Drug Recalls and Court Actions: A Comparison of Research-Intensive and Nonresearch-Intensive Pharmaceutical Firms

Abstract

The rate and volume of product recalls of the large, research-intensive (RI) pharmaceutical firms (23 firms that account for at least two-thirds of United States drug sales and 80% of research and development expenditures) was compared to that of the remaining, generally nonresearch-intensive (NRI) firms. Data were compiled on all drug recalls occurring between 1970 and 1978 (including over-the-counter products, Class I, II, and III recalls, and citations for failure to file NDAs) by combining the data used as the basis for three previous studies. Analysis of these data indicated that, while larger (RI) firms have a higher number of recalls per firm, the relative amount of material recalled as a percent of material produced is actually less than that of smaller (NRI) firms. When all firms are dichotomized as RI or NRI, the NRI firms had 1.5 times more of their product recalled; accounted for 86% of all recalls; had a seven-fold greater rate of involuntary recalls (22% of their total); and accounted for 97% of all FDA drug seizures and civil injunctions as well as all five FDA prosecutions for criminal violations during the period studied. the estimated dollar value of all recalls of products of NRI firms was $803 million as against $305 million in recalled products of RI firms. for an equivalent dollar amount or volume of product sold, the larger, research-intensive firms thus had a substantially lower rate of product citations by the FDA.     

The role of outsourcing facilities in overcoming drug shortages

BackgroundThe Drug Quality and Security Act passed in 2013 created a new voluntary category of compounders, referred to as outsourcing facilities. The regulatory landscape allows these facilities to compound on a larger scale in comparison with the typical compounding pharmacies, which positions them to potentially serve a role in overcoming drug shortages.ObjectiveThe purpose of this article is to identify the number of drug products on shortage as reported by the Food and Drug Administration (FDA) that were also compounded by outsourcing facilities.MethodsAll current and resolved drug shortages through January 27, 2020, as reported by FDA, were compared with the 503B product reports from July 2018 through June 2019 submitted to FDA by outsourcing facilities. The active pharmaceutical ingredient (API) and dosage form for each product on shortage were compared with the 503B product reports to identify similarities.ResultsThere were 344 unique APIs on the FDA drug shortage list and 774 unique APIs on the 503B product reports. After comparison of the APIs on the drug shortage list with those on the product reports, 27% of unique APIs (74 of 272) were included on both lists, and of these, 18% (50 of 272) of the APIs on the drug shortage list were compounded by outsourcing facilities in the same dosage form as what was on shortage.ConclusionThe regulatory landscape positions outsourcing facilities to play an important role in providing access to medications while on shortage. However, when comparing the drugs on shortage as reported by FDA with the 503B product reports, there was minimal overlap. Additional research into why outsourcing facilities are not taking on a larger role in overcoming drug shortages should be explored.     

Food and Drug Administration monitoring of adverse drug reactions

Food and Drug Administration requirements for reporting adverse drug reactions (ADRs), processing of ADR reports, and actions in response to these reports are described. FDA requires that drug manufacturers report ADRs to the FDA Division of Epidemiology and Surveillance; 90% of the ADR reports received are from manufacturers. Of the remaining 10%, one third are from pharmacists. FDA regulations were revised in 1985 to specifically define reportable ADRs and procedures for reporting; manufacturers are required to report within 15 days reactions that are serious and unlabeled. For newly approved drugs, reports on ADRs must be submitted quarterly for three years; subsequently, annual reporting is required. Any increase in the frequency of serious, labeled reactions must be reported. Serious reactions not listed in the product labeling must be reported for products marketed before 1962 for which new drug applications or abbreviated new drug applications were not filed. ADR information received by FDA is coded into standard terms and entered in a computerized database for evaluation by reviewers. If an important reaction is suspected, the report is entered in a tracking system for further monitoring. ADR reports may result in requirements for changes in product labeling, "Dear Doctor" letters, requirement of further study by the manufacturer, or withdrawal of the product. Information about ADRs is communicated to health-care practitioners in product labeling and in the literature. Pharmacists are encouraged to report suspected serious and unlabeled reactions to FDA so that the medical community and the public can benefit from current information about drug safety.     

