Drug Administration Database Research Articles

Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries.

GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs. EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs. CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs. Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

Software-related recalls in computer-assisted hip and knee arthroplasty.

Computer-assisted arthroplasty supports the surgeons in planning, simulating, and performing the replacement procedure, using robotic or navigation technologies. However, the safety of the technology has not been widely ascertained. Food and Drug Administration (FDA) database was interrogated about software-related recalls in computer-assisted arthroplasty, aiming to assess: (1) the incidence, (2) the root causes, and (3) the actions taken due to recalls. The Medical Device Recalls database was investigated about software-related recalls in computer-assisted hip and knee arthroplasty surgery, between 2017 and 2022. The incidence of the software-related recalls, the root causes according to FDA and manufacturers, and the corrective actions taken by firms were determined. Eighteen recall numbers could be identified (1.6%), corresponding to 11 recall events. A total of 4634 units were involved. The FDA determined root causes were: software design (66.6%), design change (22.2%), manufacturing deployment (1, 5.6%), and design manufacturing process (5.6%). Among the manufacturers' reasons for recalls, a specific error was declared in 16 cases (88.9%). In seven cases (43.8%), a coding error about lower limb alignment assessment was identified. Seventeen software-related recalls (94.4%) were classified as class 2; only one case was class 3 (5.6%). Return of the device was the main action taken by firms (8, 44.4%), followed by software update (7, 38.9%). Software-related recalls in computer-assisted hip and knee arthroplasty were quite uncommon among all the recalls, deemed non-life threatening and usually due to software design errors. The main actions taken by manufacturers were the return of the device or the software update.

The Origin of Ferritin Reference Intervals: A Systematic Review

Background: Iron-deficiency is one of the most prevalent conditions worldwide and causes significant morbidity and mortality. Iron-deficiency most commonly affects individuals of lower socio-economic status (SES). Previous research has shown that those of lower SES are both less likely to be diagnosed and treated for iron deficiency. Ferritin is an iron-storage protein that is a sensitive diagnostic marker of iron-deficiency. However, the utility of ferritin is limited due to discrepancies in the thresholds used in clinical guidelines and clinical laboratories. There is growing concern that the lower limit of "normal" ferritin is inappropriately low, particularly for females, and is underestimating and promulgating the prevalence of iron-deficiency. As such, we conducted a systematic review to evaluate the data informing ferritin reference intervals (RIs) in adults. Methods: A systematic review was conducted as per PRISMA guidelines using MEDLINE, EMBASE and CENTRAL databases from inception to November, 2021 to identify studies that reported ferritin RIs in the adult population. Additional articles were hand-selected from screening the reference lists of included studies and the first ten pages of Google Scholar in July, 2022. A search of the grey literature was also conducted using Health Canada, European Medicines Agency, and the U.S. Food and Drug Administration databases to review the manufacturer product inserts for the five most commonly used assays globally. Two reviewers screened and performed data abstraction based on the protocol submitted to PROSPERO. The objectives were to summarize the research studies on the derivation of ferritin RIs and to conduct a quality assessment based on a modified version of the Clinical and Laboratory Standards (CLSI) guidelines for establishing RIs as well as quality indicators specific to iron-deficiency. We also aimed to describe reported ferritin lower limit of normal (LLN) in general and in relevant subgroups of patients using descriptive statistics (i.e., median, range). Results: 2307 studies were screened, and 62 full texts were included. The included studies consisted of "apparently healthy individuals", but only 5 (8%) studies assessed for bleeding history/conditions, 5 (8%) for menstrual history, 7 (11%) for menopause status, 22 (35%) for pregnancy status, 9 (14%) for diet history, and 16 (25%) for iron supplementation. 36 (58%) studies measured the hemoglobin, 19 (31%) measured the mean corpuscular volume, and 22 (35%) measured inflammatory markers. For the quality of the studies, only 28 (45%) referenced a RI guideline, 21 (34%) performed outlier detection, 46 (74%) described RI calculation method, and 18 (29%) reported confidence intervals. The top 5 commercial ferritin lab assays report ferritin RIs with a median LLN of 10.5 μg/L (range: 5-13) for females and 22 μg/L (18-30) for males. One lab assay provided a ferritin RI for pre-menopausal versus post-menopausal women. The studies informing the ferritin lab assays did not explicitly exclude patients at risk of iron-deficiency and none adhered to CLSI RI establishment guidelines. 40 studies were included in the analysis of ferritin LLN in a general population which were comprised of a total of 30,474 females (20-8678 females per study) and 29,615 males (20-8913 males per study). The median ferritin LLN was 8 μg/L (0-40) in females and 27 μg/L (6-133) in males. 11 studies analyzed ferritin RIs in presumed pre- and post-menopausal females with an age threshold of 45-50 years. A median ferritin LLN of 6 μg/L (2-31) was found in pre-menopausal versus 11 μg/L (0-70) in post-menopausal females. There were 4 studies of pregnant individuals (n=1599), and we found a median ferritin LLN of 5.6 μg/L (0-9.3) among them. Conclusions: This systematic review showed that the published literature on numerous ferritin assays have a LLN well below 30 μg/L, despite robust evidence suggesting a ferritin below 30 μg/L is in keeping with clinical iron-deficiency. Data driving existing ferritin RIs appear at high risk of bias given the lack of exclusion of individuals at risk for iron-deficiency and lack of adherence to CLSI standards in the presumed "normal" sample. Therefore, we suggest adoption of evidence-based laboratory clinical decision limits to help clinicians detect and treat iron-deficiency to minimize propagation of related health inequity and medico-social injustice.

Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Historical and projected public spending on drugs for rare diseases in Canada between 2010 and 2025

ObjectiveRare diseases are life-threatening, debilitating, or serious chronic conditions that affect < 50/100,000 people. Canadians can only access approximately 60% of drugs for rare diseases (DRDs), which is partially related to high per-patient costs and payers’ affordability concerns. However, limiting access to DRDs can reduce survival and quality of life among patients and caregivers. Therefore, we projected Canadian non-oncology DRD spending relative to total public drug spending to provide perspective for decision makers.MethodsCandidate historical (2010–2020) and pipeline (2021–2025) Canadian-marketed non-oncology DRDs were identified using definitions from the European Medicines Agency and the US Food and Drug Administration databases. Inclusion and exclusion criteria were applied to identify eligible DRDs. Public payer claims data, prevalence rates, regulatory, and health technology assessment factors were used to project DRD spending in relation to total Canadian public drug spending.ResultsWe included 42 historical DRDs and 122 pipeline DRDs. Public spending on DRDs grew from $14.8 million in 2010 (11 DRDs) to $380.9 million in 2020, then a projected $527.6 million in 2021 (59 potential DRDs) and $1.6 billion in 2025 (164 potential DRDs). Projected DRD spending increased from 3.2% of $16.5 billion public drug spending in 2021 to 8.3% of $19.4 billion in 2025. These projections do not include confidential manufacturer discounts, health outcome-related offsets, or additional safety-related costs.ConclusionsProjected DRD spending shows robust growth but remains a fraction of total public drug spending. Limiting DRD access because of this growth is not aligned with Canadian patient or societal values. Given the renewed interest in a Canadian DRD framework, our results may help guide discussions that aim to balance control of public drug spending with the well-being of patients with rare diseases.

Overview of the US Food and Drug Administration's Medical Device Databases and Applications for Healthcare Technology Management Professionals

Healthcare technology management professionals play a role in assisting hospital leadership teams to make informed decisions related to the purchase, maintenance, and management of medical devices and other healthcare technologies. To do so, they use various resources both internal and external to their organization. One such external source is the US Food and Drug Administration databases. The intent of this article is to provide an overview of US Food and Drug Administration's medical device databases that may be relevant to healthcare technology management professionals and an explanation of how healthcare technology management professionals can leverage this information during their day-to-day operations.

Side effect profile of early immunotherapy after radiotherapy: a pooled analysis of studies in the US Food and Drug Administration database

Side effect profile of early immunotherapy after radiotherapy: a pooled analysis of studies in the US Food and Drug Administration database

Are Pivotal Clinical Trials for Drugs Approved for Leukemias and Multiple Myeloma Representative of the Population at Risk?

