FDA, Sponsors Gear Up for User-Fee Action

The campaign has begun to enact new policies to "improve" the drug approval process through legislation to reauthorize the drug user fee program; that always carries multiple initiatives designed to spur biopharmaceutical innovation. After a year of consultation with all interest groups, regulators and manufacturers reached agreement last spring for renewing the Prescription Drug User Fee Act (PDUFA), on track to transmit the PDUFA V plan to Congress next January. The current user fee program expires September 30, 2012, and a new program has to be in place before then for the Food and Drug Administration (FDA) to be able to continue collecting industry payments.

Jill Wechsler

The debate will be shaped by growing pressure on the Obama administration and Congress to cut government spending, which promises to curb resources for the FDA and further squeeze drug reimbursement. Legislation adopted in August to extend the national debt ceiling established a new "super" deficit reduction committee to identify $1.5 trillion in spending cuts for the next 10 years. If the panel fails to reach agreement on a savings plan, the default is an 8% across-the-board reduction in government spending, a tough cut for agencies like FDA that are required by recent legislation to expand oversight programs.

The situation makes it even more important for Congress to quickly approve user fees to offset anticipated curbs on appropriated funding. Even though user fees already support some 60% of FDA's expenditures on assessing new drugs and biologics, the demand for more resources will make policy makers less likely to complain that fees make FDA overly dependent on industry.

PDUFA deal

The basic PDUFA V proposal, which FDA posted September 1, is not radically different from the current program and by itself should win congressional support fairly easily. FDA is looking to boost user fee revenue by about $40 million a year, a "modest" 6% annual increase that will bring in nearly $700 million in fiscal year 2013. The most notable change gives FDA an extra two months to review applications, here in the guise of a 60-day "administrative filing period" after submission of an application; this will permit agency reviewers to fully vet the filing before starting the official review clock.

The larger fees will support more meetings between reviewers and sponsors, and a new cadre of FDA liaison officials will be assigned to enhance communications. The plan also calls for standardizing risk evaluation and mitigation strategies (REMS); expanding FDA's Sentinel system to improve post-market drug safety surveillance; and implementing an electronic submissions system for clinical data—something that has long been on the agenda for FDA and for the industry.

Along with PDUFA, FDA and manufacturers are working on a new user fee program for generic drugs, while also discussing a formula for fees for new biosimilar product applications. There's strong support for renewing pediatric drug development and research incentives, preferably on a permanent basis. The aim is to move away from the five-year sunset-and-reauthorization process linked to PDUFA for the Best Pharmaceutical for Children Act and the Pediatric Research Equity Act to encourage more pediatric product development.

The Medical Device User Fee Act (MDUFA) also is up for renewal, and negotiations on that program have been much more contentious than for drugs. FDA is embroiled in evaluating proposals for overhauling its 510k regulatory process for low-risk devices, which threatens to expand clinical research requirements for certain products. A recent Institute of Medicine (IOM) report advises FDA to find a better way to assess the safety and efficacy of these products, but industry fears proposed changes will stymie medical device innovation and product development.

Adding on

The main obstacle to speedy approval of PDUFA V legislation is the tendency of members of Congress to hang multiple pet programs on the user-fee legislation "Christmas tree." There will be numerous proposals designed to generate savings for government health programs, such as bills to legitimize drug reimportation, to reduce exclusivity related to biosimilars, and to curb brand-generic patent settlements. The White House eyes hefty new revenues from a plan to impose rebates on generics drugs prescribed to Medicare beneficiaries who previously received drug benefits from state Medicaid programs, a policy that manufacturers vehemently oppose as a first step towards price controls.

Instead, industry would like to see added incentives for developing new antibiotics and revisions in FDA's orphan drug program, along with efforts led by Rep. John Dingell (D-Mich) to strengthen oversight of imported drugs and active ingredients, which would enhance FDA authority to mandate recalls and import controls. There's bi-partisan support for REMS reform and for revisions in FDA financial conflict-of-interest policies that appear to exclude many qualified experts from seats on FDA advisory committees.

