Now that FDA has its new five-year Prescription Drug User Fee Act (PDUFA) agreement in place, the agency’s plate appears full with numerous new initiatives to implement on drug safety, the review of drug proprietary names, first-cycle drug review enhancements, and expediting drug development. An FDA Webview assessment of FDA’s just-posted PDUFA Reauthorization Performance Goals and Procedures (Goals document) reveals that drug safety enhancement will have the most profound impact at both CDER and CBER over the next half decade. The document says “user fees will provide support for 1) preparing and implementing a five-year plan to modernize drug safety, including improving communication and coordination between the post-market and pre-market review staff, 2) conducting and/or supporting activities designed to modernize the process of pharmacovigilance, 3) developing with sponsors, reviewing, and monitoring implementation of risk management plans, and 4) related activities.”

First off, a draft of the monumental five-year drug safety plan is due before 4/1/2008. The five-year safety plan will be open for public comment, according to the goals document, and a final version should be in place by the end of 2008. It should include:

• An assessment of current and new methodologies on collecting adverse event information at various points during a product’s lifecycle;
• Epidemiology best practices and related guidances to be developed that are identified from input from academia, industry, and the general public;
• New databases acquired for targeted post-marketing surveillance and epidemiology;
• Procedures for developing and validating risk management and risk communication tools, including assessing the effectiveness of risk management plan agreements and developing, implementing, and evaluating mechanisms for public communications about the benefits and risks of drugs and biological products;
• Ways to improve post-market information technology systems (e.g., AERS 2, safety tracking systems); and
• Details on improved communication and coordination between CDER’s Office of Surveillance and Epidemiology and the Office of New Drugs, and CBER’s Office of Biostatistics and Epidemiology and the Center’s pre-market product review, including activities to assess the impact and value of routinely including post-market review staff on pre-market review teams.

On the pharmacovigilance side, FDA’s goals document has the agency accepting proposals from outside research organizations by 10/08 on how to research and determine the best way to collect and report serious and non-serious adverse events (AE) occurring throughout a product’s life cycle. “Central to addressing this question are determining the number and type of safety concerns discovered by AE collection, the age of products at the time safety concerns are detected by AE collection, and the types of actions that are subsequently taken to protect patient safety,” it says.

FDA next year will hold a public workshop to identify epidemiology best practices, which will be used to develop a guidance document. PDUFA funds will also be used to acquire access to population-based epidemiological data and other types of observational data resources. “Access to these types of data will expand the FDA’s capability to carry out targeted post-marketing surveillance, look at class effects of drugs, and potentially carry out signal detection using data resources other than reports from AERs system,” the document says.

Regarding risk management and risk communication tools, the goals document has FDA in 2008 developing a plan to evaluate certain Risk Minimization Action Plans (RiskMAPS) and current risk management and risk communication tools. “Starting in FY 09, FDA will conduct annual systematic public discussion and review of the effectiveness of one to two risk management program(s) and one major risk management tool,” the document says. Findings from these assessments will be publicly released.

New to PDUFA for the next five years are drug/biologic drug proprietary name review enhancements intended to reduce medication errors related to look-alike and sound-alike proprietary names. The user fee initiatives will also target “unclear label abbreviations, acronyms, dose designations, and error prone label and packaging design,” according to the goals document. It includes detailed review timelines for proprietary names submitted as early as end-of-Phase 2 (e.g., 50% of IND-submitted proprietary names must be reviewed within 180 days by FY 2009). There are also quicker review timelines for those names submitted during an NDA/BLA submission.

A guidance document is required to be developed by 10/2008 on the contents of a complete submission package for a proposed proprietary drug/biological product name, the goals document says. By 10/2009, FDA will prepare a MaPP (Manual of Policies and Procedures) to ensure that FDA review divisions are consistent in meeting the proprietary name review goals. By 10/2010, FDA will have published a draft guidance on best practices for naming, labeling and packaging drugs and biologics to reduce medication errors (a final guidance is expected by 10/2011). And by 10/2012, a draft guidance is expected on proprietary name evaluation best practices.

A pilot program will be rolled out in 2009 for firms to evaluate their own proposed proprietary names and to submit the data generated from those evaluations to FDA for review, the document says. FDA in 2008 will also discuss with industry the possibility of “reserving” proprietary names for companies once the names have been tentatively accepted by the agency.

Under first-cycle drug review enhancements, FDA’s goals document says the agency will provide drug and biologic sponsors with an NDA or efficacy supplement review timeline that will include a target date for receiving feedback from a review division on any proposed labeling and postmarketing study commitments (PMCs) the agency will be requesting. The review timeline will be sent after FDA’s 60-day filing date review and it will be attached to any notification of issues identified during the initial 60-day review. If a sponsor submits any major amendment and the review division intends to review it during the review cycle, then the planned review timeline will no longer be applicable. Additionally, the goals document says, “in the event FDA determines that significant deficiencies in the application preclude discussion of labeling or PMCs by the target date identified in the planned review timeline (e.g., failure to demonstrate efficacy, significant safety concern(s), need for a new study(ies) or extensive re-analyses of existing data before approval), FDA will communicate this determination to the applicant in accordance with GRMP (good review management practices) and no later than the target date.”

The goals document also outlines a number of guidance documents FDA intends to publish during the next five years in order to expedite drug development. These include:

1. Clinical Hepatotoxicity – FY 2008
2. Non-inferiority Trials – FY 2008
3. Adaptive Trial Designs – FY 2008
4. End of Phase 2(a) Meetings – FY 2008
5. Multiple Endpoints in Clinical Trials – FY 2009
6. Enriched Trial Designs – FY 2010
7. Imaging Standards for Use as an End Point in Clinical Trials – FY 2011

Additionally, FDA said it will participate in workshops to develop guidance documents on predictive toxicology, biomarker qualification, and missing data. It also says workshops will be held to “explore new approaches to a structured model for benefit/risk assessment. The results of these interactions will be used to assess whether pilot(s) of such new approaches can be conducted during PDUFA-4.”