A Review of Class I and Class II Pet Food Recalls Involving Chemical Contaminants from 1996 to 2008

Commercial pet food in USA is generally safe, but adulteration does occur. Adulterated food has to be recalled to protect pets and public health. All stakeholders, including food firms, distributors, and government agencies such as the Food and Drug Administration (FDA) participate in food recall. The objective of this review is to describe the pet food recall procedure from start to finish, and to review class I and II pet food recalls from 1996 to 2008, with a specific focus on those due to chemical contaminants/adulterants. Information was requested from the FDA by Freedom of Information Act. Only those recalls backed by the FDA scientific review were considered. The legal framework for food recalls in the Code of Federal Regulations, Title 21, Chapter 1, Part 7 and in the Food and Drug Administration Amendments Act of 2007, Title X was reviewed. From 1996 to 2008, there were a total of 22 class I and II pet food recalls. Of these, only six (27%) were due to chemical adulterants. The adulterants were aflatoxins, cholecalciferol, methionine, and melamine, and cyanuric acid. The causes of adulteration included inadequate testing of raw materials for toxins, use of wrong or faulty mixing equipment, and misformulation of raw materials. Overall, pet food manufactured in the USA is safe. Even with shortcomings in the recall process, the incidence of illness associated with pet food adulteration is low. Added changes can only make the system better in the future to safeguard pet and public safety.     

AMCP Format dossier requests: manufacturer response and formulary implications for one large health plan

BACKGROUND: The Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, a template for health plans to use in developing formulary submission guidelines, has been widely adopted since its initial release in 2000. Many health plans request a dossier (a standardized set of clinical and economic evidence prepared by pharmaceutical manufacturers) to provide information for consideration during the formulary decision-making process. While dossier quality has reportedly improved over time, there is no recent research examining the response rate to dossier requests and the quality of dossiers received. OBJECTIVE: To perform an evaluation of pharmaceutical manufacturers. response to a request for a product dossier prepared using the AMCP Format, and to determine if dossier receipt was associated with a favorable formulary placement. METHODS: The pharmacy and therapeutics (P&T) committee of a mid-Atlantic health plan with approximately 3 million members reviewed 43 drug products from February 2004 through December 2005. A university-based clinical evaluation subcontractor requested dossiers in the AMCP Format by telephone and e-mail from the manufacturers. drug information center about 8 weeks before the committee meeting. A retrospective evaluation of the materials received from the manufacturers was performed. A logistic regression model was developed to determine if dossier receipt increased the likelihood of second-tier copayment formulary placement for new product reviews. RESULTS: Dossiers were requested for 43 products. We received dossiers for 25 products (58%), other drug information (e.g., journal reprints, product labeling) for 10 products (23%), a formulary kit for 4 products (9%), and no response for the remaining 4 products (9%). Of the 25 dossiers, 21 (84%) generally followed the AMCP Format. Unlocked interactive budget impact models were included in 5 dossiers (20%), and modeling reports (without an unlocked interactive model) were included in 12 dossiers (48%). Dossiers were more likely to be received when the time between U.S. Food and Drug Administration (FDA) approval and dossier request was >/- 4 months (65% vs. 27% when <4 months; P <0.05) and when requested from a large manufacturer (top 25 in sales) compared with smaller manufacturers (75% vs. 43%; P <0.05). Dossier receipt did not improve a product.s likelihood for preferred formulary placement; none of the new products for which dossiers were received were assigned to the second copayment tier compared with 33% of the new products with no supporting dossier. The logistic regression model failed to find any correlation between dossier receipt and preferred formulary placement. CONCLUSIONS: Manufacturers met the request for a dossier nearly three fifths of the time. The dossiers were of high quality and generally followed the AMCP Format; the models included in dossiers varied widely in their design and utility. The product manufacturer.s size and the time between FDA approval and dossier request influenced the likelihood of dossier receipt. Receipt of a dossier did not appear to influence the likelihood of a product attaining preferred formulary status.     

272例FDA医疗器械产品一级召回事件分析和探讨

目的通过对272例FDA医疗器械产品一级召回事件进行分类统计分析,探讨严重医疗器械风险事件的发生规律,为上市后医疗器械风险管理工作提供参考。方法检索2001—2012年FDA官网发布的最严重的医疗器械产品一级召回事件,对其中不涉及假劣、伪造等非法原因的272个事件案例进行分类统计和分析。结果构成比排前10位的产品种类占到90％的事件数量;能量型危害是主要危害形式,占79．4％;产品组件失效是最主要的直接原因,占76．1％。结论从产品的角度,严重医疗器械风险事件的产生主要与应用部分、组件可靠性及其功能、能量控制、可用性等主要因素有关。     

