 |
About CDER - Report |
U.S. Food and Drug Administration • Center for Drug Evaluation and Research |
|
About CDER - Report |
 |
CDER Report to the Nation: 2001 Drug Safety and QualityIndex
MissionProtect the public health by ensuring that human drugs are safe and effective. HighlightsThe practical size of premarketing clinical trials means that we cannot learn everything about the safety of a drug before we approve it. Therefore, a degree of uncertainty always exists about the risks of drugs. This uncertainty requires our continued vigilance, along with that of the industry, to collect and assess data during the post-marketing life of a drug. We monitor the quality of marketed drugs and their promotional materials through product testing and surveillance. As Americans are increasingly receiving the benefits of important new drugs before they are available to citizens of other countries, we must be especially vigilant in our surveillance. In addition, we develop policies, guidance and standards for drug labeling, current good manufacturing practices, clinical and good laboratory practices and industry practices to demonstrate the safety and effectiveness of drugs. Highlights of drug safety and quality activities include:
Actual use data now availableWe awarded three contracts that give us access to commercial databases that contain non-patient-identifiable information on the actual use of marketed prescription drugs in adults and children. This information will significantly augment our ability to determine the public health significance of reports we receive through AERs and other sources. New expert panelWe will be able to consult with a new Drug Safety and Risk Management Subcommittee to the Advisory Committee for Pharmaceutical Science. The new panel is composed of nationally recognized experts in the areas of risk perception, risk management, pharmacoepidemiology, clinical pharmacology, clinical research and medication errors who will advise us on general and product-specific safety issues. Types of Risks from MedicinesProduct quality defects. These are controlled through good manufacturing practices, monitoring and surveillance. Known side effects. Predictable adverse events are identified in the drug's labeling. These cause the majority of injuries and deaths from using medicines. Some are avoidable, and others are unavoidable.
Medication errors. For example, the drug is administered incorrectly or the wrong drug or dose is administered. Remaining uncertainties. These include unexpected side effects, long-term effects and unstudied uses and populations. For example, a rare event occurring in fewer than 1 in 10,000 persons won't be identified in normal premarket testing.
Medication errorsWe help ensure the safe use of drugs we approve by identifying and avoiding brand names that contribute to problems in prescribing, dispensing or administration of the product. Our comprehensive Web site on medication errors is at http://www.fda.gov/cder/drug/MedErrors/default.htm. Drug SafetyWe evaluate the ongoing safety profiles of drugs available to American consumers using a variety of tools and disciplines. We maintain a system of postmarketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug development process. We monitor adverse events such as adverse reactions, drug-drug interactions and poisonings. We use this information to update drug labeling and, on rare occasions, reevaluate the approval or marketing decision. As we discover new knowledge about a drug's safety profile, we make risk assessments and decisions about the most appropriate way to manage any new risk or new perspective on a previously known risk. Risk management methods include new labeling, "Dear Health Care Practitioner" letters, restricted distribution programs or product marketing termination. Information technologyA powerful drug safety tool is the Adverse Event Reporting System. This computerized system combines the voluntary adverse drug reaction reports from MedWatch and the required reports from manufacturers. These reports often form the basis of "signals" that there may be a potential for serious, unrecognized, drug-associated events. When a signal is detected, further testing of the hypothesis is undertaken using various epidemiological and analytic databases, studies and other instruments and resources. AERS offers paper and electronic submission options, international compatibility and pharmacovigilance screening.
