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User fee reauthorization is crucial to implementing the Cures Act and refining the approval process.
Congress surprised Washington policy makers in December 2016 by enacting the 21st Century Cures legislation after two years of deliberations. The new law shores up FDA operations, streamlines drug development, and funds National Institutes of Health (NIH) research programs, including the Obama administration’s cancer “moonshot” and personalized medicine initiative. Support on Capitol Hill was near-unanimous after adding language promoting regenerative medicine and funding state programs to treat opioid addiction and bolster mental health services.
Now it’s all hands on deck as FDA devises a plan for implementing the many Cures requirements for furthering patient-focused drug development, biomarker qualification, pediatric research, and the development of needed antibiotics and treatments for rare conditions. FDA has to issue many new guidance documents and reports within set timeframes and establish specified processes and procedures (1). FDA commissioner Robert Califf highlighted how the Cures Act will improve FDA’s ability to hire and retain scientific experts, probably the most important provision for agency managers struggling to fill hundreds of vacant positions (2). Biopharma companies developing new drugs gained more flexibility to use novel clinical trial designs and to rely more on real-world evidence to expand indications on marketed medicines.
The Cures Act also provides an additional $4.8 billion over 10 years for NIH and $500 million for FDA. But these funds are not appropriated, opening the door to cutting these promised resources.
Implementing the Cures Act, therefore, depends on timely reauthorization of user fee programs for drugs (Prescription Drug User Fee Act [PDUFA]), biosimilars (Biosimilar User Fee Act [BsUFA]), and generic drugs (Generic Drug User Fee Amendments [GDUFA]) before they expire on Sept. 30, 2017. Normally, enacting legislation as extensive as the Cures Act should smooth the path on Capitol Hill for user fee bills. The Cures Act already has tackled several controversial issues, such as greater reliance on real-world evidence in regulatory decision-making, expansion of priority review voucher programs to spur drug development, and more flexibility for manufacturers to present healthcare economic information on unapproved drug uses.
But drug user fees need to be enacted by late summer 2017 for FDA to avoid issuing pink slips to staffers supported by fee revenues. FDA officials and industry representatives spent the past two years negotiating the fee agreements and want to avoid changes at this point from Congress and Trump administration officials. Another wrinkle is that the Center for Drug Evaluation and Research (CDER) has been working with non-prescription drug manufacturers to devise a user-fee program to support modernization of the over-the-counter monograph process, which could take more time. And legislators on both sides of the aisle talk about curbing high prices on new and old drugs by enacting proposals that were not included in the Act.
Senate Democrats are pressing the new President to take more aggressive action on drug pricing. Trump has called for Medicare to negotiate drug prices and for FDA to approve competitive generic drugs more quickly to provide market competition. And they all propose broader disclosure of pharma R&D and manufacturing costs to clarify production outlays.
Exorbitant price increases on old off-patent drugs are targeted in a report from the Senate Special Committee on Aging, released in December 2016. It documents four such cases that generated huge profits for the manufacturers, while imposing prohibitive costs for patients and payers (3). Susan Collins (R-Me), chair of the Aging Committee, and colleagues seek to prevent such behavior by boosting competition in monopoly drug markets. Specific proposals would authorize targeted prescription drug importation, help generic-drug makers access therapies needed for bioequivalency testing, speed FDA review of generic versions of sole-source drugs and those in short supply, and offer priority review vouchers to firms that develop needed alternative products. The legislators also criticize manufacturers’ patient assistance programs for steering patients to too-costly therapies and seek more transparency in negotiated drug prices and rebates.
Meanwhile, the outgoing Obama administration gave up on its plan to test a range of new pharmaceutical payment models for Medicare Part B, anticipating its sure demise under the Trump administration. Pharma companies and physicians had criticized the Part B demonstration as overly focused on saving money, as opposed to improving outcomes, and a threat to patient access to life-saving therapies. Despite growing interest in developing value-based payment models for medicines, the backlash to the proposal from the medical community illustrates the difficulties facing most drug price control strategies.
