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Pink Sheet – A “Breakthrough” Reality Check: Sponsors Seek FDA Flexibility On Manufacturing, Diagnostics

Pink Sheet – A “Breakthrough” Reality Check: Sponsors Seek FDA Flexibility On Manufacturing, Diagnostics

FDA’s much-anticipated guidance on expedited programs for drug development fills in some blanks on the new breakthrough designation, but simply advising sponsors they will need to pick up the pace on manufacturing plans and development of companion diagnostics leaves aspiring applicants wanting more, stakeholders said at DIA.

FDA is likely to be more accepting of off-the-shelf companion diagnostics for “breakthrough” therapies as it works out ways to move the diagnostic component through development at the same accelerated rate the breakthrough program affords drugs, stakeholders agreed during a June 25 panel discussion at the DIA annual meeting in Boston.

There have been indications that FDA will be flexible about use of an available CLIA (Clinical Lab Improvements Act) assay that does not have to go through the traditional diagnostic approval process with a pre-market approval application, with the idea of doing a post-approval assessment of some kind after the drug is on the market. In general, though, FDA is taking a more conservative stance on lab-developed tests (“Lab-Developed Test Regulations In Spotlight With Citizen Petition, Hamburg Speech” — “The Pink Sheet” DAILY, Jun. 10, 2013).

FDA released draft guidance on expedited programs for serious conditions, including a section on the new breakthrough designation, June 25 (“FDA Expedited Programs Guidance: “Available Therapies” Depends On U.S. Standard Of Care” — “The Pink Sheet” DAILY, Jun. 25, 2013). In it, the agency notes that “a sponsor should be prepared for a more rapid pace for other aspects of the drug development (e.g., manufacturing, development of a necessary companion diagnostic).”

The guidance does not go into further detail on companion diagnostics, but FDA’s drug and device centers both have acknowledged the need to work out a way for companion diagnostics to be better incorporated into the breakthrough program.

The test case likely will be Janssen Pharmaceuticals Inc./Pharmacyclics Inc.’s ibrutinib, which has won the designation in three B-cell malignancy indications, one of which is a form of chronic lymphocytic leukemia that affects only patients with a 17p chromosome deletion, which is identified by an assay (““Breakthrough” Therapies: Pharmacyclics Gains More Access, Certainty For Ibrutinib” — “The Pink Sheet,” Jun. 10, 2013).

FDA typically requires parallel approval of a targeted therapy and its companion diagnostic, per a 2011 draft guidance on companion diagnostics. However, that guidance also allows for approval of a targeted therapy intended to treat a serious or life-threatening condition absent a specifically approved companion diagnostic (“In Long-Awaited Guidance, FDA Lays Out Approval Path For Drugs And Companion Dxs” — “The Pink Sheet” DAILY, Jul. 12, 2011).

“In our case, for this deletion there is actually an FDA-cleared CLIA assay available, but it is not cleared for this exact patient population that we are after,” panelist Urte Gayko, Pharmacyclics’ senior VP for global regulatory affairs, said. Gayko said she is “generally supportive” of in vitro diagnostics being under FDA oversight but that she is “sure there will also be scenarios where a CLIA-developed test can be sufficient. … We will have those discussions.”

In Pharmacyclics’ experience, FDA’s Center for Devices and Radiological Health is not part of accelerated development planning under the breakthrough program. Gayko said she asked the FDA device center whether “they are participating or they are formally part of this designation, and they said no,” but CDRH told her “of course they would work as closely as possible with the clinical division.”

“From what I’ve heard from [CDER Deputy Director for Clinical Science] Bob Temple, he’s more or less in favor of taking off-the-shelf tests that might have not gone through a formal CDRH assessment and approval in order to release a breakthrough product,” said panelist Earl Dye, director of technical regulatory policy at Genentech, a member of the Roche Group. “I think there is some flexibility at the agency.”