Adverse event reporting
Report types
AERS on InternetYou can learn more about the Adverse Event Reporting System at http://www.fda.gov/cder/aers/default.htm. Electronic submissionsAERS was designed and implemented so that the majority of the reports would be entered electronically. We are in the process of migrating the reporting format from paper to electronic. In a pilot program, we are accepting electronic individual case safety reports from five major drug firms. In 2001, electronic submissions into AERS represented 15 percent of the total expedited reports we received. We estimate the cost of receiving a report is cut from $18 per report to $5 per report for those submitted electronically. Adverse event reporting enforcementWe enforce regulations on postmarketing adverse event reporting to ensure that reports are accurate, timely and complete. We develop regulatory strategies and initiate inspections to determine industry compliance with the regulations. We use a risk-based approach to identify firms for inspection. We focus on firms with:
We evaluate the inspection findings and determine if enforcement action is appropriate. Risk management case studyWe have learned in recent years that our traditional methods for informing prescribers of changes in a drug's risks and benefits have little effect once prescribing patterns have been well established. One example is the new risk management program for isotretinoin. The drug is very effective in treating the most serious form of acne, but its use carries significant potential risks, including birth defects and even fetal death. In recent years, as more women receive prescriptions for isotretinoin, the risk that pregnant women may be inappropriately using the drug has increased. On advice from our expert panel and in consultation with us, the manufacturer made significant changes to isotretinoin's risk management program for pregnancy prevention. MedWatch Outreach and ReportingWe administer the MedWatch program that helps promote the safe use of drugs by:
Last year, subscribers to our e-mail notification service more than doubled to about 20,000. We issued about 40 safety alerts for drugs. Notifications were posted on the Internet and e-mailed to individuals and our 190 MedWatch partner organizations. Each month, our subscribers and partners received 25 to 45 safety-related labeling changes for drugs. MedWatch drug safety Internet resourcesThe latest medical product safety information can be found at http://www.fda.gov/medwatch/. You can sign up for immediate e-mail notification of MedWatch safety information at http://www.fda.gov/medwatch/new.htm. Drug ShortagesWe work to help prevent or alleviate shortages of medically necessary drug products. Drug shortages occur for a variety of reasons including manufacturing difficulties, bulk supplier problems and corporate decisions to discontinue drugs. Because drug shortages can have significant public health consequences, we work with all parties involved to make sure all medically necessary products are available within the United States. Drug shortage program aids counterterrorism effortUtilizing data obtained from manufacturers and distributors, our drug shortage program provides supply and production information in response to federal government requests in relation to counterterrorism efforts. Drug shortages on the InternetWe have a Web site that lists current drug shortages, describes efforts to resolve them and explains how to report them.
Cyber Letters for Foreign CiprofloxacinIn the wake of the public health crisis surrounding anthrax-contaminated mail, we issued "cyber letters" to 11 Web sites selling unapproved foreign ciprofloxacin. We issued warnings to Internet vendors abroad who were offering ciprofloxacin to American consumers. We informed consumers that they should be aware of these risks associated with obtaining a prescription drug over the Internet:
Buying medicines onlineMany consumers find it saves time and money to buy their medicines online. We have information to help consumers determine whether a Web site is a licensed pharmacy in good standing. You can find out more about buying medicines online at http://www.fda.gov/oc/buyonline/default.htm. Drug-induced liver injuryDrug-induced liver injury is the most common cause for removing approved drugs from the market, limiting a drug to second-line use or requiring special monitoring or restricted use. We cosponsored a two-day conference and workshop to help foster consensus on principles and areas for research and further work. Conference materials are available at http://www.fda.gov/cder/livertox/default.htm. We have been working with manufacturers to address how to carry out studies in patients with impaired liver function to provide information on dose adjustment in such patients. Drug Promotion ReviewThe information about a drug available to physicians and consumers is just as important to its safe use as drug quality. We promote and protect the health of Americans by ensuring that drug advertisements and other promotional materials are truthful and balanced. We operate a comprehensive program of education, surveillance and enforcement about drug advertising and promotion.
Drug promotion review statisticsWe issued a total of 880 drug promotion letters last year.
