Trial Exclusion Criteria Research Articles

To what degree could clinical trials in evidence based medicine reflect reality in the treatment of candidemia?

Evidenced based medicine (EBM) is necessary to standardize or treatment for infection since EBM is established based on the results of clinical trials. Entry criteria for clinical trials are very strict, and many patients have difficulties in being enrolled in any clinical trials regarding candidemia. It is questionable if the results of clinical trials reflect the real world of general medicine in this case. For the purpose of examining how many patients could join any randomized clinical trials for the treatment of candidemia, we reviewed all the candidemia patients in our institute during 2014-2018. The patients were divided into two groups: patients who were eligible for clinical trials (participation possible group), and those who were not (participation impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials. A total of 70 patients was enrolled in this study. The median age was 73 years (range 36-93 years). Of these, 41 patients (59%) were male. As for site of infections, catheter related blood stream infection was most frequently seen in 37 (53%). Seventeen patients (24%) were classified as participation possible group and 53 patients (76%) were participation impossible group. Comparing the two groups, participation possible group patients have much better performance status, have less comorbidities and have longer overall survival times than participation impossible group patients. Only 24% of candidemia patients were eligible for the clinical trials. Thus, we can see that clinical trials might not correctly reflect the real world among candidemia patients.

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

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

13674 Eligibility criteria related to hormone therapy in acne clinical trials

Despite multiple guidelines on acne management, there is a paucity of high-quality data on the treatment of acne among patients receiving hormone therapy. In the United States, this potentially impacts the treatment of acne among 9.1 million women using oral contraceptive pills in 2015-2017 and 2.3 million cisgender and transgender men receiving testosterone replacement therapy. We examined exclusion criteria of acne clinical trials to identify potential barriers to the enrollment of patients receiving hormone therapy. We searched clinicaltrials.gov using the term “acne” from 1/1/2009 to 5/16/2019 for exclusion criteria of acne interventions. Of the 115 studies included, 33% had exclusion criteria related to hormone therapy, including recent changes in therapies such as oral contraceptives, estrogens and anti-androgenic medications within specified time ranges (4 weeks to 1 year). Patients with medication-induced acne or a hormone disorder were excluded in 8.7% and 2.6% of trials, respectively. Other exclusion criteria included current use of oral contraceptives (2.6%), androgen blockers (3.5%), hormone-replacement therapy (1.7%), or any medication (5.2%). Findings were limited to the interventions posted on clinicaltrials.gov. Acne is the most common dermatologic condition in the United States, yet robust evidence guiding the optimal treatment of acne in patients receiving hormone therapy remains scarce. These data highlighted limitations in generalizability of many existing acne clinical trials, as well as the need to expand the eligibility criteria to improve real-world effectiveness of acne treatment across large and diverse populations receiving hormone therapies.

Patterns of revascularization in stable ischemic heart disease in the pre-ISCHEMIA era

Abstract Introduction New evidence on the role of myocardial revascularization in stable ischemic heart disease (SIHD), recently presented, showed that revascularization guided by the presence of moderate-to severe ischemia relieves angina more effectively than optimal medical therapy (OMT), without a significant benefit in hard clinical endpoints. Aim To assess the representativeness of the ISCHEMIA trial in a real-world population and compare management strategies between patients who fulfill the eligibility criteria of the trial (Group 1, G1) and those who do not (Group 2, G2). Methods and population Single centre retrospective analysis including all consecutive patients referred to coronary angiography (CA) for SIHD from January 2018 to December 2019. Patients were stratified in two groups (G1 and G2) according to the ISCHEMIA trial inclusion and exclusion criteria. G1 was compared with G2 and with a subset of G2 with obstructive coronary artery disease (CAD), defined as ≥70% luminal stenosis in at least one coronary artery or >50% for the left main. Results A total of 1020 patients underwent CA, of whom only 124 (12.2%) would have been eligible for the ISCHEMIA trial (G1). Overall, there were no significant differences in baseline characteristics between the two groups. G1 patients had more extensive and severe disease, presenting more frequently with proximal left anterior descending (LAD) involvement (26.6% vs 10.4%; p<0.001), two vessel disease without proximal LAD stenosis (23.4% vs 10.3%; p<0.001) and three vessel disease (18.5% vs 5.9%; p<0.001). These patients had higher rates of revascularization, both CABG (25.8% vs 10.8%, p<0.001) and PCI (56.5% vs 39.5%, p<0.001). However, when comparing G1 with the subset of G2 patients with obstructive CAD, G1 patients had higher rates of CABG (26.8% vs 17.8%, p=0.034) but there were no differences on the rates of PCI (58.0% vs 56.9%, p=0.916). Conclusions Patients included in the ISCHEMIA trial are underrepresented in a real-world population of SIHD patients referred to coronary angiography. PCI rates were similar among patients with at least one significant coronary artery stenosis, regardless of previous evidence or severity of ischemia. Our findings underline the need for further refinement in criteria for revascularization in SIHD. Funding Acknowledgement Type of funding source: None

