Time Of Approval Research Articles

Use of pembrolizumab among older adults with cancer in the United States, before and after FDA approval of its tumor-agnostic indication.

Pembrolizumab, an anticancer immunotherapy agent, has received multiple approvals since its first approval by the U.S. Food and Drug Administration (FDA) in 2014. Limited data exist on its real-world use and shifts post tumor-agnostic approval in 2017 for the treatment of patients with any microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) solid tumors. This study analyzes pembrolizumab's pre and post-tumor-agnostic approval use among older U.S. adults, revealing its evolving role in oncology practice. Using the Surveillance, Epidemiology and End Results (SEER)-Medicare data (2014-2019), we examined the cancer sites of pembrolizumab recipients before and after tumor-agnostic approval. Cancer sites were classified based on the timing of site-specific approvals (before/after tumor-agnostic approval) or no site-specific approval, and inclusion in MSI-H/dMMR clinical trials. The total number of pembrolizumab recipients increased from 4221 in the pre-agnostic period to 20 479 in the post-agnostic period. Pembrolizumab was used for a broad range of cancer types, including cancers that had no FDA-approved site-specific indications at the time of use (25.8% in pre- and 24.6% in post-agnostic periods). The proportion of pembrolizumab recipients receiving pembrolizumab for cancers with site-specific approvals before tumor-agnostic approval decreased from 77.3% to 70.8%. The proportion of pembrolizumab recipients receiving pembrolizumab for cancers that gained site-specific approvals following tumor-agnostic approval almost doubled (6.8% to 13.0%). The proportion of pembrolizumab recipients with cancers included in MSI-H/dMMR trials also doubled (12.3% to 25.5%) following tumor-agnostic approval. Pembrolizumab use has expanded over time among older adults with cancer, extending beyond those with FDA-approved site-specific indications.

Impact of institutional review board stipulations on turnaround time for approvals of surgical studies.

We have examined the number and types of stipulations received following the submission of surgical study protocols to the Institutional Review Boards (IRBs) for review, and their effect on turnaround time for approval. This analysis will enable our organization to improve the quality of applications and design of study protocols, which can streamline the approval process and increase efficiency of the startup phase for clinical research. IRB stipulations for 48 surgical studies were analyzed. Various factors were assessed: surgical specialty, type of study by design, clinical trial phase, type of investigational product, type of IRB utilized (local or centralized), study complexity score, type of review (e.g., exempt, expedited, or full board), turnaround time, and number of stipulations received. Statistical analyses were performed to examine associations between the number/type of stipulations received during the IRB review process and any of the aforementioned study-related factors. For analyzed surgical studies, the number of stipulations allotted to a study and time taken for approval had moderate association with the complexity of the study. The turnaround time for approval was the highest for randomized, controlled trials and studies undergoing full board review. This study elucidates characteristics that are associated with increased time for IRB approval. Analysis of IRB stipulations can help improve the turnaround time for the approval process, increase efficiency of startup phase, and transition to execution phase faster, which will allow more time for enrollment of research subjects, and increase return on investment made into research and development programs.

An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022.

The FDA's Oncology Center of Excellence's (OCE) launch of Project Optimus signals increased focus on dose optimization approaches in oncology drug development, particularly toward optimization in the premarket setting. Although sponsors continue to adapt premarket study designs and approaches to align with FDA's expectations for dose optimization, including consideration of the optimal dosage(s), there are still instances where questions remain at the time of approval about whether the approved doses or schedules are optimal. In these cases, FDA can exercise regulatory flexibility by issuing postmarketing requirements (PMR) and avoid delaying patient access to promising therapies. This landscape analysis demonstrates that over the past decade (2012-2022), FDA frequently used PMRs to answer additional questions about dosing for novel oncology approvals. We found more than half of drugs (78/132, 59.1%) had a dosing PMR and observed a recent increase in PMRs intended to evaluate whether a lower dose could be more optimal. These results suggest there are opportunities to adapt premarket dose optimization strategies and leverage innovative development tools to ensure timely identification of the optimal dose.

