User fee reauthorization process kicks off in Congress

The House Energy & Commerce health subcommittee on Thursday held the first hearing in the process to reauthorize the US Food and Drug Administration’s user fee programs for human drugs and biosimilars.
 
Top FDA officials Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research (CDER), and Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), testified to the success of the agency’s current user fee programs and on the enhancements to those programs the agency seeks.
 
Reauthorization
 
Last month, after lengthy negotiations with industry, FDA transmitted its user fee packages for the next iterations of the Prescription Drug User Fee Act (PDUFA VII), Generic Drug User Fee Amendments (GDUFA III) and the Biosimilar User Fee Amendments (BsUFA III) to Congress ahead of a statutory deadline.
 
Notably absent was an agreement for the reauthorization of the fifth iteration of the Medical Device User Fee Amendments (MDUFA V), which are still being negotiated with industry.
 
The user fee programs were last reauthorized under the FDA Reauthorization Act of 2017 (FDARA) and are set to expire on 1 October 2022 unless Congress acts to reauthorize them.
 
The programs, which are used to fund FDA’s reviews of medical products, have grown in size and scope since their initial iterations.
 
“With these new programs, the FDA estimates that user fees for PDUFA will average $1.4 billion per year – that is a hefty amount of money – the user fees for GDUFA will average over $600 million per year and the user fees for the biologics program will average $51 million per year,” said Subcommittee Chair Anna Eshoo (D-CA). “It’s my hope that Congress will act quickly to reauthorize these user fee programs, to ensure that companies can continue to innovate, and FDA can quickly assess the next wave of lifesaving medications.”
 
Ranking Member Brett Guthrie (R-KY) expressed his interest in using the reauthorization process to allow drug and device makers to communicate additional information to payers to speed coverage of newly approved products.
 
“A top priority for me will be to ensure the FDA approved drugs or devices receive coverage by both public and private insurers as quickly as possible. This will be possible by allowing drug or device companies to share real-time economic and clinical data with payers to plan ahead for formulary placement,” Guthrie said.
 
Guthrie noted the critical nature of the user fee programs and urged their on-time reauthorization. “I cannot underscore how critical it is for this committee and for Congress to reauthorize these agreements before September 30th, doing so is imperative for patients to have access to lifesaving treatments,” he said.
 
Frank Pallone (D-NJ), who chairs the full committee, agreed. “As we continue to face the COVID-19 pandemic, we simply cannot put FDA’s funding in jeopardy, and that’s why we must act expeditiously to reauthorize these important user fees,” he said.
 
Pallone raised concerns about the agency’s inability to reach an agreement with industry on the MDUFA V program. “This is troubling because we’re now more than two weeks past the statutory deadline for Congress to receive the agreement. This deadline is set by law, it’s not a mere suggestion,” he added.
 
Pallone asked both center directors what would happen if Congress failed to reauthorize the agreements.
 
“I am not exaggerating by saying that not reauthorizing these programs would be disastrous for FDA and for patients,” Cavazzoni said, noting that these programs fund more than 80% of FDA’s medical product staff. “These staff are of course critical for reviewing applications and for making sure that we continue to have this incredible flow of new drugs or new affordable generic drugs for the American people.”
 
Marks added that CBER’s “ability to review novel cell and gene therapies, innovative products, would be basically devastated. It would be an incredible blow to our gene therapy leadership.”
 
Program enhancements
 
Both Cavazzoni and Marks touched on some of the priorities embedded in the three agreements.
 
For all three programs, Cavazzoni characterized the resource increases as “incremental” and said that most of the increased revenue will go to hiring additional staff.
 
PDUFA VII would also support several additional initiatives and pilot projects, including a pilot for speeding the review of certain efficacy supplements, enhancing FDA’s model-informed drug development (MIDD) and complex innovative design (CID) programs, and pilots to advance the development of drugs for rare diseases and expand the use of real-world evidence in regulatory decision-making. During the negotiation process for PDUFA VII, FDA held more than 100 negotiation sessions with industry, six stakeholder meetings and two public meetings.
 
“Based on the maturity and success of the PDUFA program, the recommendations for PDUFA VII focus on ensuring FDA has the capacity to review new and innovative products, including cell and gene therapy products,” Cavazzoni and Marks noted in written testimony. In total, the PDUFA VII agreement would provide funding for 352 new staff members and “critical investments in program infrastructure, such as data IT modernization,” which would be phased in over the five-year program.
 
The two overarching aims of GDUFA III, Cavazzoni said, are to increase the number of first cycle approvals and “to facilitate and accelerate the development of complex generics.” To do so, the agreement includes provisions to increase the efficiency of the review process, as well as commitments to issue additional product-specific guidances and enhance communication with manufacturers of complex products.
 
BsUFA III similarly will focus on “increasing the efficiency of biosimilar development and review,” and will specifically target the approval of additional interchangeable biosimilar products. Last year, FDA approved the first two interchangeable biosimilars, Mylan’s Semglee (insulin glargine-yfgn), which is interchangeable with Sanofi’s Lantus (insulin glargine), and Boehringer-Ingelheim’s Cyltezo (adalimumab-adbm), which is interchangeable with AbbVie’s Humira (adalimumab) (RELATED: FDA approves Semglee as first biosimilar interchangeable insulin, Regulatory Focus 28 July 2021; Cyltezo approved as interchangeable biosimilar with Humira, Regulatory Focus 18 October 2021).
 
