FDA Actions Against Health Economic Promotions, 2002–2011

ObjectiveTo investigate Food and Drug Administration (FDA) regulatory actions against drug companies' health economic promotions from 2002 through 2011 to understand how frequently and in what circumstances the agency has considered such promotions false or misleading.MethodsWe reviewed all warning letters and notices of violation (“untitled letters”) issued by the FDA's Division of Drug Marketing, Advertising and Communications (DDMAC) to pharmaceutical companies from January 2002 through December 2011. We analyzed letters containing a violation related to “health economic promotion,” defined according to one of several categories (e.g., implied claims of cost savings due to work productivity or economic claims containing unsupported statements about effectiveness or safety). We also collected information on factors such as the indication and type of media involved and whether the letter referenced Section 114 of the Food and Drug Administration Modernization Act.ResultsOf 291 DDMAC letters sent to pharmaceutical companies during the study period, 35 (12%) cited a health economic violation. The most common type of violation cited was an implied claim of cost savings due to work productivity or functioning (found in 20 letters) and economic claims containing unsubstantiated comparative claims of effectiveness, safety, or interchangeability (7 letters). The violations covered various indications, mostly commonly psychiatric disorders (6 letters) and pain (6 letters). No DDMAC letter pertained to Food and Drug Administration Modernization Act Section 114.ConclusionThe FDA has cited inappropriate health economic promotions in roughly 12% of the letters issued by the DDMAC. The letters highlight drug companies' interest in promoting the value of their products and the FDA's concerns in certain cases about the lack of supporting evidence.     

Approval of Cancer Drugs With Uncertain Therapeutic Value: A Comparison of Regulatory Decisions in Europe and the United States

Policy Points

• Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed.
• In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period.
• Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA''s Accelerated Approval and the EMA''s Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards.

ContextRegulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit‐risk profiles of new cancer drugs by comparing decisions for the world''s two largest regulatory bodies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—over a 5‐year period.MethodsWe systematically identified a set of cancer drug‐indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA''s use of Accelerated Approval (AA) or the EMA''s use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies.FindingsWe identified 21 cancer drug‐indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single‐arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty‐one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow‐up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed.ConclusionsUS and European regulators often deemed early and less complete evidence on benefit‐risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence.     

Assessing risk by analogy: a case study of us medical device risk management policy

Medical devices occupy an increasingly important place in global medical care, and yet the risk management systems that govern them are largely overlooked in academic literatures. In the US, home to the largest medical devices market, Food and Drug Administration (FDA) regulation allows most medical devices to enter the market based on analogy, or substantial equivalence, with previously marketed devices. Thus, risk assessment is administered without premarket clinical trials for safety and efficacy. This system represents a permissive regulatory regime based in neoliberal tenets, where risk, in the form of adverse events, is inherently tolerated within governance structures, evidencing risk colonisation. This paper employs a case study approach, examining market clearances of vaginal mesh surgical devices, which have been the subject of US multi-district litigation. We identified 266 devices cleared before 31 December 2017 and analysed the complicated web of device ‘ancestry’ whereby devices as disparate as cardiac patches and hernia mesh allowed clearance of surgical devices for urogynecology. Perhaps of greatest concern, 10 recalled or withdrawn devices influenced new device clearances for up to 17 years after their market-removal. While the FDA must balance its dual mandate to safeguard patients and promote innovation, we find that medical device regulation structurally favours innovation over safety. ‘Light touch’ risk assessment is not counterbalanced with postmarket mechanisms to safeguard against residual and developmental risks that are associated with medical devices, particularly permanent implants. The proportionality principle associated with a precautionary approach should inform medical device risk management.     

