Stakeholders ask FDA to be more flexible on rescinding breakthrough drugs designations

Regulatory NewsRegulatory News | 26 August 2022 |  By 

Pharmaceutical stakeholders want the US Food and Drug Administration to be more flexible when revoking breakthrough therapy designations (BTD). In comments on a recent draft guidance, they made several suggestions including allowing breakthrough drugs to stay on the market in certain cases even if an alternative treatment becomes available.
In June, the FDA published a draft guidance titled, Considerations for Rescinding Breakthrough Therapy Designation. While the agency has long asserted authority to rescind BTD drugs for several reasons, the proposed guidance seeks to clarify when regulators will consider pulling a drug off the market and lists a number of scenarios where that might happen (RELATED: FDA explains when it will rescind breakthrough designations, Regulatory Focus 23 June 2022).
In the proposed guidance, the FDA says it may pull a BTD drug if “emerging data for the designated drug no longer support a finding that ‘preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies.’” However, several stakeholders said that might be short-sighted.
The pharmaceutical lobby group PhRMA asked regulators to clarify the policy.
“We recommend that FDA clarify that rescission will not occur unless FDA makes an affirmative determination that there is no preliminary clinical evidence suggesting that the BTD-designated therapy offers a substantial improvement over the newly approved available therapy,” the industry group said. “In other words, the guidance should confirm that approval of a different drug will not de facto result in rescission of BTD,” the organization wrote in its comments. “FDA should also make more explicit in the guidance’s main text that to the extent rescission is even warranted in such a situation, rescission would be limited to circumstances where the existing therapy is approved for use in the same indication and age that is targeted by the BTD drug.”
The Cystic Fibrosis Foundation also took issue with the proposed policy saying it undervalues the benefit of bringing multiple treatments to an underserved population. The patient advocacy group said the agency should take into consideration that patients may have varying results from the available treatments.
“A drug awarded BTD and subsequently approved may offer substantial improvement over existing available therapies to wide proportions of a patient population,” wrote the foundation. “Current BTD policies, however, do not account for patients whose condition may not respond to the approved drug, patients who may not tolerate the approved drug, or patients for whom the approved drug is not an appropriate option for other reasons such as drug-drug interactions.”
Similarly, the Alliance for Regenerative Medicine (ARM) supports allowing a BTD drug to remain on the market even when a newly approved therapy becomes available. The group said it would be useful if the agency further clarified that approval of a product that goes through the accelerated pathway would not automatically mean a BTD drug would be rescinded.
“It should be noted that, even if a different drug/therapy is approved to treat the unmet need, BTD should be considered for retention if the BTD-bearing investigational agent/therapy presents the potential to demonstrate substantial clinical/safety benefit over the approved agent(s),” the alliance said. “As written, the example could be misinterpreted to mean that anytime a different drug is approved, the BTD drug will, by default, not meet the BTD criteria and the designation would be rescinded.”
The draft guidance also noted that the FDA will generally apply greater weight to larger trials and those that “use a well-understood and widely accepted, well-constructed clinical endpoint, and incorporate certain design features,” such as randomization or blinding, noting that the quality of available evidence can play a role in its decision-making. ARM expressed concern with the policy and argued that the size of the population should not affect the agency’s decision.
The alliance instead said the robustness of the results should be what matters regardless of the population size. It also said it does not agree that features such as blinding should weigh into the decision.
“ARM reminds the Agency that blinding is often impossible in the cell and gene therapy trial space and noting this as an example in the guidance establishes unrealistic regulatory policy for advanced therapies,” the organization said.
ARM also objected to the FDA’s implication that rare disease trials or those lacking endpoints or design features may be of lower quality.
“We respectfully request that FDA remove this language and educate reviewers on the science of small studies, novel endpoints, and innovative trial design,” the alliance said. “ARM recommends seeking input from the Accelerating Rare Disease Cures (ARC) program within CDER or rare disease experts within CBER on how to assess rare disease data and endpoints to speed and increase the development of effective and safe treatments of rare diseases before discounting the data collected from a small sample size of a rare disease patient study population.”
ARM, PhRMA and Gilead Sciences – a drugmaker who is also a member of PhRMA – all asked the FDA to incorporate the Center for Drug Evaluation and Research (CDER) Manual of Policies and Procedures (MAPP) and the Center for Biologics Evaluation and Research (CBER) Standard Operating Policy and Procedures (SOPP) into the guidance.
“We request that any final version of the draft guidance expressly include the notification and sponsor opportunity to respond processes set forth in CBER’s SOPP 8212 and CDER’s MAPP 6025.6,” said Gilead. “Specifically, we request that the General Considerations Section of the draft guidance explicitly state that a sponsor be notified of FDA’s intent to rescind a BTD and the sponsor’s right to respond to an FDA request to rescind a BTD by submitting additional data and justification to support BTD and/or requesting a meeting to discuss.”
Gilead also asked the FDA to consolidate two previous guidances – the Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance and the Expedited Programs for Serious Conditions—Drugs and Biologics Guidance – into the new proposed guidance to ensure the guidances are consistent with each other and provide better clarity to sponsors.
“Since BTD is discussed in all of the aforementioned guidance documents, the provisions of rescinding a BTD as per the proposed draft guidance, if finalized, would seemingly apply to each of the guidances,” said Gilead Sciences. “Also, there is a description of the process for rescinding Regenerative Medicine Advance Therapy (RMAT) designations within the Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance document and although BTD is also referred to in the same guidance, there is no information about rescinding BTD… Any processes for rescinding each (RMAT and BTD), to the extent that the designations overlap, should be aligned.”
In its comments to the draft guidance, PhRMA has also asked the FDA to clarify where it has the authority to rescind BTDs in general. The group noted that under the Food, Drug and Cosmetic Act (FD&C), the agency has the authority to approve a BTD within certain time frames but says it does not specify that regulators should reevaluate those products on an ongoing basis or give explicit authority to rescind a BTD.
“PhRMA acknowledges the ‘resource-intensive nature of the BTD program’ and understands FDA’s position as articulated in the draft guidance and the agency’s guidance on ‘Expedited Programs for Serious Conditions – Drugs and Biologics,’ but recommends that FDA identify, in the final guidance, the legal authority enabling rescission of BTD,” said PhRMA.
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