Executive Summary

Agency has targeted 40 older generic chemotherapeutics for revised labeling; FDA will develop the new labeling, which will include currently accepted uses, but needs the cooperation of reference product holders who would actually have to submit the supplement.

The US FDA is embarking on a mission to update labeling of generic chemotherapy drugs, but the initiative’s success may depend upon the cooperation of reference product sponsors.

Under an initiative dubbed Project Renewal, FDA plans to modernize the labeling of approximately 40 older generic chemotherapeutics, according to Amy McKee, deputy director of the Oncology Center of Excellence (OCE) and supervisory associate director in the Office of Hematology and Oncology Products (OHOP).

Speaking at the Friends of Cancer Research annual meeting Nov. 13, McKee said the goal of this admittedly “big project” is to ensure that labeling reflects how these older drugs are being used in clinical practice today.

The MODERN Act would authorize FDA to modify outdated generic drug labeling to reflect accepted uses when the reference listed drug has been withdrawn.

FDA will do the work of developing an updated label but needs the cooperation of the reference product holder (where there is still an active reference listed drug), who would actually be on the hook for submitting the labeling supplement.

Generic labeling must then conform to any changes in the reference product’s labeling.

User fees for new drug application (NDA) supplements were eliminated under the sixth iteration of the Prescription Drug User Fee Act, removing a financial disincentive for reference product sponsors to pursue a labeling change.

However, if the reference product sponsor refuses to go along with FDA’s proposed labeling change, the agency cannot force the NDA holder to submit the supplement.

At the FOCR meeting, McKee asked reference product sponsors for their cooperation.

“Any of you out there who are from companies who are NDA holders for some of these, expect to hear from us to invite you to participate with us in this project,” McKee said.

FDA said it will kick off the project with products where there is an active NDA holder with which the agency can negotiate labeling changes. FDA currently does not have the authority to update generic labels where the reference labeled drug has been withdrawn. (Also see “US FDA’s Label Updating Effort Needs Legislation To Impact Generics” – Pink Sheet, 20 Mar, 2018.)

However, there is a legislative fix on the horizon.

On Sept. 27, Sen. Orrin Hatch, R-UT, and Michael Bennet, D-CO, introduced the Making Objective Drug Evidence Revisions for New Labeling Act (S.3519). The MODERN Act would authorize FDA to modify outdated drug labeling, including for drugs with accepted uses that are not reflected in the approved labeling. The legislation applies to labeling changes for off-patent generics where the reference listed drug has been withdrawn.

When Generic Labels Get Stale

Labeling for older, off-patent drugs may not reflect their current use in clinical practice, either because the reference product sponsor has no incentive to add a new indication or seek a labeling change, or because the reference listed drug has been withdrawn and only generic versions remain on the market

At the FOCR annual meeting in 2017, a multi-stakeholder group proposed a streamlined pathway for adding important data to labeling of older drugs to bring them into line with current real-world practice. At the time, the idea seemed to lack strong support from FDA and the generic drug industry due to a host of factors, including complexity, resources, and product liability concerns.

Center for Drug Evaluation and Research Director Janet Woodcock pointed out that while FDA has authority to order safety-related labeling changes even if a reference listed drug has been withdrawn, changing substantial information in a generic label without a reference sponsor is difficult, and the agency would not be able to add indications on its own. (Also see “Labeling Updates For Old Drugs Could Be Faster Under Streamlining Proposal” – Pink Sheet, 28 Nov, 2017.)

Nevertheless, the idea stayed on FDA’s radar, and the agency’s 2018 Strategic Policy Roadmap described plans for a pilot initiative to “create a structure enabling the FDA to have its own capacity to more routinely update old generic drug labels with new safety and efficacy information.” (Also see “US FDA Looks To Proactively Update Old Generic Drug Labels Under Pilot” – Pink Sheet, 28 Jan, 2018.)

The agency’s budget request for FY 2019 included a $37.6m increase for modernizing generic drug development and review, including a one-time investment in an updated review platform. “As part of modernizing the regulatory processes for generic drugs, this investment will also support efforts to update generic drug labeling, with an initial focus on oncology products, as part of the FDA’s efforts to ensure that patients and their providers have access to up-to-date information to inform clinical decisions,” FDA budget documents state.

The House and Senate appropriations committees have passed FDA funding bills for FY 2019, but the measures have not yet been voted on by either chamber. The Senate measure proposes to fully fund FDA’s request for an additional $37.6m to modernize the generic drug review process, while the House measure would give the agency $27m.

Updating Labels ‘From Soup To Nuts’

McKee said the agency heard complaints from pharmacists that they frequently have to justify orders for older chemotherapy drugs simply because product labeling does not reflect their use as the current standard of care.

“We have a fair number of chemotherapeutics that are generic and so the person who holds the NDA may not be motivated to update it, and so we’re going to do it for them,” McKee said.

“We’ve identified at least 40 or so products where there are generics available that are still used in clinical practice, so we’re not going to spend time on things that really are not used and don’t have a place for our resources,” McKee said.

“We’re going to update the labels so that they appropriately reflect how they are used today.”

The list of 40 products includes drugs with and without active reference listed drugs, FDA told the Pink Sheet.

“We are going to use the same evidentiary standards we use for any indication, but we will be updating the entire label, from soup to nuts,” McKee said, noting this will include information on dosing, pediatric use and new indications. “Some of these labels haven’t been updated in 25, 30 years, so the uses that are actually listed are not really in practice anymore, and some of the diseases that are listed are not the terminology that we use anymore.”

The agency expects to be able to update at least five labels in the first year, after which the process will be accelerated, she said.

OHOP Changes Should Help

OCE is leading Project Renewal, with the participation of OHOP and other partners within the agency, FDA said. The initiative will be aided by some structural changes in OHOP.

Under the proposed reorganization of the Office of New Drugs, OHOP would expand from three clinical divisions to five and be renamed the Office of Oncologic Diseases. (Also see “Office Of New Drugs Reorg Is Bigger Than Expected: US FDA Adds 11 Review Divisions ” – Pink Sheet, 4 Jun, 2018.) “We want to flatten the organization,” said Gideon Blumenthal, acting deputy director of OHOP and OCE deputy director.

A unified, harmonized labeling team within the OHOP immediate office should help with updating legacy labels under Project Renewal, FDA’s Blumenthal said.

OHOP also is centralizing safety analytics and labeling functions.

“A lot of our drugs sort of span across the different tumor types, so we found it really made a lot of sense to centralize the safety analysis within the immediate office. There’s a need for … harmonization of how we conduct our safety analysis, both premarketing and postmarketing,” Blumenthal said. “We’ve had a safety analytics team that we’ve formed within our immediate office to help our medical officers.”

“Similarly for labeling, again our drugs span a lot of the clinical divisions, so we want … a unified, harmonized labeling team within the immediate office,” Blumenthal aid. “And that could also help with this Project Renewal in terms of updating older legacy labels as well.”

https://pink.pharmaintelligence.informa.com/PS124262/Project-Renewal-US…