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CDER Report to the Nation: 2005 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 In other cases, a drug is determined to be unsafe for continued marketing and must be withdrawn completely.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. Spike in 2005 recallsOne firm had more than 100 recalls in 2005, which caused a spike in the recall figures. Drug recalls in fiscal year 2005
Click image for larger chart, click here for accessible text. Top 10 reasons for drug recalls in fiscal year 2005
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. The 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 (click here). Our time periods are based on when we received an application rather than when we approved it. Beginning Oct. 1, 2003, approvals include new therapeutic biologics. Applications exempt from user fees are also counted.
Click image for larger chart, click here for accessible text. Four safety withdrawals of NMEs or new BLAs in 2005n Valdecoxib, a COX-2 selective non-steroidal anti-inflammatory pain reliever, was withdrawn because it carried an increased risk of serious skin reactions in addition to the risk of heart disease associated with prescription NSAIDs. n Pemoline, a central nervous system stimulant treatment for attention deficit hyperactivity disorder, was withdrawn because of its overall risk of liver toxicity and association with life-threatening liver failure. n Natalizumab, a treatment for multiple sclerosis, was withdrawn because three patients developed a serious viral infection of the brain. It was reintroduced in 2006 with a special restricted distribution program. n Technetium (99m Tc) fanolesomab, a radiological imaging agent for unclear signs and symptoms of appendicitis, was withdrawn for fatal and life-threatening cardiopulmonary arrest occurring shortly after administration. One non-NME safety withdrawal in 2005n Palladone, a brand of hydromorphone hydrochloride extended-release capsules, was withdrawn because serious and potentially fatal adverse reactions could occur if the drug was taken with alcohol, which harmed the extended-release mechanism and could lead to dose-dumping. 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
n
Natalizumab
n
Technetium (99m Tc) fanolesomab
n
Pemoline Drug Promotion ReviewThe information about a drug available to physicians and consumers is critically important to its safe use. 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. Regulatory letters citing violationsWe issued 60 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.
Click image for larger chart, click here for accessible text.
Click image for larger chart, click here for accessible text. Launch campaign advisory lettersWhen requested, we review advertisements and other promotional materials before drug companies launch marketing campaigns that introduce either new drugs or new indications or dosages for approved drugs. In 2005, we issued 158 advisory letters to companies regarding their promotional materials for launch campaigns. Other advisory lettersWe issued 348 other advisory letters to the industry regarding proposed promotional pieces, both professional- and consumer-directed. We also issued 122 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 prescription of a treatment that is not the one advertised but a treatment that is more appropriate for the patient. But physicians and others are concerned that consumers may not always get a balanced view of the benefits and risks of a product and may sometimes be given drugs they do not need or are not the best choice. Public meeting addresses DTC promotion issuesIn November 2005, we took part in a two-day FDA public hearing on direct-to-consumer promotion of regulated medical products, including prescription drugs for humans. We heard more than 30 presentations representing the viewpoints of consumers, patients, caretakers, health professionals, managed care organizations, insurers and the regulated industry. Topics included: n Various ways of presenting risk and benefit information to consumers, including what and how it should be presented in consumer friendly language. n The impact of DTC promotion on the diagnosis and treatment of disease. n How DTC promotion might impact under-treated and under-diagnosed medical conditions. n Data from research conducted related to DTC promotion. n The use of celebrities in DTC promotion. n The use of disease awareness campaigns. n The impact of images and graphics on promotions and reminder advertisements. We are reviewing the comments from the meeting and an additional 1,200 written comments submitted to us. DTC promotion lettersIn 2005, 203 or 30 percent of the 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 letters addressing promotion have been:
DTC promotion researchWe are conducting three studies to help find the best way or ways to present information in the “brief summary”—the page of risk information in a print ad: n Purpose. The first study will concern the purpose of the brief summary—how do people use it and what topics do they find most useful. We hope to have data collected for this study by the end of summer 2006. n Content. The second study will address content issues in the brief summary, including the amount of common side effect information and the inclusion of numerical context. n Format. The third study will examine format issues, such as graphics, layout and font. 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. Criteria for risk-based sampling
Compounded drugsWe generally defer to state authorities regarding the regulation of traditional pharmacy compounding—on-site compounding of reasonable quantities of drugs by a pharmacist in response to a practitioner’s prescription for an individual patient to accommodate the specialized medical needs of that particular patient. 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 seizure 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. Protecting consumers from misbranded or fraudulent drugsWe protect consumers from mislabeled, fraudulent or hazardous products. We locate and identify these products on the Internet and other outlets, and we take steps to prevent their sale and to remove them from the market. These steps include issuing enforcement letters and pursuing enforcement actions, such as seizures of violative products and injunctions against firms and individuals. We also work with other federal agencies to coordinate enforcement action against firms and individuals who violate federal law. We may also take steps to warn the public about misbranded and fraudulent products. These steps include issuing press releases and MedWatch alerts to warn consumers about the potential health risks associated with these products. 