Details on FDA-industry deal for PDUFA V: it's about meetings, not money

After ten months of negotiations, FDA, BIO and PhRMA have agreed on a PDUFA V formula that trades a $100 million increase in fees over five years and an additional two months of review time for new drugs in the hope that the time and money will make it possible to complete a higher percentage of reviews on schedule.

High quality reviews performed on a predictable timetable has been the industry's primary objective for PDUFA since the program's inception in 1992. But as user fees have exploded over the decades and have been allocated to a widening range of activities, success in achieving their principal goal has been elusive.

FDA has consistently managed to approve about 60% of priority NDAs for new molecular entities (NMEs) and original BLAs within a single review cycle, but has done so only by pulling staff away from standard reviews.

Although about 80% of all NDAs and BLAs are eventually approved, there has never been much more than a one-in-three chance that a standard NME or BLA would be approved in the first cycle (see "First Cycle Approval Rates vs. User Fees," A2).

To increase first-cycle approval performance, the PDUFA V agreement adds a two-month "filing period" to the start of the review process for NME NDAs and original BLAs, establishes a mid-cycle meeting to allow sponsors to attempt to get errant reviews back on track, and sets up a late-cycle meeting to smooth any advisory committee meetings or negotiations over labels or risk evaluation and management strategies (REMS).

Indeed, commitments for more meetings runs throughout the PDUFA V agreement, and when FY13 starts in October 2012, there will be a lot more meetings and discussions among agency officials and drug sponsors, patients, physicians, and academic scientists.

All of the talking is integral to a number of process changes intended to expand and improve FDA's interactions with drug sponsors, patients and the scientific community along the regulatory continuum from IND filing through NDA and BLA reviews and the postmarket period.

In addition to improving communications with sponsors, the agency plans to create new fora for patients, along with formal procedures for integrating patient perspectives into review criteria.

The intensified interaction between FDA and patients could prove to be one of the most important aspects of PDUFA V because the injection of patient perspectives may be the only way to inoculate the agency from politically induced risk aversion.

The agency has explicit plans over the course of the PDUFA V period to change the way it assesses benefits and risks, as well as the endpoints used to assess safety and efficacy, based on advice it receives from patients.

The industry also has agreed that FDA can use PDUFA money to hire over 100 staff to bring new scientific expertise into the agency. Nevertheless, the total tab for PDUFA V over five years is expected be about $3 billion, compared to $2.9 billion for PDUFA IV.

Thus the begging question will be whether the added review time and communications commitments, rather than money, will achieve the kind of agency performance that has not been reached in prior user fee agreements.

FDA officials, BIO and PhRMA member company executives and staff who negotiated the PDUFA V agreement declined to speak about the deal for attribution. But they have acknowledged that FDA has not agreed to specific goals for improving first-cycle performance.

Moreover, the agency's Office of Surveillance and Epidemiology (OSE) has not been present in the negotiations, which could be a sign the agreement will not resolve poor coordination and bureaucratic in-fighting.

Enhanced communications

BIO and PhRMA signed off on the PDUFA deal on May 25, more than a month later than FDA had hoped to complete negotiations.

The deal was held up by BIO's insistence that FDA address complaints from its small company members that the agency's reliance on formal communications, especially during early development, routinely causes months-long delays, according to people involved in the negotiations.

BIO members say that in recent years reviewers have refused to return telephone calls regarding routine questions, such as what species of rat to use in a toxicology experiment. Instead, companies are forced to submit questions in writing, to wait 30 days for a response, and often to wait another month or two for a ping pong of clarification questions and responses to resolve an issue.

FDA rejected BIO's suggestion that PDUFA V incorporate requirements for reviewers to provide informal feedback to sponsors, telling the trade associations that any agency advice should and will be considered definitive, according to individuals who discussed BIO's proposal with FDA.

PhRMA, whose members often hire former FDA staffers with intimate knowledge of its requirements, was less enthusiastic about the enhanced communications initiative than BIO. PhRMA suggested reducing the cost of any new IND-stage communications procedures by applying them only to small companies.

In the end, FDA and the industry groups agreed on a sweeping policy that applies to all companies and is intended to make the drug review culture more interactive and collaborative.

A letter formally spelling out the PDUFA V goals states: "FDA's philosophy is that timely interactive communication with sponsors during drug development is a core Agency activity to help achieve the Agency's mission to facilitate the conduct of efficient and effective drug development programs, which can enhance public health by making new safe and effective drugs available to the American public in a timely manner."