Prospective Evaluation of Automated Contouring for CT-Based Brachytherapy for Gynecologic Malignancies

PurposeThe use of deep learning to auto-contour organs-at-risk (OARs) in gynecologic radiation treatment is well-established. Yet, there is limited data investigating the prospective use of auto-contouring in clinical practice. In this study, we assess the accuracy and efficiency of auto-contouring OARs for CT-based brachytherapy treatment planning of gynecologic malignancies. Materials and MethodsAn in-house contouring tool automatically delineated five OARs in gynecologic radiation treatment planning: the bladder, small bowel, sigmoid, rectum, and urethra. Accuracy of each auto-contour was evaluated using a 5-point Likert scale: a score of five indicated the contour could be used without edits, while a score of one indicated the contour was unusable. During scoring, automated contours were edited and subsequently used for treatment planning. Dice similarity coefficient (DSC), mean surface distance (MSD), 95% Hausdorff Distance (95HD), Hausdorff Distance (HD), and dosimetric changes between original and edited contours were calculated. Contour approval time and total planning time of a prospective auto-contoured (AC) cohort were compared to times from a retrospective manually contoured (MC) cohort. ResultsThirty AC cases from January 2022 to July 2022 and thirty-one MC cases from July 2021 to January 2022 were included. The mean (±SD) Likert score for each OAR was the following: bladder 4.77 (±0.58), small bowel 3.96 (±0.91), sigmoid colon 3.92 (±0.81), rectum 4.6 (±0.71), and urethra 4.27 (±0.78). No auto-contours required major edits. All OARs had a mean DSC > 0.86, MSD < 0.48mm, 95HD < 3.2mm, and HD < 10.32mm between original and edited contours. There was no significant difference in DVH metrics (D2.0cc/D0.1cc) between original and edited contours (p-values > 0.05). The average time to plan approval in the AC cohort was 19% less than the MC cohort. (AC vs. MC, 117.0 + 18.0 minutes versus 144.9 ± 64.5 minutes, p=0.045). ConclusionsAutomated contouring is useful and accurate in clinical practice. Auto-contouring OARs streamlines radiation treatment workflows and decreases time required to design and approve gynecologic brachytherapy plans.

Characteristics and outcomes of new molecular oncology drug approvals, in combination or monotherapy

ImportanceUnderstanding the factors that are associated with new molecular entity (NME) cancer drug approvals as a single agent and in combination, and European Society for Medical Oncology (ESMO) scores, can aid in identifying suitable factors to consider in trial designs for future drugs. In addition, the association between the various outcomes can aid in determining benefit when surrogate outcomes are used in approval consideration. ObjectiveThis study aims to (1) use the measures used in evaluating clinical trials by ESMO scores to determine the differences in the characteristics of 2013–2022 Food and Drug Administration (FDA) oncology NME drug approvals for those approved for use in combination or as a monotherapy, and (2) analyze the association between survival outcomes and the response rate for monotherapy NME drugs and/or drugs approved in combination. DesignCross-sectional analysis. SettingUS FDA Oncology Drug Approvals (2013–2022) ParticipantsUS FDA Oncology Drug Approvals (2013–2022) ExposuresTrial-level characteristics (tumor types, basis of approval, randomized or not, phase) and associations between overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) and whether NME drugs were approved as monotherapy or in combination . ResultsDrugs approved for use as a monotherapy are less likely to be approved using a randomized study (p < 0.001) and more likely to be approved via the accelerated pathway (p = 0.012) and be open-label (p < 0.001). Drugs approved for use as a combination or monotherapy significantly differed on their approval basis (p = 0.002), phase of trial at the time of approval (p = 0.02), and ESMO scores (p = 0.02). There was low correlation between response rate and either PFS or OS metrics. However, nearly all of the drugs with large improvements in OS (> 5months) were drugs with robust ORR. Conclusions and relevanceDrugs approved as monotherapy with a low response rate are likely to have marginal benefit in OS and PFS.

Factors influencing the time to ethics and governance approvals for clinical trials: a retrospective cross-sectional survey

