomes a part of the present therapeutic landscape which complicates patient enrolment in such studies.

“ The arguments around the predictive value of surrogate markers and conducting acceptable confirmatory studies which upholds the predictions are sensible”, Dr. Smaldone Alsup, reflects. “ However, the decision making in the oncology field will continue to be challenging as there are always new treatments and regimens that impacts outcome.”


Learning from the examples

While we don’t know how these deliberations will impact FDA decision making in the future, we offer three major considerations for Accelerated Approvals in general and in oncology in particular: 

Pressure-test your assumptions. Is your surrogate or intermediate endpoint “reasonably likely” to predict the intended clinical benefit of your drug? Is your data robust enough and consistent across subpopulations and endpoints to justify the necessary trade‐off? How else can you bolster the evidence through other data sets to increase confidence in an early approval?

Prepare your confirmatory studies in terms of design, timeline, and enrolment incentive. Is your study population adequately reflecting real-world patients? Is your study designed to draw the right conclusions? Are you prepared to course-correct your program mid-flight? In the best of worlds, the confirmatory study should already be underway at the time of approval.

Stay updated on the treatment landscape and emerging therapies of the indication your drug is targeting. The entry of further new treatments can complicate matters. Confirmatory trials become difficult to complete and interpret if the treatment landscape is shifting.


The 6 indications reviewed in the ODAC meeting were:

Votes displayed: Yes (green) = maintaining the approval, No (red) = not maintaining the approval

Atezolizumab (Tecentriq)

In combination with paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours express PD-L1. (vote 7-2)

Result: Maintaining the approval

For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. (vote 10-1)

Result: Maintaining the approval


Pembrolizumab (Keytruda)

For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. (vote 5-3)

Result: Maintaining the approval

For the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumours express PD-L1, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy, and if appropriate, HER2-targeted therapy. (vote 2-6)

Result: Not maintaining the approval

For the treatment of patients with HCC who have been previously treated with sorafenib (Nexavar). (vote 8-0)

Result: Maintaining the approval


Nivolumab (Opdivo)

As a single agent for the treatment of patients with HCC who have been previously treated with sorafenib. (vote 4-5)

Result: Not maintaining the approval



Reference material:


The Author

Dr Ingela Loell

Scientific Writer


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