Microbial diversity in pharmaceutical product recalls and environments

Identification of microbial contaminants in product recalls and environmental samples provides important information on the possible contamination sources and distribution of microbial species in pharmaceutical environments. Analysis of FDA product recall data for 134 non-sterile pharmaceutical products from 1998 to September 2006 demonstrated that 48% of recalls were due to contamination by either Burkholderia cepacia, Pseudomonas spp., or Ralstonia picketti, while yeast and mold contamination were found in 23% of recalls. Gram-negative bacteria accounted for 60% of recalls, but only 4% were associated with Gram-positive bacteria. Of the 193 recalls of sterile products, 78% were due to the lack of sterility assurance and 7% for yeast and mold contamination. For sterile products, Gram-negative bacteria accounted for 6% of recalls, with only 1% due to Gram-positive bacteria. For non-sterile and sterile products, B. cepacia was the most frequently isolated microbial species with 22% and 2.5% of recalls, respectively. Based upon the review of the scientific literature, B. cepacia, Pseudomonas spp., or Ralstonia picketti may be associated with water contamination, while yeast and mold and Gram-positive bacteria may have indicated deficient environmental controls. The presence of unculturable microbial populations in pharmaceutical waters and clean rooms was reported, but no evidence has been published that product quality was negatively affected.     

Weak links: Instabilities and areas for improvement in the drug supply chain

ObjectiveTo evaluate the current pharmaceutical supply chain, from both a regulatory and market perspective, to identify instabilities as well as propose methods to ensure consistent drug quality and access.Data sourcesData sources include publicly available Food and Drug Administration (FDA) databases.SummaryRecent recalls of important drugs such as angiotensin receptor blockers, heparin, epinephrine, and acyclovir highlight the importance of ensuring access to essential medications. However, the current drug supply chain has multiple weaknesses from both regulatory and market perspectives. A lack of adequate inspection and quality standards means that quality issues often go unfound, but when they are found, disruptions to the supply chain are amplified by a dependence on India and China for active pharmaceutical ingredients. The mutual recognition agreement, India Pilot Program, and increased number of FDA foreign inspectors were steps in the right direction, but more must be done to ensure access.ConclusionEnsuring drug quality and access is not possible without first providing greater transparency into the drug supply chain. This allows both health care consumers and the FDA to respond to drug quality issues. Additionally, extra steps including broadening the scope of the mutual recognition agreement, encouraging increased self-regulation in China and India, and mandating unannounced inspections of foreign manufacturers may help in providing a more stable supply chain.     

Examination of risk evaluation and mitigation strategies and drug safety in the US

BackgroundThe Food and Drug Administration Amendment Act of 2007 (FDAAA 2007) enabled the US Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) for a drug or biologic to ensure that its benefits outweigh the risks.ObjectiveThis study sought to evaluate REMS approved and released by the FDA since the program inception in 2008, to assess the characteristics of REMS approved and to calculate the time lag between FDA drug application approval and REMS approval.MethodsData were derived from Approved Drug Products with Therapeutic Equivalence Evaluations, Approved REMS and Drugs@FDA. Data included generic availability, application type and approval date, therapeutic class and FDA review class, orphan designation, priority review and market status.ResultsThe FDA approved REMS for 259 marketing applications (217 new drug applications -NDAs, 10 abbreviated NDAs, and 32 biologic license applications) in the study period. The FDA granted orphan designation to 11.4% of active ingredients with REMS and priority review to 38.4% of the NDAs with REMS. The largest number of REMS approvals was for nervous system products (31.8% of total approved REMS) and antineoplastic and immunomodulating agents (15.3%).ConclusionsThe FDA approved REMS for one in three biologics and one in thirteen chemical entities available in the market. A pharmaceutical product can be in the market for an average of 14 years before the FDA identifies and evaluates the risk problems that warrant the approval of a REMS.     

国产厂家与原研厂家卡托普利片的质量比较研究

目的 对国产厂家与原研厂家生产的卡托普利片的质量进行比对研究。方法 按照《中国药典》第一增补本的方法对不同厂家的卡托普利片进行实验,测定二硫化物、溶出曲线、含量测定等项目,综合评定产品质量。结果 各厂家质量均符合标准规定。国产厂家在二硫化物、溶出曲线等项目与原研厂家存在差异性。结论 国内部分厂家与原研厂家质量存在差异,建议提高工艺水平,提高药品质量。     

Focusing pharmacoeconomic activities: reimbursement or the drug life cycle?

