Incidence and Risk Factors of Heterotopic Ossification in the Knee After Reamed Tibial Nailing.

INTRODUCTION: Heterotopic ossification (HO) in the knee after tibial intramedullary nailing (IMN) has yet to be thoroughly investigated. Our aim was to assess frequency and associated factors for HO in the knee after tibial IMN. METHODS: This is a retrospective review at a single level 1 urban trauma center of 213 patients who underwent reamed tibial IMN. Plain radiographs were reviewed postoperatively and on final follow-up (≥6 weeks). Chart review was performed for surgical approach (suprapatellar versus infrapatellar), demographics, injury characteristics, and clinical follow-up. The primary outcome was frequency of HO. RESULTS: HO on final follow-up (mean: 41.43 weeks) was recorded in 15% cases. Postsurgical retroinfrapatellar reaming debris (odds ratio [OR], 4.73), Injury Severity Score (OR, 1.05), intensive care unit admission (OR, 2.89), chest injury (OR, 3.4), and ipsilateral retrograde femoral IMN (OR, 5.08) showed a notable association with HO development. No association was observed in HO formation between surgical approach, knee pain, or range-of-motion deficits. DISCUSSION: Radiographic evidence of HO in the knee after reamed tibial IMN is not uncommon and is associated with retained reaming debris, Injury Severity Score, chest injury, intensive care unit admission, and ipsilateral retrograde femoral nailing. No differences were noted in HO formation between approaches. HO was not associated with knee pain or range-of-motion deficits.

False or Misleading Claims in Online Direct-to-Consumer Ketamine Advertising in Maryland.

This cross-sectional study evaluates the prevalence of false or misleading information in online direct-to-consumer advertising for off-label and unapproved ketamine in Maryland.

Medical use and combination drug therapy among US adult users of central nervous system stimulants: a cross-sectional analysis.

OBJECTIVE: Examine patterns of adult medical use of amphetamine and methylphenidate stimulant drugs, classified in the USA as Schedule II controlled substances with a high potential for psychological or physical dependence. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Prescription drug claims for US adults, age 19-64 years, included in a commercial insurance claims database with 9.1 million continuously enrolled adults from 1 October 2019, through 31 December 2020. Stimulant use was defined as adults filling one or more stimulant prescriptions during calendar 2020. OUTCOME MEASURES: The primary outcome was an outpatient prescription claim, service date and days' supply for central nervous system (CNS)-active drugs. Combination-2 was defined as 60 days or more of combination treatment with a Schedule II stimulant and one or more additional CNS-active drugs. Combination-3 therapy was defined as the addition of 2 or more additional CNS-active drugs. Using service date and days' supply, we examined the number of stimulant and other CNS-active drugs for each of the 366 days of 2020. RESULTS: Among 9 141 877 continuously enrolled adults, the study identified 276 223 individuals (3.0%) using Schedule II stimulants during 2020. They filled a median of 8 (IQR, 4-11) prescriptions for these stimulant drugs that provided 227 (IQR, 110-322) treatment days of exposure. Among this group, 125 781 (45.5%) combined use of one or more additional CNS active drugs for a median of 213 (IQR, 126-301) treatment days. Also, 66 996 (24.3%) stimulant users used two or more additional CNS-active drugs for a median of 182 (IQR, 108-276) days. Among stimulants users, 131 485 (47.6%) were exposed to an antidepressant, 85 166 (30.8%) filled prescriptions for anxiety/sedative/hypnotic medications and 54 035 (19.6%) received opioid prescriptions. CONCLUSION: A large proportion of adults using Schedule II stimulants are simultaneously exposed to one or more other CNS-active drugs, many with tolerance, withdrawal effects or potential for non-medical use. There are no approved indications and limited clinical trial testing of these multi-drug combinations, and discontinuation may be challenging.

Inclusion of Participants with CKD and Other Kidney-Related Considerations during Clinical Drug Development: Landscape Analysis of Anticancer Agents Approved from 2015 to 2019.

