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IOM Recommendations: FDA Actions Update

Main report: Changing the Future of Drug Safety: FDA Initiatives to Strengthen and Transform the Drug Safety System

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In 2005, the Food and Drug Administration (FDA or agency) commissioned the Institute of Medicine (IOM) to convene a committee of experts to assess the U.S. drug safety system and make recommendations to improve risk assessment, surveillance, and safe use of drugs.  On September 22, 2006, the IOM issued its report on that study.[1]  The report included 25 recommendations related to improving the drug safety program and creating a more robust and comprehensive system for better ensuring the safe use of medical products.  Fourteen of the recommendations in the report were directed to FDA. 

After reviewing the IOM report and recommendations, FDA issued its response in January 2007 stating that it was in substantial agreement with the majority of the recommendations directed to FDA.[2]  The agency also described a series of specific actions it was taking, or planned to take, to improve medical product safety and committed to track those actions and report their progress in 1 year.[3]  The following table shows the IOM recommendations, agency actions, and status of those actions as of July 2008.  IOM recommendations are listed in the far left column with FDA actions and status updates in the adjacent columns.  

In September 2007, while FDA was working on its safety initiatives, the President signed the Food and Drug Administration Amendments Act of 2007 (FDAAA)-sweeping legislation that contained many provisions directed at improving medical product safety.  FDAAA established new authorities for FDA to ensure medical product safety and specified actions to improve collaboration between drug review and drug safety staff at FDA.  Section 919 of FDAAA directs FDA, within 1 year of enactment, to issue a report assessing how it has implemented the recommendations in the IOM report.  This Report to Congress fulfills that commitment.

As the table that follows illustrates, FDA has made significant progress in the three key areas identified in its initial response: Operations and Management, Science of Drug Safety, and Communication and Information Flows.  FDA has also included notations in the table where new authorities and/or resources from FDAAA have resulted in changes and/or additions to our efforts to strengthen the FDA's drug safety programs.

IOM RecommendationsFDA ActionsStatus
3.1 Amend FD&C Act to require that the FDA Commissioner, currently appointed by the President with the advice and consent of the Senate, also be appointed for a 6-year term of office.Not directed to FDA 
3.2 Secretary of HHS appoint an external Management Advisory Board to advise the FDA Commissioner in shepherding CDER (and all of FDA) to implement and sustain the changes necessary to transform the Center's culture by improving morale and retention of professional staff, strengthening transparency, restoring credibility, and creating a culture of safety based upon a lifestyle approach to risk-benefit.FDA is engaging external management consultants to help CDER/FDA develop a comprehensive strategy for improving CDER/FDA's organizational culture.[4]

CDER had begun planning Center organizational changes to effect a change in its culture prior to its January 2007 response to the IOM report. Since that time, the center has done the following.

CDER's senior management team (SMT) began laying the foundation for this work in November 2006, when they embarked on a course of action to strengthen the SMT and to develop their vision for CDER.

  • In September 2007, CDER awarded a contract to the Center for Professional Development, Inc. (CPD). The period of performance is September 21, 2007 to September 20, 2009.
  • The SMT meets regularly, including quarterly 2-day off-site meetings, to manage the change process.
  • Led by experts from CPD and working with a cross section of Center staff, CDER has defined and validated its vision for the desired culture changes. Regular meetings with the CDER Workplace Culture Team (WCT) continue to take place.
  • The CPD is required to assess and diagnose the current culture at CDER by evaluating all relevant data. The CPD developed a custom organizational effectiveness survey to give all CDER employees an opportunity to provide feedback on CDER's culture. Nearly half of CDER's employees responded to the survey, which demonstrates a high level of interest and confidence in the culture transformation process.
  • The survey results were reported to the SMT and CDER employees in early February 2008. CDER will use the results to identify areas where improvements are needed.
  • The CPD plans to repeat the survey in 18 months to measure what improvements have been made and determine what future actions are needed.
3.2, continuedOn January 19, 2007, the Commissioner proposed the creation of the Office of Chief Medical Officer, which will oversee scientific operations for FDA.The Commissioner created the position of Chief Scientist and filled it in April 2008.
3.3 Secretary of HHS direct FDA Commissioner and CDER Director, with the assistance of the Management Advisory Board, to develop a comprehensive strategy for sustained cultural change that positions the agency to fulfill its mission, including protecting the public health.See response to 3.2See progress in 3.2
  3.4 CDER appoint an OSE staff member to each NDA review team and assign joint authority to OND and OSE for post approval regulatory actions related to safety.

In 2007, FDA initiated two pilot projects to (1) evaluate various models for involving OSE staff in reviews, including the logistics and value of having an OSE staff person participate in each biologics license application (BLA) and new drug application (NDA) review; and (2) evaluate various models for more significant involvement of OSE in postmarket decision making. The agency is committed to ensuring that safety staff has a strong voice in pre- and postmarket safety decision making.

As described above, FDA has already created two process improvement teams that have made recommendations about specific ways to increase communications between review staff and drug safety staff. Their recommendations to (1) establish an Associate Director for Safety and a Safety Regulatory Project Manager in each OND review division within CDER; and (2) conduct regular safety meetings between OSE and all of the OND review divisions have been implemented.

 Another outgrowth of the process improvement teams discussed above is the creation of new procedures to improve the decision making processes related to postmarket drug safety. These procedures will address issues such as how decisions are made to request further studies and labeling changes.

The proposed performance goals under PDUFA IV also include provisions for enhancing and improving communication and coordination between OSE and OND in CDER, the Office of Biostatistics and Epidemiology, and the premarket product review offices in CBER, including activities to assess the impact and value of routinely including postmarket review staff on premarket review teams. 

Progress on these proposed actions has been substantial since 2006. Significant operational changes have been made in CDER respecting the involvement of safety staff in drug reviews. To provide a framework for these activities and other drug safety efforts, CDER launched Safety First Safe Use. The Safety First Safe Use initiative has two parts. Safety First refers to steps CDER is taking to strengthen and modernize its internal policies and processes to manage significant drug safety issues. Specific objectives of CDER's Safety First initiative include:

  • Create and maintain a collaborative, multidisciplinary, team-based approach to the review of drug safety;
  • Apply world-class project management to ensure FDA focuses the same attention on postmarket safety issues as it does on premarket review;
  • Align policies and processes to ensure that the most appropriate and best-qualified experts lead and have an equal voice in regulatory decisions;
  • Build the scientific, administrative, and technological capacity to carry out the provisions of FDAAA and the Prescription Drug User Fee Act (PDUFA); and
  • Ensure that significant postmarket safety issues are CDER's highest priority.

Recently, under the Safety First initiative, a memorandum of agreement was finalized and signed in July 2008 by OND, OSE, and CDER's Director. The agreement affirms CDER's commitment to a multidisciplinary, team-based approach to the review of drug safety that ensures that the best-qualified experts lead or have an equal voice in regulatory decisions. CDER is in the process of identifying all internal processes that need to be adjusted or developed to ensure that this “equal voice” philosophy is embodied in center operations.

OND has established the positions of Deputy Director for Safety and Safety Regulatory Project Manager in each review division. Recruitment to fill these positions is under way with approximately half of the positions now occupied. During the application approval process, OND and OSE work closely together on certain aspects (trade name reviews, REMS, and labeling review) of the NDA/BLA review. OSE becomes involved at the pre-NDA or pre-BLA stage of review and attends and provides input at preapproval milestone meetings, which occur throughout the NDA/BLA review cycle.

