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CDER Report to the Nation: 2004 Print version
2 Drug Safety and Quality (continued)Index
Drug RecallsIn 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 left. In other cases, a drug is determined to be unsafe for continued marketing and must be withdrawn completely. Manufacturers 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. Drug recalls in fiscal year 2004
Top 10 reasons for drug recalls in fiscal year 2004
Safety-based Drug WithdrawalsIn some cases, there is an intrinsic property of a drug that makes it necessary to withdraw the drug from the market for safety reasons. Record of safety-based market withdrawalsThe rates of safety-based withdrawals of new molecular entities are similar for an earlier period before we collected user fees and for the period, beginning Oct. 1, 1992, when we collected user fees. Beginning with this report, our pre-PDUFA and PDUFA periods are based on when we received an application rather than when we approved it. The receipt date more accurately reflects whether we reviewed an application under user fee performance goals (click here). Starting with Oct. 1, 2003, our chart includes our approvals of new therapeutic biologics. PDUFA-era applications exempt from user fees are also counted.
One safety-based withdrawal in 2004In September, the manufacturer of rofecoxib voluntarily withdrew the COX‑2 selective non-steroidal anti-inflammatory pain reliever because it was found to increase the risk of heart disease. Further analysis and a public meeting led us in 2005 to require boxed safety warnings on all prescription NSAIDs and the safety withdrawal of valdecoxib, a COX-2 selective NSAID, because of an increased risk of serious skin reactions. Discontinuations determined to be safety withdrawalsWe considered the 2003 marketing discontinuation of levomethadyl a safety-based withdrawal. The manufacturer of the treatment for managing opiate dependence discontinued its sale based on reports of cardiac arrhythmias and cardiac arrest and the availability of safer alternatives. We determined the 1999 marketing discontinuation of etretinate to be a safety withdrawal because it poses a greater risk of birth defects than acitretin, the active metabolite of etretinate used in its replacement product. Recent safety-based NME withdrawals
Drug name
n
Azaribine
n
Ticrynafen
n
Benoxaprofen
n
Zomepirac
n
Nomifensine
n
Suprofen
n
Encainide
n
Temafloxacin
n
Flosequinan
n
Fenfluramine
n
Terfenadine
n
Bromfenac
n
Mibefradil
n
Grepafloxacin
n
Astemizole
n
Cisapride
n
Troglitazone
n
Alosetron
n
Cerivastatin
n
Rapacuronium
n
Etretinate
n
Levomethadyl
n
Rofecoxib
n
Valdecoxib 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. Surveillance of drug promotion activitiesDrug advertising and promotion must be truthful, fair, balanced and not misleading. We issue letters to ensure compliance with our regulations when asked or as a result of our own surveillance. 811 total letters issued on drug promotion activitiesIn 2004, we issued 811 letters concerning drug promotion. These were:
Regulatory letters citing violations. We issued 56 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 violative promotions include exhibit hall displays, oral representations, Internet sites, plus traditional materials such as journal advertisements, sales brochures and TV ads. Launch campaign advisory letters. When 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 2004, we issued 184 advisory letters to companies regarding their promotional materials for launch campaigns. Other advisory letters. We issued 423 other advisory letters to the industry regarding proposed promotional pieces, both professional and consumer directed. We also issued 148 other types of correspondence to the pharmaceutical industry, such as letters of inquiry, closure letters or acknowledgement letters. Direct-to-consumer promotionWe are reviewing and developing methods to increase our effectiveness in the oversight of direct-to-consumer advertising. Evidence from our own studies as well as those conducted by consumer groups and other entities consistently shows that direct-to-consumer ads encourage some patients to seek care for undertreated conditions. This often results in a different treatment that is more appropriate for the patient than the advertised drug. But physicians and others are concerned that consumers may not always get a balanced view of the benefits and risks of a product. 217 letters issued on direct-to-consumer advertisingIn 2004, 217 or 27 percent of the 811 letters we issued concerned direct-to-consumer promotion. We issued guidance on direct-to-consumer broadcast advertisements in 1997. Since then, the number of letters addressing direct-to-consumer promotion and their percentage of the total of letters addressing promotion have been:
Research on direct-to-consumer advertisingWe published the final report of our two national telephone patient surveys and one physician survey in November 2004 (http://www.fda.gov/cder/ddmac/researchka.htm). Our main objective in the studies was to assess the variety of ways direct-to-consumer advertising could influence the doctor-patient relationship. The three surveys found both positive and negative effects: n Disease awareness increased. By and large, consumer ads seem to increase awareness of conditions and treatments, motivate questions to ask a healthcare provider and help patients ask better questions. n No increase in doctor visits. Our data provided no evidence of increased visits as a result of consumer advertising, and few patients reported that advertising motivated physician visits. On the contrary, most people reported that health reasons prompted their visits. It is clear, however, that direct-to-consumer advertising also has effects that may not be positive: n Physicians feel some pressure to prescribe. Although few physicians report excessive pressure to prescribe requested drugs from patients who have seen advertisements, nearly half report feeling at least a little pressure to prescribe. n Patients, physicians say efficacy overstated. Both patients and doctors indicate that consumer directed advertisements overstate drug efficacy and do not present a fair balance of benefit and risk information. n Patients rate brief summary modestly understandable. Patients gave only modest ratings to the understandability of the “brief summary” that is included in print advertisements. This is information meant to provide a more complete picture of the advertised product’s risks. n Patients find recent ads less useful than previously. Patients also expressed some negative opinions about direct-to-consumer advertising. Perhaps more importantly, fewer