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CDER Report to the Nation: 2004 Print version
2 Drug Safety and QualityIndex
HighlightsThe practical size of premarketing clinical trials means that we cannot learn everything about the safety of a medicine before we approve it. Therefore, a degree of uncertainty always exists about the risks of a medicine, not only when we approve it but also after we approve it. This uncertainty requires our continued vigilance, along with that of the industry, to collect and assess safety data for medicines on the market. 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. We also monitor the quality of marketed drugs and their promotional materials through product testing and 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 medication safety and quality activities in 2004 include:n Processing and evaluating more than 400,000 reports of adverse drug events, including more than 20,000 submitted directly from individuals. n Reviewing about more than 35,000 reports of medication errors. n Issuing more than 800 letters to help ensure manufacturers comply with regulations concerning drug promotion. Included in the total were more than 200 concerning direct-to-consumer advertising. n Evaluating more than 3,000 reports concerning problems that occur in the manufacturing, processing, packing, labeling, storage or distribution of drugs. n Promulgating a regulation that calls for bar codes on over-the-counter medicines commonly used in hospitals and most prescription medicines. n Issuing Public Health Advisories on non-steroidal anti-inflammatory pain medicines and on antidepressant use in children, adolescents and adults. n Approving Medication Guides for two drugs. n Implementing our initiative to encourage adoption of state-of-the-art manufacturing processes. Safety System for MedicinesOur current system for evaluating drug safety provides: n Extensive premarket testing with rigorous review, including evaluation of remaining uncertainties. n Risk management strategies before and after approval. n Voluntary adverse event reporting systems with additional population-based information. n Proposed user-friendly communication through an improved drug label compatible with e-prescribing and electronic decision support. Capacities of current safety systemn Profile of common adverse events in populations studied during development. n Understanding of medication metabolism and common metabolism-based drug-drug interactions. n Management and evaluation of certain anticipated risks. n Identification of rare serious adverse events that occur after marketing. Knowledge gaps in current safety systemn Detection of differences in the frequency of events occurring both in those who take a drug and those who don’t take the drug. n Time-dependent events. n Adverse events that occur more frequently in populations not normally studied in trials such as those who are very sick or on multiple drugs. n Adverse events that occur more frequently with off-label use. n A tendency for medical errors or abuse. Approaches to resolving knowledge gapsn Use emerging electronic medical record systems for surveillance. n Randomized trials or registries conducted in practice settings after marketing. n More surveillance systems in specialized settings such as emergency rooms or nursing homes. Types of risks from medicines
Product 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. n Avoidable. Drug therapy requires an individualized treatment plan and careful monitoring. Other avoidable side effects are caused by known drug-drug interactions. n Unavoidable. Some known side effects occur with the best medical practice even when the drug is used appropriately. Examples include nausea from antibiotics or bone marrow suppression from chemotherapy. 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 1 in 10,000 persons won't be identified in normal premarket testing. Drug Safety SurveillanceWe evaluate the safety 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 medication errors. We have access to commercial databases that contain non-patient-identifiable information on the actual use of marketed prescription drugs in adults and children. This dramatically augments our ability to determine the public health significance of adverse event reports we receive. 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 may include new labeling, drug names, packaging, “Dear Health Care Practitioner” letters, education or special risk communications, restricted distribution programs or product marketing termination. Adverse Event Reporting SystemA powerful drug safety tool is the Adverse Event Reporting System, known as AERS. 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 reportingIn 2004, we received 422,889 reports of suspected drug-related adverse events:
Adverse event reporting complianceWe monitor the pharmaceutical industry’s submission of adverse event reports. A firm’s procedures for collection, evaluation and submission may affect the transfer and quality of safety data that we have for analysis. Our surveillance of industry is based upon the risks associated with specific drug products and specific data processing procedures. Risk-based inspectionsWe inspect drug firms' adverse event reporting based upon risk criteria associated with specific drug products and corporate performance. These include:
Inspection outcomeIn fiscal year 2004, our field investigators inspected 68 domestic and 10 foreign firms to assess compliance with our regulations for adverse event reporting. We sent 10 firms official notification that they had significant uncorrected deficiencies. We were able to work with other firms to obtain voluntary correction of deficiencies identified by our monitoring. Outreach and educationIn addition to our inspectional program for adverse event compliance, we improve safety reporting through educational presentations to industry. These provide industry with a direct opportunity to expand their understanding of reporting requirements and best practices in drug safety and to alert them to pending regulatory changes. These meetings also serve to expand our own knowledge of industry’s worldwide pharmacovigilance activities. Our educational activities include formal presentations at global industry meetings and training for FDA field investigators. Adverse event electronic submissionsElectronic submission of adverse event reports permits more timely receipt and evaluation at considerable cost savings for us and industry. Our initiative to encourage electronic reports continues to make progress and remains a high priority. We provide useful information on electronic adverse event reports at http://www.fda.gov/cder/aerssub/default.htm. AERS on InternetYou can learn more about the Adverse Event Reporting System at http://www.fda.gov/cder/aers/default.htm. MedWatch Outreach and ReportingWe administer the MedWatch program that helps promote the safe use of drugs by: n Rapidly disseminating new safety information on the Internet and by providing e-mail notification to health professionals, institutions, the public and our MedWatch partners consisting of professional societies, health agencies and patient and consumer groups. n Providing a mechanism for health professionals and the public to voluntarily report serious adverse events, product quality problems and product use errors for all