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FDA's Role in Identifying and Communicating Drug Safety Issues

Statement of

Paul Seligman, M.D., M.P.H.
Associate Director of Safety Policy and Communication
Center for Drug Evaluation and Research
Food and Drug Administration


the House Committee on Veterans’ Affairs

July 9, 2008


Mr. Chairman and Members of the Committee, I am Dr. Paul Seligman, Associate Director of Safety Policy and Communication in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA or the Agency), which is part of the Department of Health and Human Services (HHS). I am accompanied today by Dr. Robert Temple, Director of the Office of Medical Policy in CDER. We are pleased to be here today to discuss FDA’s role in identifying and communicating about drug safety issues, as well as our role in the protection of human subjects. In my testimony, I will first discuss the importance of FDA drug regulation, including several new initiatives to improve the drug safety system. I will then discuss how the Agency manages drug safety issues and informs the public when drug safety concerns arise. Lastly, I will discuss FDA’s role with respect to protection of human subjects.


FDA promotes public health through the regulation of prescription and over-the-counter drugs, which are an increasingly critical component in improving the health of many Americans.

FDA’s responsibilities for oversight of the entire life cycle of drugs–from premarket drug testing and development through drug approval, postmarket surveillance, and risk management–have never been more important. FDA continuously seeks to provide the means for translating new scientific advances -into benefits for patients (for example, biomarkers and pharmacogenomics), take advantage of new ways to monitor the performance of marketed drugs, and communicate this information to health care professionals and patients to help ensure the safe use of drugs.

One aspect of assuring the most appropriate use of marketed drugs is to study them carefully before approval. FDA’s drug review process is recognized worldwide as the gold standard, and we actively monitor the scientific bases for our processes to ensure that they reflect advances in medical science. FDA approves drugs after they undergo comprehensive safety evaluations. It is not always recognized, but at least half of the effort by FDA’s premarket reviewers is dedicated to the assessment of safety. Major changes have taken place in how drugs are evaluated, including a complete evaluation of their metabolism, their interactions with other drugs, and potential differences of effectiveness or safety in people of different genders, ages, and races. In addition, FDA staff perform systematic assessments of safety that yield comprehensive reviews, focusing on the potential problems with the greatest clinical importance.

The other critical aspect to assuring the most appropriate use of marketed drugs is the process FDA has in place to assess drugs after they are approved. FDA grants approval to drugs after sponsors demonstrate that the drugs meet the Federal Food, Drug, and Cosmetic (FDC) Act’s standard for safety and efficacy. However, no amount of premarket study can provide all of the information about effectiveness or all the risks of a new drug when it is used by the general population in the myriad ways not studied during clinical trials. As a result, FDA’s postmarket drug safety program plays an essential role by collecting and assessing information about adverse events and medication errors identified after approval. A key role of our postmarket safety system is to detect serious unexpected adverse events and take definitive action when needed.


Within the last year, FDA has launched several new initiatives to ensure drug safety. Outlined below are some examples.

Food and Drug Administration Amendments Act of 2007 (FDAAA)

As you know, in September 2007, Congress passed FDAAA, which included new resources for medical product safety and new regulatory tools and authorities to ensure the safe and appropriate use of drugs. For example, under Title IX-Enhanced Authorities Regarding Postmarket Safety of Drugs, FDA can require drug sponsors to make certain safety-related labeling changes and conduct postmarketing studies and clinical trials instead of relying on voluntary actions. In addition, under FDAAA, if FDA determines that a risk evaluation and mitigation strategy (REMS) is necessary to ensure that the benefits of a drug outweigh the risks of the drug, FDA can require manufacturers to submit a REMS when a drug comes on the market, or later if FDA becomes aware of new safety data.

Sentinel Initiative

FDAAA requires the HHS Secretary to develop methods to obtain access to disparate data sources and to establish a postmarket risk identification and analysis system to link and analyze health care data from multiple sources. On May 22, 2008, FDA launched the Sentinel Initiative with the ultimate goal of creating and implanting the Sentinel System—a national, integrated, electronic system for monitoring medical product safety. The Sentinel System will strengthen FDA’s ability to ensure that safe and effective new drugs are available as quickly as possible and that marketed drugs remain safe and of the highest quality.

Action Plan for Import Safety

Another critical aspect to drug regulation is the safety of products imported into the United States. On November 6, 2007, Secretary Leavitt presented to President Bush the “Action Plan for Import Safety” completed by the Interagency Working Group on Import Safety. The Import Action Plan presents broad recommendations and specific short- and long-term action steps, categorized under the organizing principlesof prevention, intervention, and response. On July 1, 2008, FDA issued the “Import Safety – Action Plan Update.” The update outlines the significant progress FDA has made and the key steps that are planned for the future to enhance the safety of imported goods. Thus far, FDA has taken strong enforcement actions, signed agreements with key trading partners, hosted bilateral and multilateral discussions, shared critical information on safety and best practices, and began a process to improve safety practices, both inside and outside of government.