S0183 NER1006 1 Liter Polyethylene Glycol (PEG)–Based Bowel Preparation Safety Profile in Patients With Mild or Moderate Renal Impairment: A Pooled Analysis of Two Phase 3 Trials

INTRODUCTION: NER1006, a 1 L PEG-based bowel preparation, was approved in the US in 2018 for colon cleansing in preparation for colonoscopy in adults. In patients with decreased renal function, bowel preparations may increase the risk of electrolyte imbalances or worsen renal function. The current aim was to evaluate the safety profile of NER1006 in adults undergoing colonoscopy, subgrouped by renal insufficiency. METHODS: Data were pooled from two phase 3, randomized studies (NOCT/MORA) of patients (aged 18–85 y) undergoing colonoscopy. Patients were randomized to NER1006 as a 2-day evening/morning (pm/am) or 1-day morning/morning (am/am) split dosing regimen. Per protocol, mild renal insufficiency was defined as creatinine clearance (CrCl) ≥60 to < 90 mL/min/1.73 m2 and moderate as CrCl, ≥30 to < 60 mL/min/1.73m2. Moderate renal insufficiency was an exclusion criterion in NOCT, and severe disease (CrCl < 30 mL/min/1.73 m2) was an exclusion criterion in both trials. Safety (adverse events [AEs] and clinical lab testing) was assessed, per protocol, through 7 ± 1 days post-colonoscopy. Worsening renal function (increase from baseline in creatinine >0.3 mg/dL or decrease from baseline in calculated CrCl of >25%) definition was derived from RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. RESULTS: 524 adults who received pm/am regimen of NER1006 (renal insufficiency: mild [n = 340; 64.9%], moderate [n = 14; 2.7%], none [n = 166; 31.7%], or unknown [n = 4; 0.8%]) and 269 adults who received am/am regimen (renal insufficiency: mild [n = 184; 68.4%], moderate [n = 14; 5.2%], none [n = 68; 25.3%], or unknown [n = 3; 1.1%]) were included. The most common AEs in the study were GI-related, regardless of renal function status (Table 1). To assess a risk of worsening renal function, patients who showed an increase from baseline in creatinine >0.3 mg/dL or a decrease from baseline in calculated CrCl of >25% were identified. The number of patients, subgrouped by renal insufficiency, meeting 1 or both of these criteria was low, with no signal of renal injury related to NER1006 observed (Table 2). In addition, these changes did not persist; only 1 patient (baseline mild renal insufficiency; am/am split dose) with a change in renal function at Day 2 ± post-colonoscopy (Table 2) met the same criteria (for CrCl) at 7 ± 1 days post-colonoscopy. CONCLUSION: Data support the overall safety profile of 1 L PEG-based NER1006 as a bowel preparation, including in patients with mild-to-moderate renal insufficiency.Table 1Table 2

Prognostic Significance of Extranodal Extension in HPV-Mediated Oropharyngeal Carcinoma: A Systematic Review and Meta-analysis.