BackgroundThe findings from multi-centre trials are central to the practice of evidence-based medicine, enabling the development and implementation of new treatments. The time it takes to commence clinical trials at sites can be long, and ethics and governance approvals are key steps on the pathway to site activation. The goal of this study was to explore factors influencing the times to ethics approval, governance approval and site activation for multi-centre clinical trials.MethodsThis paper assessed the associations of trial characteristics (disease area and trial phase), site characteristics (government or private ownership, country) and characteristics of the ethics and governance processes (scope guidelines, mutual acceptance requirements and triage of projects by risk) with times to approvals and activation. Median times were compared between site initiations that were and were not exposed to each characteristic using non-parametric tests in univariable and multivariable regressions.ResultsThere were data from 150 site activations done across 91 sites, 16 trials and 5 countries from November 2013 to November 2021. The overall median time to activation was 234 days (range 74 to 657), with ethics approval taking a median of 48 days (0 to 369) and governance approval a median of 34 days (0 to 489). Both the univariable and multivariable analyses identified associations of disease area, particularly oncology (p univariable = 0.012, p multivariable = 0.044), use of scope guidelines (p < 0.001, p = 0.020) and use of a triage process (p < 0.001, 0.043) with shorter median times for governance approval. These characteristics (all p < 0.001) plus early trial phase (p = 0.028) were also predictive of shorter median times for ethics approval in univariable analyses, but none remained predictive in multivariable models (all p > 0.054). The only factors associated with reduced overall time to site activation in both univariable and multivariable analyses were the early trial phase (p < 0.001, p = 0.013) and mutual acceptance of ethics approvals (p = 0.031, p = 0.030).InterpretationTimes to ethics and governance approvals were only one third of total trial start-up time. Factors influencing times to approval and activation were somewhat inconsistent across analyses, but it seems likely that the introduction of selected governance and ethics processes can reduce approval times.

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Delay in prior authorization of biologic therapy: Another possible cause of healthcare disparity in IBD patients

Biologics, a mainstay in inflammatory bowel disease (IBD) treatment, typically require prior authorization from insurance companies. Multiple studies show that African Americans are less likely to be prescribed biologics. The prior authorization process may perpetuate disparities in healthcare. This study evaluated the approval time for biologics in IBD. A chart review of IBD patients seen in a university gastroenterology clinic over 5 years was performed. Patient gender, race, IBD subtype, biologic use, and insurance type were recorded. Insurance type was classified as private or public (Medicaid or Medicare). Biologic agents evaluated included infliximab, adalimumab, vedolizumab and ustekinumab. Length of time to approval (TTA) and length of time to first infusion or administration (TFI) were recorded. Analysis was performed using t-testing, Fisher's exact testing, and ANOVA with significance set at p<0.05. The study was IRB approved. 458 charts were analyzed. 66 patients were being treated with a biologic. 42 had private insurance, 16 Medicaid and 8 Medicare. 37 patients had ulcerative colitis, 27 Crohn's disease, and 2 indeterminate colitis. There were 38 men and 28 women. 32 patients were white, 26 African American, 1 Asian, 5 other, and 2 declined identification. Average TTA was 30.5 days (range 1-145) and average TFI was 45.3 days (range 2-166). African Americans were more often on public insurance compared to whites (p=0.0001). Crohn's disease compared to ulcerative colitis patients were more often on public insurance (p=0.017). Significantly more private compared to public insurance patients were on infliximab (p=0.001). Medicaid and Medicare patients had significantly longer mean TTAs than private insurance patients (49.1 and 52.7 vs 19.4 days, p=0.007). African Americans had significantly longer mean TTA compared to whites (45.9 vs 24.8 days, p=0.044). Crohn's disease compared to ulcerative colitis patients had significantly longer mean TTA (39.7 vs 21.8 days, p=0.050). This study shows that prior authorization for biologic therapy was longer for African Americans. Patients on public insurance also tend to have a longer TTA, and more African Americans were on public insurance compared to White patients in this study which may explain the difference in biologic access for African Americans.

Lisocabtagene Maraleucel in Relapsed/Refractory Large B-Cell Lymphoma: Real World Analysis from the Cell Therapy Consortium

