Renewing the Call for Reforms to Medical Device Safety-The Case of Penumbra.

Importance: Strengthening premarket and postmarket surveillance of medical devices has long been an area of focus for health policy makers. The recent class I recall (the most serious of the US Food and Drug Administration [FDA] recalls) of reperfusion catheters manufactured by Penumbra, a US-based medical device company, illustrates issues of device safety and oversight that mandate attention. Objectives: To review the regulatory history and clinical evidence of the Penumbra JET 7 Reperfusion Catheter with Xtra Flex Technology (JET 7) and use the device recall as a case study of the challenges associated with clinical evaluation, transparency, and oversight of medical devices in the US. Evidence: Regulatory history and clinical evidence for the Penumbra medical devices were analyzed through a qualitative review of decision letters in the Access FDA database for medical devices and medical device reports in the Manufacturer and User Facility Device Experience database and a review of market data (eg, earnings calls, company communications) and clinical literature. Findings: The JET 7 device was subjected to a class I recall following more than 200 adverse event reports, 14 of which involved patient deaths. Regulatory analysis indicated that each of the Penumbra reperfusion catheters was cleared under the 510(k) pathway (which allows devices to be authorized with limited to no clinical evidence), with limited submission of either new clinical or animal data. Clinical evidence for Penumbra devices was generated from nonrandomized, single-arm trials with small sample sizes. The regulatory issues raised by JET 7 are reflective of broader challenges for medical device regulation. Opportunities for reform include strengthening premarket evidence requirements, requiring safety reporting with unique device identifiers, and mandating active methods of postmarket surveillance. Conclusions and Relevance: The case study of JET 7 highlights the long-standing gaps in medical device oversight and renews the impetus to build on the Institute of Medicine recommendations and reform FDA medical device regulation to protect public health.

Post-market surveillance of consumer products: Framework for adverse event management.

Analysis of spontaneous reports of adverse events is an important source of information that can be used to improve consumer products. Various agencies have adverse event reporting requirements and many companies collect such data directly from consumers. Nonetheless, a universal framework is absent that identifies and evaluates spontaneously reported adverse events, and, most important, assesses the potential association between exposure and adverse events. We are presenting a three-part framework: Phase I - Intake and Documentation of Original Incidents; Phase II - In Depth Review and Follow-up of Phase I Incidents (enhanced, tailored questionnaire); Phase III - Association Assessment. The basis for scoring the strength of association between exposure and adverse events requires assessment of standard factors of association including: temporality; biological, physiological, or pharmacological plausibility; results of de-challenge; results of re-challenge; and consideration of confounding factors. Scores tied to the answers to these questions are totaled for each incident to determine the strength of association between exposure and reported adverse event. We propose that consumer product companies come together to adopt such an association assessment framework to improve adverse event management, obtain maximum value from the data obtained, and use the knowledge derived to improve overall product safety for consumers.

The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P = 0.04), orphan products than nonorphan products (393 vs. 1,606, P < 0.001), and for products with fast-track designation (617 vs. 1,455, P < 0.001), priority review (630 vs. 1,735, P < 0.001), and accelerated approval (475 vs. 1,164, P < 0.001), than products without that designation. The median number of postmarket safety label updates and issues added to the label were higher with larger premarket exposure among nonorphan products, but not among orphan products. Products with accelerated approval using a surrogate end point had a higher median number of safety issues added to the label than those with full approval, but this did not vary with the size of the safety population; fast-track and priority review were not associated with the number of safety issues added to the label. A smaller safety population size was associated with a longer time to first safety outcome for nonorphan products but not orphan products. For orphan and nonorphan products combined, smaller premarket safety population size is not associated with the number or timing of postmarket safety outcomes, regardless of expedited program participation.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. METHODS: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. RESULTS: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. CONCLUSIONS: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

Analysis of completeness for spontaneous reporting of disease-modifying therapies in multiple sclerosis.