A Biotechnology Industry Organization (BIO) wish list is less conventional, calling for FDA to become an independent agency and to de-politicize it by appointing the FDA commissioner to a fixed six-year term. BIO wants to require FDA to tell sponsors specifically why it's not approving an application and proposes a "progressive" drug approval procedure that permits therapies for diseases that lack effective treatment to come to market on a limited basis while the sponsor completes clinical studies.

Congress opens debate

FDA laid out its goals for user-fee-renewal legislation at House and Senate committee hearings in July. Commissioner Margaret Hamburg outlined for the Senate Health, Education, Labor, and Pensions Committee how user fees support patient access to new drugs and medical products. Panel leaders expressed strong support for renewing user fees for drugs and devices, hopefully by next spring, although Sen. Richard Burr (R-NC) threatened to block PDUFA reauthorization if FDA doesn't fix the medical device approval process.

There was similar high praise for the fee program at a hearing before the House Energy and Commerce Health Subcommittee. The main Republican concerns, as laid out by E&C chairman Fred Upton (R-Mich), are that REMS requirements thwart new drug development, and that "rigid and unrealistic" conflict-of-interest policies prevent advisory committees from vetting new drug candidates in a timely manner.

Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER), provided the panel with a fairly positive report on FDA's drug approval process, describing how proposed PDUFA V enhancements will further address drug access and safety issues. Woodcock credited the 20-year-old user fee program for establishing a more efficient, predictable drug approval system that has sped up the review process for new drugs and biologics "without compromising the agency's high standards for demonstration of safety, efficacy, and quality of new drugs." FDA has provided patients with access to more than 1,500 new drugs over the past two decades, she commented, including important cancer therapies that often are available to US patients before reaching the market in Europe, according to a recent study.

Woodcock was able to report that FDA is on track to approve more new medicines in 2011 than in recent years, with 20 new drugs already okayed at mid-year; the number rose to 21–the 2010 total—soon after when FDA added Astra-Zeneca's Brilinta to the list. Woodcock also noted that CDER's rate of first-cycle approvals for priority new molecular entities is going up, citing recent action on landmark treatments for hepatitis C and for late-stage melanoma. She credited the REMS program for facilitating access to high risk products, such as a new thyroid cancer treatment that FDA approved with a REMS to limit access to truly needy patients.

Support for innovation

The real problem, said Woodcock, is not slow approvals, but that too many experimental drugs continue to fail during development. PDUFA support for more FDA meetings with sponsors should help improve success rates, along with added resources to develop guidance and new methods for testing and evaluating experimental drugs.

This fits with FDA plans to tap user fees to promote its Regulatory Science agenda, as spelled out in FDA's "Strategic Plan for Regulatory Science," published in August. The report outlines opportunities to enhance preclinical toxicology testing, improve drug manufacturing, assess new gene and cellular technologies, and improve the agency's data analysis capabilities. A key initiative is to refine clinical trial design, endpoints, and statistical analysis methods to support the development of personalized medicine and companion diagnostics. The report urges novel trial designs for orphan and pediatric studies, along with modeling and simulation methods to improve protocols. Collaborative research could advance meta-analysis methodologies, enhance the use of biomarkers and pharmacogenomics, and further develop patient reported outcomes and other endpoint assessment tools.

Similarly, a July CDER report on scientific priorities cites the need to refine statistical methods for assessing missing data and multiple endpoints and to further assess the value of non-inferiority studies and methods for improving the selection of study endpoints. One idea is to evaluate failed trials to identify alternative designs appropriate for limited study populations. To ensure patient safety and clinical trial data quality, the agency looks to identify the most relevant parameters for assessing risk to guide research site inspections.

Jill Wechsler is the Washington Editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com