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Pink Sheet – Accelerated Approval: US FDA Wants Comprehensive Development Plan From Oncology Sponsors

Pink Sheet – Accelerated Approval: US FDA Wants Comprehensive Development Plan From Oncology Sponsors

The US Food and Drug Administration is asking cancer drug sponsors to think about the studies intended to support accelerated approval, as well as those aimed at confirming clinical benefit postapproval, as a single package when bringing their development plans to the agency.

The goal is to have an early, comprehensive discussion with the agency to ensure that appropriate data are generated for accelerated approval and the confirmatory trials are completed in a timely fashion, Oncology Center of Excellence director Richard Pazdur said at a Friends of Cancer Research meeting on 20 September and in a subsequent interview with the Pink Sheet.

Taking a concurrent, rather than sequential, approach ideally would minimize the risk of granting accelerated approval by reducing the time between approval and confirmatory trial completion, he said.

The ‘Aha’ Moment

“Frequently we find sponsors that kind of stumble on a finding and they say, ‘Aha, I want to do accelerated approval,’” Pazdur said. “Well, we really have to have a discussion on what is going to be your confirmatory study, when is it going to be submitted in relationship to that accelerated approval, how many patients are going to be entered on that confirmatory study before accelerated approval is granted.”

Rather than taking a sequential approach of deciding on accelerated approval and then thinking about the confirmatory trial in the 11th hour, “we would like to have these discussions occur at the same time that we’re discussing what constitutes the accelerated approval,” Pazdur said. “There’s no reason why somebody cannot be doing the accelerated approval study at the same time that they’re doing the confirmatory study because usually they are done in different indications.”

Some companies frequently run multiple studies at  the same time. For instance, in the case of the “dangling” accelerated approval indications for several PD-1/L1 inhibitors that failed their intended confirmatory trials, for some drugs there were other ongoing studies that potentially could serve to verify clinical benefit, Pazdur said.

However, during the Oncologic Drugs Advisory Committee’s recent review of six dangling indications for three checkpoint inhibitors the panel found that in some cases pending studies would be insufficient to confirm benefit due to differences in study design, population and indication. (Also see “ODAC Report Card: Six Takeaways From Accelerated Approval Reviews Of Checkpoint Inhibitors” – Pink Sheet, 30 Apr, 2021.)

OCE recently started asking sponsors to adopt a comprehensive accelerated approval development plan approach, with concurrent rather than sequential studies, because “we would really like to codify it better,” Pazdur said.

“This is kind of a sea change, but I think it’s something that we really want to have a careful discussion of, not just what is the accelerated approval but what is the confirmatory study, when is it going to be done, what should the accrual be at the time of the granting of accelerated approval.”

Improving The Pathway

The new approach to accelerated approval development plans reflects Pazdur’s interest in improving the pathway, which the OCE director recently described as “under attack” by critics taking a one-sided view of the program. (Also see “FDA’s Pazdur: Accelerated Approval Is ‘Under Attack,’ Supporters Can’t Afford To Remain Silent” – Pink Sheet, 29 Jul, 2021.)

Such criticisms are often aimed at the length of time it takes accelerated approval drugs to complete confirmatory trials, and the continued market availability of some drugs despite the failure to verify clinical benefit in postapproval studies.

Pazdur has acknowledged the need for improvements and last year asked a multi-stakeholder working group convened by FOCR to take a fresh look at the program. Among the possible reforms floated at that time were reframing the program’s focus on a drug’s benefit/risk profile, rather than the effect on a surrogate endpoint. (Also see “Accelerated Approvals Could Be Improved By Focusing On Benefit/Risk, Making Withdrawal Easier” – Pink Sheet, 9 Feb, 2021.)

Pazdur and other FDA staff also would like a mechanism to more easily remove from the market drugs that fail to verify clinical benefit after approval.

“I am always open for reanalyzing pathways and where we’re at, at a particular time,” Pazdur said. “I think that many good things have come from the accelerated approval pathway. They’ve expedited very important drugs to the American public.”

“When we take a look at problematic accelerated approvals, these have generally focused on studies that did not have confirmatory studies ongoing at the time of accelerated approval, so this picture that I want to paint is an early discussion of what constitutes the entire package for accelerated approval and I think that’s one of the major issues that I’d like to get across here.”

Pazdur’s comments are notable given that one of highest profile and most controversial accelerated approvals in recent years, Biogen, Inc. and Eisai Co., Ltd.’s Alzheimer’s disease drug Aduhelm (aducanumb-avwa), did not have a confirmatory trial underway or even designed at the time of approval. (Also see “Aducanumab Accelerated Approval Reflects US FDA Flexibility But Raises Doubts About Confirmatory Trial” – Pink Sheet, 7 Jun, 2021.)

The agency’s late-in-review decision to use the accelerated approval pathway for Aduhelm also was a surprise given FDA staff’s statements at an advisory committee meeting that it did not view amyloid plaque reduction as a surrogate endpoint.

Pazdur, who was consulted on the expedited pathway’s use for Aduhelm, has said the regulatory action on the Alzheimer’s drug highlights many of the issues the oncology review office has dealt with over the years, including when confirmatory trials should begin and how much data are needed for initial approval. (Also see “Pazdurcanumab: US FDA’s Top Cancer Official Weighs In On That Big Neurology Approval” – Pink Sheet, 9 Jun, 2021.)

Defining Due Diligence

OCE also could be taking a closer look at whether sponsors are conducting their confirmatory trials with “due diligence.”

“We have to have some authority over this and this is one of the other areas that may need to be looked at as far as what is the definition” of due diligence, he said.

“I’ll give you the Dr. Pazdur definition of due diligence, and that is with the same resources, seed, etc. that a company would exert in doing their pivotal trial for registration. No major pharmaceutical company or even a small biotech company would take five or six or 10 years to do a trial that could be done in one or two years, that’s for sure.”

At the FOCR meeting, panelist and breast cancer patient Katherine Couvillon explained why completing confirmatory trials in a timely fashion is important to the patient community.

When longer-term data show a lengthening of time to progression for a drug one is currently taking, “it gives us a lot of hope,” she said. “We kind of wait with baited breath to see what the next report is going to say.”

“The people that are not yet on those drugs, that’s the data that they look at,” Couvillon said. “You want to have the most up-to-date data to know if you’re making an informed decision on which treatment you’ll do next, because sometimes a specific treatment might then preclude you from taking a later treatment.”

Think About Diversity Earlier

In addition to a comprehensive plan on accelerated approval, OCE is pressing sponsors to better address minority representation and racial and ethnic differences earlier in clinical development.

“We are asking sponsors … to have that discussion about what is their plan for diversification in the clinical development program,” Pazdur said.

Many times diversification and equity issues are examined in the pivotal trial, but this is too late of a starting point, he said.

“We need to start that from the beginning when patients are first entered on those Phase I studies and even earlier in preclinical studies looking [at] are there potential for genetic, ethnic differences,” he said. “The spectrum of drug development has to encompass the concept of racial diversity and representation of under-represented minority groups. We are particularly in oncology emphasizing that in our breakthrough discussions with sponsors.”