Dr. David Acheson
Associate Commissioner on Foods
Food and Drug Administration
U.S. Department of Health and Human Services
Is the VA meeting the Pharmaceutical needs of Veterans? An Examination of the VA National Formulary, Issues of Patient Safety, and Management of the Pharmacy Benefits Program
Committee on Veteran’s Affairs
Subcommittee on Health
United States House of Representatives
Tuesday September 22, 2009
Mr. Chairman and Members of the Committee, I am Dr. Solomon Iyasu, Director, Division of Epidemiology, within the Office of Surveillance and Epidemiology 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 pleased to be here today to discuss FDA’s role in identifying and communicating drug safety issues, as well as our collaboration with the Department of Veterans Affairs (VA). We will first discuss the importance of FDA drug regulation, including how the Agency manages drug safety issues and informs the public when drug safety concerns arise. We will also discuss some specific examples of how FDA and the VA have collaborated in furthering our mission to protect the public health and keep our drug supply safe.
FDA Drug Regulation
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 is charged by Congress with the authority to review new drug applications for safety and effectiveness. 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.
Approval of a drug product is based on FDA’s acceptance and review of data collected during the course of the drug’s development, including the results of clinical trials, demonstrating that the drug is safe and effective for its intended use. 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. Adverse reactions reported during the clinical trials of the drug are included in the labeling information, even if they occurred in a small number of individuals, so that health professionals are aware of the scope of the potential reactions and can advise their patients accordingly.
All drug products contain risks as well as benefits, and it is often impossible to predict which individuals may have increased sensitivity to particular drugs. Before approving a drug, FDA takes into account the known risks associated with the drug, along with the benefits the drug will provide. 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. 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.
Health professionals may observe differences from clinical trial results in both the incidence and/or types of adverse drug experiences. FDA is committed to improving the ability of health care professionals to predict which patients might experience adverse events with a given drug. FDA continuously seeks to provide the means for translating new scientific advances into benefits for patients (for example, biomarkers and pharmacogenomics) to take advantage of new ways to monitor the performance of marketed drugs, and to communicate this information to health care professionals and patients to help ensure the safe use of drugs.
Another critical aspect to drug regulation is the safety of products imported into the United States. 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. 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 begun a process to improve safety practices, both inside and outside of government. FDA has increased its presence abroad by establishing offices in China, India, Europe, and Latin America at present. FDA is seeking to ensure that imported drug products are safe and effective prior to reaching U.S. ports of entry. Among other things, FDA is pursuing this goal by maximizing foreign product preapproval inspections, 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 providing technical assistance to countries that have less developed regulatory systems to ensure product safety.
Below we will discuss how FDA manages drug safety issues in general, and we will highlight initiatives in place to further enhance FDA’s postmarket drug safety monitoring program.
HOW FDA MANAGES DRUG SAFETY ISSUES
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 adverse events, and periodically for other adverse events. 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 the public, 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 association, if any, with medication usage. 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. 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. 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. 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), disseminating educational/special risk communications, requiring restricted distribution programs, or withdrawing a drug’s approval.
HOW FDA COMMUNICATES ABOUT DRUG SAFETY ISSUES
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. 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 that 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). In addition, FDA may require Medication Guides, a type of patient-directed labeling, for products it determines pose a serious and significant public health concern (21 CFR 208) as part of a risk evaluation and mitigation strategy (REMS). 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 to keep health care professionals and the general public informed of postmarket safety issues that are currently being evaluated by FDA. Early Communications 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. They reflect FDA’s current analysis of available data concerning these drugs; posting the information as an Early Communication 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, Early Communications have included a time frame for when FDA anticipates completing the safety review and providing follow up.
Public Health Advisories (PHAs). FDA issues 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 CDER’s 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.
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.
Manufacturers 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.
INITIATIVES TO IMPROVE DRUG SAFETY
Drug Safety Oversight Board
The Drug Safety Oversight Board (DSB or the Board) was established in 2005 to oversee the management of drug safety issues and communication to the public about the risks and benefits of medicines. The Board’s responsibilities include conducting timely and comprehensive evaluations of emerging drug safety issues for health care professionals and patients, and ensuring that experts both inside and outside of FDA give their perspectives to the Agency. The DSB also makes recommendations regarding disputes over scientific data and implements drug safety policies. In addition to making FDA’s decisions on drug safety more transparent, the Board is a means to assure the public and medical profession that guidance has not been unduly influenced by the pharmaceutical industry.
The DSB oversees drug safety issues within FDA’s CDER, and is made up of FDA and medical experts from other government health agencies and government departments, including the VA. Along with other FDA colleagues, I am a primary participant from the Office of Surveillance and Epidemiology (OSE), in addition to the OSE Director and my counterpart in OSE’s Division of Pharmacovigilance. In addition to the VA, other federal agency Board members include representatives from the National Institutes of Health, the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, and the Department of Defense.