Introduction: Considering the need for effective postmarketing surveillance of disease-modifying therapies (DMTs) in multiple sclerosis (MS), we analyzed the potential of the spontaneous reports for safety signal detection, verifying the completeness of the reports in the FDA Adverse Event Reporting System (FAERS).Methods: All reports with DMTs for MS considered the primary suspect cause of ADRs and registered between January 2004 and June 2019 were selected. The vigiGrade completeness score was applied and reports with a score greater than 0.80 were considered well documented. Descriptive statistical analysis and comparisons of well-documented reports by DMTs were performed.Results: A total of 297,926 reports were analyzed. The lowest completeness rates were observed for type of report (13.5%), dose (62.7%), and time from treatment start to the ADR (79.0%). Overall, 80.8% of reports were classified as well documented and those related to natalizumab had the highest proportion (92.4%, p < 0.001), while the lowest was observed for reports sent in 2017 (53.1%, p < 0.001) and for teriflunomide (48.5%, p < 0.001).Conclusions: The high proportion of well-documented reports for DMTs indicates that they can be a valuable source for safety signal detection. A more careful analysis should be performed for data from the groups identified with low completeness to avoid the disclosure of spurious results.

Postmarket Safety Communication for Protection of Public Health: A Comparison of Regulatory Policy in Australia, Canada, the European Union, and the United States.

In the wake of the withdrawal of the nonsteroidal anti-inflammatory drug rofecoxib, regulators worldwide reconsidered their approach to postmarket safety. Many have since adopted a "life cycle" approach to regulation of medicines, facilitating faster approval of new medicines while planning for potential postmarket safety issues. A crucial aspect of postmarket safety is the effective and timely communication of emerging risk information using postmarket safety advisories, commonly issued as letters to healthcare professionals, drug safety bulletins, media alerts, and website announcements. Yet regulators differ in their use of postmarket safety advisories. We examined the capacity of regulators in the United States, Europe, Canada, and Australia to warn about postmarket safety issues through safety advisories by assessing their governance, legislative authority, risk communication capabilities, and transparency.

Antibiotics Approved for Marketing in Populations Specifically Excluded From Premarketing Trials, 1999-2018.

Approval by the US Food and Drug Administration (FDA) of a drug for a given indication is thought to reassure clinicians, other health care providers, and patients that substantial evidence of effectiveness exists for specific indicated populations (patients and diseases). This study examines whether FDA approval of certain antibiotics should be so reassuring for all patient populations identified in the FDA-approved labels. Specifically, this study compared patient populations covered by FDA-approved labels for 21 novel antibiotics approved between 1999 and 2018 to the patient exclusion and inclusion criteria of pivotal trials that supported those approvals. We found that every FDA-approved label for these antibiotics included at least one identifiable patient population that was explicitly excluded from enrolling in the supporting pivotal trials. Two antibiotics, bedaquiline and ceftazidime-avibactam, were approved for use in populations that were fully excluded from enrolling in registration trials.

Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

Information on rare adverse effects is often limited when a medication is initially approved for marketing. Medicines regulators use safety advisories to warn health professionals and consumers about emerging harms. This study aimed to identify characteristics and advice provided in cardiac safety advisories released by regulators in Australia, Canada, the United Kingdom, and the United States. This was a retrospective study of safety advisories about cardiac-related adverse events issued by these four international medicines regulators between 2010 and 2016. A descriptive overview was followed by a more detailed content analysis, focusing on recommended actions for health professionals, including monitoring advice. For the latter, we applied the systematic information for monitoring (SIM) scale to assess adequacy. Over this period, 164 safety advisories about cardiac harms were issued by the four regulators. There were 61 drugs with advisories of cardiac risk, only 9 (14.7%) of which had advisories from all regulators in countries where the drug was approved. The most common adverse events were cardiac arrhythmias (n = 97, 59.1%) and coronary artery disorders (n = 39, 23.8%). The most frequent advice to prescribers was to monitor patients (n = 74, 45.1%), although only 41.2% of these advisories provided detailed advice on how monitoring should occur. We found many differences in the decision to warn and the advice provided. Patient monitoring was most often recommended, but key information such as frequency or thresholds for action was often lacking. Healthcare professionals and consumers need consistent information about rare serious harms so that they can make informed decisions.