OSE staff attends preapproval safety conferences, during which OND and OSE staff discuss complex safety issues and make recommendations for postmarket studies and trials and other possible postmarket safety activities. In addition, reviewers from OND and OSE together evaluate proposed proprietary names, REMS proposals, and proposed patient labeling. The recently signed MOA gives OSE sign-off authority for certain postmarket actions dealing with medication errors, proposed proprietary name review, and epidemiological studies. The implementation of the transfer of this responsibility from OND to OSE is under way.

Within CDER, both OND and OSE collaborate regularly on safety reviews with the Office of Biostatistics and Epidemiology and other offices in CDER, and also ensure cross-center coordination by involving CBER in many of the implementation activities for Safety First and FDAAA.

3.4, continuedCDER is creating a standard operating procedure for presenting postmarket safety issues to an Advisory Committee (AC) or other body. This new procedure will articulate the division of responsibility between OND and OSE for planning presentations, Advisory Committee configuration, and a process for compiling background materials for Advisory Committees.OSE and OND have jointly worked on several postmarket safety issues in the past year that have gone to Advisory Committees. The standard operating procedure will formalize this process. It was discussed at a recent Advisory Committee meeting.
3.5 Congress should introduce specific safety-related performance goals in the Prescription Drug User Fee Act IV in 2007.

The proposed recommendations for PDUFA IV included the following safety-related performance goals (changes, as reflected in the status update, have been made to these goals as a result of FDAAA):

FDA would develop a plan to (1) identify, with input from academia, industry, and others from the general public, risk management tools and programs for the purpose of evaluation; (2) conduct assessments of the effectiveness of identified Risk Minimization Action Plans (RiskMAPS) (under FDAAA called REMS) and current risk management and risk communication tools; and (3) conduct annual systematic review and public discussion on the effectiveness of one to two risk management programs and one major risk management tool (codified in FDAAA in Section 901(f)(4))

  •  FDA would post reports of these discussions on its Web site. 
  •  In addition, FDA would hold a public workshop to obtain input from industry and other stakeholders regarding the prioritization of the plans and tools to be evaluated.

  FDA held a public workshop on June 25 and 26, 2007, to identify ways to implement RiskMAPS (now Risk Evaluation and Mitigation Strategy -REMS) to support the quality use of pharmaceuticals.

  • Following the workshop, CDER and the Office of Special Health Issues began developing materials for a RiskMAP Web site. As a result of Sections 901 and 915 of FDAAA, this project has evolved to accommodate new requirements (e.g., Risk Evaluation and Mitigation Strategies (REMS)). A consolidated Web page containing drug safety information for patients and practitioners will be available soon to fulfill the requirements of Section 915. (See additional discussion on Section 915 below.)
  • Building on the input from this workshop and new authorities from FDAAA, CDER is also developing a process for quality assessment and has been conducting inspections of several risk management programs each year. CDER is finding that risk management programs are being implemented.
  • FDA is in the early planning stages of a public meeting to take place during 2009 with the purpose of obtaining outside input on the priority, frequency, and methodology for evaluating elements to assure safe use. The focus of the meeting will be, among other things, to obtain outside input on the priority for evaluating REMS, how frequently they should be evaluated, and what specific tools should be evaluated.
3.5 continued
  • FDA would publish a request for proposals from outside research organizations that would be interested in conducting research on determining the best way to maximize the public health benefits associated with collecting and reporting serious and nonserious adverse events (AEs) 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.

A public meeting was held on January 29, 2008 (“Maximizing the Public Health Benefit of Adverse Event Collection Throughout a Product's Marketed Lifecycle”). The goal of the meeting was to solicit information and views from interested persons on best research approaches and methods for assessing the public health benefit of collecting and reporting all adverse events.

  • The input from this workshop was used to publish a request for information (RFI) (April 29, 2008) to determine the types of outside organizations that may be interested in, and have the capability to, conduct the research described above. The RFI will be followed by a request for proposal (RFP), which is planned for fiscal year 2008, and the eventual award of a contract in fiscal year 2009.
  • Title VI of FDAAA establishes a conduit for private funding through the Reagan-Udall Foundation that may prove supportive of FDA drug safety activities. The Foundation is to identify unmet scientific needs in the development, manufacture, and evaluation of the safety and effectiveness of FDA regulated products, including postmarket evaluation, and establish scientific projects and programs, including funding, to address those needs.
3.5 continued
  • FDA would use PDUFA funds to obtain access to additional databases and to hire the additional epidemiologists and programmers needed to use these databases.

Relevant to additional databases, see progress in 4.1

With regard to the hiring of additional epidemiologists:

During the July 2008 hiring fair, OSE hired eight epidemiologists. One additional epidemiologist was hired through an advertised position, bringing the total hired to nine.

3.5 continued
  • FDA, with input from pharmacoepidemiologists in academia and industry, would develop guidance on conducting scientifically sound pharmacoepidemiologic studies using observational data based on large healthcare data sets. FDA would hold a public workshop the first year of PDUFA IV to identify best practices for observational epidemiologic studies using large healthcare data sets. CDER and CBER would then jointly develop and issue a draft guidance document that recommends epidemiology best practices for this type of study. 

On May 7, 2008, FDA held a meeting entitled "Developing Guidance on Conducting Scientifically Sound Pharmacoepidemiologic Safety Studies Using Large Electronic Healthcare Data Sets" to discuss how to conduct scientifically sound pharmacoepidemiologic studies using observational data, based on large automated healthcare data sets.

  • Topics discussed at the meeting included best practices on designing and evaluating pharmacoepidemiologic studies and providing consistent review criteria for FDA to use in evaluating protocols and study reports submitted by industry.
  • Using input from both the internal and public meetings, the working group has begun writing the draft guidance and anticipates publication of the draft for comment in fiscal year 2010. Plans are to finalize the guidance in fiscal year 2011.
3.5 continued
  • Under PDUFA IV, to improve safety assessments supporting NDAs and BLAs, FDA would develop guidance for industry on how to test, detect, and prevent safety problems during drug development. For example, FDA would develop the following guidances:

- Guidance on clinical hepatotoxicity to make recommendations on how to evaluate a drug for possible hepatotoxicity during drug development and how FDA will review an application to look for signs that a drug may be a significant hepatotoxin.

-   Guidance on enriched trial designs to focus on approaches to enrich the clinical trial population to better define the efficacy and safety of the drug under development.

  • In October 2007, FDA published draft guidance for industry onDrug-Induced Liver Injury: Premarketing Clinical Evaluation. The comment period closed on December 24, 2007. Only one comment was received.
  • In conjunction with PhRMA and the American Association for the Study of Liver Diseases (AASLD), FDA held a meeting on March 26 and 27, 2008, on detecting and investigating drug-induced liver injury during clinical trials.
  • Approximately 250 people attended the meeting.
  • The comments on the initial draft guidance as well as input from the transcripts will be taken into consideration when revising the guidance.
  • The goal is to publish a final guidance by the end of 2008.