While Congress enacted Cures, FDA officials were delivering the troubling news that fewer new medicines came to market in 2016 than in the previous two years. CDER approved 22 new molecular entities (NMEs), a significant drop from the near-record 45 new drugs in 2015, reported John Jenkins, just before he retired as director of CDER’s Office of New Drugs (OND). Jenkins speculated that the 2016 decline may be a blip, as CDER continues to approve most novel drugs in the first review cycle and to provide expedited action on breakthrough therapies. He attributed the decline in new drugs to fewer new applications filed with the agency in the first place, plus an increase in incomplete or inadequate submissions.
That increase was evident in a sharp rise in Complete Response Letters (CRs)-14 in 2016 compared to three a year earlier-including five citing manufacturing difficulties. For example, in May 2016, Astra Zeneca announced a CR from FDA for a new treatment of hyperkalaemia that had failed a pre-approval manufacturing inspection (4). FDA cited Valeant for GMP deficiencies with a new Bausch + Lomb ophthalmic solution (5), and in October 2016, Sanofi and Regeneron acknowledged that a CR citing problems with its fill/finish facility in France would delay launch of a potential blockbuster new treatment for rheumatoid arthritis (6). And Cempra was hit with a CR at year-end that cited safety concerns for its new antibiotic Solithera, along with manufacturing deficiencies at contract manufacturers Wockhardt and Hospira (7). Roche didn’t get a CR but had to announce in December 2016 that problems with its commercial production process would mean a three-month delay in its user fee approval date for a much-anticipated new treatment for a serious form of multiple sclerosis (8).
Perhaps these developments will compel manufacturers to look more seriously at investing in modern pharmaceutical manufacturing processes to ensure reliable quality production of critical drugs and biologics. In reviewing FDA’s achievements for this past year at the FDA/CMS Summit in Washington, DC in December, CDER director Janet Woodcock cited progress in ensuring drug quality, partly due to CDER development of an inventory of facilities all over the world that produce drugs for the United States. She anticipated further gains from implementing a risk-based inspection program through reorganization of FDA’s field inspection force.
The Cures legislation supports these efforts by authorizing grants for research by academic institutions on continuous manufacturing methods for drugs and biologics. Woodcock also looks to expand agreements for mutual reliance on European GMP inspections and to extend such agreements to other regions and to additional types of inspections.
More reliable drug manufacturing operations would help CDER remedy the approval slow-down. A priority for 2017, Woodcock said, is for CDER to establish a Pharmaceutical Platform for new drugs, along with clear data standards for drug submissions and effective IT policies, similar to the automated Panorama management system recently completed to manage generic-drug application review and approval.
1. House of Representatives, Committee on Rules, Division A: 21st Century Cures.
2. R. Califf, “21st Century Cures Act: Making Progress on Shared Goals for Patients,” FDAVoice.
3. Senator Susan M. Collins and Senator Claire McCaskill, “Sudden Price Spikes in Off-Patent Prescription Drugs: The Monopoly Business Model that Harms Patients, Taxpayers, and the U.S. Health Care System,” Special Committee on Aging United States Senate, December 2016.
4. AstraZeneca, “AstraZeneca receives Complete Response Letter from US FDA for sodium zirconium cyclosilicate (ZS-9) for oral suspension for treatment of hyperkalaemia,” Press Release, May 27, 2016.
5. Valeant, “Valeant Pharmaceuticals Receives Complete Response Letter From The FDA,” Press Release, July 22, 2016.
6. Sanofi, “Sanofi and Regeneron Receive Complete Response Letter from FDA for Sarilumab, an Investigational Treatment for Rheumatoid Arthritis,” Press Release, Oct. 28, 2016.
7. Cempra, “Cempra Receives Complete Response Letter From FDA For Solithromycin NDAs,” Press Release, Dec. 29, 2016.
8. Roche, “FDA extends review of application for OCREVUS™ (ocrelizumab),” Press Release, Dec. 20, 2016.
Vol. 30, No. 2
When referring to this article, please cite it as J. Wechsler, "User Fees Needed to Help FDA Manage its Full Plate," BioPharm International 30 (2) February 2017.