patients in the 2002 survey than in the survey conducted three years earlier indicated that advertising was useful in their interaction with their doctor and in their healthcare decision making. Compliance OversightWe 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 three basic strategies to meet this goal: n Evaluate the findings of inspections that examine the conditions and practices in plants where drugs are manufactured, packed, tested and stored. n Monitor the quality of finished drug products in distribution, through sampling and analysis. n Monitor drug products to ensure that they comply with applicable approval and labeling requirements. We identify, evaluate and analyze inspection findings for trends in deficiencies. We publish guidances to assist drug manufacturers in gaining a better understanding of our regulations. We communicate the expectations of compliance through outreach programs. We review and evaluate for regulatory action all reports of FDA inspections of foreign drug manufacturing facilities. We determine which foreign manufacturers are acceptable to supply active pharmaceutical ingredients or finished drug products to the U.S. market. 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 criteria
Compounded drugsWe generally defer to state authorities regarding the regulation of traditional pharmacy compounding—on-site compounding of reasonable quantities of drugs following a valid prescription for an individual patient from a licensed practitioner. Manufacturing disguised as compoundingSome pharmacies manufacture and distribute compounded drugs in a way that goes beyond traditional pharmacy practice. Many of these pharmacies make large quantities of unapproved drugs in advance of receiving valid prescriptions. They also copy commercially available drugs when there is no medical need to do so. We hold pharmacies that manufacture drug products under the guise of pharmacy compounding to the same federal legal requirements as drug manufacturers. Furthermore, some pharmacies have compounded drugs that are contaminated, dangerously subpotent (weak) or superpotent (strong). In these situations, we take steps to protect the public from these products. These steps include issuing enforcement letters, referring complaints to state authorities, providing support when states ask, and pursuing enforcement actions, such as seizures of violative products. Misbranded drugs, unsubstantiated claimsMislabeled, fraudulent, hazardous products. We often encounter mislabeled and fraudulent products that make unsubstantiated claims. Consumers may use these products inappropriately. They may use a fraudulent product for treating a serious disease in place of an approved, effective treatment, or they may delay the use of a proper treatment in favor of a fraudulent remedy. Fraudulent products may also contain toxic compounds or other hazardous substances that have the potential to cause serious illness, injury or even death. For these reasons, products that are mislabeled, fraudulent or make unproven claims may pose a significant health risk. Drugs sold without required applicationsWe identify drugs that are marketed without an approved new or generic drug application. The marketing of products that lack required FDA approval may present safety risks and threatens to undermine the U.S. drug development and approval process, as well as the over-the-counter drug review process. We estimate that there are several thousand illegally marketed drug products in the United States, comprised of several hundred unique molecules. We issued a draft guidance in 2003 that describes how we intend to: n Encourage companies to sponsor unapproved drugs through the approval process. n Avoid unnecessarily restricting patient access to useful medicines. n Use risk-based criteria for enforcement action. Regulation of OTC promotional statementsInformation that accompanies or is displayed with an over-the-counter drug is critical to its safe use. Approved drug applications and OTC drug monographs (click here for more) define acceptable consumer labeling and promotional statements for drugs sold over-the-counter. We monitor the statements that accompany these products to make sure they comply with the appropriate application or monograph. We also monitor promotional materials associated with over-the-counter drugs marketed without an approved application or pursuant to a monograph, including fraudulent drugs, and take enforcement actions against these products. Drug importationInternational commerce in pharmaceuticals provides challenges, particularly in counterfeit drugs and counterterrorist activities. We work to: n Implement law. With FDA’s field force, we implement legal requirements establishing which drugs may be imported by manufacturers, distributors and consumers. n Block counterfeits. We take steps to ensure that imported drugs are not counterfeit or mislabeled and that they meet applicable legal requirements relating to safety and effectiveness. n Improve technology. Along with the pharmaceutical and advanced technology industries, the states and other federal agencies, we are developing and implement anti-counterfeiting technology that will trace a drug product through the U.S. drug distribution system. Protection of federal fundsFederal law prohibits the expenditure of federal funds for drug products determined to be less than effective for their labeled indications. Under an intra-agency agreement between the Centers for Medicare and Medicaid Services and FDA, we identify drugs that are not eligible for CMS’s Drug Reimbursement Program. These include dietary supplements and drugs still on the market that have been identified as less-than-effective in Federal Register notices. This process has saved American taxpayers millions of dollars and has made those funds available for reimbursement of eligible drug products. 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 periodic inspections to make sure a firm can consistently manufacture the product with the required quality. We develop compliance programs to guide the investigators in conducting these inspections, and we identify facilities that are high priority for inspection based on their identified risk potential. 1,375 preapproval inspectionsDuring fiscal year 2004, FDA evaluated:
1,825 good manufacturing practice inspectionsThere were 1,825 good manufacturing practice inspections in fiscal year 2004. n We approved 45 field recommendations for regulatory action. These included 40 warning letters, three injunctions and two seizures. n We reviewed 184 foreign establishment inspection reports, resulting in one warning letter, one import alert and several regulatory meetings.