Drug safety and the safety of patients: The challenge to medicine and health from permissive expert risk assessments of triazolam (Halcion)

When assessing the risks and benefits of medical drugs, the approach may be precautionary or permissive. If these different approaches actually influence the analysis and interpretation of technical medical data, then they are not merely a matter for discussion among philosophers, but should be debated by those concerned about medical risks and public health. To examine the interaction between expert risk-benefit assessments of drugs, on the one hand, and permissive/precautionary approaches, on the other, the triazolam (Halcion) case is scrutinised. Specifically, the assessments of triazolam by the FDA's 1992 Psychopharmacological Drugs Advisory Committee (PDAC) and the National Academy of Sciences' 1997 Institute of Medicine (IoM) are analysed. Both the PDAC and the IoM exhibited permissiveness towards triazolam. The PDAC gave priority to anecdotal evidence about triazolam in use, when assessing efficacy, but to controlled clinical trial data, when assessing safety. In each instance the types of data which favoured triazolam were given priority. While a lack of compelling evidence of efficacy from clinical trials was regarded as insufficient to negate the drug's benefits, compelling evidence from clinical trials was required to confirm signals of lack of safety. The IoM and the PDAC avoided the problem of patient safety in 'the real world' by limiting their conclusions to the safety of the drug under the conditions of use recommended on the label. Whether or not a society adopts a precautionary or permissive approach to the risk assessments of new technologies is not merely a matter for technical experts and science, it is also a social and political matter. A precautionary approach to drug safety could yield different expert assessments. It might require compelling evidence of drug efficacy where good alternative therapies exist; integrate how a drug can be used safely into evaluation of controlled clinical trial data; and put more emphasis on the correlation between disaggregated clinical trial data and spontaneous reports of adverse drug reactions.     

Parents' decision following the Food and Drug Administration recommendation: the case of over‐the‐counter cough and cold medication

Background In 2007, the Food and Drug Administration (FDA) recommended against parents administering over‐the‐counter cough and cold medications (OTC‐CCM) to children under 2 years of age because serious and potentially life‐threatening side effects can occur. This study examined the impact of FDA's recommendations against giving children under 2 years old OTC‐CCM. Methods We asked parents (n= 377) whether they knew of and trusted the FDA recommendations, as well as whether they intended to follow them. We also examined parents' knowledge, perceptions and behaviours with respect to OTC‐CCM. Results About 33% of our sample had never heard of the FDA recommendations. Of those who were aware, 32.9% intended to continue administering OTC‐CCM, and another 36.7% were not sure what to do. Our results indicate that parents who trust the FDA recommendations are significantly more likely to stop giving OTC‐CCM to their children. However, almost half did not trust the FDA recommendations or were not sure whether to trust them. Our results indicate that parents who trust the FDA recommendation are significantly more likely to discontinue using OTC‐CCM. Our data also reveal that many parents give more than one drug simultaneously (32.9%), cannot identify the active ingredient(s) (28.9%) or fail to store the medications in a safe place (86.1%). Conclusion Parents' confidence in the FDA recommendations predicted whether they would continue or stop administering OTC‐CCM to their children. Our findings illustrate the urgent need for widespread public education about OTC‐CCM products to ensure children's safety.     

Comparisons of Food and Drug Administration and European Medicines Agency Risk Management Implementation for Recent Pharmaceutical Approvals: Report of the International Society for Pharmacoeconomics and Outcomes Research Risk Benefit Management Working Group

Objective1) To compare the Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency’s (EMA’s) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products.MethodsFDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs.ResultsWe identified 95 drugs on FDA’s REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%).ConclusionsBoth REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.     

Expanded safety and acceptability of the candidate vaginal microbicide Carraguard® in South Africa

BackgroundCarraguard's safety and acceptability was assessed among women in Gugulethu and Ga-Rankuwa, South Africa.Study DesignA randomized, placebo-controlled, triple-blind trial was conducted in HIV-negative, nonpregnant women who inserted Carraguard or placebo at least three times a week, including before vaginal sex, for 6 to 12 months. Monthly visits included pelvic examination, sexually transmitted infection (STI) testing/treatment and HIV counseling/testing. Acceptability was assessed quarterly.ResultsOf 400 women (205 Carraguard, 195 placebo) enrolled, 328 (77%) completed at least 6 months. Incidence of genital epithelial disruption was similar between the Carraguard (13.6 per 100 woman-years) and placebo (21.3 per 100 woman-years) groups (relative risk, 0.64; 95% confidence interval, 0.37–1.10); there were no significant differences in rates of HIV/STI, though the study was not powered to determine effectiveness. Only 2% of adverse events were judged possibly related to (either) gel. More than 94% of women reported at least once liking the gel very much.ConclusionsCarraguard was not associated with more vaginal, cervical or external genital irritation than placebo, and it was acceptable when used approximately 3.5 times per week, including during sex.     