There are significant disparities in care and outcomes for patients with leukemias and multiple myeloma (MM). To evaluate the extent to which clinical trials (CTs) match the demographic and geographic diversity of populations affected by leukemias and MM. CTs leading to drug approval were identified from the US Food and Drug Administration databases. Demographic and geographic data were collected from ClinicalTrials.gov and primary manuscripts. Standard descriptive statistics were used to summarize the data in frequencies and proportions, including 95% CIs, by race, ethnicity, sex, and malignancy subtypes. A total of 41 (67.2%) trials leading to drug approval reported data on race and 20 (48.8%) on ethnicity. These trials included 13,731 patients, of whom 11,209 (81.6%) were White. Among minorities, Asian-Pacific Islanders and Blacks had the highest representation in chronic myeloid leukemia, 147 (12.7%) and 61 (5.3%), and lowest in chronic lymphocytic leukemia, 55 (3%) and 20 (1.1%), respectively. Proportions for Blacks, Native Americans, and Hispanics were significantly low, reflecting under-representation in trials compared with the proportion in the general population. Females were also under-represented in acute myeloid leukemia (44.7% v 60.5%, P < .0001), and males in MM (55.3% v 60.2%, P < .0001) and chronic myeloid leukemia (55.2% v 62.9%, P < .0001). The geographic distribution of trials showed inadequate regional and state participation compared with mortality for all malignancies except MM. There are significant demographic and geographic under-representation and imbalances in pivotal CTs leading to drug approvals for leukemias and MM compared with the population affected. These disparities need to be addressed to make results applicable to all relevant populations.

US Food and Drug Administration Approval of High-risk Cardiovascular Devices for Use in Children and Adolescents, 1977-2021

This study uses data from US Food and Drug Administration (FDA) databases to quantify approval of high-risk cardiovascular devices for use in pediatric populations and assess the clinical evidence supporting the approvals.

Are pivotal clinical trials for lymphomas that led to drug approval representative of the population affected by these diseases?

6531 Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.

The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

Association of Radiation Therapy With Risk of Adverse Events in Patients Receiving Immunotherapy

Immune checkpoint inhibitors (ICIs) and radiation therapy (RT) are widely used to treat various cancers, but little data are available to guide clinicians on ICI use sequentially with RT. To assess whether there is an increased risk of serious adverse events (AEs) associated with RT given within 90 days prior to an ICI. Individual patient data were pooled from 68 prospective trials of ICIs submitted in initial or supplemental licensing applications in the US Food and Drug Administration (FDA) databases through December 2019. Two cohorts were generated: (1) patients who received RT within the 90 days prior to beginning ICI therapy and (2) those who did not receive RT within the 90 days prior to beginning ICI therapy, and AE frequencies were determined. A 1:1 propensity score-matched analysis was performed. All patients received an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab); 1733 received RT within the 90 days prior to starting ICI therapy, and 13 956 did not. The primary outcome was frequency and severity of AEs. Incidence of AEs was compared descriptively between participants who did vs did not receive RT in the propensity score-matched set. Because all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate. A total of 25 469 patients were identified; 8634 were excluded because they lacked comparators who had received RT (n = 976), did not receive an ICI (n = 4949), received RT outside of the target window (n = 2338), or had missing data in 1 or more variables used in the propensity analysis (n = 371), leaving 16 835 patients included in the analysis. The majority were younger than 65 years (9447 [56.1%]), male (10 459 [62.1%]), and White (13 422 [79.7%]). Patients receiving RT had generally similar rates of AEs overall to those patients who did not receive RT. The average absolute difference in rates across the AEs was 1.2%, and the difference ranged from 0% for neurologic AEs to 8% for fatigue. No difference in grade 3 to 4 AEs was observed between the 2 groups (absolute difference ranged from 0.01% to 2%). These findings persisted after propensity score matching. In this pooled analysis, administration of an ICI within 90 days following RT did not appear to be associated with an increased risk of serious AEs. Thus, it would appear to be safe to administer an ICI within 90 days of receiving RT. These findings should be confirmed in future prospective trials.

Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018

BackgroundInformation about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors.MethodsThis retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events.ResultsAmongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02–3.73)] and approved for long-term use [IRR: 2.76 (1.52–5.00)].Conclusions and RelevanceIn this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.