To determine the prognostic role of extranodal extension (ENE) among patients with human papilloma virus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) through a systematic review and meta-analysis of institutional studies. MEDLINE, Embase, Scopus, and PubMed. Two independent authors searched the databases on December 3, 2019, to identify studies of HPV+ OPSCC comparing prognostic outcomes stratified by ENE. The I2 statistic was used to determine study heterogeneity. Fixed and random effects models were used to determine hazard ratios (HRs) with 95% CIs. Eighteen observational studies met inclusion criteria, yielding 3603 patients with HPV+ OPSCC (1521 ENE+ and 2082 ENE-) with a median follow-up of 49 months. The presence of pathologic ENE (pENE) and radiologic ENE (rENE) was associated with decreased overall survival (pENE HR, 1.89 [95% CI, 1.15-3.13], I2 = 35%; rENE HR, 2.64 [95% CI, 1.46-4.78], I2 = 75%) and distant recurrence (pENE HR, 3.23 [95% CI, 1.25-8.33], I2 = 0%; rENE HR, 3.83 [95% CI, 1.88-7.80], I2 = 0%). Neither pENE nor rENE was associated with locoregional recurrence (pENE HR, 0.75 [95% CI, 0.20-2.84], I2 = 0%; rENE HR, 2.03 [95% CI, 0.86-4.79], I2 = 0%). pENE was not associated with disease-specific survival (pENE HR, 1.45 [95% CI, 0.84-2.49], I2 = 0%). pENE and rENE are moderately associated with an increased risk of all-cause mortality and recurrence with distant metastasis in a cohort of patients with HPV+ OPSCC. These findings may be used to inform exclusion criteria for deintensification trials and assist in refined risk stratification.

Characterizing inclusion and exclusion criteria in clinical trials for chimeric antigen receptor (CAR) T-cell therapy among adults with hematologic malignancies

ObjectiveRestrictive eligibility criteria are a known barrier to patient enrollment into clinical trials. With the introduction of chimeric antigen receptor T-cell (CAR-T) therapy, it is imperative to ensure trials are generalizable to the intended population with appropriate safety guiderails. MethodsUsing the U.S. National Library of Medicine's clinical trial database, we identified 84 clinical trials and characterized inclusion/exclusion criteria for CAR-T therapy in hematologic malignancies with a focus on age, performance status, and comorbidities, and the relationship to sponsorship, disease type, and study phase. ResultsThe overwhelming majority of CAR-T trials imposed restrictions on upper age (n = 54, 64%), performance status (n = 72, 86%), and renal function (n = 76, 90%). Institution-sponsored studies were more likely to have age restrictions (n = 29) than industry-sponsored (n = 20), (83% vs 45%, p < 0.01). There was no relationship between study phase and use of upper age limit restriction or study phase and affiliation with performance status restrictions. Inclusion criteria for renal function was highly variable and ambiguous; creatinine <1.2–3.0 mg/dL, creatinine clearance >20–60 mL/min, and GFR >30–70 mL/min. ConclusionThese results suggest highly variable inclusion/exclusion criteria for early phase CAR-T studies that may limit patient accessibility to therapy and emphasize the need for a standardized, evidence-based approach to patient enrollment.

Real-world outcomes of advanced melanoma patients not represented in phase III trials.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision‐making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune‐ or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE‐006 and CHECKMATE‐067/‐066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan‐Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population‐based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3‐year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long‐term survival is possible. The prognosis of ineligible patients with advanced melanoma in real‐world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM.

Impact of COAPT trial exclusion criteria in real-world patients undergoing transcatheter mitral valve repair

BackgroundThe generalizability of the COAPT trial results on the benefit of TMVR in patients with secondary mitral regurgitation is unclear. MethodsFunctional and long-term clinical outcome were examined in 122 consecutive patients with secondary mitral regurgitation and reduced ejection fraction undergoing TMVR. “COAPT-like” patients were defined according to principal COAPT inclusion/exclusion criteria if all of the following was fulfilled: symptomatic mitral regurgitation grade 3+ or more according to American guidelines; left ventricular ejection fraction ≥ 20%, left ventricular end-systolic dimension ≤ 70 mm, estimated pulmonary artery systolic pressure ≤ 70 mmHg, mitral valve orifice area ≥ 4 cm2, no prior mitral valve procedure, no right sided congestive heart failure, no COPD requiring home oxygen therapy and NYHA class less than IVb. Results51% of 122 patients (mean age 74 ± 10 years, 76% male) showed COAPT-like characteristics. COAPT-like patients showed a significantly lower hazard for the composite endpoint of mortality and heart failure hospitalization (HR 0.51, 95%CI 0.30–0.89, p = .017) during a mean follow-up of 16 ± 6 months, with an estimated 1-year event rate of 20% vs 43%, respectively. The improvement in functional outcomes 6 min walking distance (76 ± 136 m vs. 31 ± 90 m), Minnesota Living with Heart Failure Questionnaire (−6 ± 19 vs. −10 ± 23) and Short Form 36 physical component score (3.8 ± 10 vs. 5.5 ± 11) was similar in COAPT-like and the other patients. ConclusionIn this first real world cohort half of the patients undergoing TMVR showed COAPT-like characteristics and these patients showed a substantially better clinical outcome. The mid-term functional benefit was similar in COAPT-like and other patients.