Indeed, during a conference last November sponsored by Friends of Cancer Research and the Engelberg Center for Health Care Reform at Brookings, Temple said, “We’re going to urge that the test be brought through the system, that it be refined,” but “if you have a dramatic effect on something with a shelf test … we would probably approve it because it would be irresponsible not to.”

CDRH is exploring “how they could be a part of this,” FOCR Executive Director Jeff Allen said at DIA. “They share the desire that the companion diagnostic not slow things down for these particularly promising drugs.”

At CDRH’s behest, the advocacy organization has commissioned an advisory group to separate the data elements of the device pre-market approval that are completely essential and would need to be prioritized upfront in the case of a breakthrough therapy, from those that could possibly be shifted to the post-market setting, while still making regulators comfortable with that assay, Allen said. The report should be available in early September.

Meanwhile, he said, prospective breakthrough applicants need to figure out how to get the necessary diagnostic data generated early in a condensed clinical development program. The thought of having a CDRH reviewer look at the “intent to submit the information down the road” on paper and think they might never get that data should be “a motivation that these data sets are really important to you,” he said.

Manufacturing Flexibility Not As Clear

Sponsors have also been concerned that even as FDA works with them on the clinical side to speed up drug development, lack of similar advantages on the manufacturing side might be a rate-limiting factor (““Breakthrough Therapy” Development Speed May Be Tempered By Manufacturing Hurdles” — “The Pink Sheet,” Nov. 26, 2012).

The draft guidance includes a specific appendix on the need to accelerate manufacturing steps to meet advanced development and review timelines (see sidebar).

“FDA hasn’t been willing to discuss the degree of flexibility they are willing to extend to sponsors of these products, and they’ve made it very clear that their expectations are that the sponsors of the breakthrough products get started on their manufacturing activities early,” Dye said.

Sponsors are expected to go to FDA “to talk about what that plan looks like in terms of what the expected market demand is going to be, which facilities you’re going to be making the product in, and what’s the timeline of activities that are going to occur up to the time of submission of an application or launch of the product to ensure that you’ve got a quality product that meets the demand of the commercial market,” Dye said.

However, though publicly “there has not been much discussion around flexibility” from FDA, Dye said there are some areas where “I believe we can work with the agency” on a case-by-case basis.

“I don’t think you can make blanket statements about the kind of flexibility that would be extended to any particular program. It would very much depend on the risk/benefit assessment, degree of sponsor’s understanding of the product and its process and the assurance that they can actually make their product,” he said.

Still, process validation activities, where “you might not have three full commercial batches of material that you’ve finished validation studies on” are the most likely candidates to be pushed to a submission during review or even to post-marketing, Dye said.

For example, “it may be that you have data from development runs that you can leverage and build upon that knowledge and understanding to create a validation protocol for your commercial process,” providing assurance that the “protocol is a sound protocol and [that in] these initial qualification runs you’ve been able to meet the requirements of that validation protocol,” he said.

Then “you can launch subsequent validation batches … so long as you can consistently demonstrate that you’re meeting the particular components of the validation protocol.” It also would be important to demonstrate that “you have means for identifying defective product and doing something about it quickly if something doesn’t go well.”

The Genentech Approach

Genentech realized early on that managing manufacturing considerations in the case of a shortened clinical development timeline would require “some significant thinking from across functional groups,” including the process development, analytical medicines, quality and regulatory organizations, Dye said.

In response, the company formed a cross-functional team with experience in both large and small molecule drugs and charged the group with developing timelines “around a five-year base-case assumption that we would potentially launch a product,” he said, adding that the five-year timeline starts with Phase I studies and ends at the time of launch. The timelines are now being vetted with the various functional areas within the company.

Roche/Genentech’s nominal successor to Rituxan (rituximab), obinutuzumab, has been granted breakthrough status based on initial results of a Phase III registrational study in patients with chronic lymphocytic leukemia (“FDA “Breakthrough Therapy” Designations” — Pharmaceutical Approvals Monthly, June 2013). Marketing applications are pending with FDA and European authorities.