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.

Should the Same Safety Scrutiny of Antiobesity Medications be Applied to Other Chronic Usage Drugs?

Obesity treatment is highly stigmatized, mainly because of the stigma of obesity itself. The frequent withdrawal of medications, lorcaserin being the last example, contributes to this stigma, but it is also probably a reflection of it, as data suggest that the threshold for a withdrawal is lower than with other classes of drugs. Safety should always be an absolute priority for every new medication, especially when used on a chronic basis; however, the safety scrutiny given to antiobesity medications is not given for other medications, such as postmenopausal hormone therapy and central nervous system drugs for psychiatric use. The withdrawal of medications for obesity can also impact future research in the area, so we need transparency and equality. Transparency in knowing exactly what reason led to a drug being discontinued and equality in long-term safety should be a concern with any medication prescribed for chronic diseases.

Descriptive analysis of postmarket surveillance data for hip implants.

PURPOSE: Recent safety issues involving medical devices have highlighted the need for better postmarket surveillance (PMS) evaluation. This article aims to describe and to assess the quality of the PMS data for a medical device and, finally, to provide recommendations to improve the data gathering process. METHODS: A descriptive analysis of medical device reports (MDRs) on the use of MRA, a specific type of hip implant replacement submitted to the Food and Drug Administration Manufacturer and User Facility Device Experience database from 1 January 2008 to 31 December 2017. The number of reports was described as the number of MDRs per unique MDR number and stratified by different variables. The quality was assessed by the level of completeness of the collected PMS data. RESULTS: The total number of reports related to MRA was 2377, and the number of MDRs per year ranged between 84 in 2009 and 452 in 2017. Most of the reports were reported by manufacturer Depuy Johnson & Johnson and were reported by a physician. In 44.9% of the reports, the device problem was reported as "Unknown." When the device problem was known, in the majority of cases, it was related to an implant fracture. The quality of the collected data was assessed as low due to missing information. CONCLUSION: The underlying data should meet high quality standards to generate more evidence and to ensure a timely signal generation. This case study shows that the completeness and quality of the MDRs can be improved. The authors propose the development of tools to ensure a more dynamic complaint data collection to contribute to this enhancement.

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.

A Worldwide Overview of Regulatory Frameworks for Tissue-Based Products.

Over the past decades, a wide range of tissue-based products (TBPs) have emerged as new therapeutic alternatives to conventional approaches, giving an opportunity to treat pathologies that have not been cured yet. TBPs are constituted by living/nonliving and genetically/nongenetically modified cells or tissues, which might be combined with materials that support their structure, molecules that favor the cellular environment, and even medical devices to create functional substitutes. These medicinal products are used for the repair, replacement, restoration, or regeneration of a damaged tissue in the patient. The clinical translation of these innovative products has led to the establishment of new and comprehensive regulatory schemes by regulatory bodies. The knowledge and adaptation to these regulatory shifts is essential for the pharmaceutical industries and academia, as it promotes the development of TBPs and their approval and marketing. TBPs follow different regulatory approaches depending on the jurisdiction in which the product is intended to be marked. The European Union and United States of America have developed a clear and specific regulatory pathway for TBPs. However, in other jurisdictions, the oversight of these products remains still challenging. This review describes and updates the main legal considerations, which must be implemented throughout the marketing authorization application process of a TBP, defining the regulatory framework of the main health agencies and outlining the major differences between them. Impact statement Tissue-based products (TBPs) are complex to regulate since many jurisdictions do not have an adapted legislation for these. Thus, researches may not consider crucial regulatory aspects during the development of these products, leading to failure for their marketing approval by regulatory bodies. This review describes how a TBP is overseen under several key jurisdictions and offers an overview of the steps that sponsors should follow until the product launch onto the market. Thus, this study provides guidance for nonexperts in regulatory affairs, boosting the understanding of the regulations governing these products, fasting, and easing the development of the same.

Diagnostic capacity of commercial extracts vs prick-by-prick in the study of sensitization to peanut: which technique should we use?

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