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 over-the-counter drugsThe formulation of OTC drugs and the information that accompanies them or is displayed with them is critical to their safe use. Approved drug applications and OTC drug monographs (click here) define acceptable formulations and the consumer labeling and promotional statements for drugs sold over-the-counter. We monitor the statements that accompany these products along with their formulations to make sure they comply with the appropriate application or final monograph. We also monitor the formulations, labeling and promotional materials associated with over-the-counter drugs marketed without an approved application or final monograph, including fraudulent drugs, and take enforcement actions against these products where necessary. Council for Pharmaceutical QualityFDA formed a Council for Pharmaceutical Quality in 2005 to oversee policy development and implementation, including the ongoing implementation of internal quality management systems relating to drug quality regulations. Through our active participation in this program, we have provided the Pharmaceutical Inspectorate advanced training on risk-based approaches to inspections, modern quality systems and the legal and scientific application of good manufacturing practice regulations to manufacturing operations. We certified the first class of these highly trained investigators and are preparing for the next class.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. Prioritizing sites for inspectionOur 2004 white paper, Risk-Based Method for Prioritizing CGMP Inspections of Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking Model, creates a formal risk ranking of manufacturing plants by using an analytical process to: n Pose a risk question. n Identify potential hazards and risks. n Characterize factors that can be used as variables for quantifying risk. n Mathematically combine the variables to yield an overall risk score. This program continues to be refined and improved by better evaluation of the risk factors available to us. For example, we added adverse experience reports data to the model in addition to the many data sources already being used. This allows us to maximize our limited resources by focusing our field force on those sites that most affect product quality and safety. Good manufacturing practice enforcementWe have acted under our regulatory enforcement program to address products not manufactured under current good manufacturing practice regulations. We provide expert technical support that employs science and risk-based principles in applying these regulations. As a result, many corrections are achieved voluntarily or through administrative means. Some corrections, though, require the involvement of the judiciary system. One case of note resulted in a court-ordered injunction against a firm violating cGMPs and selling unapproved drugs. The judge in this case stated that he was “simply unwilling as a court of equity to place the health, safety and welfare of the general public at risk in order to accommodate the economic well-being of defendants.” Domestic drug plant inspectionsIn fiscal year 2005, FDA field office inspections included: n 188 preapproval inspections in support of:
n 1,437 current good manufacturing practice inspections For these, we approved 22 field recommendations for regulatory action, including:
n 152 medical gas inspections We reviewed 152 medical gas inspections and approved two warning letters. Biologics license inspectionsOur experts conduct the preapproval inspections in support of biologics license applications and supplements to them. In fiscal year 2005, there were:
In other work to ensure the quality of biologics, we reviewed:
We held 38 meetings with industry and answered 38 inquiries about good manufacturing practices. Foreign drug inspectionsThere were 213 foreign current good manufacturing practice inspections and 234 foreign preapproval inspections in 2005 (click here). CorrectionIn previous editions of this report, the data labeled “preapproval inspections” were for “establishment evaluation requests.” All requests are evaluated, but only some trigger an in-plant inspection. 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
Click image for larger chart, click here for accessible text.
Click image for larger chart, click here for accessible text. 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 ScienceThe Pharmaceutical cGMPs for the 21st Century Initiative (click here) stresses the need to apply more scientific and engineering knowledge to regulatory decision making and to the evaluation of manufacturing processes. The goal is to improve upon the overall efficiency and effectiveness of manufacturing processes and to enhance product quality. We have looked closely at manufacturing science to develop recommendations for improvements. One of the areas that we focused on was the Process Analytical Technologies Initiative. The capability to use process analytical technologies encourages manufacturers to be innovative and to apply state-of-the-art quality assurance methodologies to their manufacturing processes. 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. 2005 progress highlightsWe moved into the implementation phase after the release of our final PAT guidance in 2004. We note the following highlights: n PAT review and inspections. PAT applications and implementations have been approved or passed inspection for brand-name products, generics, over-the-counter drugs and active pharmaceutical ingredients. n Training. There have been a number of training sessions for PAT, including training of the Pharmaceutical Inspectorate. We have developed plans for extensive internal training on PAT concepts to prepare our reviewers to routinely incorporate PAT evaluation into standard reviews. n Industry interactions. We continue to facilitate the adoption of PAT. Dialogue continues with all segments of the industry. n Academics. We note the development of several academic programs dedicated to PAT both domestically and in Europe and Asia. We continue to evaluate those scientific and engineering tools that support a better understanding of product and process and that will help:
PAT Web siteMore information on process analytical technologies can be found 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). We have a new program to advance rapid microbiology test methods.
Date created: August 14, 2006 |
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