BACKGROUND: The US Food and Drug Administration has prioritized efforts to expand availability of therapies, including anticancer agents, for patients with CKD. US Food and Drug Administration Guidance recommends inclusion of study participants with CKD in clinical trials, improving pharmacokinetic characterization in people with decreased GFR, and using contemporary GFR assessment methods during drug development. We performed a landscape analysis of anticancer agents approved from 2015 to 2019 to evaluate inclusion of study participants with CKD and GFR assessment methods used during drug development and subsequent translation to kidney-related safety and dosing data in product labeling. METHODS: Oncology drugs approved from 2015 to 2019 and associated pivotal trials were identified. We evaluated inclusion of study participants with CKD in pivotal trials and pharmacokinetic analyses, investigated GFR assessment methods used for pivotal trial eligibility and renal pharmacokinetic analyses, and identified kidney-related adverse drug event and dosing information. RESULTS: A total of 55 drugs and 74 pivotal trials were included. Of the pivotal trials, 95% contained kidney-related eligibility criteria, including 68% with GFR-based eligibility. The median lower limit of GFR required for inclusion was 45 ml/min or ml/min per 1.73 m 2 . Pharmacokinetic analyses were performed in CKD stages 4-5 and hemodialysis for only 29% and 6% of drugs, respectively. Estimated creatinine clearance was used in over 60% and 80% of pivotal trials and pharmacokinetic analyses, respectively. Reporting of kidney-related adverse drug events was highly variable. Product labeling for 49% of drugs contained no kidney dosing information. CONCLUSIONS: Study participants with CKD continue to be excluded from anticancer drug development, and GFR estimation in pivotal trials and renal pharmacokinetic analyses remains imprecise and heterogeneous. Furthermore, kidney-related safety and dosing information is scarcely and inconsistently presented.

Radiographic Prediction of Soft Tissue Injury Associated with Tibial Plateau Fractures: The Direction of Articular Depression Matters.

This investigation aimed to evaluate the impact of coronal articular fragment displacement of Schatzker type II tibial plateau fractures on concomitant soft tissue knee injuries. One hundred consecutively treated patients were included. Depression depth and coronal articular fragment displacement were measured radiographically, and medial collateral ligament (MCL) and lateral meniscus (LM) injury, and pain and range of motion (ROM) on final follow up, were recorded. Multivariable regression was then performed. Coronal articular fragment displacement was medially and laterally hinged in 74% and 26% of patients, respectively. MCL injuries were significantly higher in the lateral hinge group (odds ratio [OR]: 3.25; confidence interval [CI]: 1.07 to 9.84; p = 0.03). No difference was found in LM injury incidence and amount of articular depression between groups. At final follow-up, average pain and ROM was similar between groups. Findings demonstrate a significant correlation between laterally hinged articular depression in Schatzker II tibial plateau fractures and concomitant MCL injury. (Journal of Surgical Orthopaedic Advances 32(4):270-275, 2023).

Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review.

Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.

Fixation vs Arthroplasty for Femoral Neck Fracture in Patients Aged 40-59 Years: A Propensity-Score-Matched Analysis.

Background: Internal fixation (IF) has historically been favored for the treatment of femoral neck fractures (FNFs) in young, nongeriatric patients. However, recent literature reporting high reoperation rates among those receiving IF, taken in conjunction with favorable survivorship of modern bearing surfaces in total hip arthroplasty (THA), has begun to question this paradigm. Our study sought to compare outcomes between IF and THA for FNFs in patients aged 40-59 years. Methods: Using the Truven MarketScan Database, we performed a retrospective propensity-score-matched cohort study on patients aged 40-59 years who underwent surgical management of an isolated FNF (THA or IF). Patients with pathologic fracture were not included. Analysis was conducted on patients aged 40-49 and 50-59 years separately. A subgroup analysis was performed on those patients with 1 year and 3 years of follow-up. Multivariate analysis, controlling for baseline patient information, was then performed. Results: Seven hundred sevety-eight 40- to 49-year-old patients and 3470 50- to 59-year-old matched patients (IF and THA) were included in this study. A multivariate analysis found that patients aged 40-49 years who underwent IF were at higher odds of both 1-year (odds ratio 2.35, 95% confidence interval 1.22-4.54, P = .011) and 3-year (odds ratio 5.68, 95% confidence interval 2.21-14.60, P < .001) reoperation. Similar results were found in those aged 50-59 years. While complication rates were similar, postoperative anemia and 90-day visits to the emergency room were more common after THA in both age cohorts. Conclusions: While THA is associated with increased postoperative anemia and resource utilization compared with IF, patients aged 40-59 years who undergo IF for FNF are at increased risk of reoperation in the first 3 postoperative years. This information should be used to assist in shared decision-making with patients in this age group.

Changes in medical use of central nervous system stimulants among US adults, 2013 and 2018: a cross-sectional study.