Use of real-world data to understand barriers to interventional clinical trial enrollment in community oncology clinics (COC).

2061 Background: Increasing enrollment in clinical trials remains a national priority, yet there are limited data from COCs on the degree to which common trial exclusion criteria (EC) and socioeconomic factors play a role in low enrollment rates. Methods: We analyzed data from the nationwide Flatiron Health electronic health record (EHR) derived de-identified database. COC were eligible if they had given a clinical trial study drug to ≥2 patients (pts)/year. We included pts with one of eight advanced or metastatic solid tumors who received ≥1 line of systemic anticancer therapy between 1/1/2014 and 11/30/2019. We defined EC as either: creatinine &gt; 1.5 mg/dl or Ccl &lt; 45 ml/min, Hb &lt; 9 g/dL, ANC &lt; 1500/ul, plts &lt; 100,000/ul, bilirubin &gt; 1.5 upper limit of normal (uln) or AST/ALT &gt; 2.5 uln within 30 days or ECOG performance status (PS) ≥ 2 within 60 days prior to start of therapy. We calculated the percentage of pts with ≥1 EC relative to the group of candidate pts, stratified by therapy line (1L, 2L, 3L+). We used multivariate logistic regression models to evaluate the effect of EC and socioeconomic factors (age, race, Medicaid) on the likelihood of receiving a clinical study drug for each line of therapy. Results: In this sample of 35 COCs, 26,988 pts received ≥1 systemic therapy. Pts with ≥ 1 EC: 28.4% in 1L, 34.2% in 2L, 37.4% in 3L. Percentages of pts with an ECOG PS ≥ 2 were: 15.6% (1L), 18.2% (2L), 19.8% (3L). Pts receiving a clinical study drug: 1.7% of 26,988 in 1L, 2.0% of 12,738 in 2L, 2.9% of 5,333 in 3L+, and 3.1% in any line. Excluding pts with ≥1 EC from the denominator modestly improved overall accrual: 2.0% of 19,729 in 1L, 2.3% of 8,588 in 2L, 3.7% of 3,470 in 3L+. In multivariate logistic regression, ECOG PS ≥ 2 was strongly associated with not receiving a study drug [odds ratio (95% CI); 1L: 0.25 (0.16-0.4); 2L: 0.28 (0.17-0.49); 3L: 0.21 (0.1-0.44)]. The likelihood of receiving a clinical study drug (any line) was lower for pts who are Black [0.63 (0.48-0.82)], Latino [0.49 (0.32-0.75)], and pts older than 70 years [0.63 (0.54-0.72)]. Medicaid pts were not significantly less likely to receive study drug [0.83 (0.64-1.07)]. Conclusions: In COC, common trial EC reduce pt availability for trials by &gt; 25%. Poor PS is highly prevalent and influential. These EC and complex trial requirements challenge COC’s ability to recruit representative pt populations. Future efforts to increase enrollment in trials must consider common EC along with well known barriers to enrollment of unrepresented groups.

Repurposing current therapeutics for treating COVID-19: A vital role of prescription records data mining.

Since its outbreak in late 2019, the SARS‐Cov‐2 pandemic already infected over 3.7 million people and claimed more than 250,000 lives globally. At least 1 year may take for an approved vaccine to be in place, and meanwhile millions more could be infected, some with fatal outcome. Over thousand clinical trials with COVID‐19 patients are already listed in ClinicalTrials.com, some of them for assessing the utility of therapeutics approved for other conditions. However, clinical trials take many months, and are typically done with small cohorts. A much faster and by far more efficient method for rapidly identifying approved therapeutics that can be repurposed for treating COVID‐19 patients is data mining their past and current electronic health and prescription records for identifying drugs that may protect infected individuals from severe COVID‐19 symptoms. Examples are discussed for applying health and prescription records for assessing the potential repurposing (repositioning) of angiotensin receptor blockers, estradiol, or antiandrogens for reducing COVID‐19 morbidity and fatalities. Data mining of prescription records of COVID‐19 patients will not cancel the need for conducting controlled clinical trials, but could substantially assist in trial design, drug choice, inclusion and exclusion criteria, and prioritization. This approach requires a strong commitment of health provides for open collaboration with the biomedical research community, as health provides are typically the sole owners of retrospective drug prescription records.

