FDA’s proposal that the indication statement for accelerated approval drugs reflect the conditions for “continued approval” has drawn objections from two biopharmaceutical industry groups.

In May 27 comments on a recent FDA draft guidance, the Pharmaceutical Research and Manufacturers of America says such a statement is not the type of scientific information that a health practitioner needs when prescribing the product.

In separate comments, the Biotechnology Industry Organization said the “continued approval” language implies that accelerated approval is an incomplete approval and may not only raise uncertainty among prescribers and patients about the product’s benefits but could threaten reimbursement as well.

The trade groups also take issue with FDA’s proposal to include a statement in the Indications and Usage section that a drug was approved under accelerated approval. Information pertaining to the regulatory process under which a drug is approved is either unnecessary or better left to the label’s Clinical Studies section, they said.

Zykadia Label Reflects Draft Guidance

Released in March, FDA’s draft guidance on labeling for accelerated approval drugs proposes language in the Indications and Usage section stating that a product received accelerated approval on the basis of a specific surrogate or clinical endpoint, and that continued approval may be contingent upon verification or demonstration of clinical benefit in a post-marketing study. The guidance also discussed labeling changes that could be necessitated by withdrawal of accelerated approval ([A#14140324002]).

FDA developed the guidance with an eye toward better reflecting the conditional nature of approval under the expedited regulatory pathway.

The guidance also should bring greater uniformity to how accelerated approval drugs are labeled across review divisions within the Center for Drug Evaluation and Research. For example, although the indication statements for recently approved oncology drugs generally reflect the surrogate or clinical endpoint upon which accelerated approval is granted, other review divisions have not adopted this approach.

Nevertheless, the Office of Hematology and Oncology Products remains out in front on this issue; the recent approval of Novartis AG’s lung cancer drug Zykadia (ceritinib) suggests the guidance’s principles are being followed even though they technically remain in draft form.

FDA’s final labeling guidance should be applied prospectively to mitigate the burden of labeling changes, PhRMA said.

Zykadia received accelerated approval April 29, making it the first novel drug cleared under the expedited pathway since the draft guidance’s release. In keeping with the guidance, the drug’s indication states accelerated approval was based on tumor response and duration of response.

“An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials,” the Indications and Usage section states ([A#00140505015]).

Although PhRMA’s comments do not specifically reference the Zykadia approval by name, they appear to take a swipe at how FDA handled labeling for that accelerated approval drug.

FDA should consider all stakeholder comments and publish a final guidance before implementing the draft document’s provisions, the group said, adding that implementation of the draft provisions runs contrary to the agency’s own Good Guidance Practice regulations.

“PhRMA is concerned that there could be negative public health consequences to implementing the draft guidance as currently written and believes that FDA should wait to implement this guidance after its finalization. Additionally, to mitigate the burden of any necessary labeling changes, such final guidance should only be applied prospectively.”

Agency use of draft guidance has also generated congressional attention Also see "FDA’s Regulatory Rock And Hard Place: How To Handle Draft Guidances" - Pink Sheet, 12 May, 2014..

Confusion For Prescribers, Patients, Payers

Both PhRMA and BIO say the draft guidance’s proposals for new limitations and caveats in the Indications and Usage section could sow confusion among providers and patients, who may get the mistaken impression that drugs cleared under accelerated approval do not meet the same efficacy and safety standards that non-accelerated approval drugs are required to meet.

In turn, such confusion could lead to reduced use of accelerated approval products, which would undermine the purpose of the pathway and Congress’ desire, as expressed through the FDA Safety and Innovation Act, for increased use of the approval route.

“There is a lack of public understanding of the regulatory distinctions among FDA’s expedited programs for serious diseases,” BIO's comments state. The group submitted its comments several days before FDA announced the publication of a final guidance on the qualifying criteria and features of its four expedited drug development and approval programs (see related story, [A#00140609002]).

The group warns that the draft labeling provisions could have important, negative ramifications for reimbursement of accelerated approval drugs.

“Most insurers, including Medicare and Medicaid, will typically cover or provide physician reimbursement for FDA-approved therapies that are medically necessary. However, insurers will not always pay for therapies perceived as experimental or investigational,” BIO said.

Aetna has already expressed skepticism about products approved with “breakthrough” status ([A#00130916004]).

BIO argues, “It is important that the FDA-approved label not send mixed messages to payers that a product approved under accelerated approval is anything less than a full approval that meets the same standard as other approvals, i.e., FDA’s substantial evidence standard. Any suggestion that a product is a ‘conditional approval’ or has not fully demonstrated clinical benefit could result in non-coverage of the product by an insurer, which would undermine the intent of accelerated approval to improve patient access to treatments for serious and life-threatening conditions.”

The industry groups raise concerns that the draft labeling proposals would create an imbalance in how benefit and risks are presented.

“The draft guidance does not propose that the ‘Indications and Usage’ statement disclose that these products have satisfied the substantial evidence standard or that the agency deemed the clinical endpoints ‘reasonably likely’ to predict the specific clinical benefit,” PhRMA’s comments state.

“Instead, FDA’s proposed ‘Indications and Usage’ statement emphasizes the lack of an established clinical benefit and the fact that the product is subject to withdrawal if the confirmatory trials do not verify and describe the clinical benefit. Highlighting these limitations without providing the larger context leads to an unbalanced presentation of approval standards and supporting evidence.”

Only Essential Information, Please

The groups urged FDA to remove the continued approval language from the Indications and Usage section of labeling, with PhRMA saying this proposed statement “is not essential scientific information that a practitioner needs for the safe and effective use of the drug.”

If FDA does not agree to remove such language entirely, then the information should be reflected in the label’s Clinical Studies section with a statement that confirmatory studies are planned or ongoing, PhRMA said.

Similarly, the Clinical Studies section is the appropriate place for any language about a specific clinical benefit not yet having been established, PhRMA said.

The group recommends either removing the reference to accelerated approval in the Indications and Usage section, or including a statement that an accelerated approval drug has satisfied the substantial evidence standard or that FDA considers the surrogate or intermediate clinical endpoint upon which approval was based to be likely to predict specific clinical benefit.

BIO suggests removing any reference to the drug’s regulatory approval pathway from the Indications and Usage section. “The I&U section should only contain information that is presented in a succinct, factual, and meaningful manner to the prescriber identifying 1) the approved indication based on data/substantial evidence criteria supporting it, and 2) a comprehensive account of limitations of use information and what confirmatory studies are planned/ongoing,” BIO said.

Accelerated Approval Labeling Caveat Draws Industry Ire

More from Approval Standards

More from Pathways & Standards