OBJECTIVE: To assess the 5-year changes in the adult medical use of central nervous system (CNS) stimulants with higher risk of dependence and evaluate the population characteristics of users and their medical and/or neurological conditions. DESIGN: Cross-sectional study. SETTING: Annual US Medical Expenditure Panel Survey, a stratified random sample of approximately 30 000 persons designed to produce national population estimates. It focuses on reported medical spending, medical services used, health status and prescription medications. PARTICIPANTS: Adults age 19 years and older who reported obtaining one or more prescriptions for amphetamine or methylphenidate products during two survey years, 2013 and 2018. MAIN OUTCOMES MEASURES: Prescriptions obtained, the specific stimulant product and annual treatment days of drug supplied. RESULTS: In 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported prescriptions for CNS stimulants, having filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions with a mean of 226 (95% CI 210 to 242) days' supply. Compared with 2013, the estimated number of adults reporting using CNS stimulants in 2018 increased by 1.8 million (95% CI 1.0 million to 2.7 million) or 79.8%. Most 2018 adult stimulant users reported taking psychoactive medication for one or more mental, behavioural or neurodevelopment disorders. Overall, 77.8% (95% CI 72.6% to 83.0%) reported some medication for adult attention deficit disorder, 26.8% (95% CI 22.2% to 31.5%) took medication for anxiety, 25.1% (95% CI 19.9% to 30.3%) for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug treatment for other mental or neurological disorders. Adult CNS stimulant use was higher in females, in younger age cohorts and among individuals of white race/ethnicity. CONCLUSIONS: Adult medical use of prescription stimulants increased markedly in 5 years and occurred in a population often reporting multiple mental or neurological disorders. Further action is needed to understand and manage this new resurgence in drugs with high risks of dependence.

Risk of Hospitalization and Death Associated With Pimavanserin Use in Older Adults With Parkinson Disease.

BACKGROUND AND OBJECTIVES: To determine the risk of hospitalization and death associated with pimavanserin use. METHODS: We conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively. RESULTS: The study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06-1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99-1.24) or with 30-day mortality (aHR 0.76, CI 0.56-1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02-1.41) that persisted after 180 days (aHR 1.28, CI 1.13-1.45) and 1 year (aHR 1.56, CI 1.42-1.72). DISCUSSION: Pimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

Association of Pharmaceutical Industry Payments to Physicians With Prescription and Medicare Expenditures for Pimavanserin.

OBJECTIVE: This study aimed to quantify the association between pharmaceutical industry payments to physicians for pimavanserin and both pimavanserin prescription volume and Medicare expenditures. METHODS: This retrospective cross-sectional study used 2016 and 2017 data from Open Payments and the Medicare Part D Prescriber Public Use Files. The authors used Poisson regression models to quantify the association between physician payments for pimavanserin and pimavanserin prescription volume and linear regression models to quantify the association with Medicare expenditures for pimavanserin. RESULTS: Of 1,609 physicians who prescribed pimavanserin, 45% received payments, which totaled to $6,369,922. Each $10,000 in physician payments was associated with a 14% increase in pimavanserin prescription volume (incident rate ratio=1.14, 95% confidence interval [CI]=1.13-1.14). Every $100 in physician payments was associated with a $175.84 increase in Medicare pimavanserin expenditures (95% CI=$161.55-$190.13). CONCLUSIONS: Extensive physician payments have been associated with increased pimavanserin prescription volume and Medicare expenditures.

Assessment of Availability, Clinical Testing, and US Food and Drug Administration Review of Biosimilar Biologic Products.

Importance: Biosimilar biologic products were authorized in 2010, after the US Congress established an expedited pathway for approval of clinically similar versions of approved biologic products. Unlike for most small-molecule generic drugs, approval requirements for a biosimilar included animal studies and a comparative efficacy clinical trial. Objective: To analyze the evidence required to support a biosimilarity license application, examine the US Food and Drug Administration (FDA) evaluation process, and estimate the costs of the key clinical trial evidence. Design: This study evaluated all biosimilar biologic products approved from January 2010 through October 2019, using the publicly available FDA review documents, disclosures from ClinicalTrials.gov, and the published peer-reviewed literature. The costs of efficacy clinical trials were estimated using licensed proprietary software. Main Outcomes and Measures: The following elements of each approved biosimilar were evaluated: the extent of human clinical testing to establish that the biosimilar had no clinically meaningful differences with the reference product, results of comparative animal studies, and FDA-cited application deficiencies. The cited deficiencies included the following categories: (1) facility inspection, (2) manufacturing or product quality, (3) animal studies, (4) laboratory analytical studies, (5) phase 1 and/or immunogenicity studies, and (6) phase 3 comparative efficacy trials. Results: As of October 2019, the FDA had approved 23 biosimilar biologics for 9 reference products. The 29 clinical trials that established that the efficacy of the biosimilar products was comparable to that of the reference products enrolled a median (interquartile range [IQR]) of 504 (258-612) patients, had a median (IQR) estimated cost of $20.8 ($13.8-$35.3) million, and had a median (IQR) treatment duration of 52 (28-68) weeks. Substantial deficiencies temporarily halted the review of 9 applications, and the most frequent deficits were failed facilities inspections (n = 5) and manufacturing process quality problems (n = 6). The approved biosimilar submissions included 51 animal studies on species that included mice, rats, rabbits, dogs, and cynomolgus monkeys. Negative outcomes in 2 animal studies were attributed to differences between human and test species. The FDA generally met the standard 12-month review deadlines or stopped the review clock when serious deficiencies were identified. Conclusions and Relevance: This study found that most comparative efficacy trials supporting the FDA approval of biosimilars appeared to be as rigorous as and often larger, longer, and more costly than pivotal trials for new molecular entities. Further research is needed into whether less costly comparative efficacy trials could provide adequate evidence of biosimilarity and whether animal studies contribute useful scientific evidence.

