FDA releases draft 5-year drug safety plan.

FDA April 7 released a five-year plan to communicate the agency's strategy "for meeting the commitments for enhancing and modernizing the drug safety system within the context of the PDUFA IV program," particularly the agency's plans for spending the drug safety enhancement user fees it will receive.

The plan is based on the assumption that the agency will receive additional revenues of $29.29 million in fiscal year (FY) 2008, with an annual inflation factor each year through fiscal year 2012.

Under the FDA Amendments Act (FDAAA) of 2007, Congress authorized the agency to collect additional user fees to broaden the emphasis on drug safety. The plan focuses on "the enhancement resources intended to cover the negotiated drug safety commitments," including added responsibilities for drug labeling, risk communication, post-market safety studies, adverse event reporting systems and signal detection.

Before FDAAA, except in limited situations, drug companies were asked to "voluntarily" commit to conducting post-marketing clinical trials and FDA had little enforcement recourse if they failed to follow through. The act allows the agency to require post-marketing studies or clinical trials at the time of approval, or after approval based on new safety information.

FDA can now require Risk Minimization Action Plans (RiskMAPs) or Risk Evaluation and Mitigation Strategies (REMS) when it approves new products, or after approval based on new safety information. REMS elements include, at a minimum, a timetable for assessments of the REMS and may also include a Medication Guide, patient package insert or other steps to assure safe use, such as restricted distribution. REMS can also require a communication plan to health care providers. (See related story beginning on front page)

FDAAA contains new provisions regarding the agency's responsibilities when it determines that new safety information should be included in drug labeling. FDA must notify a product sponsor if it learns of new safety information and "must adhere to strict timelines for initiating and concluding discussions and ordering changes to the label." FDA will develop procedures for ensuring safety labeling changes are made as necessary and for determining how to handle violations of required changes, the agency's plan stated.

The agency must now develop methods to obtain access "to disparate data sources and to develop validated methods for establishing a post-market risk identification and analysis system to link and analyze safety data from multiple sources." The legislation also requires FDA to provide for "active adverse event surveillance using several data sources including Federal health-related electronic data, private sector health-related electronic data, and other data necessary to identify adverse events and potential drug safety signals."

The Center for Drugs is expanding its Office of Surveillance and Epidemiology (OSE), which is responsible for monitoring post-market adverse event data and for providing risk management expertise. This office also reviews proposed product names, product labels and packaging "for any potential to result in medication errors and the analysis of reports of medication errors." CDER is increasing the staff in OSE significantly this fiscal year, FDA stated, with new staff members "distributed across the office, strengthening the capability and capacity of the organization in its post-marketing safety role."

Similarly, the Center for Biologics "has taken steps to support and strengthen its post-market safety activities" by boosting the staff in its Office of Biostatistics and Epidemiology. Since 2005, CBER has included a member of the Division of Epidemiology on all new vaccine BLA committees "to review pharmacovigilance plans for post-marketing safety studies submitted by manufacturers. This activity expanded to other products areas in 2006 through 2008."

With additional user fee funding, FDA will strengthen its post-market safety activities by recruiting and hiring additional staff throughout FY 2008 and into FY 2009, including safety evaluators, epidemiologists, risk management experts, medication error experts, and others.

A key focus will be efforts to improve the collection and analysis of adverse event data, FDA noted. The agency will "evaluate the impact of collecting and using spontaneous adverse event reports throughout the product life cycle" to detect and characterize on drug safety risks.

Such spontaneous reports provide "valuable information for detecting adverse events, particularly those that are rare. However, under-reporting, the often poor quality of reports and the lack of systematic feedback to health care providers and consumers" limit the usefulness of the information. FDA said more research is needed to "address the role of spontaneous reports in safety-related regulatory decision making throughout the product life cycle."

The agency said it will apply significant new resources to developing good epidemiological practices guidance and increasing access to large electronic administrative databases. In May, CDER and CBER will hold a public workshop to solicit information and views on best practices and principles for the design and evaluation of pharmacoepidemiologic safety studies using large data sets. The agency will issue draft guidance on epidemiology best practices by the end of fiscal year 2010 and final guidance by the end of fiscal year 2011.

FDA will also use its resources to expand database acquisition and for targeted post-marketing surveillance and epidemiology.

Over the last several years, FDA obtained access to external data sources for drug use, patient outcomes and special populations through contracts with health insurers, academia and other institutions. In addition to expanding its access to these data sources, the agency will use additional funds to access new data sources and to conduct population-based epidemiological studies. The agency expects to enter into inter-agency agreements with the Centers for Medicare and Medicaid Services (CMS) and the Veterans Health Administration (VHA) to access their data.

FDA will develop a plan to identify, develop and validate RiskMAPs and REMS elements, including risk communication tools, and will also conduct an assessment of their effectiveness, the five-year plan stated.

The agency will hold a public workshop--date still undetermined--to obtain input regarding the prioritization of the RiskMAPs, REMS and communication tools to be evaluated, and "will conduct annual, systematic, public discussion and review of the effectiveness" of these tools. FDA will also continue to review proposed and implemented RiskMAPs and REMS to assess their effectiveness.

Post-market IT systems will be developed and implemented, including the MedWatch Plus Portal, FDA Adverse Event Reporting System, the Sentinel System and the Phonetic and Orthographic Computer Analysis (POCA) system.

FDA has initiated MedWatchPlus with the goal of developing a single internet portal for reporting adverse events. This new agency-wide submission system will replace the current AERS data entry and electronic submission functionality.

A critical step toward automating adverse event information is standardization of reporting. FDA, the Centers for Disease Control (CDC) and the National Institutes of Health (NIH) have been working with HL73 "on standards-based solutions for electronic adverse event reporting that meets the needs of all stakeholders." The HL7 Individual Case Study Report (ICSR) Release 2 Draft Standard for Trial Use, approved in January 2007, creates a message standard for both adverse event and product defect reporting.

Each Center within FDA has its own systems and processes that collect safety data from various sources. To improve the effectiveness of adverse event report analysis, "FDA is exploring the use of a single adverse event reporting repository for multiple regulated product types. FAERS will provide FDA with a modernized, comprehensive, state-of-the-art electronic system for adverse event report analysis across FDA."

FDA is also working with other agencies to develop an integrated "virtual" national medical product safety system--the Sentinel System--that would enable the electronic flow of safety information to and from the point of care. The system will build on existing public and private efforts through multiple, broad-based, public-private collaborations.

With additional resources from PDUFA IV, FDA will be able to increase the staff responsible for the trade name review process. FDA will establish a working group with representatives from CDER and CBER to draft procedures and modify automated tracking systems to ensure that FDA can meet the review targets in the PDUFA IV commitment letter.

By Rebecca Mashaw, Managing Editor