Ensuring a sponsor’s manufacturing operations are keeping pace with its clinical program has a significant impact on product process development and commercial launch considerations, Dye said. “You can’t do less, which means you have to do more and do it sooner, and that is very resource intensive.”

“These accelerated timelines will result in a new approach to product and process development,” he said.

In addition to the resource commitment, communication between the clinical development program and the process development people has to be good “so there are no surprises” if a breakthrough designation comes through, he said. For that to work, “you need to prioritize the pipeline, look at the pipeline very closely, maybe even before you have clinical data” that might support a breakthrough application, and ”start making decisions about the [chemistry, manufacturing and controls] development activities” that have to take place to make sure the product can launch successfully.

Of crucial importance, said Dye, is the handoff between the clinical manufacturing and the commercial operations.” That transition must be “managed very carefully in order to ensure that it goes smoothly and the product transitions to a point that it’s ready for review and inspection at the time of launch.”

Pharmacyclics’ Experience

In terms of what the breakthrough designation means to a sponsor, “we’ve gotten what is described, meaning that we have gotten even better, more frequent communication with the FDA,” Gayko said. And while the company did have good communications with regulators all along, she said, “what has changed is the additional responsiveness.”

Indeed, according to the expedited programs draft guidance, “FDA intends to expedite development and review of the breakthrough therapy by, where appropriate, intensively involving senior managers and experienced review staff in a proactive collaborative, cross-disciplinary review.”

In addition, the guidance explains that the agency “intends to assign a cross-disciplinary project lead for the review team to facilitate an efficient review of the development program.” That project lead “will serve as a scientific liaison between the members of the review team … for coordinated internal interactions and coordinated communications with the sponsor through the review division’s Regulatory Health Project Manager.”

That is how it has played out for ibrutinib, said Gayko. The cross-functional leader assigned to the case is the clinical group leader, she said. That person has attended all of Pharmacyclics’ various regulatory meetings “with the goal of resolving any issues on whatever question there might be in regards to what would be rate-limiting for future registration.”

Gayko also talked about the decision making that went on internally before applying for breakthrough status, highlighting the factors she thinks contributed to Pharmacyclics’ success.

Although breakthrough applications are not limited to monotherapy data and the designation has been granted to therapies being studied in combination (Genentech’s obinutuzumab among them), Pharmacyclics determined that it would first submit monotherapy data for ibrutinib, which is being studied in at least 10 indications, some of them combinations, Gayko said. “I think you can go in earlier [with the single-agent data] because you can generate [the] initial preliminary efficacy and safety results” faster that are required for the breakthrough application.

The other consideration, said Gayko, is that two of ibrutinib’s breakthrough designations are for indications that have no approved therapeutic options. “It’s a fairly straightforward argument to make, and regulatory agencies, including FDA, are always interested in pursuing approval of drugs for indications that have no option,” she said.

Of the three indications Pharmacyclics settled on internally for submission, the decision was to first submit for relapsed or refractory mantle cell lymphoma in patients who have received prior therapy. “What I would always do or suggest,” said Gayko, is to submit the one that is the furthest along “the moment you think you feel like you have sufficient clinical data to make your argument.” The rationale, she said, is that the therapy is closer to “potential discussion and planning for filing purposes.”

For the MCL indication, Pharmacyclics submitted “fairly mature Phase II data,” Gayko said, adding that the company’s motivation for seeking the designation was to “enhance the usability of Phase II data for initial registration.”

An Added Touch

Stressing that “this is by no means a requirement,” Gayko said that one thing Pharmacyclics did as part of its breakthrough application – in addition to supplying data necessary to justify the designation – was to “put together, basically, detailed content for a proposed breakthrough NDA.”

“I wanted to do it,” she said, because “we had initiated some discussion on registration, and I really wanted to … define what the breakthrough designation ultimately means for this particular indication.”

“I can tell you that it was very successful because in our particular case what happened is we got a phone call from [FDA Office of Hematology and Oncology Products Director Richard] Pazdur … immediately, discussing details about this particular proposed NDA and the details of what it would involve. … That was very reassuring for us.”…