As a result of its partnership with FDA on the DSB, the VA shared the results of its own analysis involving the pain reliever propoxyphene with FDA. Based on these data as well as other data, in July 2009, FDA took action to require manufacturers of propoxyphene-containing products to strengthen the label emphasizing the potential for overdose when using these products, and to provide a medication guide to patients stressing the importance of using the drugs as directed. Among other things FDA is doing to further assess the safety of this product, the Agency is working with the VA to explore whether we can study how often the elderly are prescribed propoxyphene instead of other pain relievers and the difference in the safety profiles of propoxyphene compared to other drugs.
Other FDA/VA Collaborations
Collaborations between the VA and CDER’s Office of Surveillance and Epidemiology, as well as with other FDA Centers, enhance our understanding of postmarket safety issues occurring in FDA-regulated products.
In January 2007, and again in 2008, FDA and the VA signed a Memorandum of Understanding (MOU) for sharing information to enhance postmarket surveillance efforts and other drug and vaccine safety projects. The goals of the collaboration are to explore ways to promote efficient use of tools and expertise for product risk identification, validation, and analysis and to build infrastructure and processes that meet shared needs for evaluating the safety, efficacy, and use of drugs, biologics, and medical devices.
Also, in August 2008, FDA and the VA signed an InterAgency Agreement (IAA), which allowed FDA to provide funding to the VA for work on safety issues of mutual interest. The IAA allowed funding for personnel time and programming costs associated with analysis of VA data to explore questions of interest that were raised by FDA, but also of interest to VA. This agreement is currently in the process of being renewed for another year.
In addition, CBER and the VA continue collaboration on the Vaccine Safety Adverse Event Tracking and Safety Pilot Project. The focus of this initiative is the influenza immunization pilot study in the Central Veterans Health Administration (VHA) Database which will track adverse events after administration of influenza vaccine in a cohort of approximately 1 million VHA patients. It is anticipated that an additional 900,000 more persons will be added to the Central Database (bringing the total number of persons in the cohort to 2 million) in October 2009.
Also, the VA and FDA’s CDRH are working together to better understand adverse events related to cardiac catheterization procedures. The VA has developed a workflow system that allows for the integration of adverse event data reporting for review and discussion at a later date. This information is then shared with CDRH at regular intervals. The VA and CDRH are developing ways to share information in a similar fashion for endoscopes.
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 FDAAA, 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, if FDA determines that a REMS—risk evaluation and mitigation strategy—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 information.
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. The Sentinel Initiative is FDA’s response to this mandate. Its goal is to build and implement a new active surveillance system that will eventually use electronic health information to monitor the safety of all FDA-regulated products. 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 Initiative is a long-term effort that must proceed in stages, and this effort is well under way. FDA is collaborating with the federal and private sector in various activities that will inform the development of this system.
In December 2008, FDA held a public meeting on the Sentinel Initiative to obtain input from stakeholders about the structure, function, and scope of the project. The Director for the Center of Medication Safety at the VA was among the participants at this day-long meeting, presenting on the issue of risk communication.
As an initial step to creating the Sentinel System, FDA is initiating various pilot efforts to further the science of medical product surveillance. One of these pilots, known as Mini-Sentinel II, will include our federal partners. We look forward to the VA’s participation in this effort. The effort involves creating a distributed system that will focus on developing methodologies to obtain more information on emerging drug safety issues. Mini-Sentinel II is a small-scale effort to conduct the types of safety evaluations that FDA envisions doing on a larger scale with the Sentinel System. Medical product-adverse event pairs will be selected based on identification of priority safety issues from FDA’s medical product Centers. Then a protocol for a query will be developed and agreed to by participating federal partners. Subsequently, each participating federal partner will perform the analysis in their database. The query will be translated into analytical code by the partner specifically developed and suited for the partner’s database structure. Summary results of each federal partner’s analysis will be submitted to FDA for further consideration. Lessons learned from this pilot will inform the development of the Sentinel System.
The Sentinel System will augment the Agency’s current postmarketing surveillance tools and strengthen FDA’s ability to ensure that safe and effective new drugs are available to the public and that the risks of marketed drugs are well understood.
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. 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. Our ability to fulfill our mission is enhanced by our partnerships with patients, physicians, pharmacists, industry, state regulators, and other federal partners like the VA. Together we can help ensure the safe use of marketed drugs by providing the best possible information to the American public.
Once again, thank you for the opportunity to testify before the Committee today. We are happy to respond to questions.
Last revised: June 18, 2013