Prevention. FDA is seeking to ensure that imported drug products are safe and effective prior to reaching U.S. ports of entry. FDA is pursuing this goal by maximizing foreign product pre-approval inspections, increasing FDA presence in China, increasing FDA inspections, increasing the sharing and use of foreign competent authority inspection reports and other information, developing plans to use third-party certification, and increasing capacity building with countries that have less developed regulatory systems to ensure product safety.

Intervention. FDA recognizes the importance of a strong and effective intervention capacity to identify problems as they occur. FDA has several plans to enhance its Information Technology systems in ways that will enable the Agency to better utilize risk-based information from the entire life cycle of imported products. FDA is expanding laboratory capacity and developing rapid test methods for detection of pathogens and other contaminants in drugs, and ensuring that these test methods are available at ports of entry to assist in determining whether a product should be admitted into the United States. In addition to increasing pre-approval inspections, FDA is increasing surveillance inspections, as well determining which manufacturing facilities may pose a risk to the American consumer. The Import Action Plan also outlines several action steps intended to help ensure that domestic companies importing foreign source material meet their responsibility to import safe and effective medical products. FDA inspects all facilities listed in a drug application, both foreign and domestic, to determine if they meet the Agency’s quality standards. During these inspections, FDA routinely evaluates the domestic drug manufacturer’s testing and controls of ingredients (domestic and foreign-sourced) and supplies. If deficiencies are discovered, FDA may take enforcement action.

Response. FDA must be ready to take immediate action when a health threat emerges with any FDA-regulated product. The Import Action Plan calls for increased FDA and U.S. Customs and Border Protection (CBP) cooperation, including developing interdepartmental procedures for clearing and controlling shipments at ports of entry, co-locating FDA and CBP at locations to improve coordination and efficient use of resources, and increasing import information sharing between FDA and CBP through new technology applications. FDA is also working to facilitate the adoption of track-and-trace technologies to identify and track a product along the product life cycle. These technologies will facilitate the timely recovery of the violative product and reduce the opportunity for harm, as well as secure the integrity of the supply chain by providing an “e-pedigree”--an electronic record documenting that the drug was manufactured and distributed under secure conditions.


Once FDA approves a drug, the postmarket monitoring stage begins. A drug manufacturer is required to submit regular postmarketing reports to FDA on its drug. These reports include critical information about adverse events associated with the use of one or more drugs. Reports are submitted in an expedited fashion for serious and unexpected risks, and periodically for less urgent safety issues. Manufacturers submit several other types of postmarketing reports, including new clinical trial results. Also during this period, we continuously receive adverse event reports directly from sources, such as health care professionals and patients, through our MedWatch program. Stored in a computerized database, these reports are reviewed and analyzed by FDA epidemiologists and safety evaluators to assess the frequency and seriousness of the adverse events and to determine their causes. An adverse event may occur because of simple or complex reasons, including drug exposure, an interaction between one or more drugs, other therapies, environmental factors, an individual’s characteristics, and underlying diseases. Our response to information from this ongoing surveillance depends on an evaluation of the aggregate public health benefits of the product compared to its evolving risk profile.

Decisions about regulatory action in response to evidence of a drug safety risk are complex, taking into account many factors. As more becomes known about the potential risks or benefits of a drug, often its FDA-approved labeling will be revised so that it better reflects information on appropriate use. For example, FDA may seek revisions to a drug’s labeling to add information on adverse reactions not previously listed, to add new warnings describing conditions under which the drug should not be used, or to add new precautions advising doctors of measures to minimize risk. If labeling alone is inadequate to manage risks, additional actions may include revising drug names or packaging, issuing “Dear Healthcare Professional” letters (sometimes referred to as “Dear Doctor” letters), educational/special risk communications, requiring restricted distribution programs, or withdrawing a drug’s approval.


FDA uses a broad range of methods to communicate drug safety information to the public. Certain forms of communication are targeted to specific audiences (e.g., health care professionals or patients). Others are directed at more than one group to ensure widespread dissemination of information about important drug safety issues, including emerging drug safety issues. FDA continuously evaluates its communication efforts and modifies them to enhance their accessibility and effectiveness. We welcome public comment at any time suggesting ways to improve our safety communications. The different types of drug safety communications are described in more detail below.

Labeling. FDA-approved drug product labeling is the primary source of information about a drug’s safety and effectiveness, and it summarizes the essential scientific information needed for the safe and effective use of the drug. Compliance with the recently issued physician labeling rule for prescription drugs is expected to further enhance the usefulness of product labeling and further facilitate the safe and optimal use of prescription drugs.