Abstract P067: Current status of regulatory-approved immunotherapies in Saudi Arabia

Abstract Immunotherapy has been shown to successfully turn aggressive malignancies in many patients into curable diseases. Thus, immunotherapy has received so much attention internationally, and Saudi Arabia was not an exception. Here, we evaluated the status of regulatory-approved immunotherapies in Saudi Arabia using the Saudi Food and Drug Administration (sFDA) database and the ClinicalTrials.gov website. We found that not all available immunotherapies in the clinic worldwide are approved by the sFDA, and the number of Saudi immunotherapy clinical trials are very limited. In fact, out of the eight regulatory-approved immune checkpoint inhibitors, 5 have received the sFDA approval. These immune check point inhibitors are Yervoy (ipilimumab), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq) and Avelumab (Bavencio). Also, out of the 5 regulatory approved chimeric antigen receptor (CAR) T cell therapy products, only KYMRIAHTM (tisagenlecleucel) has received the sFDA approval. According to the ClinicalTrials.gov registry (accessed 27 July 2021), only 6 investigational clinical trials have been conducted in Saudi Arabia to evaluate immune check point inhibitors, and only 3 of these studies are currently ongoing. More surprisingly, no Saudi CAR clinical trials have yet been conducted. Taken together, there is an urgent need for a greater accessibility for immunotherapy in the country. Citation Format: Reham Ajina. Current status of regulatory-approved immunotherapies in Saudi Arabia [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P067.

Tracking the Presence of Software as a Medical Device in US Food and Drug Administration Databases: Retrospective Data Analysis.

Software as a medical device (SaMD) has gained the attention of medical device regulatory bodies as the prospects of standalone software for use in diagnositic and therapeutic settings have increased. However, to date, figures related to SaMD have not been made available by regulators, which limits the understanding of how prevalent these devices are and what actions should be taken to regulate them. The aim of this study is to empirically evaluate the market approvals and clearances related to SaMD and identify adverse incidents related to these devices. Using databases managed by the US medical device regulator, the US Food and Drug Administration (FDA), we identified the counts of SaMD registered with the FDA since 2016 through the use of product codes, mapped the path SaMD takes toward classification, and recorded adverse events. SaMD does not seem to be registered at a rate dissimilar to that of other medical devices; thus, adverse events for SaMD only comprise a small portion of the total reported number. Although SaMD has been identified in the literature as an area of development, our analysis suggests that this growth has been modest. These devices are overwhelmingly classified as moderate to high risk, and they take a very particular path to that classification. The digital revolution in health care is less pronounced when evidence related to SaMD is considered. In general, the addition of SaMD to the medical device market seems to mimic that of other medical devices.

Assessing population diversity in phase III trials of cancer drugs supporting Food and Drug Administration approval in solid tumors.

Our study aimed to assess inequities in the clinical trial participation for the selected patient groups. We searched the Food and Drug Administration (FDA) database and extracted phase-III clinical trial data from MEDLINE for each approved drug by the FDA between January 1, 2006, and June 30, 2020. We analyzed the inclusion/exclusion criteria, participation according to gender, ethnic group, performance score, the positivity of HBV and HCV, and HIV, having comorbidities and brain metastasis. We compared the findings with that of the general population by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We identified 142 phase III pivotal oncology trials that enrolled 105 397 patients. The proportion of female patients in trials was lower than their relative prevalence in the general population from SEER region (36% vs 49.6%, P< .001). The rates of black patients included were lower than their relative prevalence from SEER region (2.1% vs 9.8%, P< .001). 1.3% and 0.8% of patients had HBV and HCV infections, respectively. The patients' numbers with organ dysfunction were not established due to insufficient data from clinical trials. 1.6% of all patients had controlled brain metastasis. Black patients, women and patients with brain metastasis or with HBV and HCV were underrepresented. Our study underscores the importance of expanding the inclusion/exclusion criteria of pivotal oncology trials to be more representative of patients seen in clinical practice.

RNA therapeutics for mood disorders: current evidence towards clinical trials

Introduction Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. For the past decades, various pathophysiological processes have been explored and growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class for the treatment of mood disorders arose: RNA therapeutics. Areas covered We conducted a systematic review of RNA therapeutics ─ antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs) and micro-RNA (miRNA) therapeutics ─ for the treatment of mood disorders studied in pre-clinical animal models listed in PubMED, in clinical trials registered in ClinicalTrials.gov and available on the market by combining literature search and Food and Drug Administration (FDA) and European Medicine Agency (EMA) online databases. Eighteen pre-clinical studies investigated the antidepressant effects of RNA therapeutics. However, even though there is an increasing number of marketing authorizations and clinical trials for the past twenty years, no RNA therapeutic reached the clinical development pipeline for the treatment of psychiatric disorders yet. Expert opinion Several promising RNA therapeutics have been tested in pre-clinical studies for depressive disorders, whereas no molecule has been developed for BD. There are several issues to address before reaching clinical development and new challenges include stratifying patient population and predicting therapeutic response.