  A large effort has been under way at FDA during the past several years to encourage the development and use of new trial designs, including enrichment designs. As part of this effort, a series of guidances are being drafted that will provide specific guidance on innovative trial designs. The agency has also launched a long-term effort to modernize the clinical trial enterprise. Planned guidances include the following:

  • Adaptive Trial Designs—publication of a draft is anticipated in 2008. This guidance would explain FDA's perspective on the use of adaptive trial designs during drug development. Topics to be addressed include the definition of adaptive trial designs, recommended designs, and how the statistical issues should be addressed in analyzing trials.
  • Non-Inferiority Trials—publication of a draft is anticipated in 2008. This guidance would describe FDA's perspective on the design of non-inferiority (NI) trials. Topics expected to be addressed include how to select the active control, how to document the effect size of the active control versus placebo, and how to establish the non-inferiority margin of interest.
  • Multiple Endpoints in Clinical Trials—publication of a draft is anticipated in 2009. This guidance would describe FDA's perspective on the appropriate procedures and analyses for trials with multiple endpoints (e.g., a trial with multiple co-primary endpoints).
  • Enriched Trial Designs—publication of a draft is anticipated in FY 2010. This guidance would focus on approaches to enrich the clinical trial population to better define the efficacy or safety of the drug under development.

Other product-specific guidances that are in development outline the use of novel trial designs. For example, guidances on rheumatoid arthritis and systemic lupus erythematosus, which are expected to issue in draft in 2008, will provide guidance on the use of novel trial designs.

3.5 continued

In addition, IOM recommends that FDA prepare a summary analysis of the adverse drug reaction reports not previously identified, potential new risks, or known risks reported in the unusual number not previously identified within 18 months of drug launch or after exposure of 10,000 persons, whichever is later. Reports should be publicly available and posted on the agency's Web site.

This IOM recommendation was codified in FDAAA in Section 915.

FDA is working to implement the requirements of FDAAA Section 915 by developing an integrated Web site with links to drug safety information. Among the types of information that will be available:

  • A list of approved REMS, and links to a list of Medication Guides, withdrawal letters, alerts, guidances and regulations related to drug safety, among other information relevant to drug safety.
  • Between January 1, 2007, and July 1, 2008, FDA issued 16 Public Health Advisories, 26 Healthcare Professional Sheets, and one science review.
  • Beginning in August 2007, FDA began providing to the general public Early Communications (ECs) about ongoing safety reviews. From August 2007 to July 1, 2008, FDA issued 14 ECs. FDA uses EC to notify the general public (1) that important new postmarket safety information has been received; (2) that FDA intends to review, or are in the process of reviewing, that information; and (3) what specific timeframe has been identified for completion of the safety review.
  • Drugs with active safety alerts are denoted on the Index to Drug-Specific Information on the FDA Web site.

Since September 2007, CDER has been listing in its quarterly Drug Safety Newsletter recent FDA drug safety communications. 

4.1 Conduct a systematic, scientific review of the AERS system, identify and implement changes in key factors that could lead to a more efficient system, and systematically implement statistical-surveillance methods on a regular and routine basis for the automated generation of new safety signals. The Adverse Events Reporting System (AERS) database, a Web-accessible computer system is being upgraded to add signal detection and tracking tools. These tools will enable safety reviewers to more efficiently and effectively identify and track safety signals from submitted adverse events reports.
  • A contractor was selected in March 2008 to integrate the components of the new MedWatchPlus portal/FDA Adverse Event Reporting System (FAERS) project. FDA awarded the 5-year contract to SRA International, Inc.
  • Demonstrations of commercial products to meet FDA needs began in July 2008.
  • Selection of a final commercial product or suite of products is expected in October 2008.
  • AERS data analysis and preparation for migration to the new system (FAERS MedWatchPLUS is under way in parallel with commercial product analysis and selection.
  • The FAERS functional pilot is planned to begin in December 2008.
  • FAERS Release 1 in 2009 will accommodate drugs and biologics.
  • FAERS Release 2 will address devices and combination products.
  • FAERS Release 3 will address remaining products.
  • MedWatchPLUS will be operational in 2009 for all FDA-regulated products.
4.1 continued
  • During the first year of PDUFA IV, FDA would publish a request for proposals from outside research organizations who would be interested in conducting research on determining the best way to maximize the public health benefits associated with collecting and reporting serious and nonserious adverse events 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.
See progress in 3.5
4.1 continued
  • Under the proposed PDUFA IV recommendations, FDA would use PDUFA funds to obtain access to additional databases and to hire the additional epidemiologists and programmers needed to use these databases.
Relevant to hiring additional epidemiologists, see 3.5
4.1 continuedAccess to types of data other than spontaneous reports would expand FDA's capability to conduct targeted postmarket surveillance, to look at effects of classes of drugs, and to detect signals. Access to data other than spontaneous reports is essential to the transformation of the drug safety program.

Regarding access to other databases, FDA has been engaged in many activities, including pilot programs, to obtain access to other databases to look at effects of classes of drugs and detect signals. FDA has launched a number of pilots (see examples in Section III of the report) in collaboration with other organizations to explore methodologies and tools for accessing additional databases to conduct targeted postmarket surveillance, look at effects of classes of drugs, and detect signals.

  • Examples of pilots under way include:

- Pilot with CMS data

- eHealth Initiative

- Meningococcal Vaccine Study and CDC Vaccine Safety Data link

- AHRQ DEcIDE (Developing Evidence to Inform Decisions about Effectiveness) research network

4.1 continued
  • On March 7 and 8, 2007, FDA sponsored a public meeting to explore opportunities for linking private sector and public sector postmarket safety monitoring systems to create a virtual integrated, interoperable, nationwide medical product safety network. Such a Sentinel Network could integrate existing and planned private and public sector databases to enable the collection, analysis, and dissemination of safety information about medical products to healthcare professionals and patients at point of care (e.g., in the clinic, where this information is needed to make informed decisions about safe and effective treatments). FDA will engage the public and private sectors in a discussion of opportunities for public- and private-sector collaboration on activities that could develop the data collection and risk identification and analysis components of such a potential network.

After the March 2007 public meeting to explore the possibility of a nationwide system to monitor product performance, FDA began laying out its vision creating a nationwide distributed data network that would enable targeted queries, under appropriate personal security safeguards, of large databases to monitor product safety. The data sources would be at remote locations and continue to be maintained by their owners. Creation of such an active system would ultimately enable the tracking of safety, outcome, and use information for all FDA-regulated products and augment FDA's mostly passive safety monitoring system.

Also, in Section 905 of FDAAA, Congress directed FDA to collaborate with others to access large databases to enable the agency to add an active component to its mostly passive postmarket surveillance processes. Specific aggressive deadlines are set forth (see new Section 505 (k)(3) of the Federal Food, Drug, and Cosmetic Act).

FDA announced the Sentinel Initiative in May 2008.


The Sentinel report describes what such a system could look like and recommends an organizational plan for creating such a system. The Sentinel Initiative will fulfill several of the requirements in FDAAA to capitalize on the potential of existing databases to create an active system for monitoring medical products. Recent steps in the initiative include:

  • FDA has created a broad public forum to discuss issues related to the implementation of the Sentinel System. Seven meetings have been held with potential stakeholders.
  • FDA is in the process of publishing several Requests for Proposals (RFPs) to do research on specific issues that have been identified.
  • Near-term goals include establishing a public–private partnership and making progress on the pilot with CMS using Medicare data, and identifying a sustainable governance structure for the public–private partnership that will be overseeing the development and implementation of the system.