Adverse event monitoring and multivitamin-multimineral dietary supplements

A study commissioned by the Food and Drug Administration (FDA) estimated that the FDA is notified of < 1% of all adverse events associated with dietary supplements. Among the factors that may contribute to underreporting are that many consumers presume supplements to be safe, use these products without the supervision of a health care professional, and may be unaware that the FDA regulates them. In 2001 an Office of the Inspector General report identified many of the difficulties in evaluating adverse events in a voluntary system and the barriers to effective analysis of these reports to generate possible signals of concern. These include factors such as limited medical information, limited product information, limited manufacturer information, limited information on dietary supplement consumers, and limited ability to analyze trends. In addition, for dietary supplements, vital premarket information (which is available for drug products) is often missing so that possible public health concerns generated by the adverse event reporting system, such as limited clinical information, product identification, and information on consumer use, cannot be adequately assessed. Thus, the FDA is inherently limited in its ability to investigate signals of public health problems generated by the system. However, the FDA can use adverse event reports to identify areas of concern warranting further investigation. The FDA then initiates collaboration with federal partners to identify knowledge gaps in the safety of individual dietary ingredients and products and works with these partners to fill these information gaps to support appropriate regulatory action.     

Use of Real-World Evidence to Support FDA Approval of Oncology Drugs

ObjectivesReal-world evidence (RWE) has gained increased attention in recent years as a complement to traditional clinical trials. The use of RWE to establish the efficacy of oncology drugs for Food and Drug Administration (FDA) approval has not been described. In this paper, we review 5 recent examples where RWE was submitted in support of the FDA approvals of original or supplementary indications for oncology drugs.MethodsTo identify cases where RWE was used, we reviewed drug approval packages available at Drugs@FDA for oncology drugs approved between 2017 and 2019. Five cases were selected to present a broad overview of different types of RWE, different circumstances under which RWE has been used for regulatory approvals, and how FDA evaluated the data in each case. The type of RWE submitted, the indication, limitations identified by FDA reviewers, and the outcome of the submission are discussed.ResultsRWE, particularly historical controls for rare or orphan indications, has been used to support both original and supplementary oncology drug approvals. Types of RWE included data from electronic health records, claims, post-marketing safety reports, retrospective medical record reviews, and expanded access studies. Small sample sizes, data quality, and methodological issues were among concerns cited by FDA reviewers.ConclusionBy bridging the gap between the constraints of the trial setting and the realities of clinical practice, RWE can add value to a regulatory submission. These early examples provide insight into how regulators evaluated RWE submitted as evidence of efficacy for oncology drugs.     

Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS)

The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) conduct post-licensure vaccine safety monitoring using the Vaccine Adverse Event Reporting System (VAERS), a spontaneous (or passive) reporting system. This means that after a vaccine is approved, CDC and FDA continue to monitor safety while it is distributed in the marketplace for use by collecting and analyzing spontaneous reports of adverse events that occur in persons following vaccination. Various methods and statistical techniques are used to analyze VAERS data, which CDC and FDA use to guide further safety evaluations and inform decisions around vaccine recommendations and regulatory action. VAERS data must be interpreted with caution due to the inherent limitations of passive surveillance. VAERS is primarily a safety signal detection and hypothesis generating system. Generally, VAERS data cannot be used to determine if a vaccine caused an adverse event. VAERS data interpreted alone or out of context can lead to erroneous conclusions about cause and effect as well as the risk of adverse events occurring following vaccination. CDC makes VAERS data available to the public and readily accessible online.We describe fundamental vaccine safety concepts, provide an overview of VAERS for healthcare professionals who provide vaccinations and might want to report or better understand a vaccine adverse event, and explain how CDC and FDA analyze VAERS data. We also describe strengths and limitations, and address common misconceptions about VAERS. Information in this review will be helpful for healthcare professionals counseling patients, parents, and others on vaccine safety and benefit-risk balance of vaccination.     

