Assessment of Data Sources That Support US Food and Drug Administration Medical Devices Safety Communications.

Importance: Medical Device Safety Communications (MDSCs) are used by the US Food and Drug Administration (FDA) to convey important new safety information to patients and health care professionals. The sources of initial safety signals that trigger MDSCs have not been described previously. Objective: To assess the sources of initial safety signals that trigger publication of MDSCs and the potential associations among MDSC data source, type of safety issue, and subsequent FDA action. Design, Setting, and Participants: In this cross-sectional study, all MDSCs published on the FDA website between January 1, 2011, and December 31, 2019, were assessed. The MDSC characteristics, sources of initiating safety signals, regulatory approval or clearance pathways of the related medical devices, and subsequent FDA actions were collected from the FDA website. Main Outcomes and Measures: The main outcome was the distribution of sources of initial safety signals that led to publication of MDSCs. Secondary aims included exploration of potential associations among safety signal sources (direct reporting vs other), type of safety issue (death vs other), and FDA action (withdrawal vs other). Results: A total of 93 MDSCs were evaluated. Median time from device approval to MDSC posting was 10 years (interquartile range, 6-16 years). The most common data sources that triggered MDSCs were direct reports to the FDA through the Medical Device Reporting (MDR) program (44 of 93 [47%]) followed by regulator-initiated assessments (32 [34%]). Common safety issues included patient injury (25 [27%]), potential wrong diagnoses (19 [20%]), and death (18 [19%]). Frequent FDA action after MDSC posting included recommendation for increased vigilance and caution (47 [51%]), complete device withdrawal (12 [13%]), and warnings of specific lots or clinics (12 [13%]). There was a statistically significant correlation between direct reports of adverse events to the FDA through the MDR program and risk of death as a safety issue (14 of 44 [32%] for direct reporting vs 4 of 49 [8%] for any other data sources, P = .007). Conclusions and Relevance: In this cross-sectional study, the most common source of initial safety signals that triggered MDSCs was direct reports of real-world adverse events to the FDA through the MDR program. The delayed detection of postmarketing adverse events highlights the importance of proactive identification of emerging device-related safety issues.

Prevalence of zolpidem use in France halved after secure prescription pads implementation in 2017: A SNDS database nested cohort study.

Our objective was to quantify the impact on the use of zolpidem of the obligation implemented in France in 2017 to use secure prescription pads to prescribe it. We conducted a cohort study within the French SNDS healthcare database. Patients aged over 18 years of age were considered for inclusion. The number of prevalent users and incident episodes of zolpidem use were compared before the change in law (July 1, 2016 to January 1, 2017) and after (July 1, 2017 to January 1, 2018). A prevalent user was a patient who has been reimbursed for zolpidem at least once. An incident episode of zolpidem use was defined by a first administration of zolpidem without any prior administration within the previous six months. Regarding prevalence of zolpidem users, we observed a decrease from 2.79% (CI95%:2.75-2.83) to 1.48% (1.44-1.51), with a number of patients who stopped taking it after the change in law being approximately 4.3 times higher than the number of patients who started. We observed a negative association between the post-law change period (OR = 0.52 (0.51-0.53)) and the probability of receiving zolpidem, adjusting for sex, aging, low income and chronic disease. We observed a decrease from 183 treatment episodes per 100,000 insured months on average to 79 episodes per 100,000 insured months, with an incidence rate ratio (IRR) equal to 0.43 (0.38-0.49). The use of secure prescription pads seems to have reduced the exposure of the French population to zolpidem.

Vaccine safety.

The purpose of this article is to offer evidence that vaccine safety is taken very seriously and various examples to support this premise are described. The article covers adverse event reporting following vaccination, the difference between events which occur after vaccination and events which are caused by vaccination, the comprehensive safety monitoring required when vaccines are first introduced, international vaccine withdrawals because of safety concerns and some vaccine changes in New Zealand where safety was an important consideration. Finally, recent developments in vaccine safety monitoring are outlined. It is hoped that this will be a useful resource for those involved in the complex issue of counteracting vaccine hesitancy.

Completion Rate and Reporting of Mandatory Pediatric Postmarketing Studies Under the US Pediatric Research Equity Act.