Launches and advisoriesWhen requested, we review advertisements and other promotional materials before drug companies launch marketing campaigns that introduce new drugs or campaigns that introduce new indications or dosages for approved drugs. In fiscal year 2001, we issued 178 advisory letters to companies regarding their promotional materials for launch campaigns. We issued 313 other advisory letters to the industry regarding proposed promotional pieces, both professional and consumer directed. In addition, we issued 284 other types of correspondence to the pharmaceutical industry, such as letters of inquiry, closure letters or acknowledgement letters. Regulatory actionsWe issued 105 regulatory action letters to companies for prescription drug promotions determined to be false, misleading, lacking in fair balance of risks and benefits or that promoted a product or indication before approval. These were either "untitled" letters for violations or "warning" letters for more serious or repeat violations. Examples of specific types of violative promotions include promotional exhibit hall displays (20 letters), oral representations (11 letters), Internet Web sites (10 letters), plus traditional materials such as journal advertisements and sales brochures. Direct-to-consumer promotionIncluded in our letters were 190 regarding direct-to-consumer promotion. This compares with 215 letters in 2000. Of last year's letters, 50 were for launch campaigns, 123 for non-launch advisories, and 16 were regulatory letters. Of the regulatory letters, seven were for advertisements broadcast on television or radio, five for print advertisements, three for a combination of broadcast and print advertisements, and one for a Web site. We initiated two national telephone surveys. One is a follow-up to our 1999 survey of patients' attitudes and behaviors associated with direct-to-consumer advertisements. The other is a new survey of physicians' attitudes and behaviors associated with direct-to-consumer advertisements. Patient information for prescription drugsWe continued our research activities in support of the private plan to provide patients with useful information about their prescription drugs. The target goal is for 75 percent of patients to receive useful information with new prescriptions. This past year we worked on evaluating the written patient medication information materials received. Additionally, we carried out a telephone survey of U.S. consumers about where they get their information about prescription drugs. Medication GuidesWe may require specific written patient information for selected prescription drugs that pose a serious and significant public health concern. These are called Medication Guides. They must be distributed to patients with each prescription dispensed. We determine if a drug requires a Medication Guide because information is necessary for patients to use the product safely and effectively or to decide to use or continue to use the product. Last year we issued Medication Guides for three products. Medication Guides issued in 2001:
Proposed rule to revise prescription drug labelingWe received more than 100 comments on our December 2000 proposal to revise the content and format of prescription drug labeling. Companies, associations, academicians and individuals commented, and we will respond when we publish the final regulation. The main purpose of labeling is to communicate essential information about prescription drugs to health care providers. The proposal would add a highlights section of critical prescribing information and an index. It would reorganize and reorder labeling to make the information easier for practitioners to find, read and use. We expect the proposed changes to contribute to our risk communication efforts by improving the accessibility of labeling information and consequently enhancing the safe and effective use of prescription drugs. Drug Recalls and WithdrawalsIn some cases, a drug product must be recalled due to a problem occurring in the manufacture or distribution of the product that may present a significant risk to public health. These problems usually, but not always, occur in one or a small number of batches of the drug. The most common reasons for drug recalls include those listed in the column at the right. In other cases, a drug is determined to be unsafe for continued marketing and must be withdrawn completely. RecallsManufacturers or distributors usually implement voluntary recalls in order to carry out their responsibilities to protect the public health when they need to remove a marketed drug product that presents a risk of injury to consumers or to correct a defective drug product. A voluntary recall of a drug product is more efficient and effective in assuring timely consumer protection than an FDA-initiated court action or seizure of the product.
How we coordinate drug recallsWe coordinate drug recall information, assist manufacturers or distributors in developing recall plans and prepare health hazard evaluations to determine the risk posed to the public by products being recalled. We classify recall actions in accordance to the level of risk. We participate in determining recall strategies based upon the health hazard posed by the product and other factors including the extent of distribution of the product to be recalled. We determine the need for public warnings and assist the recalling firm with public notification about the recall. Top 10 reasons for drug recalls in fiscal year 2001:
Safety-based withdrawals in 2001In some cases, there is an intrinsic property of the drug that makes it necessary to withdraw the drug from the market for safety reasons. For example, these drugs were withdrawn from the U.S. market last year for safety reasons:
Record of safety-based market withdrawalsWhen drug withdrawals are compared based on year of approval, the recent period when we applied user-fee review goals is similar to the previous period.
Recent safety-based drug withdrawalsDrug name (year approved/ year withdrawn)
Drug Product QualityWe provide comprehensive regulatory coverage of the production and distribution of drug products. We manage inspection programs designed to minimize consumer exposure to defective drug products. We have two basic strategies to meet this goal:
We identify, evaluate and analyze inspection findings for trends in deficiencies. We develop guidances to assist drug manufacturers in gaining a better understanding of our regulations. We communicate the expectations of compliance through outreach programs. We review all international pharmaceutical inspection reports. We determine which foreign manufacturers are acceptable to supply active pharmaceutical ingredients or finished drug products to the U.S. market. Reporting systems for drug quality problemsTwo important tools help us rapidly identify significant health hazards associated with the manufacturing and packaging of drugs:
Risk-based surveillance sampling of drugsWe monitor the quality of the nation's drug supply through surveillance and sampling of foreign and domestic finished dosage forms and bulk shipments of active ingredients. The drug products surveyed are selected according to a risk-based strategy that targets products with the greatest potential to harm the public health. FDA district offices conduct follow-up inspections to determine the cause of sample failures and to assure corrective action by the firms. Sampling criteriaCriteria for our risk-based surveillance sampling of drugs include:
Prescription drugs sold without approved applicationsWe identify drugs that are marketed without an approved new or generic drug application. We assess unapproved drugs to maximize protection of the public health and make best use of FDA's limited resources. We prioritize drugs that may be subject to compliance actions into risk-based categories. These begin with those posing the most saftey considerations and effect on public heatlh. Manufacturing plant inspectionsFDA field offices conduct inspections of domestic and foreign plants that manufacture, test, package and label drugs. Before a drug is approved, FDA investigators must determine if data submitted in the firm's application are authentic and if the plant is in compliance with good manufacturing practices. After a drug is approved, FDA conducts an inspection to make sure a firm can consistently manufacture the product. Finally, routine inspections evaluate the firm's entire operations.