Other Sentinel-related activities under way:

  • On January 24, 2008, Brookings held the "Brookings Roundtable on Postmarket Evidence." Participants explored the need, feasibility, and technical hurdles to establishing a postmarket surveillance system.

  A June 2008 meeting sponsored by Brookings continued discussions of Sentinel that began in January.

  • Since 2006, FDA has been an active and key participant in the IOM Sectoral Strategies Roundtable on Evidence Based Medicine. In the fall of 2007, FDA recommended to the Roundtable the development of a "sentinel system" (for more information, see http://www.iom.edu/CMS/28312/RT-EBM.aspx). FDA is participating in the development of a national priority list of safety problems that could be researched as part of broad collaborations.

See progress in 4.2

4.2 To facilitate formulation and testing of drug safety hypotheses, CDER should increase intramural and extramural programs that access study data from large automated healthcare databases, include program studies on drug utilization patterns and background incidence rates for adverse events of interest, and develop and implement active surveillance of specific drugs and diseases as needed in a variety of settings.

FDA would use PDUFA funds to obtain access to additional databases.

See response in 4.1


In addition, outside of PDUFA IV, FDA has embarked on other initiatives to obtain access to data:

  • Data use agreement with the Agency for Healthcare Research and Quality (AHRQ)
  • FDA and Veterans Health Administration (VHA) agreement to share information and expertise
  • Active monitoring and analysis of influenza vaccine safety

See progress in 4.1

FDA has added funds to its existing epidemiologic study contracts with HMO Research Network, Kaiser Permanente of California, Ingenix, and Vanderbilt University to conduct additional drug safety studies. FDA is also planning to issue a new RFP in 2008 to expand this program to include more funding for studies, as well as additional sites for collaboration. The award of the new contracts is expected in September 2008.

  • FDA conducted a pilot study to evaluate the use of data from Medicare Parts A and B (Centers for Medicare & Medicaid Services); the analyses were completed during the last quarter of 2007, and FDA is writing up the results. In the interim, FDA has initiated an inter-agency agreement to work with CMS on pilot studies of several drug safety issues using data from Parts A, B, and D, as well as providing funding for linking Medicaid data from all 50 states together in a format suitable for conducting medical product safety surveillance. The pilot studies were initiated in June 2008; the Medicaid data initiative is planned for fiscal year 2009.
  • FDA has initiated an interagency agreement with AHRQ to provide funding for collaborative research in four defined areas with the AHRQ-supported Centers for Education and Research on Therapeutics (CERTs). These areas include (1) comparative effectiveness of antipsychotic agents, with special attention to safety; (2) safety risks of biologic immune modulators; (3) methods work in safety outcomes and confounders, and (4) characterization of key national drug use scenarios. This funding opportunity announcement was sent to the 14 CERTs sites for limited competition in March 2008 and is expected to be awarded by September 2008.
  • FDA is actively sharing safety information with the VHA and DoD.
4.2 continuedMany of the Critical Path initiatives will also help in the formulation and testing of drug safety hypotheses.

In addition to assisting with Sentinel, the Critical Path Initiative is assisting other activities to support testing of drug safety hypotheses. For an overview as well as detailed descriptions of specific projects, see the Critical Path Web page at http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/. Specific examples include the following:

Develop and qualify techniques for predictive toxicology;

  • Identify cardiovascular risk of drugs, including drug eluting stents;
  • Prevent drug-induced liver injury;
  • Use pharmacogenomic and other information to guide safer and more effective use of drugs (40 voluntary genomic data submissions received so far);
  • Use new scientific tools to enhance blood safety; and
  • Enhance the long-term safety of gene therapy.

Related efforts:

  • Created Cardiac Safety Research Consortium (CSRC). A research team is evaluating normal values for electrocardiogram) ECG parameters using data from the ECG Warehouse. This project should lead to more efficient study designs.
  • Formed the CSRC Publications Committee to produce a series of white papers on topics of general interest related to evaluation of cardiac safety. The Publications Committee has produced a first draft of a paper on points to consider in evaluating oncology products for effect on QT.
  • Established a CRADA between Entelos, Inc. and FDA to develop a computer model of drug induced liver injury. The goal is to use this model to guide the development of clinical biomarkers and preclinical assays to identify patient types and drug combinations that increase the risk of developing liver injury.

  Developed and published draft guidance, Premarket Evaluation of Drug Induced Liver Injury. A public meeting to discuss this guidance is scheduled for March 2008. See progress in 3.5

This project will be the first phase of a long-term project to use empirical evidence to focus the serious adverse reaction reporting system on the most effective methods for identifying true adverse events caused by therapies.

The initial phase will address the issue of SUSARs that must be reported in an expedited fashion in the current regulatory system.

The goal will be to improve the ability of the system, including investigators, institutional review boards, regulatory groups in industry, and the FDA to obtain the type of adverse event data that is most informative in the most efficient manner.


4.3 The Secretary of HHS working with the Secretaries of Veterans Affairs and Defense should develop a public–private partnership with drug sponsors, public and private insurers, for-profit and not-for-profit healthcare provider organizations, consumer groups, and large pharmaceutical companies to prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health importance. Congress should capitalize the public share of this partnership.The Veterans Health Administration (VHA) and FDA are working under a recently signed memorandum of understanding (MOU) to allow sharing of certain information related to the use of drugs, vaccines, other biological products, and medical devices. The purpose of the project is to enhance knowledge and efficiency through the sharing of information and expertise between FDA and VHA regarding medical product safety, effectiveness, and patterns of use. See progress in 4.2

4.4 CDER should assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Plans (RiskMAPs).


FDA would develop a plan to (1) identify, with input from academia, industry, and others from the general public, risk management tools and programs for the purpose of evaluation; (2) conduct assessments of the effectiveness of identified Risk Minimization Action Plans (RiskMAPS) and current risk management and risk communication tools; and (3) conduct annual systematic review and public discussion of the effectiveness of one to two risk management programs and one major risk management tool. FDA would post reports of these discussions on its Web site. In addition, FDA would hold a public workshop to obtain input from industry and other stakeholders regarding the prioritization of the plans and tools to be evaluated. See progress in 3.5
4.5 Develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the pre-approval and post approval settings.  On May 30 and 31, 2006, FDA and IOM held a workshop to hear about new proposals in quantitative benefit-risk assessment. FDA is continuing to explore the possible use of best practices in this area, with a goal of ultimately identifying and testing quantitative tools that could be of use. In the interim, FDA has introduced several training courses to help medical reviewers conduct better safety assessments. 

In 2006, FDA began work toward the long-term goal of more systematic quantitative approaches to risk-benefit assessment, with a workshop hosted by the IOM. Developing a more systematic approach will involve many facets, including, for example:

  • Identifying candidate analytic methods and tools;
  • Identifying regulatory decisions that would realize the greatest value from application of these methods; and
  • Building the IT, data, and analytic infrastructure to more easily apply more quantitative and systematic approaches.