Importance: Many medicines prescribed to children have not been studied or formally approved for pediatric use. The Pediatric Research Equity Act of 2003 authorized the US Food and Drug Administration (FDA) to require pediatric clinical studies. Objective: To evaluate the characteristics, completion rate, and transparency of study design and results for mandatory pediatric postmarketing studies required under the Pediatric Research Equity Act. Design and Setting: A retrospective cohort study was conducted of pediatric postmarketing studies required for new drugs and new indications approved by the FDA between January 1, 2007, and December 31, 2014, with follow-up through December 1, 2017. Information on the status, design, and results of pediatric studies was obtained from publicly available FDA databases and ClinicalTrials.gov, direct communication with the FDA, and searches of MEDLINE, EMBASE, and Web of Science for peer-reviewed publications. Main Outcomes and Measures: Characteristics and transparency of pediatric studies, results reporting (in ClinicalTrials.gov, peer-reviewed literature, or FDA documents), and availability of pediatric information in drug labels. Rates and times to study completion were evaluated using Cox proportional hazards regression models. Results: Between 2007 and 2014, the FDA approved 114 new drugs and new indications for already approved drugs that were subject to Pediatric Research Equity Act requirements. These drugs were associated with 222 required pediatric postmarketing clinical studies. Overall, 75 pediatric studies (33.8%) were completed as of December 1, 2017. The rates of completion were significantly lower for efficacy studies (38 of 132 [28.8%]) compared with pharmacokinetic studies (19 of 34 [55.9%]; adjusted hazard ratio, 0.31; 95% CI, 0.12-0.82). Information on randomization, blinding, comparator, end point, and study size could not be identified for 74 studies (33.3%), and no reason for discontinuation was provided for 29 of the 42 discontinued studies (69.0%). Among the completed studies, the results were reported for 57 (76.0%). At the time of approval, 18 of 114 drug approvals (15.8%) had any pediatric efficacy, safety, or dosing information in their labels. After a median duration of follow-up of 6.8 years (interquartile range, 4.7-9.1 years), 47 of 114 of drug labels (41.2%) had any pediatric information. Conclusions and Relevance: Only 33.8% of mandatory pediatric postmarketing studies have been completed after a median follow-up of 6.8 years, and most drug labels do not include information important for pediatric use. To improve evidence-based prescribing of medicines to children, more timely completion of pediatric drug studies is needed.

The Role of European Healthcare Databases for Post-Marketing Drug Effectiveness, Safety and Value Evaluation: Where Does Italy Stand?

Enormous progress has been made globally in the use of evidence derived from patients' clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.

Evaluation of Postmarketing Reports from Industry-Sponsored Programs in Drug Safety Surveillance.

INTRODUCTION AND OBJECTIVE: Adverse event reports from industry-sponsored programs, such as patient support programs, have contributed to a rise in the number of individual case safety reports in the US Food and Drug Administration Adverse Event Reporting System database. This study aimed to characterize individual case safety reports from industry-sponsored program and non-industry-sponsored program sources and compare their usefulness in safety signal detection. METHODS: Individual case safety reports of six drug and biological products were identified in the Food and Drug Administration Adverse Event Reporting System database between the date of Food and Drug Administration product approval and the first quarter of 2017. A random subset of industry-sponsored program and non-industry-sponsored program individual case safety reports were then compared to identify differences in reporters, outcomes, data completeness, and usefulness. The 'usefulness' of individual case safety reports was assessed by manually reviewing the availability of key information in the narrative (e.g., temporality, comorbidities). RESULTS: Compared with non-industry-sponsored program reports, more industry-sponsored program reports were associated with a serious outcome (51.4% vs. 58.8%, p = 0.02) and were reported by consumers (35.5% vs. 50.4%, p < 0.01). Industry-sponsored program reports tended to contain more data elements than non-industry-sponsored program reports (i.e., age, sex, indication for use), but completeness was variable across products. No significant difference in usefulness was identified between non-industry-sponsored program and industry-sponsored program individual case safety reports (30.6% vs. 28.5%, p = 0.42). Useful reports that contained at least one serious, unlabeled adverse event represented only 4% and 6.2% of the non-industry-sponsored program and industry-sponsored program report cohorts, respectively. CONCLUSIONS: Our study suggests that reports obtained from industry-sponsored programs in the Food and Drug Administration Adverse Event Reporting System database contain more data elements but are similar to non-industry-sponsored program reports with regard to 'usefulness' in signal detection.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.

Registry Assessment of Peripheral Interventional Devices (RAPID): Registry assessment of peripheral interventional devices core data elements.

