We ask FDA to explain “dangling” accelerated approvals—and this week’s ODAC agenda

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Julia Beaver, MD

Chief of Medical Oncology, Oncology Center of Excellence, FDA

Richard Pazdur, MD

Director, Oncology Center of Excellence, FDA

Earlier this week, the FDA Oncologic Drugs Advisory Committee met in a three-day marathon meeting to consider PD-1/PD-L1 drugs that received accelerated approvals but weren’t shown to provide a benefit in confirmatory trials.

“We have been closely following the anti-PD-1 and PD-L1 antibody trials and waiting to get a complete picture of these as we began to see the confirmatory trials reporting. We are thus convening this ODAC meeting to get advice for the anti-PD-1 and PD-L1 antibody indications that have not confirmed benefit,” Julia Beaver, chief of medical oncology at the FDA Oncology Center of Excellence, said to The Cancer Letter.

Beaver and Pazdur spoke with Paul Goldberg, editor and publisher of The Cancer Letter.

A story about the April 27-29 meeting appears here.

Paul Goldberg: I was hoping we could discuss the upcoming ODAC at a high level—not focusing on specific indications, which you can’t do anyway. Why are you convening this ODAC?

Julia Beaver: We continuously evaluate accelerated approval programs and their confirmatory trials to determine if there is still patient benefit.

Since the inception of the accelerated approval program in 1992, there have been over 150 accelerated approvals in oncology, accounting for over 85% of recent accelerated approvals across all of FDA. While the majority of the completed confirmatory trials do confirm benefit, there are occasions where this is not the case and further evaluation is required.

We have been closely following the anti-PD-1 and PD-L1 antibody trials and waiting to get a complete picture of these as we began to see the confirmatory trials reporting. We are thus convening this ODAC meeting to get advice for the anti-PD-1 and PD-L1 antibody indications that have not confirmed benefit.

Given the results of the confirmatory trials, we are looking for a discussion regarding if the risk benefit calculation has changed and if these indications should be maintained while additional confirmatory trials are completed or conducted.

Richard Pazdur: In addition to Dr. Beaver’s comments, one of the overarching issues is impact of new approvals subsequent to the accelerated approvals. Some of these approvals have significantly changed the therapeutic landscape and have demonstrated survival advantages in the disease.

Because accelerated approval requires the drug to provide advantages over available therapies in the indication being studied, we want the committee to consider if drugs approved subsequent to the accelerated approval would impact this analysis. For single arm trials that support accelerated approval, we generally view these drugs as having to address an unmet medical need. The essential question is the following—Does this unmet medical need still exist given the population studied and the subsequent approval in the time interval since original accelerated approval?

In the past we have convened advisory committee meetings to discuss accelerated approval indications, the last in 2011. We have also consistently sought the advice of ODAC for recommendations on granting accelerated approval to therapies for cancer indications. Going forward we may continue public discussions of these evaluations on a more regular periodic basis which would increase transparency.

PG: It seems FDA has been approving PD-1/PD-L1 drugs at a fast clip. That’s 75 approved indications in six years. And 35 accelerated approvals. Is this unprecedented? Why so many, why so fast?

JB: Yes, the number and speed of these approvals is definitely unprecedented—for oncology or for any other therapeutic area. This rapid and successful development is a direct result of the transformative results we have seen with the introduction of these therapies. These antibodies have provided meaningful survival advantages to patients across multiple cancer types.

For the accelerated approvals, all occurring in indications with substantial unmet medical need, long durations of response in subsets of patients have resulted in years of response and clear benefit to those patients.

PG: In your recent NEJM paper, you mention something called “dangling accelerated approvals.” Just making sure, as someone who follows the FDA lexicon, this is a new term—yes? What is a dangling accelerated approval?

RP: Yes, I coined this term. This term represents accelerated approval indications where a required trial did not confirm benefit—hence, this indication is “dangling” between an accelerated approval status and market withdrawal.

When this happens, we examine the evidence in support of the original accelerated approval, the circumstances of the confirmatory trial, and the current unmet medical need of patients in this indication. I want to emphasize that a “failed” trial does not mean a “failed” drug.

One of the advantages of having several drugs studied in near identical indications—some of the trials positive and others negative—is the opportunity to explore potential reason for these discrepant results between the anti-PD-1/PD-L1 antibodies. Some of the issues include differences in primary endpoints, power calculations, hierarchical statistical testing procedures, trial design, or inability to detect patients most likely to respond.

PG: You have identified 10 dangling approvals, and four of them have been pulled. Another six are heading to ODAC tomorrow. Does it mean that their goose is cooked?