美国FDA医疗器械说明书和标签指导原则介绍

目的:为我国完善和发展医疗器械标签和说明书的管理提供借鉴。方法:采用内容翻译和分析方法,主要资料是美国食品药品管理局网站发布的《医疗器械标签和说明书指导原则》。结果:分章介绍了美国医疗器械标签和说明书的指导原则,包括定义、安全有效性考虑、预期用途、禁忌症、警告说明、注意事项、特殊适用群体、不良事件、处方器械等12项内容。结论:我国应从FDA管理经验中得到启示,分类管理处方器械和非处方器械,建立相关指导原则,以确保医疗器械安全、有效地使用。     

Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990–2013

Background23-Valent pneumococcal polysaccharide vaccine, trade name Pneumovax^®23 (PPSV23), has been used for decades in the Unites States and has an extensive clinical record. However, limited post-licensure safety assessment has been conducted.ObjectiveTo analyze reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following PPSV23 from 1990 to 2013 in order to characterize its safety profile.MethodsWe searched the VAERS database for US reports following PPSV23 for persons vaccinated from 1990 to 2013. We assessed safety through: automated analysis of VAERS data, crude adverse event (AE) reporting rates based on PPSV23 doses distributed in the US market, clinical review of death reports and reports involving vaccine administered to pregnant women, and empirical Bayesian data mining to assess for disproportional reporting.ResultsDuring the study period, VAERS received 25,168 PPSV23 reports; 92% were non-serious, 67% were in females and 86% were in adults aged ≥19 years. When PPSV23 was administered alone, fever (43%), injection site erythema (28%) and injection site pain (25%) were the most commonly reported non-serious AEs in children. Injection site erythema (32%), injection site pain (27%) and injection site swelling (23%) were the most commonly reported non-serious AEs in adults. Of serious reports (2129, 8% of total), fever was most commonly reported in both children (69%) and adults (39%). There were 66 reports of death, four in children and 62 in adults. Clinical review of death reports did not reveal any concerning patterns that would suggest a causal association with PPSV23. No disproportional reporting of unexpected AEs was observed in empirical Bayesian data mining.ConclusionsWe did not identify any new or unexpected safety concerns for PPSV23. The VAERS data are consistent with safety data from pre-licensure clinical trials and other post-licensure studies.     

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010–2015

BackgroundLimited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups.MethodsVAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo.ResultsDuring the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11–18 years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., “incorrect drug dosage form administered”, “wrong technique in drug usage process”). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy.ConclusionsIn our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine.     

Adverse events following adenovirus type 4 and type 7 vaccine,live, oral in the Vaccine Adverse Event Reporting System (VAERS), United States,October 2011–July 2018

BackgroundIn March 2011, the U.S. Food and Drug Administration licensed adenovirus type 4 and type 7 vaccine, live, oral (Barr Labs, Inc.) (adenovirus vaccine) for use in military personnel 17 through 50 years of age. The vaccine was first universally administered to U.S. military recruits in October 2011. We investigated adverse event (AE) reports following the adenovirus vaccine submitted to the Vaccine Adverse Event Reporting System (VAERS).MethodsWe searched the VAERS database for U.S. reports among persons who received adenovirus vaccine during October 2011 through July 2018 including participants in a military observational study. We reviewed all serious reports and accompanying medical records. We compared the proportion of serious reports in a proxy military recruit population and reviewed all reports of suspected allergic reactions following adenovirus vaccination.ResultsDuring the analytic period, VAERS received 100 reports following adenovirus vaccination; 39 (39%) were classified as serious and of these, 17 (44%) were from the observational study. One death was reported. Males accounted for 72% of reports. Median age of vaccinees was 19 years (range 17–32). The most frequently reported serious AEs were Guillain Barré syndrome (GBS) (n = 12) and anaphylaxis (n = 8); of these, two GBS and all the anaphylaxis reports were reported in the observational study. Reports documented concurrent receipt of multiple other vaccines (95%) and penicillin G (IM Pen G) or other antibiotics (50%).ConclusionsThe reporting rate for serious AEs was higher than with other vaccines administered in the comparison military recruit population (39% vs 18%); however, we identified no unexpected or concerning pattern of adenovirus vaccine AEs. Co-administration of vaccines and IM Pen G was commonly reported in this military population. These exposures may have contributed to the GBS and anaphylaxis outcomes observed with the adenovirus vaccine. Future adenovirus vaccine safety studies in a population without these co-administrations would be helpful in clarifying the vaccine’s safety profile.     