 In November 2007, the Agency held a 2-day meeting ("Assessing Drug Benefits and Risks in Regulatory Decisions: Framing the Need, Evaluating the Tools, and Deciding Next Steps") as follow-up to the May 2006 workshop. The November meeting was designed to support FDA staff in determining the applicability of current tools to regulatory decisions, research projects that will lead to greater confidence in current tools, and gaps in current tools that may lead to new tool development.

 The agency is currently developing a white paper summarizing the meeting discussions. In addition, FDA is planning to hold a public meeting later in 2008 to continue to explore the application of analytic tools and issues related to effective communication of benefits and risks.

4.5 continuedIn 2006, CDER created the Quantitative Safety and Pharmacoepidemiology Group (QSPG) to promote science-based, data-supported, regulatory decisions on the safe use of medicinal therapeutics. This group of internal experts will develop quantitative methods for safety evaluation, develop and disseminate best practices for reviews of safety aspects of study protocols during product development, and provide consistency in review practices and analytical approaches across review divisions to the extent possible. 

The Quantitative Safety and Pharmacoepidemiology Group (QSPG), created in 2006, have successfully completed a number of projects, and several new efforts are under way. Several accomplishments and ongoing efforts are described below.

The QSPG has developed a curriculum for core competencies in safety review (pre- and post-marketing) for clinical, epidemiological and statistical reviewers in the Office of New Drugs (OND), the Office of Biostatistics (OB), and the Office of Surveillance and Epidemiology (OSE). Courses currently offered include the following:

- Introduction to the use of MedDRA terminology for adverse event analysis;

- Advanced Signal Detection;

- Introduction to submission data standards: The CDISC (Clinical Data Interchange Standards Consortium, http://www.cdisc.org/ ) Model;

- Principles for data collection, retrieval, and analysis for pre- and post-market safety assessment; and

- Identification, Testing and Use of analytical tools for pre- and postmarket safety review.

QSPG continues to enrich the curriculum and has provided training on introductory and advanced safety signal detection to approximately 240 reviewers from OND, OSE, and OB.

  • To ensure clinical and statistical staff readiness to request and review standardized clinical trial data, didactic and practical training courses were offered to approximately 150 reviewers.
  • QSPG has also held several workshops on statistical methods of particular importance in the assessment of epidemiologic safety data.
  • An effort is under way to establish partnerships with academic institutions to leverage targeted expertise not yet available within the FDA.
  • The QSPG developed a proposal to obtain additional staffing and other resources to increase the internal capacity of the FDA in quantitative safety; the proposal was positively received. Two of the proposed resources (personnel and IT infrastructure) were allocated (January 2008). Subsequently, QSPG has been aggressively recruiting and hiring staff with the specific skills necessary to provide safety-related quantitative support to OSE, OND, and OCP as well as to build a coordinated quantitative safety research program within CDER.
  • A guidance for industry on Meta-Analysis of Safety Data is under development, and FDA expects to publish the draft by December 2009.
  • QSPG has recently entered into an interagency collaboration with the National Cancer Institute to explore ways to improve the manner by which safety data is collected through the use of patient reported outcomes tools.
  • QSPG has been working with OSE to develop a curriculum to provide additional quantitative safety-related training to the OSE staff.
4.5 continuedFDA and the National Toxicology Program of the National Institute of Environmental Health Sciences are developing and validating an animal model to examine factors that may increase the risk of cancer that has been associated with various gene therapies. The model can be used by sponsors to test modifications to gene therapy vectors to mitigate cancer risk while preserving effectiveness. In November 2006, FDA provided a new, risk-based guidance to sponsors on long-term follow up of such therapies.The collaboration between FDA and the National Toxicology Program to develop an animal model is ongoing.
4.5 continued

CBER (Center for Biologics Evaluation and Research) has already implemented an integrated approach to benefit risk analysis, including cross-cutting product safety teams, and has built a quantitative risk assessment unit that it uses for scientific and modeling support of its more mathematically complex, highest priority product and public health safety issues (e.g., quantitative assessment of risks of transmissible spongiform encephalopathy (mad cow disease) in plasma-derived Factor VIII products).

See response 4.2 for Critical Path initiatives

See response 5.4 Pilot for NMEs

4.5 continuedFDA is strengthening and standardizing the process used by safety evaluators in OSE. These safety evaluators critically review adverse event reports that have been submitted to the agency's AERS reporting system by sponsors of approved applications, healthcare professionals, consumers, and other sources. The goal of this initiative to strengthen the safety evaluation process is to identify best review practices and develop a quality assurance system including standardized methodologies, training and mentoring, workload prioritization, and management tools to optimize the use of resources to ensure efficient risk management. 

Since January 2007, OSE has developed and implemented discipline competencies and staff development plans for safety evaluators and a tracking system.

OSE is conducting in-house training for safety evaluators and clinical and statistical staff: an introductory course is designed to provide a basic understanding of the scope, structure, characteristics, and maintenance of MedDRA (Medical Dictionary for Regulatory Activities) and the relevant regulations concerning its use. In addition, the training provides an overview of coding with MedDRA and applications of MedDRA in data retrieval and analysis, including use of Standardized MedDRA Queries in safety signal detection and case identification. The following is a link to the MedDRA training that is being offered:


Other training and staff development programs that are in place include: OSE Tools and Methodology courses, AERS and WebVDME training manuals for adverse event signal evaluation and detection, an ongoing Safety Evaluators Best Practices Work Group for safety data evaluation and analysis principles, processes and procedures, and Safety Evaluators mentorship resources.

  • Standard review templates including a methodology section were introduced in early 2007.

 In addition, OSE has established a new employee mentoring check-list and has identified several mentors (eight experienced safety evaluators) for new employees. OSE will be evaluating the mentor program on a regular basis.  In addition, OSE has drafted a standard operating procedure for managing the receipt and triage of AERS data.

4.5, continuedCDER is now implementing an electronic system to track postmarket drug safety issues. This system, which will replace multiple office- and division-specific systems, will enable CDER reviewers and managers to prioritize more effectively their work on safety issues and ensure that different organizational units have the same information.

CDER's Associate Director for Safety Policy and Communication Staff collaborated with the Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) working group in CDER's Office of Business Process Support to develop a postmarket drug safety tracking system.

The DARRTS Safety Issue Application was launched in January 2007. This application is used for monitoring serious peri- and postmarket safety issues that have the potential to lead to a significant regulatory action, including, but not limited to, the withdrawal of the drug product or an indication, the institution of a REMS, a significant labeling change such as the addition of a boxed warning, or the need for a postmarket safety study or trial. The system is also used for planning joint safety meeting agendas and to identify postmarket safety issues that would benefit from risk communication messages being sent to healthcare professionals and the public by the Safety Policy and Communication Staff.

  • Use of the tracking system will help ensure timely resolution of postmarket safety issues and facilitate the communication of safety information to the public and other health-related stakeholders.

In August 2008, a work plan functionality was added to the DARRTS safety issue application. This work plan enables OND and OSE staff to more easily plan for and monitor postmarket safety issues, enhancing efficiency and improving communication among CDER staff working on such issues. Additional functionalities, such as reviewer reminders, will be added in future updates.

4.6 Build internal epidemiologic and informatics capacity to improve the postmarket assessment of drugs.See response 3.5 and 4.2 for access to databasesSee progress in 3.5 and 4.2

4.7 Commissioner should demonstrate

commitment to building the agency's scientific research capacity by:

Appointing Chief Scientist in OC to oversee, coordinate, and ensure quality and regulatory focus of FDA's intramural research programs.