Medical gas inspectionsWe reviewed 171 medical gas inspections and four recommendations for warning letters, of which we approved one. Drug Quality Surveillance SystemsOur reporting tools help us rapidly identify significant health hazards and quality problems associated with the manufacturing and packaging of medicines. Problems that may affect a medicine’s safety, purity or potency may occur during manufacturing, processing, packing, labeling, storage or distribution. We evaluate reports and FDA field inspections to identify specific firms with manufacturing quality problems with the most potential impact on public health. We target these candidates for inspection and further product sampling and laboratory analysis. We recommend appropriate corrective actions based upon our analysis of the findings. We may take enforcement action in some cases. Drug quality reports
Types of reportsn Drug Quality Reporting System. Through MedWatch (click here), we receive reports from consumers and health care professionals of observed and suspected product quality defects. Our central reporting system assists us in evaluating and prioritizing these data to identify potential manufacturing quality problems and industry trends. n Field Alert Reports. Firms are required to promptly notify FDA district offices about possible quality and labeling problems that may represent a safety hazard. Experts in FDA district offices evaluate the reports and conduct further investigations when needed. n Biological Product Deviation Reports. Manufacturers are required to report any event associated with the manufacturing of a therapeutic biological that may affect its safety, purity or potency. Product Quality ScienceEncouraging innovation, state-of-the-art manufacturingWe have implemented an initiative to encourage manufacturers to be innovative and to apply state-of-the art quality assurance methodologies to their manufacturing processes. The Process Analytical Technologies Initiative is part of our efforts to ensure the continued availability of the highest quality pharmaceuticals to the American public. We developed the initiative—a key element in our Pharmaceutical cGMPs for the 21st Century (click here for more)—with these essential precepts in mind: n Testing products after manufacturing is not sufficient to guarantee product quality. n Monitoring and controlling product quality during manufacturing provides a much higher degree of quality assurance. Process analytical technologies incorporate assessment of a product’s characteristics in real-time and feed that information back into process control systems that maintain the desired state of product quality throughout manufacturing. Final guidance establishes scientific tools, regulatory schemeOur final guidance on process analytical technologies, issued in 2004, includes biotechnology products and establishes a framework that both facilitates innovation and enables risk-based regulatory decisions. The framework has two components: n A set of scientific principles and tools supporting innovation. n A strategy for regulatory implementation that will accommodate innovation. The regulatory implementation strategy includes creation of a process analytical technologies team approach to our review of the chemistry manufacturing and controls section of an application and to inspections of current good manufacturing practices. It includes specialized, joint training and certification of reviewers and inspectors. To review applications using these new technologies, we bring together the appropriate experts in analytical and physical chemistry, pharmaceutical science, regulatory compliance and chemical engineering to provide a comprehensive assessment of the manufacturing process. Process analytical technologies Web siteOur effort to facilitate the introduction of new technologies to the manufacturing sector of the pharmaceutical industry has its own Web page at http://www.fda.gov/cder/OPS/PAT.htm. Laboratory supportWe assessed several analytical technologies for characterizing active pharmaceutical ingredients and guarding against counterfeit product marketing. We applied near infrared, Raman, Isotope ratio mass spectrometry to the problem of distinguishing between production sources of active pharmaceutical ingredients and finished dosage forms. We developed methodology to better characterize nasal spray products. We evaluated a new aerodynamic particle size analyzer. We evaluated instrumentation for the determination of particle size and particle size distribution for cyclosporin drug products. We are developing physicochemical methods to assess quality changes in liposomal drug products. 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 (click here for more). We have a new program to advance rapid microbiology test methods.
Date created: Aug. 22, 2005 |
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