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Pink Sheet – Biosimilar Guidance Development Timelines Criticized By Docs And Patients

Pink Sheet – Biosimilar Guidance Development Timelines Criticized By Docs And Patients

Executive Summary

FDA’s user fee deal with sponsors sets target dates for documents on interchangeability, naming and labeling, but non-industry stakeholders urge agency to accelerate their release; guidance development efforts will get boost in BsUFA II with funding for new dedicated biosimilars unit starting in fiscal year 2018.


The FDA/industry-negotiated agreement to renew the biosimilar user fee program provides too much lag time for issuing and finalizing key guidance documents, representatives from consumer and professional groups said at an Oct. 20 meeting.


However, the agreement’s target dates for a long-delayed draft guidance on interchangeability, and final guidance documents on nonproprietary naming and labeling, seemed to be the biggest complaints leveled against the proposed framework for the second iteration of the Biosimilar User Fee Act (BsUFA) program.


Stakeholders were happy to see guidance development timelines but thought they were too long.

Industry representatives, patient and public health advocates, and health care professionals agreed that FDA needed additional resources for its biosimilar review activities so that it could provide timely development advice to sponsors, conduct efficient application reviews and enable biosimilars to reach market faster.


And while the BsUFA II agreement contains target dates for FDA action on specific biosimilar guidance documents, it also provides a funding and staffing boost for the agency’s guidance development efforts related to the 351(k) approval pathway.

New Funding And Review Model Changes

Under the BsUFA II agreement, the agency will get a massive funding boost for its biosimilar review program operations with a proposed user fee revenue goal of $45m in FY 2018, enough to fund approximately 158 full-time equivalent (FTE) staff. The user fee program’s structure will be divorced from that of the Prescription Drug User Fee program, with new flexibility built into the program around how fees are set. (Also see “Biosimilar User Fee Agreement Offers FDA Funding Boost, Fee Structure Overhaul” – Pink Sheet, 16 Sep, 2016.)


The agreement also includes changes in the review process, including moving biosimilars to the same 12-month filing and review model adopted under the PDUFA V “program” for new molecular entities and novel biologics. (Also see “Biosimilars Will Get PDUFA-Style Reviews Under New User Fee Plan” – Pink Sheet, 28 Sep, 2016.)


The commitment letter includes target dates for release of initial drafts, or revised draft or final versions, of nine guidance documents applicable to biosimilars. (Also see “Biosimilar User Fee Agreement Puts FDA On Hook For Delayed Guidances” – Pink Sheet, 22 Sep, 2016.)


Two of these documents – on interchangeability and statistical considerations for analytical similarity data – initially were targeted for release in 2015 but carried over into the Center for Drug Evaluation and Research’s guidance agenda for 2016. Under the commitment letter, FDA agreed to publish the draft guidance documents by Dec. 31, 2017.


Draft guidance documents on nonproprietary naming and labeling were published in August 2015 and March 2016, respectively, and the agency has agreed to work toward revising or finalizing both of those documents by May 31, 2019.

Calls To Accelerate Guidance Timelines

The delay in issuing an interchangeability guidance has become a touchpoint for criticism of the agency’s implementation of the 351(k) pathway, particularly as more biosimilars come to market.


FDA has licensed four biosimilars, none of which have been determined to be interchangeable with their reference products. Only one biosimilar has reached the market, Sandoz Inc.’s Zarxio (filgrastim-sndz), which references Amgen Inc.’s Neupogen (filgrastim). However, Pfizer Inc. has announced plans to launch Celltrion Inc.’s Inflectra (infliximab-dyyb), a biosimilar to Janssen Biotech Inc.’s Remicade (infliximab), in late November. (Also see “How Risky Is Pfizer’s Launch Of Its Remicade Biosimilar?” – Pink Sheet, 18 Oct, 2016.)


Stakeholders were happy to see guidance development timelines but thought they were too long.


“We were pleased to note that the draft BsUFA II commitment letter identifies a hard deadline on guidance on the interchangeability of biologic medications,” said Jillanne Schulte, director of federal regulatory affairs for the American Society of Health-System Pharmacists. “While we understand that the agency has to be thorough and deliberative in its processes … we really encourage FDA to, if at all possible, move this guidance even faster than the Dec. 31, 2017 deadline.”


“A lot of what’s done at the state level around substitution, a lot of our educational initiatives for our own members, are really inextricably linked to interchangeability guidance,” Schulte said. “The sooner we have that, the easier it is for us to move forward with educating our members on how to use these medications appropriately, especially in hospitals and health system settings.”