Designate FDA's Science Board as the extramural Advisory Committee to the Chief Scientist.

Include research capacity in the agency's mission statement.

Apply resources to support intramural research approved by the Chief Scientist.

Ensure adequate funding to support intramural research program is requested in the agency's annual budget request to Congress.

The Commissioner asked the FDA Science Board to undertake a comprehensive formal review of scientific needs and activities across the agency. The vast majority of FDA scientific programs are related to regulated product safety.

 See response 3.2

Upon the recommendation of the Commissioner, the FDA Science Board performed an extensive review of agency operations with the goal of identifying possible gaps and scientific needs. After approximately 6 months of program review, including meeting with agency and center staff, the Science Board report subcommittee presented the report to the full Science Board in early December 2007. The report is available on the Advisory Committee Web page at: Dockets Management.

The Science Board unanimously accepted the report. (Two additional reviews of the National Center for Toxicological Research (NCTR) and the Office of Regulatory Affairs (ORA), which were not included in the initial investigation, were presented to the Science Board at its May 30, 2008 meeting. Final versions of both reviews have been accepted by the Science Board and transmitted to the agency.)

4.8 FDA should have its advisory committees review all NMEs either prior to approval or soon after to advise in the process of ensuring drug safety and efficacy or managing drug risks.See response 5.4 Pilot for NMEs 

CDER has implemented the provision in FDAAA Title IX Section 918 that requires FDA to refer to an Advisory Committee prior to approval, or state in the approval letter why the NME was not referred. If FDA does not refer such a product to an Advisory Committee, FDA is required to summarize the reasons in the approval letter. To date, when an NME has not been referred to an Advisory Committee, the reasons have been summarized in the approval letter.

  See progress 5.4

4.9 Advisory committees, and any other peer review effort such as mentioned for CDER-reviewed product safety, should include a pharmacoepidemiologist or an individual with comparable public health expertise in studying the safety of medical products.FDA will also increase the involvement, to the extent feasible, of pharmacoepidemiology and other experts in each Advisory Committee meeting when safety issues are an important component of the issues before the Committee. These individuals may be current members of the Drug Safety and Risk Management Committee or brought in as special government employees.

  FDA has increased the pool of epidemiologists available as special government employees (SGEs) for CDER Advisory Committees.

 See response to 4.10

4.10 FDA should establish a requirement that a substantial majority of AC members be free of significant financial involvement with companies whose interests may be affected by the committee's deliberations.

Under the oversight of the FDA Commissioner, the agency will issue 3 guidances in 2007 making Advisory Committee operations more consistent, transparent, and predictable.

  One guidance document will present new thinking about the criteria for granting waivers for conflicts of interest for members of all of our Advisory Committees.

  • A second guidance will address the disclosure of conflict of interest waivers.
  • A third guidance will improve the release of Advisory Committee briefing materials to the public.

  FDA has made a number of changes to its processes for managing Advisory Committees. For example, FDA issued three guidances that will help improve and clarify the advisory committee operations and processes:

Draft guidance on Procedures for Determining Conflict of Interest and Eligibility for Participation in FDA Advisory Committees (March 2007);

  • Draft guidance on Public Availability of Advisory Committee Members' Financial Interest Information and Waivers (October 2007); and
  • Guidance on Advisory Committee Meetings — Preparation and Public Availability of Information Given to Advisory Committee Members (February 2007).
4.10, continuedIn addition, FDA will make recruitment of potential members of Advisory Committees more transparent and open by issuing a standardized list of current and future Advisory Committee vacancies.

FDA has also begun making recruitment of potential members of Advisory Committees more transparent and open. For example, FDA added information on current vacancies to its Web site (About Advisory Committees) so that individuals can readily access this information. The Web page is updated periodically.

In addition, FDA publishes Federal Register notices soliciting nominations to Advisory Committee vacanciesat least four times a year. This fiscal year nine notices were published. FDA also updated its Web site to include information on how to apply for membership to an FDA Advisory Committee
(Advisory Committee Membership).

4.11 Congress should require industry sponsors to register in a timely manner at www.ClinicalTrials.gov, at a minimum for all Phase 2 through 4 clinical trials, wherever they may have been conducted, if data from the trials are intended to be submitted to the FDA as part of an NDA, sNDA, or to fulfill a post-market commitment. Include a posting of structured field summary of efficacy and safety results of the studies.Not Directed to FDA, but FDAAA, Title VIII, requires extensive FDA and NIH effort to expand the clinical trials data bank and make substantive information related to clinical trial drugs available through links to both FDA and NIH Web sites. 

Although this IOM recommendation was not directed to FDA, FDAAA has provided related requirements, for example, to expand the existing ClinicalTrials.gov registry to:

  • Include additional information about applicable clinical trials of drugs, biologics, and devices;
  • Develop processes for adding information about serious and frequent adverse events observed in a trial and for expanding the registry and results database; and
  • Provide links in the data bank from a specific drug to relevant safety information, including, for example, related summary documents from Advisory Committee meetings on the drug, any public health advisories regarding the drug or device that FDA may have issued, and other relevant information about the safety and effectiveness of the drug.

These efforts will provide the public with substantial additional information and access to information about drugs that have been or are being studied in clinical trials. FDA and NIH are working closely to implement these provisions.

4.12 Post all NDA review packages on the agency's Web site, including all supplemental NDA review packages.


Not accepted by FDA. However, Section 916 of FDAAA contains similar requirements: (1) post NDA new molecular entity (NME) and BLA action packages within 30 days of approval and (2) post all other action packages within 30 days of receiving the third Freedom of Information Act request for the package. 

FDA is attempting to comply with this provision in FDAAA in a timely manner. FDA is dedicating additional resources to improve the timeliness of posting of action packages:

Additional employees have been hired to perform disclosure reviews and Web posting. The employees are in various stages of training; and

  • Procedural changes were implemented to increase the efficiency of the disclosure and Web posting staffs interactions.
4.13 Review teams regularly and systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information. 

FDA recognizes the importance of communicating information about the safety of drugs. However, many postmarket assessments contain recommendations that are the subject of ongoing discussions within FDA and other information that is predecisional in nature. Release of such information could have adverse public health impacts. For example, release of information about a safety signal that is later determined to be erroneous could result in patients who could benefit from the drug not receiving it. Therefore, decisions to publicly disclose assessments of postmarket safety studies have to be made on a case-by-case basis. 

In the first quarter of 2007, FDA will issue a final guidance on communicating important drug safety information, including emerging drug safety information, to the public. This guidance formalizes FDA's commitment and current efforts to ensure that it communicates to healthcare professionals, patients, and other consumers the latest safety information with the potential to influence the way physicians prescribe and patients use medicines. 


In 2007, FDA planned to regularly publish a newsletter on the FDA Web site containing summaries of the results, including methods, of FDA postmarket drug reviews. The summaries will not include confidential commercial or predecisional information. FDA believes it is important, particularly for healthcare professionals, for FDA to make readily available and easily accessible the results of our postmarket reviews of adverse events. In addition, this regular newsletter will contain information on emerging safety issues, as well as provide information on recently approved products both to inform healthcare professionals and to encourage reporting to the agency.  