Obstetrics risk Assessment: Evaluation of selection criteria for vaccine research studies in pregnant women

Vaccines designed for use in pregnancy and vaccine trials specifically involving pregnant women are rapidly expanding. One of the key challenges in designing maternal immunization trials is that developing exclusion criteria requires understanding and quantifying the background risk for adverse pregnancy outcomes in the pregnancy being studied, which can occur independent of any intervention and be unrelated to vaccine administration.The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project has developed and published case definitions and guidelines for data collection, analysis, and evaluation of maternal immunization safety in trials involving pregnant women. Complementing this work, we sought to understand how to best assess obstetric risk of adverse outcomes and differentiate it from the assessment of vaccine safety. Quantification of obstetric risk is based on prior and current obstetric, and maternal medical history. We developed a step-wise approach to evaluate and quantify obstetric and maternal risk factors in pregnancy based on review of published literature and guidelines, and critically assessed these factors in the context of designing inclusion and exclusion criteria for maternal vaccine studies. We anticipate this risk assessment evaluation may assist clinical trialists with study design decisions, including selection of exclusion criteria for vaccine trials involving pregnant women, consideration of sub-group classification, such as high or low risk subjects, or schedule considerations, such as preferred trimester of gestation for an intervention during pregnancy. Additionally, this tool may be utilized in data stratification at time of study analyses.

Letter: Emerging Therapeutic Targets in Chordomas: A Review of the Literature in the Genomic Era

Letter: Emerging Therapeutic Targets in Chordomas: A Review of the Literature in the Genomic Era

A Review of Drug Therapy of Lung Cancer with Interstitial Lung Disease

间质性肺病（interstitial lung disease, ILD）是肺癌发生的危险因素，临床上经常出现肺癌合并间质性肺病（lung cancer associated with ILD, LC-ILD）患者。治疗LC-ILD过程中有导致患者ILD急剧加重甚至死亡的风险，同时合并ILD成为多数肺癌前瞻性临床试验的排除标准，因此当肺癌合并ILD时常常成为肺癌的治疗难点。由于LC-ILD患者在临床中占有一定的比例，因此有必要探寻其最佳的治疗方案。在此我们综述了现有的临床研究结果以供参考。

Adult-Onset Atopic Dermatitis: Presentations and Progress.

Atopic dermatitis (AD) is a chronic skin disease characterized by barrier dysfunction and immune dysregulation that affects approximately 20% of children and 2-5% of adults worldwide. Traditionally, AD has been considered a disease of childhood with many cases resolving before adulthood. However, in recent years, the prevalence of adult AD is increasingly recognized to be substantial, but it is uncertain whether this increase is due to increased childhood-persistent or relapsed AD, or new adult-onset AD. This highlights a need for further investigation into the adult AD population and evaluation of phenotypes in the adult-onset cohort. In this literature review, we examine five studies focused on adult-onset AD phenotype, conducted between 2013 and 2017. The most commonly reported body regions affected in adult-onset AD were the hands, eyelids, neck, and flexural surfaces of the upper limbs. These vary from childhood-onset AD findings, which are less specific to body regions other than flexural areas. These findings have implications for diagnostic accuracy and treatment of AD, including considerations for therapeutic choices and inclusion and exclusion criteria in clinical trials.

Are Current Technical Exclusion Criteria for Clinical Trials of Magnetic Resonance-Guided High-Intensity Focused Ultrasound Too Restrictive?: Early Experiences at a Pediatric Hospital.