The guidance target date “still permits a considerable period of time during which additional products will be approved and brought to market without final policy decisions,” Biologics Prescriber Collaborative’s Cryer said.

Dennis Cryer with the Biologics Prescribers Collaborative said that while the group understands the challenges in developing guidance documents, “we are concerned about the timelines. … If that could be accelerated in some way, that would be wonderful.”


“While it’s important that a timeframe has been provided for receiving a draft guidance on interchangeability by December of next year, and revised draft or final guidances on nonproprietary naming of biologics and on labeling of biosimilars by May of 2019, we are concerned that this still permits a considerable period of time during which additional products will be approved and brought to market without final policy decisions,” Cryer said.


“As such, we encourage FDA to consider the implications of the lack of finalized guidances, as it may negatively impact physician confidence but, more importantly, it may impact patient safety.”


RetireSafe President Thair Phillips said the question of whether a biosimilar is interchangeable is becoming moot in the absence of FDA guidance. “The lack of guidance on interchangeability has allowed health insurers, beginning in January, to in essence declare some biosimilars interchangeable by excluding the reference product from their formulary,” Phillips said. “FDA needs to respond to this safety threat.”


Similar concerns about non-medical switching of patients from reference products to biosimilars not yet deemed interchangeable were aired at an Oct. 18 meeting sponsored by Friends of Cancer Research and the Duke-Robert J Margolis Center for Health Policy.


At that meeting, Leah Christl, associate director for therapeutic biologics in CDER, suggested the agency is still trying to get the interchangeability and statistical considerations draft guidances out the door before the end of 2016.


“CDER and FDA continue to be pushing toward release of these guidances in this calendar year for the guidance agenda,” Christl said. “We know that these are both considered valuable guidance to industry as well as public stakeholders, and we do continue to focus on getting these out and putting resources towards them. And our hope is that these will be published this year.”

Dedicated Biosimlars Unit

FDA’s guidance development efforts should benefit under BsUFA II from the creation of a dedicated biosimilar unit, an idea proposed by the agency during the user fee negotiations with industry. (Also see “FDA Proposes Dedicated Biosimilar ‘Unit’ For BsUFA II” – Pink Sheet, 12 May, 2016.)


It is anticipated that this unit will encompass the current Therapeutic Biologics and Biosimilars Team, which currently consists of 10 positions and is led by Christl, with the addition of 15 new FTEs targeted for hiring in FY 2018 to enhance capacity for development of regulations and guidance, reviewer training and communication.


The dedicated unit would not be responsible for reviewing biosimilar applications but, rather, would provide centralized oversight and coordination of biosimilar policy and be involved in guidance development, education and outreach, and communication, Christl said in an interview.


“BsUFA II will provide resources to establish dedicated centralized staff capacity … known as the biosimilars unit, to provide a focal point for biosimilar regulatory and policy activities,” said Sasha Haverfield, senior vice president of science and regulatory advocacy at the Pharmaceutical Research and Manufacturers of America.

PhRMA was one of four trade associations involved in the BsUFA negotiations. The others were the Biotechnology Innovation Organization, Biosimilars Forum and Generic Pharmaceutical Association’s Biosimilars Council.


Haverfield said the biosimilar unit’s responsibilities “will include scientific coordination among review staff and policymakers, development of biosimilar policy through the publication of new draft guidances and finalization of existing guidances, educational outreach to … stakeholders that will allow the delivery of information on biosimilars to the public in a more timely manner and, last but not least, the enhanced communication responses … related to biosimilar reviews.”


Sally Greenberg, executive director of the National Consumers League, also voiced support for the dedicated unit.


“We think that’s a very good idea, to provide a focal point for coordination to facilitate the scientific, policy development resources, operations management, program governance and internal training as well as educational research and enhanced communications related to biosimilars,” she said.

Next Steps For BsUFA Agreement

FDA will weigh stakeholder comments on the BsUFA II agreement in deciding whether any revisions are warranted before the user fee package is transmitted to the authorizing congressional committees, which must occur by Jan. 15.


Like the prescription drug and generic drug user fee programs, the biosimilar program must be reauthorized before it expires on Sept. 30, 2017.


Theresa Mullin, director of CDER’s Office of Strategic Programs, said FDA representatives recently briefed staff from the Senate Health, Education, Labor and Pensions Committee and the House Energy and Commerce Committee about the BsUFA II agreement.


Mullin said congressional staffers have noted potential challenges in moving the user fee programs through the reauthorization process in 2017.


“It’s a rather unique set of circumstances for the reauthorization of these user fee packages because we have an administration change occurring in January as well as a potential leadership change in Congress,” Mullin said. “So it creates some additional challenges for them.”…