Marks noted the massive demand CBER faces in keeping up with the influx of submissions for advanced therapies. “FDA has experienced exponential growth in cellular and gene therapy submissions over the past 7 years, with close to 2,000 active development programs,” he said, noting an 85% increase in investigational new drug applications (INDs) and a 158% increase in formal meeting requests.
 
“To meet the demands of this rapidly expanding cell and gene therapy portfolio, PDUFA VII proposes new enhancements to CBER’s capacity. The proposal will allow the agency to produce multiple guidances, host public meetings to examine new technologies and approaches, patient-focused drug development meetings to better understand patient perspectives on gene therapy products, and public outreach to facilitate product development and approval,” Marks said.
 
Marks said he is particularly excited about PDUFA VII provisions for initial targeted engagement for regulatory advice on CBER/CDER products (INTERACT) meetings and the split real-time application review (STAR) pilot program.
 
Rep. Lori Trahan (D-MA) asked Marks about any pandemic preparedness measures or lessons learned from the COVID-19 pandemic baked into PDUFA VII.
 
Marks replied that some of the key pieces of PDUFA VII that could help in future pandemics are the enhanced meeting offerings that would be enabled by the agreement.
 
“I know it sounds very boring but that early input that sponsors can get – the INTERACT meeting provisions that are now put into the commitment letter will help sponsors get early, relatively informal, regulatory advice that will hopefully set them on the right track towards the development of their products. If they don’t make mistakes and waste time and money early on in development, they’re able to move forward more quickly,” Marks said.
 
Later in the hearing, Rep. Michael Burgess (R-TX) asked whether any of the mechanisms used during the COVID-19 public health emergency with Operation Warp Speed would be useful for accelerating the development of medical products beyond the pandemic.
 
Marks again pointed to the importance of meetings and having an ongoing dialogue with sponsors. “Probably the most important piece that I would say is … the dialogue that we have had with sponsors, starting very early on and going on continuously through the drug development process. I can tell you that at least with the vaccine development process, we have often had back-and-forths with the vaccine sponsors where, in 24 hours, there has been turnaround of multiple questions. Now, normally in development, that same process might take over a month,” he said, noting that it’s a lack of resources that prevents FDA from doing this on a wider scale.
 
Inspections and CRLs
 
Rep. Peter Welch (D-VT) asked about the agency’s use of alternative tools to complement its inspections program during the pandemic, specifically citing concerns that a dearth of inspections of generics and biosimilars facilities might be holding up approvals, thus delaying competition.
 
Marks told Welch that there are some instances when the agency has no choice but to require a physical inspection of a facility. He also expressed some hesitation about the effectiveness of the remote inspections. “We are still learning how effective these tools can be by using them. At least at our center, we have had some mixed results with using remote inspection technology, so we are still sorting through this,” Marks said.
 
Rep. Neal Dunn (R-FL) pressed Marks on providing full information from FDA’s reviews to sponsors who receive complete response letters. Dunn asked if doing so would help those sponsors address deficiencies in their applications more quickly.
 
Marks strongly rejected the notion. “No, I don’t. I actually think that could be chilling on the effect of our reviewers. Most sponsors actually know quite well what the deficiencies are in their applications before they receive a complete response letter because they are part of a process which is guided by the user fee commitments, in which they have multiple meetings leading up to this. Most often, they’ve been told – either at their mid-cycle meeting or their late-cycle meeting – of the deficiencies that ultimately lead to their complete response letter,” Marks replied.
 
Aduhelm and accelerated approval
 
During the hearing, multiple lawmakers pressed the FDA officials on the agency’s controversial decision to grant accelerated approval to Biogen’s Alzheimer’s drug Aduhelm (aducanumab). (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 7 June 2021; Woodcock calls for investigation into Aduhelm approval, Regulatory Focus 9 July 2021)
 
Guthrie questioned Cavazzoni on whether FDA was asked to consult with the Centers for Medicare and Medicaid Services (CMS) on its proposed coverage decision, which would restrict Medicare coverage of monoclonal antibodies that target amyloid for the treatment of Alzheimer’s to certain clinical trials.
 
Cavazzoni said the two agencies’ decisions were made independently of one another, to which Guthrie replied, “But if the FDA says it’s safe and effective, and CMS says, ‘no, we’re going to need more data to understand that,’ do you think that the mandated trials that CMS is asking for are duplicative?”
 
Cavazzoni stressed that FDA’s decision was based on the accelerated approval standard, which allows for approval based on a surrogate endpoint that is reasonably likely to predict clinical benefit.
 
“Do you believe that CMS’ decision to not accepted accelerated approvals in that way will hurt other research in Alzheimer’s going forward?” Guthrie asked.  “There have been some concerns raised about this. Our focus is to review these drugs. There is a very rich pipeline for Alzheimer’s,” he said.
 
Pallone also raised questions about FDA’s accelerated approval program, asking about the timing of postmarketing requirements and confirmatory studies.
 
“When it comes to confirmatory trials, those are an inherent component of the accelerated approval program, and we do agree that whenever possible, those confirmatory trials should be underway by the time the approval takes place, and ideally should have started recruitment,” Cavazzoni said.
 
She also stressed that the other component to ensuring the success of the accelerated approval program is the agency’s ability to quickly remove products from the market when the confirmatory trials do not confirm clinical benefit. “Right now, the process that we have is very cumbersome, and can take months or years because it is heavily dependent on the manufacturer’s willingness to withdraw the drug when we ask them,” Cavazzoni said.
 
Hearing