Introduction Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed CAR T cell therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the TRANSCEND (Abramson et al, Lancet 2020), TRANSFORM (Kamdar et al, Lancet 2022), and PILOT studies (Sehgal et al, Lancet Oncol 2022). Extending clinical trial results for liso-cel to the real-world setting, we performed a multicenter retrospective study to evaluate the safety and efficacy of liso-cel in standard of care practice. Methods Patients (pts) aged ≥18 years with LBCL who received commercial liso-cel infusion between February 2021 (time of FDA approval) and June 2023 at 7 academic US medical centers were identified from the Cell Therapy Consortium registry. Pt and treatment characteristics were summarized descriptively, and the Kaplan Meier method was used for survival outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. Tumor response was assessed per Lugano criteria locally by the treating clinician. Results As of 6/10/2023, 101 pts underwent liso-cel infusion. Detailed baseline pt characteristics are shown in Table 1. Median age at apheresis was 71 years (range: 30-85) with 35% of pts ≥75 years, 60% were male, 16% had an ECOG PS of ≥2 at apheresis, and 11% had active secondary CNS involvement. By histology, 86% of pts had DLBCL, 7% HGBL, 5% TFL, and 2% PMBCL. Baseline comorbidities included diabetes (18%), stage IV chronic kidney disease (5%), cerebrovascular disease (5%), impaired cardiac ejection fraction (2%), pulmonary dysfunction (2%), impaired hepatic function (2%), and active infection (3%), with 68% having a Charlson Comorbidity Index score of ≥3. Due to comorbidities, 30% of pts would have been ineligible for the TRANSCEND clinical trial. The median number of prior therapies was 3 (range: 1-8) and 16% of pts underwent prior autologous stem cell transplant. Bridging therapy was used in 62% of pts including 41% receiving polatuzumab-based treatment, 24% chemoimmunotherapy, and 21% radiation therapy. Seven (7%) pts received liso-cel on an expanded access trial (NCT04400591) due to a non-conforming product. Median time from apheresis to CAR T-cell infusion was 39 days (IQR: 34-43) and 85% of CAR T-cell infusions occurred inpatient. Any Grade CRS occurred in 49% (3% were Grade ≥3) and any Grade ICANS occurred in 26% (10% were Grade ≥3). Median onset of CRS and ICANS was 4 and 6 days following liso-cel infusion, respectively. Tocilizumab was administered in 31% and 31% of pts received steroids for toxicity management. Nine deaths (9%) unrelated to lymphoma progression occurred at a median of 1.2 months (range: 0.3-4.3) with 2 due to infectious complications, 2 due to other malignancy, 1 due to grade 5 neurologic toxicity, 1 due to concurrent grade 5 neurologic toxicity and grade 5 CRS, 1 due to accidental death, and 2 due to unknown causes. The 6-month incidence of non-relapse mortality was 8% (95% CI, 3.4% - 15%). The overall response rate (ORR) to bridging therapy, as assessed prior to lymphodepletion, was 45% with 17% achieving a complete response (CR). Following liso-cel infusion, response assessment was performed at day 30 and/or day 90 according to treating center practice, or in those determined to have clinical progression. Of the 89 pts evaluable at day 30, the ORR was 81% with 63% achieving a CR. Among 76 pts evaluable at day 90, the ORR was 63% with 58% achieving a CR. With a median follow-up of 10.3 months (range 0.3-22.8), month 6 outcomes were 62.7% (95% CI, 52.8% - 74.3%) for progression-free survival, 71.6% (95% CI, 60.9% - 84.1%) for duration of response, and 77.1% (95% CI, 68.4% - 86.9%) for overall survival ( Figure 1). Conclusions These analyses confirm that efficacy and safety are similar or superior to those of patients enrolled in liso-cel prospective clinical trials for R/R LBCL. Notably, these outcomes were achieved in pts predominately of advanced age and with a significant comorbid burden, recognizing that one-third would have been ineligible for TRANSCEND. These results also likely reflect advancements in patient selection and toxicity management including the real world utilization of novel bridging therapy to temporize and debulk disease. Follow-up is ongoing and updated data will be presented at the meeting.

Real-World Treatment Patterns Among Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) Who Initiated an Asparaginase Treatment after the Approval of Recombinant Erwinia (Rylaze)