More sophisticated than a drink cooler or an old sphygmomanometer but still not adequate for prehospital blood: A market review of commercially available equipment for prehospital blood transport and administration.

Hemorrhage is the leading cause of death in trauma patients with most fatalities occurring before reaching a higher level of care-this applies to both the civilian setting and the military combat setting. Hemostatic resuscitation with increased emphasis on blood transfusion while limiting use of crystalloids has become routine in trauma care. However, the prehospital setting-especially in combat-presents unique challenges with regard to storage, transport, and administration. We sought to evaluate available technology on the market for storage and administration technology that is relevant to the prehospital setting. We conducted a market review of available technology through subject-matter expert inquiry, reviews of published literature, reviews of Federal Drug Administration databases, internal military publications, and searches of Google. We reviewed and described a total of 103 blood transporters, 22 infusers, and 6 warmers. The risk of on-scene fatality in trauma patients and recent developments in trauma care demonstrate the need for prehospital transfusion. These transfusions have been logistically prohibited in many operations. We have reviewed the current commercially available equipment and recommended pursuit of equipment that improves accessibility to field transfusion. Current technology has limited applicability for the prehospital setting and is further limited for the military setting.

Patient-Reported Outcomes After Treatment Discontinuation: Commercial Clinical Trial Data From Four Cancer Types

ObjectivesHow frequently patient-reported outcome (PRO) data are collected in commercial cancer clinical trials after treatment discontinuation and the quality of that data are poorly understood. We reviewed treatment discontinuation follow-up PRO data collection to learn about trials collecting these data and understand data quality. The review included 4 cancer types representing potential for long- (prostate cancer), medium-/long- (breast cancer), and short-term (pancreatic cancer and hepatocellular carcinoma) follow-up owing to disease trajectory. MethodsWe reviewed registration trials in US Food and Drug Administration databases between January 2010 and January 2019. Protocols were reviewed to determine whether PROs were collected and, if so, whether these included the follow-up phase. Clinical study reports were reviewed when follow-up PROs were collected to determine completion rates. Results were summarized using descriptive analyses. ResultsOf the 46 trials containing PRO data, 46% had at least 1 follow-up PRO assessment. Follow-up schedules of assessment were wide ranging; the first assessment occurred between 30 days and 6 months after stopping treatment with follow-up for as long as 3 years. PRO completion rates were reported in 57% of 21 trials; at the first follow-up assessment, completion rates for the treatment arm ranged from 38% to 91% and from 41% to 100% in the control arm. ConclusionsThe quality of the follow-up PRO data, based on completion rates, was variable, as was the duration of follow-up. A clear research objective should be developed for follow-up PRO data, accounting for patient burden. If PRO data are collected, monitoring should be implemented to improve completion because poor completion limits data use in the benefit-risk assessment.

Adverse Events Associated with Intranasal Sprays: An Analysis of the Food and Drug Administration Database and Literature Review.

Intranasal sprays (INSs) are commonly used medications for the treatment of many rhinologic conditions. Despite their popularity, an analysis of a nationwide reporting database and comparison to the available literature has never been performed. The Food and Drug Administration Adverse Event Reporting System (FAERS) database was accessed to obtain adverse event (AE) records from 2014 to 2019 for varying INSs, including: 10 corticosteroids, 1 alpha adrenergic, and 3 antihistamines. The Proportional Reporting Ratios (PRR) and Reporting Odds Ratios (ROR) were calculated for dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache. A PRR ≥ 2 or ROR ≥ 1 was considered significant. Corticosteroids had 98 864 total reported AEs to the database, followed by antihistamines (7011) and alpha adrenergics (2071). In total, dyspnea was reported 5843 times, followed by headache (4230), epistaxis (1205), ageusia/dysgeusia (920), and anosmia (312). Overall, PRR and ROR values for dyspnea ranged from 0.51 to 4.25 and 0.51 to 4.49; for dysgeusia/ageusia from 0.56 to 6.09 and 0.56 to 6.12; and for epistaxis from 1.03 to 27.24 and 1.03 to 30.76, respectively. All medications which listed anosmia within the top AEs had PRR and ROR values exceeding 2 and 1, respectively. The PRR for headache exceeded 2 for 1 medication and the ROR exceeded 1 in 7 medications. The AEs of dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache are reported within the FAERS database for commonly prescribed INSs. When compared against the existing scientific literature, the clinical significance of this reporting tool from the FDA for these classes of medications remains unvalidated.