Executive Summary
If sponsors will not work together to ensure that labeling for all drugs used as part of a combination regimen are in sync, then US FDA should take measures to streamline process and Congress may need to step in with carrot or stick incentives, a multi-stakeholder group suggests.
Ensuring that drugs used together as part of a treatment regimen are similarly labeled for combination therapy may require a new regulatory framework in the US or even legislation to streamline the process and overcome hurdles to cross-labeling, stakeholders suggested at the recent Friends of Cancer Research (FOCR) annual meeting.
Cross-labeling of products owned by different sponsors is always easier if the companies work together, and FDA should take measures within its existing authorities to encourage such collaboration, said Marc Scheineson, a partner at Alston & Bird.
However, if sponsors will not work together, FDA should streamline the process for getting the combination use reflected in labeling across all of the individual treatments in the regimen, Scheineson said, adding that legislation also could create incentives to promote cross-labeling.
Scheineson was part of a multi-stakeholder panel encompassing cancer researchers, patient advocates and industry representatives that co-authored an FOCR draft discussion paper on data generation to support cross-labeling of indications for combination products.
“Gaps in regulatory policy and uncertainty regarding legal implications have likely contributed to irregular practices for cross-labeling.” – FOCR discussion draft
While capturing the necessary clinical data for each of the drugs in a combination regimen to inform labeling is important, issues beyond data collection also need to be considered, such as the impact on marketing exclusivity and patent life, and labeling updates that may involve drugs from different sponsors, the discussion draft states.
“Gaps in regulatory policy and uncertainty regarding legal implications have likely contributed to irregular practices for cross-labeling when approval of new combinations expands indications of an existing approved drug,” the paper states. “There is a potential that the resulting label disparities may negatively affect sharing of up-to-date safety and efficacy information with patients and physicians. Ultimately, this raises concerns that some patients may not receive the most efficacious or safe treatment available.”
Lack Of Clarity Gives Sponsors Pause
Labeling is an important consideration for sponsors as they design registrational trials for combination therapies in oncology, said Roger Dansey, senior vice president of oncology clinical research at Merck & Co. Inc.
“If on the front end in the design it’s not clear that there is a path potentially for labeling of the product of interest in the combination, that does raise some concerns and potentially some hesitation on the part of the sponsor,” Dansey said. If the late-stage trial of a combination succeeds but labeling for all of the products involved is not updated simultaneously or in sync, this creates a disparity in publicly available labeling information and has potential ramifications for patient care, he said.
Dansey suggested there should be general acceptance that when a combination trial produces results sufficient to support labeling for one component, the data are adequate to support labeling for the other drugs in the regimen.
“It’s easier if the brands collaborate with each other for approved drugs if there’s remaining exclusivity,” Scheineson said. “If there’s no brand collaboration, there are great difficulties in common labeling.”
It’s Easier When Companies Work Together…
FDA and industry officials pointed to the recent relabeling of Genentech Inc.’s interleukin-6 inhibitor Actemra (tocilizumab) as an example of what can be accomplished when sponsors collectively work toward the goal of cross-labeling.
In August, FDA approved Novartis AG’s Kymriah (tisagenlecleucel), the first chimeric antigen receptor T-cell (CAR-T) therapy, for children and young adults with refractory or relapsed B-cell precursor acute lymphoblastic leukemia. Labeling includes a boxed warning about the occurrence of fatal and life-threatening cytokine-release syndrome (CRS) reactions and directs that severe CRS should be treated with tocilizumab.
FDA simultaneously approved a supplemental indication for tocilizumab for treatment of CAR-T cell-induced severe or life-threatening CRS. The new tocilizumab indication was unusual because it was based primarily on data generated by Novartis and Kite Pharma Inc. in their CAR-T development programs, with FDA analyzing the pooled tocilizumab data across the two companies’ programs. (See sidebar for story.)
In October, FDA approved Kite’s Yescarta (axicabtagene ciloleucel) for adults with relapsed or refractory large B-cell lymphoma. As with Kymriah, Yescarta labeling also recommends use of tocilizumab to treat CRS.
“Having labels with differing information is not in anybody’s best interest, so we do have conversations with sponsors about ways they might want to think and encourage them sometimes to call up their competitors,” said Ann Farrell, director of FDA’s Division of Hematology Products.
Tocilizumab had been used in the CAR-T clinical development programs to treat CRS, and this led FDA and the companies to discuss how those data could serve as the basis for an expanded indication for Genentech’s drug.