OBJECTIVE: The current state of evaluating patients with peripheral artery disease and more specifically of evaluating medical devices used for peripheral vascular intervention (PVI) remains challenging because of the heterogeneity of the disease process, the multiple physician specialties that perform PVI, the multitude of devices available to treat peripheral artery disease, and the lack of consensus about the best treatment approaches. Because PVI core data elements are not standardized across clinical care, clinical trials, and registries, aggregation of data across different data sources and physician specialties is currently not feasible. METHODS: Under the auspices of the U.S. Food and Drug Administration's Medical Device Epidemiology Network initiative-and its PASSION (Predictable and Sustainable Implementation of the National Registries) program, in conjunction with other efforts to align clinical data standards-the Registry Assessment of Peripheral Interventional Devices (RAPID) workgroup was convened. RAPID is a collaborative, multidisciplinary effort to develop a consensus lexicon and to promote interoperability across clinical care, clinical trials, and national and international registries of PVI. RESULTS: The current manuscript presents the initial work from RAPID to standardize clinical data elements and definitions, to establish a framework within electronic health records and health information technology procedural reporting systems, and to implement an informatics-based approach to promote the conduct of pragmatic clinical trials and registry efforts in PVI. CONCLUSIONS: Ultimately, we hope this work will facilitate and improve device evaluation and surveillance for patients, clinicians, health outcomes researchers, industry, policymakers, and regulators.

A systematic assessment of key design and performance characteristics of drug exposure registries requested by the U.S. Food and Drug Administration.

PURPOSE: The purpose of the study is to evaluate contributions to postmarket safety assessments and identify potential factors for enhancing implementation and utilization of registries in regulatory decision-making. METHODS: Registry documents (e.g., protocols, reports) submitted to the FDA were identified up to January 2016 through an extensive, systematic review of internal records and resources. We characterized nonpregnancy drug exposure registries based on prespecified design elements, performance, and regulatory impact. RESULTS: A total of 65 registries were identified: 56 registries were open and 9 closed. Among open registries, 20% were pending, 14% delayed, and 16% ongoing less than ≤3 years. Most registries (82%) examined safety issues that originally arose from clinical trials; most frequent safety issues investigated included infections, gastrointestinal dysfunction, and liver toxicity. Although 74% of registries ascertained baseline health conditions and monitored concomitant medication use, fewer (45%) considered drug exposure duration or dosage. Thirty-seven percent of non pending registries had enrollment below sample size expectation. Seventeen registries published findings in journals/conference proceedings, 13 from open registries. Three closed registries generated results that contributed to product label changes. High-performance registries scored higher in design metrics related to sample size considerations (76% versus 62%) and adequate analysis plan (53% versus 35%), and interim report submission (76% versus 65%). There was a significant difference in proportion of registries with clear primary objectives between high versus not high performing registries (100% versus 78%). CONCLUSIONS: This study suggests clear objectives, patient accrual/retention efforts, adequate analysis plans, and interim reports contribute to the performance of drug exposure registries.

[Nationwide Survey on Informed Consent and Ethical Review at Hospitals Conducting Post-marketing Studies Sponsored by Pharmaceutical Companies].

Under the Japanese drug regulatory system, post-marketing studies (PMS) must be in compliance with Good Post-marketing Study Practice (GPSP). The GPSP Ordinance lacks standards for the ethical conduct of PMSs; although only post-marketing clinical trials are subject to Good Clinical Practice. We conducted a web-based questionnaire survey on the ethical conduct of PMSs in collaboration with the Japanese Society of Hospital Pharmacists and pharmacists belonging to the Society. 1819 hospitals around Japan answered the questionnaire, of which 503 hospitals had conducted company-sponsored PMSs in 2015. 40.2% of the hospitals had obtained informed consent from participating patients in at least one PMS conducted in 2015, the majority of which was in written form. The first and second most frequent reasons for seeking informed consent in PMSs were to meet protocol requirements, followed by the requirement to meet institutional standard operational procedures and the request of the ethical review board of the hospital. Ethical review of PMSs was conducted in 251 hospitals. Despite a lack of standards for informed consent and ethical review in PMSs, a considerable number of study sites employed informed consent and ethical review for PMSs. While company policies and protocols are likely to be major determinants of the ethical conduct of PMSs, the governmental regulatory agency should also play a significant role in implementing a standardized ethical code for the conduct of PMSs.

[National Antimicrobial Resistance Surveillance System (NAMRSS) external quality assessment studies: 2011-2016]. / Ulusal Antimikrobiyal Direnç Sürveyans Sistemi (UAMDSS) Dis Kalite Degerlendirme Çalismalari: 2011-2016.

