One of the significant provisions in the recently enacted Food and Drug Administration Safety and Innovation Act (FDASIA) was the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V). John Jenkins, MD, Director of the Office of New Drugs (OND), in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA) recently gave a presentation discussing PDUFA goals, trends in drug approval, and looking ahead.
First, Jenkins noted that FDA’s new workload associated with implementation of the FDA Amendments Act of 2007 (FDAAA) had an adverse impact on FDA’s ability to meet all of their PDUFA goals in FY08/09. However, even during this period, FDA’s application review performance was still in the 80‐90% on time range and many of the applications that missed their first‐cycle PDUFA goals were approved on the first cycle. Jenkins said the agency is now “back on track and meeting/exceeding nearly all of the PDUFA goals for application review.”
Jenkins then shifted the discussion to new drug approvals. He noted the “debate” about whether FDA is too slow or too fast in approving new drugs. For example, in 2007, FDA storylines were “VIOXX, Avandia, and drug safety.” Conversely, in 2012, the FDA storylines have been “innovation, jobs, breakthrough therapies, venture capital drying up, and streamlining regulation.”
Despite these “shifting storylines,” Jenkins noted that in his 20+ years at FDA, he has never received or issued an order to “speed up” or “slow down” on drug approvals. He maintained that OND reviews each application on its merits and apply FDA’s best judgment with regard to the data, the science, and the statutes/regulations. Jenkins said that OND does not have goals for numbers of approvals by year, division, etc.
In Calendar Year (CY) 2011, CDER approved 30 new molecular entity (NME) applications, the highest number since 2004. NME filings in CY11 (39) were higher than the average for recent years (e.g., 30.6/year CY06‐10). To date in CY12, CDER has approved 12 NME applications and has received 15 NME applications for filing
Jenkins cautioned, however, that PDUFA goals are not uniformly distributed across a calendar year; projections for full year data based on ½ year data are subject to significant error. First‐cycle approval rates for NME applications in PDUFA IV are at the highest levels since the start of PDUFA. Median approval times for NME applications are 10 months, a 47% reduction from CY93.
FDA Goals for PDUFA Reauthorization
The presentation then discussed the goals of PDUFA V:
- Ensure continued sound financial basis
- Stick to fundamental goals that drive public health outcomes
- Improving the science of drug development
- Improving the quality of evidence in submitted applications
- More predictable and efficient process
- Avoid proliferation of micro‐process goals that distract fromfundamentals
- Stakeholders feel that priority concerns are addressed
- Focus enhancements on:
- Increasing quality and efficiency of current program
- Maintaining public confidence
Jenkins then summarized some of the PDUFA stakeholder concerns heard over the years preparing for PDUFA V.
Patient Advocate Perspectives
- Speed drug development through greater focus on regulatory science
- Support development of innovative trial designs
- Advance development of drugs for rare diseases
- Provide clear information on benefits and risks
- Obtain patient input on REMS design
- Ensure REMS don’t unduly limit patient access
Consumer Advocate Perspectives
- Strengthen system for oversight and audit of clinical trials
- Provide patient‐friendly information on drug safety and effectiveness
- Provide for easier Adverse Event reporting
Health Care Professional Perspectives
- Consider written information for patients that is more effective than current MedGuides
- Make REMS more standardized; establish metrics to evaluate success of REMS
- Assess REMS burden on healthcare system
- Obtain pharmacist input on REMS design
Regulated Industry Perspectives
- Develop more efficient process to deal with post‐FDAAA review challenges
- Ensure offices work seamlessly
- Establish more transparent benefit‐risk standards
- Ensure greater process consistency across review divisions
- Establish more predictable timeframe for REMS requests
The reauthorization discussions yielded agreement on enhancements in several areas:
- Review program for NME NDAs and Original BLAs
- Enhancing Regulatory Science and Expediting Drug Development
- Promoting Innovation Through Enhanced Communication Between FDA and Sponsors During Drug Development
- Methods for meta‐analysis
- Biomarkers and pharmacogenomics
- Use of patient‐reported outcomes (PROs)
- Development of drugs for rare diseases
- Enhancing Benefit‐Risk Assessment
- Enhancement and Modernization of the FDA Drug Safety System
- Standardizing REMS
- Using Sentinel to evaluate drug safety issues
- Required Electronic Submissions and Standardization of Electronic Application Data
- Modified Inflation Adjuster
- Additional Evaluations of Workload Adjuster
PDUFA V “Program” for NME review
The overall goal is to improve first‐cycle approval rates for New Molecular Entities NMEs without altering the standards for approval. 60‐day filing review period “off the PDUFA clock” provides FDA staff with more time to address added complexity of modern application review (e.g., advisory committee meetings, REMS, PMRs) and time to complete additional tasks added as part of the new review process (e.g., late‐cycle meeting with applicant).