The review division “wanted to see this happen, and so we spoke with the companies and said we can’t be your go-between but we think this would be a wonderful opportunity to fix a problem,” Farrell said. “Nobody wanted to see the launch of a CAR-T therapy without an antidote, and it becomes really tricky when you have an off-label use and you’re putting it into the label as a treatment for a side effect.”
“Nobody wanted to see the launch of a CAR-T therapy without an antidote, and it becomes really tricky when you have an off-label use and you’re putting it into the label as a treatment for a side effect.” – FDA’s Farrell
Speaking from the audience, Shanthi Ganeshan, vice president and US head of oncology regulatory affairs at Novartis, said that after FDA initiated the conversations among the sponsors, Novartis spoke separately with Genentech.
“We had our discussions with them and then we basically gave them a letter to send to the FDA so FDA could cross-reference our CAR-T file to update the tocilizumab label with our data,” Ganeshan said. “It was, I think, in patients’ interest and in the two companies’ interest to really get this out there.”
Farrell said the tocilizumab experience shows how data-sharing can occur between the companies.
“I think this was a fantastic example of how companies can cooperate because to do a cytokine release trial is difficult in the setting of CAR-T therapies with all hospitals having varying protocols,” she said. “I think this moved us probably five or six years ahead just to do this, and as a result this information is on the CAR-T product approvals as well as the tocilizumab approval.”
However, the FOCR draft discussion paper notes that the mechanism for obtaining a right of reference to another sponsor’s proprietary data to update labeling may be cumbersome and serve as a disincentive to cross-labeling. “A framework to streamline this process may, at least in part, address some barriers to cross-labeling and encourage maintenance of up-to-date labels for combination therapies,” the paper states.
… But Patents, Exclusivities Can Get In The Way
Cross-labeling becomes particularly complicated when generic drugs are involved, or when a sponsor of a brand product has existing patent or regulatory exclusivities that it seeks to protect.
Patent and marketing exclusivities can delay or block the approval of certain abbreviated new drug applications (ANDAs) and 505(b)(2) new drug applications (NDAs) that seek labeling for new uses as part of a combination therapy regimen, although such applications may be able to omit or “carve out” information protected by another sponsor’s exclusivity, said James Myers, regulatory counsel in FDA’s Office of Generic Drug Policy.
In a recent citizen petition response, FDA concluded that its carve-out authority allows ANDA labeling to include a reference product’s non-protected uses even if it involves adding words to the indication statement. (See sidebar for story.)
Cross-labeling without a right of reference between NDA sponsors can raise complicated patent and exclusivity issues, and cross-labeling involving biologic license applications and NDAs is even more challenging because BLAs and NDAs are governed by different regulatory and statutory schemes, Myers said.
Exercising FDA’s Existing Authority
Nevertheless, Scheineson suggested there are ways that FDA can encourage cross-labeling within its existing authorities. For example, when a new chemical entity is approved for use in combination with older drugs, sponsors of the older drugs could be granted a right of reference and file supplemental applications for conforming labeling changes, he said.
FDA also could permit sponsors of older drugs to summarize combination study data involving newer drugs in the Clinical Trials section of labeling, Scheineson said, pointing to the agency’s approach to labeling for type 2 diabetes drugs.
Anti-diabetic drugs are approved with an indication for improving glycemic control, but specific use scenarios or combinations are not generally identified in the indication. Rather, the clinical studies supporting the indication are described in the Clinical Studies section of the prescribing information, FDA told the Pink Sheet.
This approach shows that “where there are problems from a patent standpoint on new indications, there is more flexibility for the agency to allow listing of published clinical trials in the cross-labels,” Scheineson said.
FDA can use the bully pulpit to persuade combination sponsors to collaborate, an approach that works more easily when sponsors aren’t trying to block each other from coming to market, Scheineson said. In addition, the agency’s policy on good reprint practices allows sponsors of older drugs to talk about combination trials involving new chemical entities through the distribution of peer-reviewed studies.
Can Congress Help?
Legislation is another option to encourage cross-labeling, Scheineson said.
“Legislation can also help if need be by perhaps even suggesting that you curtail exclusivity if the new chemical entity refuses to permit cross-labeling,” he said. “That’s possible to do to if you need a stick and not a carrot.”
In addition, Congress could simplify the procedures for labeling supplements or create a pathway similar to that for imaging device drugs in the FDA Reauthorization Act. Under FDARA Section 706, if a new use is cleared or approved for an imaging device, the sponsor of the contrast drug used with that device is authorized to submit a supplemental application to bring the new use onto the drug’s label.
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