For many years, FDA and sponsors have disseminated emerging drug safety information. The agency currently disseminates emerging drug safety information after having completed an analysis of available data and, in several cases, before having reached a decision about the need for a regulatory action. Agency communications about emerging drug safety information may help achieve certain longstanding public health goals, including enhanced vigilance on the part of healthcare professionals who may be prompted by the information to increase their reporting of safety observations to FDA.

  • In March 2007, FDA issued a final guidance that formalizes FDA's commitment and current efforts to ensure that it communicates to healthcare professionals, patients, and other consumers the latest safety information with the potential to influence the way physicians prescribe and patients use medicines.
  • The guidance is available on the FDA Web site at: http://www.fda.gov/cder/guidance/7477fnl.pdf.
  • A press release describing the agency's effort is available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01577.html.
  • During 2007, the Special Policy and Communication Staff (SPCS) issued four Early Communications to the public. SPCS also issued 10 Public Health Advisories and 21 Healthcare Professional Sheets in 2007.
  • In 2008 (through July 1), FDA issued six Public Health Advisories, six Healthcare Professional Sheets, and ten Early Communications.
  • FDA also publishes a quarterly newsletter for healthcare professionals, which contains emerging safety information. The first issue of FDA's quarterly newsletter, Drug Safety News, was published on September 18, 2007. The second and third issues followed in March 2008 and June 2008, respectively. See http://www.fda.gov/cder/dsn/default.htm.

5.1 The committee recommends that Congress ensure that the Food and Drug Administration has the ability to require such postmarketing risk assessment and risk management programs as needed to monitor and ensure safe use of drug products. These conditions may be imposed both before and after approval of a new drug, new indication, or new dosage, as well as after identification of new contraindications or patterns of adverse events. The limitations imposed should match the specific safety concerns and benefits presented by the drug product.


Not Directed to FDA. However, FDAAA gave FDA the authority to require risk management programs, now called Risk Evaluation and Mitigation Strategies (REMS).See Section risk management plans in 3.5
5.2 Provide oversight and enact any needed legislation to ensure compliance by FDA and drug sponsors with provisions listed above (5.1). FDA needs increased enforcement authority and better enforcement tools directed at drug sponsors, which should include fines, injunctions, and withdrawal of drug approval.Not Directed to FDA. 

However, FDAAA gave FDA many of the new enforcement authorities suggested in Section 5.1. Section 901 of FDAAA amended Section 505 of the FDCA to give the FDA new authorities to require postmarket studies and/or clinical trials, to require postmarket labeling changes based on new safety information, and to require Risk Evaluation and Mitigation Strategies (REMS) to ensure that the benefits of a drug outweigh the risks. Violations of these new provisions are associated with misbranding charges and civil penalties. FDA is working on procedures for implementing these new enforcement authorities.

 With regard to direct-to-consumer (DTC) advertising addressed in this Section, FDAAA also gives FDA the authority to require television advertisements for drugs to be submitted to the FDA 45 days before dissemination for FDA review and recommendations. Although, in general, FDA cannot require changes, FDA can require specific disclosures about serious risks if FDA determines that the advertisement would be false or misleading without the specific disclosure. These provisions are also enforceable through misbranding charges and civil money penalties.

5.3: Amend FD&C Act to require product labels carry a special symbol such as the black triangle used in the UK or an equivalent symbol for new drugs, new combinations of active substances, and new systems of delivery of existing drugs. FDA should restrict DTC advertising during the period of time the special symbol is in effect (recommended time: 2 years).

Not Directed to FDA. 

However, FDAAA, Section 904 states that FDA may consider use of a special symbol.

 “Not later than 1 year after the date of the enactment of this Act, the Commissioner of Food and Drugs shall submit to the Congress a report on how best to communicate to the public the risks and benefits of new drugs and the role of the risk evaluation and mitigation strategy in assessing such risks and benefits. As part of such study, the Commissioner may consider the possibility of including in the labeling and any direct-to-consumer advertisements of a newly approved drug or indication a unique symbol indicating the newly approved status of the drug or indication for a period after approval.”

  • FDA is working on the Report to Congress with regard to the use of a symbol. As part of the proposed Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products (65 FR 81082), which published on December 22, 2000, FDA included a provision to use a black triangle or another symbol on the professional label to denote the newness of a product.
  • After consideration of comments, in the final rule published on January 24, 2006 (71 FR 3922), FDA declined to adopt the use of symbols to emphasize or identify information in prescription drug labeling.
  • FDA determined that the use of an inverted black triangle would not be universally understood and could be confusing to both prescribers and patients, even with a concerted educational effort.
  • To communicate most effectively, the relative “newness” of a product to healthcare professionals, FDA determined that it would be best to include prominently in the highlights section of the professional label the date a product was approved. FDA determined this approach would more clearly communicate both when a product became available and how long it has been on the market (Section 201.57(a)(3) and (d)(5)).
  • Absent evidence to the contrary, FDA believes that the recently revised current professional label with a highlights section and table of contents, that is now electronically available on the National Library of Medicine's DailyMed Web site, provides a readily accessible and useful source of information about the benefits and risks of new drugs.
  • When it comes to adding a symbol to consumer-directed materials, such as Direct to Consumer (DTC) advertisements, the potential for misinterpretation is greater. Consumers could easily interpret a symbol indicating a “new approval” to mean “new and improved,” the latter interpretation being more common in advertising. Without rigorous testing of how a symbol used on DTC ads would be understood and interpreted, adding such a symbol has the potential to do more harm than good.

5.4 Evaluate all new data on NMEs no later than 5 years after approval. Sponsors will submit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer reviewed journal, and will report on the status of any applicable conditions imposed on the distribution of the drug called for at or after the time of approval.


CDER is conducting a pilot developed by its Office of Surveillance and Epidemiology (OSE) and the Office of New Drugs (OND) to review systematically and collaboratively the safety profiles of new molecular entities (NMEs) on a regularly scheduled basis to determine whether these reviews should be initiated for all NMEs as suggested by IOM recommendation 5.4. NME postmarket evaluations will incorporate data from the Adverse Events Reporting System (AERS), data mining analysis, epidemiologic data, postmarket clinical trial information, and a review of the Periodic Safety Update Reports, or U.S. Periodic Report, to identify potential safety concerns early in the product life cycle. 

 In Section 915 of FDAAA, Congress directed FDA to prepare, by 18 months after approval of a drug or after use of the drug by 10,000 individuals, whichever is later, a summary analysis of the adverse drug reaction reports received for the drug, including identification of any new risks not previously identified, potential new risks, or known risks reported in unusual number. FDA is working to implement this provision and will use the experience from the NME pilot to inform its work.

As part of CDER's effort to strengthen and standardize safety evaluation processes, OSE and OND have implemented a pilot program, which began in January 2007, to review systematically, collaboratively, and regularly the safety profiles of approved NMEs (products that include an active substance that has never before been approved for marketing in any form in the United States) to determine whether these reviews should be regularly scheduled and initiated for all, or a specified subset of, NMEs. The purpose of the pilot program is to determine the value of the periodic systematic and collaborative review of the safety of marketed drugs.

To examine the value of the reviews, a sample of NMEs with different durations of marketing and different extents of use were chosen for evaluation. The pilot program is also expected to provide valuable information about the required resources and appropriate methods for conducting such a systematic evaluation.