Ironically, FDA and industry agreed that the best way to deal with an overly bureaucratic review process is to create a new bureaucracy to liaise between sponsors and reviewers at the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

The PDUFA goals letter commits FDA to create a "dedicated drug development communication and training staff within the Office of New Drugs in CDER and augment the manufacturers assistance staff in CBER, focused on enhancing communication between FDA and sponsors during drug development." This is to happen by the end of FY13.

Industry agreed to pay for 10 FTEs to implement the enhanced communications program, as well as $100,000 annually for internal training and industry outreach.

FDA has agreed that the "liaison staff will be composed of individuals who are experienced and knowledgeable about the drug review process (and in some cases may be on detail from the review divisions), interact regularly with the staff in review divisions, and are skilled in facilitating communications between applicants and FDA staff."

The new liaison staff will "serve as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions," according to the goals letter.

The liaison officials also will try to smooth out bumps caused by communications glitches. For example, the letter states that the liaison staff will attempt to resolve instances when sponsors "have not received a response from the review team to a simple or clarifying question or referral to the formal meeting process within 30 days of the sponsor's initial request."

Under PDUFA V, the liaison at CDER's Office of New Drugs (OND) will train all CDER staff involved in IND reviews by the end of FY14.

CDER staff will be taught "best practices for triage of sponsor requests for advice from the review team and timely communication of responses to simple and clarifying questions or referral of more complex questions to the formal meeting process."

These best practices will be articulated in draft guidance, to be published in the first half of FY15.

Among other things, according to the goal letter, the guidance will "outline the types of advice that are appropriate for sponsors to seek from FDA in pursuing their drug development program" and "describe the general expectations for the timing of FDA response to sponsor inquiries of simple and clarifying questions or referral of more complex questions to the formal meeting process."

The guidance will identify "person-to-person scientific dialogue" as a best practice "to facilitate interactions between the FDA review team and the sponsor during drug development."

Stretching PDUFA

FDA plans to launch a 60-day "filing period" for NMEs and new BLAs, essentially extending PDUFA goals by two months. Sponsors and FDA will use that time to map out the review, including agreements on the timing of submission of various elements of the application.

Another new element in reviews of NDAs for NMEs and new BLAs will be a mid-cycle meeting between the sponsor and FDA to discuss the need for risk mitigation, establish timelines for the review, and possibly give sponsors advance notice of any fatal flaws in the application.

The mid-cycle meeting is intended to make it possible for FDA and sponsors to agree on a REMS within a single review cycle, something that now is almost impossible for a priority NME or BLA, and difficult for a standard application.

Poor coordination between the OND which has primary responsibility for premarket reviews, and the Office of Surveillance and Epidemiology, which must sign off on all REMS, has caused numerous delays in reviews since the REMS requirements were enacted, according to FDA officials and drug sponsors.

In many cases, OSE has made REMS requirements clear only late in a review, making it impossible to meet PDUFA goals. It can take months to get FDA approval for even the simplest REMS elements. Moreover, submission of a proposed REMS late in a review, including something as simple as a medication guide, automatically triggers a 90-day extension of the PDUFA goal (see BioCentury, May 23).

In addition to discussing REMS at mid-cycle meetings, the agreement calls for FDA to streamline the way risk management plans are integrated into the healthcare system. FDA plans to create standardized plans, or templates, that companies can use to create a REMS, and apply common approaches that will be easier for physicians and medical systems to use than the current ad hoc approach.

FDA plans to hold a series of stakeholder meetings and workshops during the five-year period covered by PDUFA V to assess the benefits of REMS, as well as their effects on patient safety and access and burdens on the healthcare system.

PDUFA V also will add a late-cycle meeting for new molecular entity NDAs and new BLAs that is intended to be a comprehensive assessment of the agency's review, including descriptions of issues that might be raised at an advisory committee meeting.

The late-cycle meeting addresses complaints from sponsors that they have learned about critical issues FDA will raise with an advisory committee only a few days before the meeting, and that often companies learn about agency concerns for the first time in a complete response letter.

For applications that will be discussed by an advisory committee, the late-cycle meeting will occur at least 12 calendar days before the panel meets. FDA will provide the sponsor with a draft of the questions the agency plans to ask the committee.

FDA has stated it will provide the briefing package at least 20 calendar days prior to a scheduled advisory committee meeting and at least 12 calendar days prior to the late-cycle meeting if a panel meeting is not planned.

FDA told industry it aims to have "discipline review" letters ready in advance of the late-cycle meeting. Discipline review letters note any deficiencies in specific sections of applications, such as the clinical, chemistry, manufacturing and controls, non-clinical pharmacology and toxicology, and the human pharmacokinetics and bioavailability sections.

But the agency resisted BIO's and PhRMA's request that it include an explicit commitment to provide all discipline review letters 8-12 days prior to a late-cycle meeting, according to published minutes of PDUFA V negotiations.