Unsubstantiated claims; fraudulent, hazardous productsWe often encounter products marketed to U.S. consumers that make illegal and unsubstantiated medical claims. These may include claims to treat serious diseases that have proven effective treatments. Products making unproven claims may, therefore, pose a significant health risk. Consumers may use a fraudulent product in place of an effective treatment or may delay the use of effective treatment. On occasion, fraudulent products are found to contain toxic components that are likely to cause serious illness or injury. In addition, the marketing of products making unsubstantiated claims threatens to undermine the U.S. drug development and approval process by interfering with the incentive for new drug development. Drug Product Quality ScienceResearchWe conduct scientific research on drug product quality issues. Last year our efforts included: Developing and validating methods for testing the quality of drug products and rapid identification of counterfeit products. This included work on near-infrared spectroscopy and near-infrared imaging. Approving shelf-life extensions for drug products on the joint FDA and Department of Defense Shelf Life Extension Program. We assess stability profiles of stockpiled drugs for risk management. Process analytical technologies initiativeWe launched an initiative to assist manufacturers in improving the capability and efficiency of the pharmaceutical process while maintaining or improving product quality. Known as process analytical technologies, these are systems for continuous analysis and control of manufacturing processes based on real-time or rapid measurements during processing. To assist in this effort, we are bringing together experts in the areas of analytical chemistry, physical chemistry, pharmaceutical technology, regulatory compliance, chemical engineering and international pharmaceutical manufacturing. These include experts from industry and academia along with our own and those from other FDA components. Product quality scientific workshopsWe cosponsored two scientific workshops to bring together our scientists with those from academia and industry to discuss our approaches and industry's experiences and perspective. The workshops were: Assuring Quality and Performance of Sustained and Controlled Release Parenterals. This workshop covered dispersed systems (microspheres, liposomes, gels and suspensions) as well as implants of small molecule and peptide therapeutics for human and animal use. Streamlining the Chemistry, Manufacturing and Controls Regulatory Process for New and Generic Drugs. This workshop discussed scientific criteria for establishing a class of drugs considered to be low risk with respect to product quality. PQRI updateWe are evaluating the first scientific recommendations from the Product Quality Research Institute (page 6). These are aimed at ensuring thorough mixing of a drug within the blend and dosage unit. PQRI has a number of working groups addressing the issues such as:
MicrobiologyWe assess product sterility, maintenance of product safety and the microbiological controls used by firms for drug development and manufacturing. Our microbiology review assures the safety of sterile and non-sterile products through scientific evaluation and communication with the industry and assures consistency through guidance documents. We promote the development of uniform and practical test methods and criteria for our own use and through the U.S. Pharmacopoeia and the International Conference on Harmonization. We initiated a new program to advance rapid microbiology test methods. This included advisory committee meetings and a proposed subcommittee to resolve administrative and technical hurdles. Export CertificatesWe promote goodwill and cooperation between the United States and foreign governments through the Export Certificate Program. These certificates enable American manufacturers to export their products to foreign customers and foreign governments. The demand for certificates by foreign governments remains high due to expanding world trade, ongoing international harmonization initiatives and international development agreements.
Export certificates issued in fiscal year 2001: 4,542The certificates attest that the drug products are subject to inspection by the FDA and are manufactured in compliance with current good manufacturing practices. Export certificates verify that drug products being exported:
FDA/Center for Drug Evaluation and Research |