In March 2008, FDA issued a progress report describing the progress to date on the pilot program. 



Two of the conclusions about the review process in the progress report include:

  • The comprehensive reviews necessary to carefully examine a drug in the pilot program are most informative after the drug has been on the market for a year or more, or has had substantial use; and
  • The optimal timing within the lifecycle of a drug will merit consideration for future NMEs examined by the pilot program.

FDA expects to issue a final report on the pilot program in the fall of 2008. The results of this pilot will be used to develop procedures to implement Section 915 of FDAAA.




6.1 Enact legislation establishing a new Advisory Committee (AC) on communication with patients and consumers. The committee would be composed of members who represent consumer and patient perspectives and organizations. The AC would advise CDER and other Centers on communication issues related to efficacy, safety, and use during the lifecycle of drugs and other medical products, and it would support the Centers in their mission to “help get the public accurate, science-based information they need to use medicines and foods to improve their health.”FDA is establishing a new Advisory Committee to obtain input to improve the agency's communication policies and practices and to advise FDA on implementing communication strategies consistent with the best available and evolving evidence. FDA will include on the Committee patients and consumers as well as experts in risk and crisis communication and social and cognitive sciences. The IOM report recommends that Congress enact legislation to establish a new Advisory Committee on communication with patients, but FDA believes it can implement the IOM's recommendation more expeditiously through administrative procedures. 

FDA has established a new Advisory Committee on Risk Communication. Although the IOM recommended a legislative approach, FDA decided that this recommendation could be implemented more expeditiously through administrative procedures. The new Advisory Committee was announced on November 5, 2007: click here to read the FDA NEWS RELEASE

 Section 917 (121 Stat 960) of FDAAA created Section 567 of the Federal Food, Drug, and Cosmetic Act providing for such an Advisory Committee.




  6.2 Office of Drug Safety Policy and Communication should develop a cohesive risk communication plan that includes, at a minimum, a review of all Center risk communication activities, evaluation, and revision of communication tools for clarity, consistency, and priority-setting to ensure efficient use of resources. FDA has established a working group, chaired by CDER's Associate Director for Safety Policy and Communication, to develop a CDER risk communication strategic plan. In the process of developing this plan, CDER will identify, clarify, and define the purpose of each communication tool and streamline the use of tools to facilitate information flow. As part of this process, CDER is also evaluating the CDER Web site and will implement changes to make it more efficient and effective. In addition, FDA's recently established Bioinformatics Board in the Office of the Commissioner has taken steps to improve the public's ability to communicate with FDA. The Bioinformatics Board has initiated an agency-wide project to create a common portal for the collection of adverse event reports and consumer complaints about products for all FDA-regulated products. The scope of this project includes developing mechanisms to improve the ease and accuracy of reporting by the public and to improve the timeliness and quality of reports submitted to the FDA.   

A plan to address current gaps in CDER's risk communication process has been completed.

  • The plan builds on recommendations of the IOM, input from other external stakeholders, new responsibilities and authorities under FDAAA, and other recent CDER safety initiatives.
  • The plan focuses on optimizing the use of CDER communication assets, including staff and supporting systems and tools, and the use of the best available science to create our messages, building and sustaining partnerships with key professional and patient groups, and monitoring and evaluating the accessibility and impact of our risk communication tools and channels.
  • One of the agency's key focuses under the Critical Path Initiative is to harness bioinformatics to manage FDA product information. FDA agency's Bioinformatics Board is helping to organize and harmonize agency information management systems. Using emerging information technologies will not only help the agency make its internal communications more efficient, but will also greatly improve communications with external parties, including the public, healthcare professionals, regulated industry, and other health-related organizations.
  • FDA has been working with NIH to create a common shared portal for the receipt of all adverse events reports and reports of problems related to FDA regulated products (MedWatchPlus portal/FAERS initiative).
  • FDA expects to pilot test the portal in 2008 and implement it for use during 2009.

See also 4.1

A series of additional activities are under way, which are described in more detail in the report (see Section V). Activities include:

  • The FDA Prescription Drug Labeling training Module for Health Professionals;
  • MedWatch Partners Program;
  • MedWatch Safety Labeling Summaries;
  • Health Professional Web site and listserv; and
  • Network of Nodes.



7.1 To support improvements in drug safety and efficacy activities over a product's lifecycle, Congress should approve substantially increased resources in both funds and personnel for the FDA.Not directed to FDA. Although not directed to FDA, through FDAAA, Congress provided FDA with additional resources to fund personnel and programs. FDAAA also provided additional funding to support drug safety activities.




 Abbreviations and Acronyms


AC - Advisory Committee

ADS – Associate Director for Safety

AE - Adverse Event

AERS - Adverse Events Reporting System

AHRQ - Agency for Healthcare Research and Quality

ANDA - Abbreviated New Drug Application

BLA - Biologics License Application

CBER - Center for Biologics Evaluation and Research

CDC - Centers for Disease Control and Prevention

CDER- Center for Drug Evaluation and Research

CDISC - Data Interchange Standards Consortium

CERT - Centers for Education and Research on Therapeutics

CMS - Centers for Medicare & Medicaid Services

C-PATH - Critical Path Institute

CPD - Center for Professional Development, Inc.

CRADA - Cooperative Research and Development Agreement

CSRT - Created Cardiac Safety Research Consortium

DARRTS - Document Archiving, Reporting, and Regulatory Tracking System

DTC - Direct to Consumer (refers to DTC advertising)

DCRI - Duke Clinical Research Institute

EC – Early Communication

ECG - Electrocardiograms

FAERS - FDA Adverse Event Reporting System

FD&C ACT (also FDCA) - Federal Food, Drug, and Cosmetic Act

FDA - Food and Drug Administration

FDAAA – Food and Drug Administration Amendments Act of 2007

HHS - Department of Health and Human Services

HIV - Human Immunodeficiency Virus

IOM - Institute of Medicine

MedDRA - Medical Dictionary for Regulatory Activities

MOU - Memorandum of Understanding

NDA - New Drug Application

NHLBI - National Heart, Lung, and Blood Institute

NIH - National Institutes of Health

NME - New Molecular Entity (never before approved)

OC - Office of the Commissioner

OND - Office of New Drugs

OSE - Office of Surveillance and Epidemiology

PDUFA - Prescription Drug User Fee Act

PSTC - Predictive Safety Testing Consortium

QSPB - Quantitative Safety and Pharmacoepidemiology Group

REMS – Risk Evaluation and Mitigation Strategy, required by FDAAA, will now replace RiskMAP

RFI - Request for Information

RFP - Request for Proposal

RiskMAP - Risk Minimization Action Plan (no longer in use)

SRPM – Safety Regulatory Project Manager

SUSAR - Suspected Unexpected Serious Adverse Reaction

VHA - Veterans Health Administration

VSD - Vaccine Safety Datalink

WCT - Workplace Culture Team


[1] The Future of Drug Safety—Promoting and Protecting the Health of the Public. http://www.iom.edu/.

[2] The Future of Drug Safety—Promoting and Protecting the Health of the Public, FDA's Response to the Institute of Medicine's 2006 Report, p. 1.

[3] Id. at 17.

[4] The actions listed are those most relevant to the specific IOM recommendation. Other related actions may not be listed.