Managing Resident Workforce and Education During the COVID-19 Pandemic: Evolving Strategies and Lessons Learned.

BACKGROUND: The novel coronavirus and associated Coronavirus Disease 2019 (COVID-19) is rapidly spreading throughout the world, with robust growth in the United States. Its drastic impact on the global population and international health care is swift, evolving, and unpredictable. The effects on orthopaedic surgery departments are predominantly indirect, with widespread cessation of all nonessential orthopaedic care. Although this is vital to the system-sustaining measures of isolation and resource reallocation, there is profound detriment to orthopaedic training programs. METHODS: In the face of new pressures on the finite timeline on an orthopaedic residency, the Emory University School of Medicine Department of Orthopaedics has devised a 5-pronged strategy based on the following: (1) patient and provider safety, (2) uninterrupted necessary care, (3) system sustainability, (4) adaptability, and (5) preservation of vital leadership structures. RESULTS: Our 5 tenants support a 2-team system, whereby the residents are divided into cycling "active-duty" and "working remotely" factions. In observation of the potential incubation period of viral symptoms, phase transitions occur every 2 weeks with strict adherence to team assignments. Intrateam redundancy can accommodate potential illness to ensure a stable unit of able residents. Active duty residents participate in in-person surgical encounters and virtual ambulatory encounters, whereas remotely working residents participate in daily video-conferenced faculty-lead, case-based didactics and pursue academic investigation, grant writing, and quality improvement projects. To sustain this, faculty and administrative 2-team systems are also in place to protect the leadership and decision-making components of the department. CONCLUSIONS: The novel coronavirus has decimated the United States healthcare system, with an unpredictable duration, magnitude, and variability. As collateral damage, orthopaedic residencies are faced with new challenges to provide care and educate residents in the face of safety, resource redistribution, and erosion of classic learning opportunities. Our adaptive approach aims to be a generalizable tactic to optimize our current landscape.

Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018.

BACKGROUND: Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. OBJECTIVE: To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. DESIGN: Cross-sectional analysis. SETTING: Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. PARTICIPANTS: Patients with pain who participated in phase 3 pivotal trials. INTERVENTION: FDA-approved opioid analgesics. MEASUREMENTS: Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. RESULTS: Most of the 48 NDAs evaluated were for new dosage forms (n = 25 [52.1%]) or new formulations (n = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. LIMITATIONS: The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. CONCLUSION: Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. PRIMARY FUNDING SOURCE: None.

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015-2017: a cross-sectional study.

OBJECTIVES: Little is routinely disclosed about the costs of the pivotal clinical trials that provide the key scientific evidence of the treatment benefits of new therapeutic agents. We expand our earlier research to examine why the estimated costs may vary 100-fold. DESIGN: A cross-sectional study of the estimated costs of the pivotal clinical trials supporting the approval of 101 new therapeutic agents approved by the US Food and Drug Administration from 2015 to 2017. METHODS: We licensed a software tool used by the pharmaceutical industry to estimate the likely costs of clinical trials to be conducted by contract research organisations. For each trial we collected 52 study characteristics. Linear regression was used to assess the most important factors affecting costs. PRIMARY AND SECONDARY OUTCOME MEASURES: The mean and 95% CI of 225 pivotal clinical trials using varying assumptions. We also assessed median estimated costs per patient, per clinic visit and per drug. RESULTS: Measured as pivotal trials cost per approved drug, the 101 new molecular entities had an estimated median cost of US$48 million (IQR US$20 million-US$102 million). The 225 individual clinical trials had a median estimate of US$19 million (IQR US$12 million-US$33 million) per trial and US$41 413 (IQR, US$29 894-US$75 047) per patient. The largest single factor driving cost was the number of patients required to establish the treatment effects and varied from 4 patients to 8442. Next was the number of trial clinic visits, which ranged from 2 to 166. Our statistical model showed trial costs rose exponentially with these two variables (R2=0.696, F=257.9, p<0.01). CONCLUSIONS: The estimated costs are modest for measuring the benefits of new therapeutic agents but rise exponentially as more patients and clinic visits are required to establish a drug effect.