According to the minutes of a March 25 meeting between FDA officials and executives from BIO, PhRMA and several member companies, "FDA reiterated that the agency's clear intent is to conduct a substantive discussion of the sponsor's application at the late-cycle meeting. FDA proposed a revision to state that, in cases where a DR [discipline review] letter is not issued in advance of the late-cycle meeting, the deficiencies identified by that discipline will be communicated in the brief memorandum that is part of the briefing package for the late-cycle meeting."

Moreover, mid-cycle meeting, late-cycle review and other PDUFA V changes will only improve on time review performance if FDA staff supports the changes. Many previous reforms have looked well designed on paper but have failed to achieve their goals because they were not embraced by agency employees.

There is already a hint the new user fee agreement may not lead to better coordination between OSE and OND. While several OND officials, including the Director John Jenkins, participated in the PDUFA V negotiations, no OSE officials were present, according to official minutes of the meetings and individuals who participated.

Regulatory science

PDUFA V includes funding to help promote regulatory science, the issue that has been at the top of Commissioner Margaret Hamburg's agenda.

The deal will fund 119 FTEs to work on regulatory science, and it commits the agency to specific actions to integrate new science as well as patient perspectives into its drug and biologics oversight.

FDA will receive funding for an initiative to inject more rigor into the conduct of meta-analyses. PDUFA V goals include holding a public meeting on best practices in meta-analysis methods, and publication of draft guidance on meta-analyses.

According to minutes of FDA meetings with industry and patient groups, the agency plans to create a small review team with the "computational capacity to conduct meta-analyses as needed and respond to those published in the literature."

FDA told patient and consumer groups in October 2010 that concerns raised by meta-analyses published in medical journals require it to "respond with its own analysis since it often holds data that are not available publicly."

The draft guidance could be used to assess the rigor and reliability of meta-analyses conducted by academic researchers and industry.

Some of the additional regulatory science staff will be dedicated to reviewing biomarkers and pharmacogenomics data. During the negotiations, FDA reported that its biomarker and pharmacogenomic workload has increased to 210 submissions in 2010, up from 56 in 2008, and it expects the number of submissions to continue to increase.

Increased input from patients is expected to be a major focus of PDUFA V, CDER Director Janet Woodcock told BioCentury This Week, BioCentury's public affairs television program, in January.

"I would like to pursue patient-centered drug development where the regulators and the developers really understand where the patients are coming from in that disease," Woodcock said. She said that "no one, the medical profession or the FDA, has done a good enough job listening from the patients how drugs feel to them and how they feel about benefits and risks."

Woodcock added that FDA is developing a semi-quantitative benefit-risk framework that will "standardize how we think and talk about benefits and risks and residual uncertainty," and that the agency plans to make it part of the review process during PDUFA V.

As part of the agency's focus on patient-centered drug development, it plans to hold four public meetings per year to obtain input from patients that can be used to identify unmet needs and learn which endpoints for specific diseases and conditions are most important to patients.

Next steps

HHS and the Office of Management and Budget have started to review the PDUFA V deal, and FDA has announced that it will release a draft of the agreement prior to a public meeting in October.

BIO and PhRMA have agreed to press Congress for a "clean" reauthorization free of provisions outside the documents they have negotiated with FDA. However, it's an open secret that industry, which knows Congress will not be able to resist the urge to put its stamp on PDUFA, is already approaching influential members of the House and Senate with PDUFA wish lists.

According to reports that lobbyists are legally required to file with Congress, numerous pharma and big biotech companies have already engaged lobbyists who have close ties to senior members of the House Energy and Commerce and the Senate Health, Education, Labor and Pensions committees to work on PDUFA.

Staff on both committees have already reached out to former FDA officials, trade associations, industry executives and non-profit groups asking them to submit suggested questions to ask FDA in correspondence and upcoming hearings about user fee reauthorization, and for FDA reform ideas that could be incorporated in PDUFA V (see "Reform Undercurrents," A4).

PDUFA IV expires Oct. 1, 2012. If Congress has not passed legislation to reauthorize user fees by early summer of 2012, FDA will be forced to send letters of possible termination to over 2,000 staffers whose salaries are paid with PDUFA money.

COMPANIES AND INSTITUTIONS MENTIONED

Abbott Laboratories (NYSE:ABT), Abbott Park, Ill.

Bill and Melinda Gates Foundation, Seattle, Wash.

Biotechnology Industry Organization (BIO), Washington, D.C.

National Cancer Institute (NCI), Bethesda, Md.

Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

U.S. Department of Health and Human Services (HHS), Washington, D.C.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.