JB: The four indications that were voluntarily withdrawn in consultation with FDA reflect situations where a confirmatory trial or trials did not verify benefit and competitor anti-PD-1 or anti-PD-L1 antibodies received regular approval in the same or earlier indication based on survival benefits, and thus, changed the treatment landscape of available therapy and unmet medical need.

These withdrawals were therefore appropriate. The remaining six indications that will be discussed at the advisory committee meeting will benefit from further discussion and we hope to hear advice from the committee regarding continuation of these accelerated approvals.

RP: This is not a guillotine so to speak, however we do have concerns about each of the indications and that is why we are bringing them for discussion at the ODAC. We want a transparent discussion of these indications.

PG: I noticed some of the confirmatory trials are in a different line of therapy or with different combinations of drugs then the original accelerated approval—is this common?

JB: Yes, it is acceptable for a confirmatory trial to include a combination therapy or different combination and is similarly acceptable for a confirmatory trial to be conducted in a different line of therapy or related disease setting.

This has typically been seen with original accelerated approvals occurring in later line refractory settings and then confirmatory trials being moved up to earlier lines of therapy. This was the case with the majority of the 10 dangling accelerated approvals. This sequence promotes further drug development in serious and life-threatening diseases by moving advances to earlier disease settings where benefit may be greater.

Having trials in different settings can also reduce patient accrual challenges to trials investigating an indication that has already been approved under accelerated approval.

PG: There has been an unprecedented push by drug companies to develop PD-1/PD-L1 drugs, and approvals seem to have been keeping up with the onslaught. Does this mean that the definition of “unmet medical need” has to be shifting continuously?

RP: No, from a regulatory standpoint to meet accelerated approval requirements, a drug should demonstrate an improvement over available therapy at the time of approval.

However, when a trial does not confirm benefit, a reevaluation is warranted to examine the treatment landscape at that time, and that time only. We are not going to be reevaluating the treatment landscape for already approved accelerated approvals unless their confirmatory trials do not confirm benefit.

PG: This could have been my first question, but I kind of like it here, near the end. From a regulatory perspective, how are PD-1/PD-L1 drugs different from, say, cytotoxic drugs. How does this difference affect accelerated approval?

JB: These are very different drugs as they impact the patients’ immune system and do not directly target the rapidly dividing cancer like cytotoxics, nor do they target specific receptors on the cancer like targeted therapies.

The requirements for accelerated approval are the same regardless of the class of drug—namely to demonstrate results based on an earlier efficacy endpoint that are better than available therapy for indications that are serious or life-threatening.

The endpoint most commonly used to support accelerated approval is response rate as this endpoint can be directly attributed to drug activity and studied in a single arm trial. Response rate with a single-arm trial design was used for 9 of the 10 dangling accelerated approvals.

We have seen other classes of drugs such as targeted therapies and chemotherapies with high response rates justifying accelerated approval.

For the immunotherapies, accelerated approval has often used lower response rates more similar to those of available therapies and been justified by improved and exceptionally long durations of response, as well as alternative safety profiles.

PG: You brought up lower response rates and all of the withdrawn indications and many of the ones you are taking to the ODAC Meeting had low response rates in their initial clinical trials resulting in the accelerated approval. What do you make of this and is it cause for concern?

RP: We have been looking at the response rate data for monotherapy immunotherapy indications and noting that despite longer durations, these lower response rates do not always translate into improvements in progression-free or overall survival. We would like the advisory committee to discuss the use of single-arm response rate trials with lower response rates to support accelerated approval for the immunotherapy drug class.

PG: Is there anything I forgot to ask? Anything you want to add?

RP: This past six years have witnessed the approval of seven anti-PD-1/PD-L1 drugs which represents an unprecedented era of drug development never witnessed in any other therapeutic area in the Agency’s history.

Almost half of these 75 indications for these drugs were accelerated approvals and have provided benefit to countless patients. For those patients who experienced responses—many lasting years—there is no question that they have received benefit.

This is different situation from the olaratumab accelerated approval (and subsequent withdrawal) in soft tissue sarcoma where we did not have evidence of an improvement in response rates. In the olaratumab approval, observations in improvement in progression-free survival and overall survival may have been due to chance in the initial trial leading to approval.

The essential problem with the current antibodies is the failure to demonstrate a meaningful clinical benefit to the larger patient population receiving the drug beyond those small number of patients with prolonged responses.

Of the greater than 150 oncology accelerated approvals, only 10 have been withdrawn—including the 4 anti-PD-1/PD-L1 antibodies. Ultimately, the accelerated approval regulations are about modulating risk in expediting drugs to patients with few therapeutic options.

As stated in our Perspective—the small percentage of drugs whose clinical benefit is ultimately confirmed should not be viewed as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases.

This story was originally published on April 26, 2021, and updated April 30, following the ODAC meeting.

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