Adverse events following vaccination with an inactivated,Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009–2012

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [Ixiaro]) for use in adults. The vaccine was licensed based on clinical trial safety data in 3558 JE-VC recipients. It is essential to monitor post-licensure surveillance data to evaluate the safety of JE-VC because rare adverse events may not be detected until the vaccine is administered to a larger population.MethodsWe reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for adults (≥17 years) who received JE-VC from May 2009 through April 2012. Adverse event reporting rates were calculated using 275,848 JE-VC doses distributed.ResultsOver the 3 year period, 42 adverse events following vaccination with JE-VC were reported to VAERS for an overall reporting rate of 15.2 adverse events per 100,000 doses distributed. Of the 42 total reports, 5 (12%) were classified as serious for a reporting rate of 1.8 per 100,000 doses distributed; there were no deaths. Hypersensitivity reactions (N = 12) were the most commonly reported type of adverse event, with a rate of 4.4 per 100,000 doses distributed; no cases of anaphylaxis were reported. Three adverse events of the central nervous system were reported (one case of encephalitis and two seizures) for a rate of 1.1 per 100,000; all occurred after receipt of JE-VC with other vaccines.ConclusionsThese post-marketing surveillance data suggest a good safety profile for JE-VC consistent with findings from pre-licensure clinical trials. Post-licensure safety data should continue to be monitored for any evidence of rare serious or neurologic adverse events.     

Endpoints for safety in health technology assessments–The experiences of the Danish Medicines Council

ObjectivesThere are no international guidelines on how the requirements for added clinical value (endpoints) should be prepared in terms of drug safety by entities performing health technology assessments (HTAs). The study aimed to review the Danish Medicines Council's drug safety endpointsMethodsSafety endpoints prepared by the Danish Medicines Council's expert committees were reviewed from their assessment reports for 50 treatments, of which 25 were for the treatment of cancer and 25 were for the treatment of other types of diseases. Similarities and differences were identifiedResultsThe 139 endpoints for safety were grouped into 14 categories. The use of endpoints varied and all endpoints were based on an expert assessment. Serious adverse reactions/events were used as an endpoint in most of the cases: 43.2% (N=60)/15.8% (N=22), following treatment discontinuation based on four different causes 16.4% (N=32). A numerical grading scale for adverse events were predominately used for endpoints for cancer treatment (19.8%, N=20 vs. 2.1%, N=2)ConclusionsThe variation in the use of endpoints reflects the complexity of safety assessments and the need for more standardization to promote stringency and transparency. The authors propose five recommendations for actions, which may promote more generalizability and transparency. International HTA entities and researchers are also encouraged to investigate the possibilities of establishing a universal grading system for adverse events and to develop international guidelines for safety assessment in HTAs.Public interest abstractNew medicines often have to be evaluated against the treatment already available in order to compare effectiveness, safety and price. If one treatment is superior, it will often be referred to as having added clinical value. This evaluation is known as a health technology assessment (HTA). All medicines can cause side effects and the assessment of safety in HTAS is therefore essential. No international guidelines for drug safety assessment in HTAs however exist. The requirements for safety prepared by the Danish Medicines Council's expert committees were therefore reviewed from their assessment reports for 50 treatments in order to present their approach to drug safety assessment. A total of 139 safety requirements, also referred to as endpoints, were identified. The use of endpoints varied which reflects the complexity of safety assessments and the need for more standardization to promote stringency. The authors propose five recommendations for actions, which may promote more generalizability and transparency in Denmark and internationally.     

Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009–2015

BackgroundThe Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9–26 years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination.MethodsWe searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions.FindingsVAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death.InterpretationNo new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data.     

The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement

Objective

Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro^TM, a dietary supplement used for weight loss and/or muscle building.

Methods

Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA''s Forensic Chemistry Center analyzed samples of OxyELITE Pro.

Results

From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required “new dietary ingredient” notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products.

Conclusions

Vigilant surveillance is required for adverse events linked to the use of dietary supplements.In the United States, surveillance for infectious and chronic diseases is well established,^1–3 as is surveillance for adverse events associated with the use of drugs, biologics, and medical devices regulated by the U.S. Food and Drug Administration (FDA).^4–6 A key instrument used for reporting adverse events linked to FDA-regulated products is MedWatch, a program launched in 1993.^7,8Surveillance of adverse events linked to dietary supplements is challenging because of the plethora of products used, the diversity of ingredients present, the heterogeneity of adverse events that may ensue, the difficulty of recognizing a link between adverse events and the use of a specific dietary supplement, and a low incidence of adverse effects that may occur following the use of certain supplements. Adverse events linked to dietary supplements may be reported to disparate authorities or surveillance systems, including poison control centers, local or state health departments, syndrome-specific surveillance entities (e.g., the Drug-Induced Liver Injury Network⁹), or to the Centers for Disease Control and Prevention (CDC), the U.S. Department of Defense, or FDA. FDA encourages health-care professionals, patients, and consumers to report adverse events or problems linked to dietary supplements in one of several ways. MedWatch forms may be downloaded⁸ and faxed (1-800-332-0178) or mailed to FDA using a postage-paid business reply form provided online.⁸ Alternatively, MedWatch reports may be submitted online at either of two websites.^7,10On September 16, 2013, health-care providers at the sole transplant medical center in Hawaii notified FDA of seven previously healthy adults who developed acute or fulminant non-viral hepatitis after ingesting OxyELITE Pro” (USPlabs, LLC, Dallas, Texas), a dietary supplement used for weight loss and/or muscle building. Henceforth, FDA began communicating regularly with the Hawaii State Department of Health (HI DOH) and CDC, which HI DOH had invited to assist with an investigation of the illnesses.¹¹ During the federal government shutdown from October 1–16, 2013, FDA initiated a laboratory analysis of OxyELITE Pro products obtained from patients and retail outlets in Hawaii, conducted a traceback of OxyELITE Pro products purchased by case patients in Hawaii, and reviewed 21 medical records submitted by the HI DOH. In this article, we describe regulatory actions taken by FDA to remove the dietary supplement from commerce and the key roles MedWatch played in identifying OxyELITE Pro-associated cases in the continental United States.     

内蒙古某三甲医院临床试验医疗器械使用安全现状分析

目的 了解临床试验医疗器械使用安全现状,分析其影响因素,提出建议,为提高临床试验医疗器械管理水平提供参考。方法 收集内蒙古某三甲医院2018年1月1日-2021年12月31日上报的31项医疗器械临床试验项目中与患者安全相关的186份研究报告,对相关数据进行描述性分析。结果 不良事件报告占28.5%,严重不良事件报告占47.8%,器械缺陷报告占0.6%,方案偏离报告占23.1%;患者主要年龄段为>50岁～70岁(57.0%);心内科项目数量占比(51.6%)和报告数量占比(50.5%)均最大;患者安全事件与试验器械有关的报告有52份(28.0%);有合并症和并发症的患者有119人(63.9%)。结论 临床试验医疗器械使用安全与器械本身、研究者能力、方案执行程度、患者自身等因素有关。应加强临床试验项目质量管理医疗器械规范化管理、使用安全管理以及患者自身管理。