Executive Summary

Commissioner Gottlieb tells Congress that concept could be used for some clinical endpoints when a large benefit is seen in a small trial, which could benefit rare disease drug development.

The US FDA is exploring a potentially dramatic expansion of the accelerated approval mechanism. Under the concept, products showing a substantial, early effect on a clinical endpoint – as opposed a surrogate endpoint used for the existing accelerated approval process – could qualify for the new expedited pathway.

Commissioner Scott Gottlieb said Nov. 30 during a House Energy and Commerce Subcommittee on Health hearing that targeted therapies sometimes show early “outsized benefits,” particularly in oncology.

To expedite review of the product, Gottlieb said the agency is considering whether approval can be granted and confirmatory trials mandated, which is allowed under accelerated approval.

“What do we do when we have a targeted drug, introduced in a properly selected group of patients, which has an outsized effect on overall survival in a rare or deadly cancer, but where that benefit is seen in a small trial, where we would still need more evidence to fully understand how to best use the drug in clinical practice?” he said in his opening statement for the hearing, which reviewed the implementation of the 2016 21st Century Cures Act.

“We might want to approve such a product earlier, and require a post-market confirmatory study to validate the finding, similar to an accelerated approval approach.”

If implemented, the change could substantially speed approval of drugs showing early promise.

“Even though the observed benefit, in this case, is on a clinical endpoint – an early look at survival – and not a surrogate measure of benefit, we believe using an accelerated approval approach often could be valuable,” Gottlieb added.

Building On FDASIA

Gottlieb said after the hearing that the agency believes the accelerated approval regulations that were put into law as part of the 2012 FDA Safety and Innovation Act could allow the agency to create the new pathway. One FDASIA provision allowed FDA to grant accelerated approval based on intermediate clinical endpoints. Gottlieb told committee members that the agency wants to better define what was meant by that language so sponsors can take advantage.

FDASIA, which reauthorized FDA’s user fee programs, also encouraged greater use of accelerated approval. (Also see “PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements” – Pink Sheet, 17 Sep, 2012.)

The idea of accelerated-style approvals based on early clinical data was among the ideas that were discussed at the Friends of Cancer Research’s 2016 annual meeting. Gottlieb’s testimony also seemed to endorse another concept, this one for supplemental cancer approvals, that was discussed at this year’s FOCR annual meeting: “reverse accelerated approval,” as it was dubbed by Richard Pazdur, director of FDA’s Oncology Center of Excellence. (Also see “Supplemental Oncology Approvals: ‘Reverse Accelerated Approval,’ Not Lowering The Bar” – Pink Sheet, 27 Nov, 2017.)

In his written remarks at the hearing, Gottlieb noted, “In keeping with the spirit of Cures, we’re working on a similar proposal for cancer drugs already approved for one indication – approval for a supplemental application, where the approval concerns a second indication, can sometimes appropriately rely on a more targeted data set, like a single-arm study. We intend to issue guidance further clarifying the circumstances in which this is appropriate.”

[Editor’s note: The FDA/CMS Summit will feature fireside chats with Gottlieb and CMS Administrator Seema Verma, along with presentations from FDA leadership including Janet Woodcock. The event will take place on Dec. 5-6 in Washington, DC. To register, please visit the conference homepage.]

Confirmation – Or Withdrawal

As for the proposal to base a form of accelerated approval on clinical endpoints, among the advantages of a pathway would be the flexibility to ensure the benefit translates to the selected patient group, since if it used a version of accelerated approval, FDA could mandate confirmatory trials.

The agency would be able to allow marketing of the product and still ensure the potential benefit manifests in the post-marketing setting. Accelerated approval also provides for a fast withdrawal should the evidence not confirm the benefit.

Even so, as FDA has seen under the current accelerated approval system, withdrawing a product already on the market would likely be very difficult. When the agency tried to withdraw the breast cancer claim for Avastin (bevacizumab), Genentech Inc. appealed, triggering a months-long adjudication process. (Also see “Lessons From Avastin: Accelerated Approval Needs “Easy On, Easy Off” Mechanism, Pazdur Says” – Pink Sheet, 26 Nov, 2012.)

FDA’s recent approval of Merck & Co. Inc.’s Keytruda (pembrolizumab) for the tissue-agnostic indication microsatellite instability-high or mismatch repair deficient solid tumors, is one example of the kind of review where the new modified pathway could apply. Agency officials said they invoked accelerated approval because they wanted long-term follow-up data on the product. (Also see “Supplemental Oncology Approvals: ‘Reverse Accelerated Approval,’ Not Lowering The Bar” – Pink Sheet, 27 Nov, 2017.)

Particular Interest For Rare Disease Sponsors

The modified accelerated approval process, should it be implemented, also could be helpful in the development of rare disease drugs, in part because sponsors often are forced to rely on small trials to show benefit.

In diseases where a validated surrogate is not available, the agency still could grant the approval and allow marketing, but mandate the confirmatory trials to ensure the drug is working as well as initially thought.

Gaining access to accelerated approval has been difficult for many rare disease sponsors, in part because a validated surrogate, i.e. one reasonably likely to predict clinical benefit, is required.

The idea seems similar to one that the EveryLife Foundation for Rare Diseases proposed when the group asked FDA to accept a biomarker as a surrogate endpoint during the pre-IND stage to help increase access to accelerated approval. The idea was intended to help small companies more easily raise capital to bring rare disease products to market. (Also see “Biomarker Approvals At Pre-IND Stage Requested For Orphan Drugs” – Pink Sheet, 1 Jul, 2013.)

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