Establishment of sustainable and evidence-based surveillance systems are recommended for prevention of microbial resistance by the World Health Organization (WHO). As a necessity of these surveillance systems, participants are recommended to implement an external quality assessment (EQA) program. In this scope, National Antimicrobial Resistance Surveillance System (NARSS) has been established within the Public Health Institute of Turkey (PHIT) in our country since 2011. In the scope of this surveillance, NARSS EQA program has been implemented in a cycle per year and four isolates were sent to participants per cycle every year since 2011. In this study, it was aimed to evaluate the six years results of the EQA programs being implemented on NARSS participants between 2011 and 2016. The surveillance system consisted of 118 laboratories. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium/faecalis and Acinetobacter baumannii bacteria included in scope of the surveillance were sent to participants. Identification of bacteria to the species level, verification of the antibiotic susceptibility test results and existence of specified resistance of the isolates performed with valid test methods required from the participants. Identified isolates were cultured with routine microbiological methods and sent to participants in ambient temperature in triple carrying pouches inside suitable carrying media via PTT Cargo. The results were entered by means of passwords prepared by PHIT and sent to the web based system. The analysis of results were made with SPSS program. A total of twenty-three isolates were sent to participants between 2011 and 2016. It was determined that participants commonly preferred automated systems for bacterial identification and antibiotic sensitivity test results. The use of MALDI TOF MS system was determined to be raised up to 15.65% in 2016. It has been determined that usually little mistakes were done in bacterial identification but the error rate was high especially in antimicrobial susceptibility test results with close clinical threshold values. Although not required for antibiotic susceptibility test results, it was determined that phenotypic tests have been used more widely in determining the specific resistance mechanisms that are important for epidemiological data. It was determined that 80% of participants have used EUCAST standards in 2016. As a result of this research, we have observed that EQA studies of NARSS EQA are a good performance tool for sustainable and evidence based surveillance studies, that the national antimicrobial resistance data quality is sufficiently good and that the data can be shared on international platforms. In addition, the regular maintenance of national surveillance studies shown that laboratories have positive reflections on self improvement in achieving up to date and accurate results.

Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.

Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-Tpeak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block.

Integration of new technology into clinical practice after FDA approval.

Development of new medical technology is a crucial part of the advancement of medicine and our ability to better treat patients and their diseases. This process of development is long and arduous and requires a significant investment of human, financial and material capital. However, technology development can be rewarded richly by its impact on patient outcomes and successful sale of the product. One of the major regulatory hurdles to technology development is the Food and Drug Administration (FDA) approval process, which is necessary before a technology can be marketed and sold in the USA. Many businesses, medical providers and consumers believe that the FDA approval process is the only hurdle prior to use of the technology in day-to-day care. In order for the technology to be adopted into clinical use, reimbursement for both the device as well as the associated work performed by physicians and medical staff must be in place. Work and coverage decisions require Current Procedural Terminology (CPT) code development and Relative Value Scale Update Committee (RUC) valuation determination. Understanding these processes is crucial to the timely availability of new technology to patients and providers. Continued and better partnerships between physicians, industry, regulatory bodies and payers will facilitate bringing technology to market sooner and ensure appropriate utilization.

E2C(R2) Periodic Benefit-Risk Evaluation Report and E2C(R2) Periodic Benefit-Risk Evaluation Report--Questions and Answers; International Council for Harmonisation; Guidances for Industry; Availability. Notice.

The Food and Drug Administration (FDA or Agency) is announcing the availability of guidances for industry entitled ``E2C(R2) Periodic Benefit-Risk Evaluation'' (E2C(R2) guidance) and ``E2C(R2) Periodic Benefit-Risk Evaluation Report--Questions and Answers'' (E2C(R2) Q&A guidance). These guidances were prepared under the auspices of the International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation. The E2C(R2) draft guidance, issued April 11, 2012, updated and combined two ICH guidances, ``E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (E2C guidance) and ``Addendum to E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (addendum to the E2C guidance). The E2C(R2) guidance is intended to describe the format, content, and timing of a Periodic Benefit-Risk Evaluation Report (PBRER) for an approved drug or biologic, and it finalizes the draft guidance. The E2C(R2) Q&A guidance is a supplementary guidance that is intended to clarify key issues in the E2C(R2) guidance.

New technology in electrophysiology: FDA process and perspective.

The Food and Drug Administration (FDA) is a large regulatory agency that monitors everything from food, tobacco, and veterinary medicine to pharmaceutical drugs and medical devices. The Mission statement of the CDRH, one of the Centers of the FDA, in its most succinct form is to protect and promote public health. This is accomplished through timely and continued access to safe, effective, and high quality medical devices. This paper aims to review the overarching principles of the Agency's review process for cardiac devices as well as highlight some of the newer programs that FDA has engaged in to facilitate innovation, device development, research, and timely market approval.