US Food and Drug Administration Safety Advisories and Reporting to the Adverse Event Reporting System (FAERS).

BACKGROUND: The US Food and Drug Administration (FDA) and other major regulators regularly issue safety advisories about licensed drugs with new adverse effects that have been documented through observational studies, clinical trials, and spontaneously reported adverse drug events. OBJECTIVE: To assess the possible effects of a representative group of FDA Drug Safety Communications on the reporting of the specific adverse effect featured in the advisory on new cases reported to the FDA Adverse Event Reporting System (FAERS). METHODS: We examined 16 FDA Drug Safety Communications issued from 2010 to 2015 that had not previously been the focus of advisories from regulators in the UK, Canada, or Australia. We compared the reports of the adverse effect in the 8 calendar quarters preceding the advisory and in the 4 quarters following. We measured change in reporting frequency by calculating the event reporting odds ratio (ROR) for the post-warning compared to the pre-warning periods. We defined a credible association of the advisory with increased reporting as a ROR ≥ 2.0 and p value of < 0.05 by Fisher's Exact Test. RESULTS: We found statistically significant increased reporting for 4/16 advisories with RORs that ranged from 3.9 to 40.6. Three advisories had smaller but still statistically significant increases that were less than the ROR ≥ 2.0 threshold. For 7 advisories, we found no statistically significant changes in reporting. CONCLUSIONS: No consistent pattern or effect was found on spontaneous reporting following these safety advisories. After results were available, we observed that some cases with the largest reporting increase also involved substantial numbers of legal claims. Changes in adverse event reporting following a warning need to be evaluated on a case-by-case basis.

Estimated costs of pivotal trials for U.S. Food and Drug Administration-approved cancer drugs, 2015-2017.

BACKGROUND: Pivotal clinical trials provide critical evidence to regulators regarding a product's suitability for marketing approval. The objectives of this study are (1) to characterize select features of trials for oncology products approved by the U.S. Food and Drug Administration between 2015 and 2017; and (2) to quantify the costs of these trials and how such costs varied based on trial characteristics. METHODS: We identified novel oncology therapeutic drugs, and their respective pivotal trials, approved between 2015 and 2017 using annual summary reports from the Food and Drug Administration. Cost estimates for each pivotal trial were calculated using IQVIA's CostPro, a clinical trial cost estimating tool based on executed contracts between pharmaceutical manufacturers and contract research organizations. Measures of drug and trial characteristics included trial design, end point, patient enrollment, and regulatory pathway. We also performed sensitivity analyses that varied assumptions regarding how efficiently each trial was conducted. RESULTS: A total of 39 pivotal clinical trials provided the basis for Food and Drug Administration approval of 30 new oncology drugs from 2015 to 2017. Among these trials, primary end points were objective response rate in 20 (51.3%), progression-free survival in 13 (33.3%), and overall survival in 6 (15.4%). Twenty trials (51.3%) were single-arm studies. The median estimated cost of oncology pivotal trials was $31.7 million (interquartile range = $17.0-$60.4 million). Trials with objective response rate as primary end point had a median estimate of $17.7 million (interquartile range = $11.9-$27.1 million), compared with trials examining progression-free survival ($42.3 million, interquartile range = $34.6-$101.2 million) or overall survival ($79.4 million, interquartile range = $56.9-$97.7 million) (p < 0.001). Estimated costs for single-arm trials ($17.7 million, interquartile range = $11.9-$23.7 million) were less than for trials with a placebo-controlled ($56.7 million, interquartile range = $40.9-$103.9 million) or active control arm ($67.6 million, IQR = $35.5-$93.5 million) (p < 0.001). CONCLUSIONS: Relative to the estimated costs of drug development, the costs of these oncology pivotal trials were modest, with trials that produced more valuable scientific information costing more than their counterparts.