Summary

The purpose of this paper is to consider the role of pharmacoeconomic activities in the drug life cycle and not just as activities to support reimbursement applications and market entry.These activities are important in establishing the value case for a drug product to both internal and external audiences. Unless these activities are fully integrated into establishing the business case for a product from the pre-phase I period of drug discovery, manufacturers run the risk of establishing a unit price for the product and claims for cost-effectiveness which are inconsistent with achieving reimbursement. Importantly, manufacturers need to consider at an early stage the evidentiary and analytical needs for product evaluation under formulary submission guidelines (AMCP; NICE) and the integration of pharmacoeconomic activities over the life cycle. These activities include justifying assumptions for business opportunity assessments and an early commitment to developing a mock reimbursement submission at post-phase II. The integration of pharmacoeconomic activities in the drug cycle is not only an antidote to excessive clinical optimism but also provides the basis for an effective assessment of the likely performance of new products in the health-care market place at a price and formulary position acceptable both to the manufacturer and the reimburser.     

注射用阿莫西林钠克拉维酸钾包材密封完整性的研究和考察

目的 考察注射用阿莫西林钠克拉维酸钾包材密封完整性，为检测产品包材密封完整性提供新的思路。方法 采用真空衰减法，选用质量较好的产品作为对照品，对4家制药企业生产的共5批注射用阿莫西林钠克拉维酸钾进行包材密封完整性检测，并采用单变量显著性分析法和Mann-Whitney U检验分析法进行数据分析；为了验证结果的可靠性，对厂家A和厂家C产品进行加速试验，并采用2020年版《中国药典》第四部通则0901第一法进行溶液颜色检查。结果 厂家A、C生产的产品的压差均值均高于对照组厂家B、D的产品，且结果离散程度较大，与对照组相比存在统计学差异；厂家A和厂家C产品进行加速试验，溶液颜色显著加深，进一步说明2家企业产品的密封性较差。结论 厂家A、C生产的产品的包材密封完整性明显差于对照组，且溶液颜色显著加深，说明两家企业产品的密封性存在问题；选用质量较好的产品作为对照品，采用真空衰减法进行包装密封完整性检测方法可行、结果可靠。     

Reasons for supply side driven drug shortages – A mixed-methods study on first-level,higher-level,and root causes from the perspective of marketing authorization holders

BackgroundDrug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021. Studies show that shortages are most frequently supply side driven and that often reasons remain unknown.ObjectiveThe aim is to develop a holistic understanding of supply side causes for drug shortages in Germany from marketing authorization holders’ perspectives and to derive implications for shortage mitigation.MethodsA mixed-methods research design, with a grounded theory approach based on a structured literature review, BfArM data analysis, and semi-structured interviews, was used.ResultsInput factor supply issues, manufacturing issues, logistics issues, product recalls, and product discontinuations were identified as first-level causes. Furthermore, a theory on their connection to higher-level causes related to business decision-making, as well as root causes linked to regulations, company values, internal processes, market dynamics, external shocks, and macroeconomic factors, was developed.ConclusionActions to mitigate drug shortages in Germany (e.g., improving business processes, diversifying tender criteria) were derived. These may thus increase patient safety and decrease the financial burden on the healthcare system.     

Bioequivalence of generic thioridazine drug products--the FDA viewpoint

The phenothiazines are among the most widely used drugs to treat symptoms commonly associated with acute and chronic psychoses. One of the commonly prescribed compounds within this class of drugs is thioridazine, available both as a generic product as well as the innovator product, Mellaril. Each of these products is coded as bioequivalent and consequently therapeutically equivalent by the Food and Drug Administration (FDA). A recent issue of this journal contained an article that raised a number of questions concerning the bioequivalence of the generic versions of thioridazine that have been approved by the FDA. Their article was based in part on information obtained from the FDA as well as information supplied to the authors by Sandoz, Inc., the manufacturer of the original thioridazine drug product Mellaril. The FDA has reviewed its original decision of bioequivalence. Based on this reassessment, the FDA strongly rejects the assertion by the authors that several of the approved generic thioridazine products are not bioequivalent. The rationale behind the FDA decisions and the FDA's viewpoint on the bioequivalence of generic thioridazine drug products is discussed in detail.     

仿制药一致性评价工作的进展与展望

目的 研究分析当前仿制药质量和疗效一致性评价的现状及存在问题,提出推进仿制药一致性评价的建议。方法 梳理并分析我国基本药物化学药品目录中口服固体制剂的品种情况、持有文号的生产企业情况、参比制剂公布情况及实施仿制药一致性评价中的问题。结果 低价药、独家品种开展一致性评价比例偏低,未来可及性风险不容忽视。结论 生产企业要落实评价主体责任,以提高质量作为企业发展要务;相关管理部门应加快出台激励政策,助推企业开展仿制药一致性评价。