FDA-regulated medical products. Reports can be filed by mail, fax, telephone or the Internet. n Educating health professionals and consumers about the importance of recognizing and reporting serious adverse events and product problems, including medication errors. Our education program includes Internet outreach, speeches, articles and exhibits. Individual healthcare professional and consumer subscribers to our e-mail notification service increased to more than 50,000. We also have 160 MedWatch Partner organizations. In 2004, these individuals and groups received: n 50 safety alerts for drugs and therapeutic biologics. n 25 to 70 safety-related labeling changes for drugs each month. MedWatch Internet resourcesn You can find the latest medical product safety information at http://www.fda.gov/medwatch/. n You can sign up for immediate e-mail notification of MedWatch safety information at http://www.fda.gov/medwatch/elist.htm. Public Health Advisories in 2004Non-steroidal anti-inflammatory pain medicinesIn December, we issued a Public Health Advisory recommending limited use of non-steroidal anti-inflammatory drug products, including those known as COX-2 selective agents. This was is an interim measure pending our further review of data about the increased risk of heart disease. Shortly after the advisory, the manufacturer of one withdrew it voluntarily from the market. In 2005, after further review and a public meeting, we withdrew another and required a boxed warning about heart disease risks on all prescription NSAIDs (click here). We concluded that over-the-counter NSAIDs are safe for short-term pain relief when used as directed on the package labeling. Antidepressant use in children, adolescents and adultsWe asked manufacturers of all antidepressant drugs to include in their labeling a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents and additional information about the results of pediatric studies. Medication GuidesWe may require specific written patient information for selected prescription drugs that pose a serious and significant public health concern. This information is called a Medication Guide. We require Medication Guides when the information is necessary for patients to use the product safely and effectively or to decide whether to use or to continue to use the product. In 2004, we approved Medication Guides for two drugs: n Abacavir sulfate and lamivudine combination (Epzicom). n Amiodarone (Cordarone) and seven generic versions. These Medication Guides must be provided to patients with each prescription dispensed. User fees support risk assessment, minimizationIn recent years, about half of all new medicines worldwide have been launched in the United States, and American patients have had access to about three-quarters of the world’s new medicines within the first year of their introduction. The law authorizing us to collect user fees (click here) allows us to spend some of those funds to increase our assessment and minimization of risks of medicines both before they are approved and after approval: n Preapproval. Sponsors are invited to submit proposed risk management plans before they submit an application for a new drug or biologic. Our drug safety experts carefully review the proposals and begin discussions with sponsors at this early stage that continue through application review and after approval. n Postapproval. User fees also fund surveillance of the safety of medicines during their first two years on the market or three years for potentially dangerous medications. It is during this initial period, when new medicines enter into wide use, that we are best able to identify and counter adverse side effects that did not appear during the clinical trials. Risk management guidances publishedWe published three risk management draft guidances for industry in 2004: n Premarketing Risk Assessment focuses on measures companies might consider throughout all stages of a medicine’s clinical development. n Development and Use of Risk Minimization Action Plans describes how to address specific risk-related goals and objectives and also suggests various tools to minimize the risks of drug and biological products. n Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment identifies recommended reporting and analytical practices to monitor the safety concerns and risks of medicines in general use. The three guidances—finalized in 2005—fulfill our commitment to the risk management performance goals that are part of the 2002 reauthorization of the Prescription Drug User Fee Act. The guidances are based on three concept papers released in 2003, on input from a subsequent public workshop and on comments received on the draft guidances. Medication Error PreventionAvoiding name, label, labeling and packaging confusionWe work hard to ensure the safe use of drugs we approve by weeding out brand names that look or sound like the names of existing products. We identify and avoid brand names, labels, labeling and packaging that might contribute to problems or confusion in prescribing, dispensing or administering drug products. We review about 300 post-marketing reports of medication errors each month. About half are due to error-prone labeling such as similar looking labels and labeling, poor package design, confusing instructions for use and confusing names. We investigate the causes and contributing factors of these errors and recommend revisions to the label, labeling and/or packaging of these products to avert further error. Our comprehensive Web site on
medication errors is at Bar codes required on medicinesOur regulation that calls for medicines to have a bar code became final in February 2004. It covers most prescription medicines and certain over-the-counter medicines commonly used in hospitals. The bar code rule aims to protect patients from preventable medication errors by helping ensure that health professionals give the right patient the right drug, at the appropriate dosages, at the right time. The rule will support and encourage widespread adoption of advanced information systems that, in some hospitals, have reduced medication error rates by as much as 85 percent. We estimate that the rule will help prevent nearly 500,000 adverse events and transfusion errors while saving $93 billion in health costs over 20 years. 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. n The site is at http://www.fda.gov/cder/drug/shortages. n We have an e-mail address to provide the public a communication tool for drug shortage information at DrugShortages@cder.fda.gov. DailyMed updateWe are collaborating on a multi-agency effort to improve patient safety through accessible medication information. Called DailyMed and scheduled to launch in fall 2005, the project will enable us—through the National Library of Medicine—to provide an up-to-date electronic repository of medication labeling in a standard format. This information will be useable in computer systems that support patient safety, such as electronic prescribing and decision-support systems. Proposed rule to revise prescription drug labelingWe continued to work on a final rule, based on comments from the public, to our proposal in 2001 to improve professional labeling so that it better communicates essential information about prescription drugs to health care providers.
Date created: Aug. 22, 2005
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