Mid‐cycle communication to applicant and late‐cycle meeting between applicant and review team will improve transparency during review and may provide an opportunity to address deficiencies identified by the review team in the first cycle. The “Program” will test the hypothesis that the review process changes can further increase first‐cycle approvals. Key elements of the “Program” include:
- Complete applications at the time of submission.
- Enforces a core principle of the PDUFA program that has been honored in the breech by applicants (and FDA) for 20 years
- Allows FDA team to plan its review and stay on track without the disruption of unsolicited late amendments
- 60‐day filing review period “off the clock”
- PDUFA clock starts when application is filed, not when submitted, effectively adding 2 months to time for review completion
- In FDA’s review process, this extra time will be added “at the end” to provide more time to address issues before the action is taken (e.g., inspection findings, REMS, labeling, PMRs)
- Mid‐cycle communication
- Conference call after internal mid‐cycle meeting to share updates with applicant and plan for remainder of review
- Discipline review letters
- Issued following completion of primary/secondary review by discipline to alert applicant to potential deficiencies
- Late‐cycle meeting
- Face‐to‐face meeting between review team and applicant to discuss review findings to date and plan for AC and remainder of review
- NOT a decisional meeting on planned action, but may facilitate addressing issues in first cycle and avoid need for CR letter
- Applicant and review team can discuss new analyses/data that maybe available and whether to submit/review in current cycle, which may prompt 3‐month extension of PDUFA goal date
- Planning for AC meeting will avoid redundancy of applicant/FDA presentations in areas of agreement and allow focus on areas of disagreement or need for committee input
FDA said that discipline review letters and late‐cycle meeting will provide applicants greater transparency into the FDA review findings well before action on the application.
Information shared could “signal” the outcome of the review on that cycle, but the reliability of the “signal” may be poor given the ongoing nature of the review.
An application that looks “positive” at the late‐cycle meeting may not be approved based on more senior (e.g., Office Director) review of the issues, unacceptable late inspection results (GCP, GMP), etc. An application that looks “negative” at the late‐cycle meeting may be approved with additional review and as issues are resolved.
Jenkins then discussed development of the benefit/risk framework. The goal is to better standardize FDA’s decision‐making process and improve transparency in communicating FDA’s decisions internally and externally. Work on project began in CDER in 2009 and is currently being pilot tested using 6 NME applications (one per OND review office) templates, and CDER SOPs as appropriate during PDUFA V. Jenkins then gave sample framework questions.
Therapeutic Area
- Analysis of condition
- Describe the condition that is treated or prevented by the drug
- What are the clinical manifestations of the condition, what is known about its natural history, and how does severity vary across sub‐populations?
- Unmet medical need
- Describe the other therapies used to treat the condition, including approved and off label pharmacological therapies and non‐pharmacological therapies
- How effective and well‐tolerated are these alternatives, and what evidence is available to support these conclusions?
Product Specific
- Benefit
- Describe the trials (including strengths and weaknesses) that were conducted to establish safety and efficacy
- What endpoints were evaluated and are they clinically meaningful? How did benefits vary across sub‐populations of responders?
- Risk
- Characterize safety concerns identified from trials. What was the incidence of the risk and did it vary by sub‐population? Did risk change with continued exposure; is it reversible when treatment is stopped?
- How might the incidence change in the post‐market setting? Is additional work needed to further characterize the risk?
- Risk Management
- What risks (if any) require mitigation or further characterization?
- What tools are recommended to address the risks, and what is the expected contribution of each tool to the overall risk management?
- What would constitute a successful risk management plan, how might it be measured, and if the desired impact is now achieved, at what point should the risk management plan be re‐evaluated?
Jenkins then provided a 2012 summary, and noted that CDER is meeting or exceeding nearly all PDUFA application review goals. 30 NME approvals in CY11 was highest total since 2004, 12 NME approvals to date in CY12. Rate of submission of NME applications remains flat. NME first cycle approval rates for PDUFA IV at all time high.
Moving forward, there will be at least 28 drugs facing FDA approval in 2012-2013.