Certain technical criteria must be met to ensure the treatment safety of magnetic resonance-guided high-intensity focused ultrasound. We retrospectively reviewed how our enrollment criteria were applied from 2014 to 2017 in a clinical trial of magnetic resonance-guided high-intensity focused ultrasound ablation of recurrent malignant and locally aggressive benign solid tumors. Among the 36 screened patients between 2014 and 2017, more than one-third were excluded for technical exclusion criteria such as the anatomic location and proximity to prosthetics. Overall, patients were difficult to accrue for this trial, given the incidence of these tumors. To increase potential accrual, screening exclusion criteria could be more generalized and centered on the ability to achieve an acceptable treatment safety margin, rather than specifically excluding on the basis of general anatomic areas.

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: a trend over decades

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: a trend over decades

Nivolumab in patients with metastatic renal cell carcinoma and chronic hepatitis C virus infection.

Hepatitis C virus (HCV) interferes with activation of innate and adaptive immune responses. Theoretically, the efficacy and toxicity of immune checkpoint inhibitors in cancer patients infected with HCV may differ. Nevertheless, HCV was an exclusion criterion in most checkpoint inhibitor trials. We evaluated the efficacy and safety of nivolumab in metastatic renal cell carcinoma (mRCC) patients with or without chronic HCV infection. In a matched cohort study, data were collected from 174 patients, retrospectively. All patients had clear-cell mRCC, chronic HCV infection (case study group), no evidence of other malignancy or cirrhosis, and had received nivolumab (3mg/kg every 2weeks) until disease progression or unacceptable toxicity. Quantitation of HCV RNA in plasma samples was performed before and during treatment with nivolumab with the automated HCV test (Hoffmann-La Roche, Switzerland). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and rate of grade 3-4 adverse events in study and control cohorts. A total of 44 matched patients were included. Groups were well balanced. HCV-infected patients had significantly longer OS and PFS. Median OS was 27.5 (95% CI 25.3-29.7) and 21.7 (20.3-23.1) in study and control groups, respectively (P = 0.005). Median PFS was 7.5 (5.7-9.3) and 4.9 (4-5.8) (P = 0.013). Despite no differences in ORR between groups (27% vs. 23%, P = 0.7), patients with HCV had significantly more durable responses (P = 0.01). Nivolumab was well tolerated in all HCV-positive patients. No unexpected toxicity was observed. Assessment of viral load during nivolumab therapy was available in 14 of 22 (64%) patients with HCV. Nivolumab did not significantly impact HCV concentration (mean change 210IU/ml, P = 0.82) in the absence of antiviral therapy. The efficacy and safety profiles observed in this study support the administration of nivolumab in mRCC patients infected with HCV and warrant further investigation.

Suicidality, Depression, and the FDA: Health Inequities and the Ethical Conduct of Research.

Persons with mental health disorders, including suicidality, are underrepresented in clinical trials, undermining the generalizability of results and possibly contributing to health inequities. This report (1) documents the exclusion of persons with suicidality in trials used to secure US Food and Drug Administration (FDA) approval for antidepressants, (2) describes barriers to inclusion, and (3) identifies possible steps for overcoming barriers. Inclusion and exclusion criteria for efficacy trials for depression or major depressive disorder described on FDA labels for 14 antidepressants approved from 1991 through 2013 were studied by reading the FDA labels, publications described on labels, and ClinicalTrials.gov entries for registered trials. Labels for drugs approved in or before 1998 were obtained through a Freedom of Information Act request filed June 26, 2018. For drugs approved after 1998, labels are on the FDA website. Publications based on the trials described on FDA labels were identified through a PubMed search on October 23, 2018, using each drug name and trial or study as the keywords and setting no date limit. For drugs approved from 1991 to 2000, of 36 publications identified, 26 did not mention suicidality, 7 excluded persons with suicidality but did not describe assessing suicidality with an instrument, 2 excluded persons with suicidality and described assessing suicidality using at least 1 instrument, and 1 included persons with suicidality. For drugs approved from 2000 through 2013, of 28 publications identified, 4 did not mention suicidality, 12 reported excluding persons with suicidality but did not describe assessing suicidality with an instrument, 12 excluded persons with suicidality and described assessing suicidality using at least one instrument, and none included persons with suicidality. More stringent criteria for assessing and excluding based on suicidality very likely were applied for drugs approved post-2000. The exclusion of persons with suicidality from antidepressant trials is common, creating uncertainty about medication safety and efficacy in parts of the target population. Information about study populations can be beneficial for prescribing clinicians, but it is not always readily available.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada

Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.