Labeling for prescription drug products is directed to health care professionals but may include patient counseling information as well. For some prescription drugs, such as oral contraceptives and estrogens, FDA determined several years ago that the safe and effective use of these drugs required additional labeling in nontechnical language be distributed directly to patients by their health care professional or pharmacist (Title 21 of the Code of Federal Regulations (CFR) 310.501 and 310.515). FDA-approved patient labeling also may be provided by manufacturers for other drugs.

Early Communications about Ongoing Safety Reviews. Since August 2007, FDA has issued Early Communications about Ongoing Safety Reviews (ECs) to keep health care professionals and the general public informed of postmarket safety issues that are currently being evaluated by FDA. ECs are issued at the beginning of FDA’s assessment, prior to conclusive determination of the clinical or public health significance of the information under evaluation and before a decision has been made about what regulatory actions, if any, should be taken. Rather, they reflect FDA’s current analysis of available data concerning these drugs, but posting the information as an EC does not mean that FDA has concluded there is a causal relationship between the drug and the emerging safety issue. It also does not mean that FDA is advising health care professionals to discontinue prescribing these products. In general, ECs have included a timeframe for when FDA anticipates completing the safety review and providing follow-up.

Public Health Advisories. FDA issues Public Health Advisories (PHAs) to provide information regarding important public health issues to the general public, including patients and health care professionals. For example, PHAs may highlight important safety information, inform the public about the completion of FDA’s evaluation of an emerging drug safety issue, announce the implementation of methods to manage the risks identified for a marketed drug, or provide other important public health information.

PHAs regularly include recommendations to mitigate a potential risk and often are issued in conjunction with other drug safety communications, such as Healthcare Professional Sheets. PHAs related to drugs are available through the CDER Web site and disseminated via the MedWatch Partners Program.

Healthcare Professional Sheets. FDA issues Healthcare Professional Sheets, which provide a summary of important and often emerging drug safety information for a particular drug or drug class. Healthcare Professional Sheets begin with a summary “Alert” paragraph, followed by more detailed sections explaining the “Alert,” including clinical considerations or recommendations for the health care professional, information that patients should be made aware of and discuss with their health care professional, a summary of the data that were the basis for the recommendations, and, when applicable, implications of the “Alert.”

Healthcare Professional Sheets are intended to provide adequate factual information to address potential questions from patients and facilitate a healthcare professional’s consideration of the drug safety issue. As with the PHAs, FDA continues to collect input on the usefulness of these communications through a variety of feedback mechanisms, and anticipates that health care professional communications will continue to evolve.

Other Methods of Communication. FDA continues to explore other methods of making its written communications more effective, as well as the use of other media such as podcasts, video broadcasts and conference calls, to disseminate drug safety information.

Sponsors also use various methods to communicate drug safety information. For example, a sponsor may distribute a “Dear Healthcare Professional” letter to convey important information regarding a marketed drug. “Dear Healthcare Professional” letters may be used to disseminate information regarding a significant hazard to health, announce important changes in product labeling, or emphasize corrections to prescription drug advertising or labeling.

To summarize, FDA has a critical role in the detection and management of safety issues that are identified after a drug is approved, including a critical role in communicating information to the public. The actions taken depend on the characteristics of the adverse events, the frequency of the reports, the seriousness of the diseases or conditions for which the drug provides a benefit, the availability of alternative therapies, and the consequences of not treating the disease. Our goal, regardless of the communication tool employed, is to make the most up-to-date drug safety information available to the public in a timely manner so that health care professionals and patients can consider the information when making decisions about medical treatment and be aware of uncertainties in the data. The Agency is committed to providing accurate, clear, reliable, and useful drug safety information.


The FDC Act and its implementing regulations are one part of a complex system of safeguards designed to protect human subjects. Several groups play key roles in the clinical research of products subject to FDA regulation-the company that sponsors the research, the clinical investigator who conducts the research, the Office of Human Research Protection within HHS, when the clinical investigation is federally funded, and the Institutional Review Board (IRB) that has a role in protecting the rights and welfare of the patients who are taking part in clinical investigations. For example, investigators must sign an FDA-Form 1572, committing to comply with their regulatory obligations, and IRBs are subject to detailed rules in 21 CFR part 56. FDA is responsible for regulating the activities of sponsors, investigators, IRBs and others involved in a clinical trial. We take very seriously our role to protect patients enrolled in clinical trials. It should be appreciated, however, that, while a broad set of protections are built into the law and regulations, the professional and ethical conduct of the parties involved in clinical research is crucial to the protection of human subjects.


At FDA, assuring the safety and effectiveness of medical products for the American people is one of our core responsibilities. Working with patients, physicians, pharmacists, industry, and state regulators, FDA plays a critical role in the detection and management of drug safety issues, by helping to ensure the safe use of marketed drugs by providing the best possible information to the American public. We also take our role in the protection of human subjects very seriously; working with many other partners to assure that clinical trials are conducted appropriately.

Once again, thank you for the opportunity to testify before the Committee today. We are happy to respond to questions.