Introduction Recombinant Erwinia (Rylaze or JZP458) was approved by the United States (US) Food and Drug Administration (FDA) on June 30, 2021, for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month and older who developed hypersensitivity to E. coli-derived asparaginase. There is currently limited evidence on the use of recombinant Erwinia outside of a clinical trial setting. Methods This retrospective, descriptive study used a US open claims dataset from Symphony Health. The aim of this study was to describe the treatment patterns among patients diagnosed with ALL/LBL who initiated an asparaginase treatment in the post-Rylaze approval time frame (July 1, 2021-January 31, 2023). Index date was defined as the first date of receiving an asparaginase treatment. Patients in this study were required to have an ALL/LBL diagnosis within 365 days prior to index date, and at least 1 medical or pharmacy claim 365 days prior to and after the index. Four asparaginase molecules were included in this study, 2 Erwinia-derived - recombinant Erwinia(Rylaze) and native Erwinia (Erwinaze), and 2 E. coli-derived - pegaspargase (Oncaspar) and calaspargase pegol-mknl (Asparlas). Patients entered cohort A when they initiated their first asparaginase. Cohort B included a subset of cohort A patients who received a second different asparaginase. Patients were followed up until index treatment discontinuation, 365 days of follow-up, or January 31, 2023 (end of data), whichever came first. Descriptive statistics were used to report patient characteristics and treatment patterns. No statistical comparisons were conducted in the analyses. Results Cohort A (n=1,495) included 1,370 (91.6%) pegaspargase, 85 (5.7%) recombinant Erwinia, 28 (1.9%) calaspargase, and 12 (0.8%) native Erwinia-treated patients. Among patients aged ≥18 years (n=350), 319 (91.1%), 28 (8.0%), and 3 (0.9%) patients initiated pegaspargase, recombinant Erwinia, and native Erwinia as the first asparaginase, respectively (Figure 1). Among pegaspargase- and calaspargase-treated patients, 32.2% and 10.7% developed a hypersensitivity reaction (HSR), respectively; also, 11.7% and 14.3% switched to recombinant Erwinia, respectively. The 3 most common comorbidities at baseline among patients in cohort A were chronic obstructive pulmonary disease (9.5%), obesity (10.2%), and liver disease (7.8%) and in patients specific to recombinant Erwinia were obesity (14.1%), liver disease (11.8%), and diabetes (9.4%). Cohort B (n=203), representing 13.6% of patients in cohort A who started a second asparaginase treatment, included 168 (82.8%) recombinant Erwinia, 19 (9.4%) calaspargase, 13 (6.4%) native Erwinia, and 3 (1.5%) pegaspargase-treated patients. Near half (46.8%) of cohort B patients had an HSR after they initiated an E. coli-derived asparaginase before they switched to the second asparaginase. Of the patients who switched to recombinant Erwinia, most were &amp;lt;18 years old (n=139, 82.8% [Figure 2]). The top 3 comorbidities at baseline among all patients in cohort B were same as cohort A. Of patients in cohort B, the majority (78.8%) switched from pegaspargase to recombinant Erwinia. Within this subgroup, a 1:6 dose replacement ratio was observed within 21 days of the switch with administrations most common on Mondays, Wednesdays, and Fridays. Discussion/Conclusions This observational study describes treatment patterns of asparaginase in patients with ALL/LBL in the 18 months after the approval of recombinant Erwinia. The majority of initial asparaginase was pegaspargase, with recombinant Erwinia as the second asparaginase. However, recombinant Erwinia was observed as the initial treatment in 5.7% of patients, with nearly one-third of those patients being ≥18 years of age. Recombinant Erwinia dosing usage appeared to align with the dosing schedule (Monday/Wednesday/Friday) approved by the FDA in November 2022 with 1 dose of pegaspargase replaced with 6 doses of recombinant Erwinia. Limitations of this study included the nature of the database used, containing mostly outpatient data, and the relatively short study time frame. Future studies with additional data are needed to fully understand the real-world asparaginase use patterns in these patient populations.

Call to action: Harmonization of pharmacovigilance regulations for post-marketing pregnancy and breastfeeding safety studies.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy

BackgroundOver the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.ObjectivesThis study reviews the FDA’s five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.MethodsWe conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.ResultsExpedited approval reduces new drugs’ time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as “breakthroughs”, are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.ConclusionSpecial FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Abstract 12237: All-Cause and Cause-Specific 30-day Readmission After Left Ventricular Assist Device Implantation: Comparing the HeartMate 3 vs Pre-HeartMate 3 Eras

Introduction: In recent years, the HeartMate 3 (HM3) has become the most commonly implanted left ventricular assist device (LVAD) for patients with end-stage HF in the United States. We assessed 30-day readmission rates and leading causes of readmission for patients newly receiving an LVAD in the pre-HM3 era compared to the HM3 era. Methods: Using the Nationwide Readmission Database (NRD), all adult admissions (age ≥18) with LVAD implantation from October 2015 - December 2020 were identified. Admissions were excluded if the patient had: died while inpatient, missing data for age, sex, or mortality, transferred to another acute care facility or December admission. Multivariable Cox regression analysis with all-cause and cause-specific readmission within 30 days as the ‘failure event’ and time from index hospitalization discharge to failure event as the ‘time to failure event’ was analyzed. Based on the timing of initial FDA approval of HM3, the study period was divided into two eras: 2015-2017 was defined as the pre-HM3 era and 2019-2020 as the HM3 era. The year 2018 was deemed the transition period and excluded from the analysis. Results: Among 13,867 hospitalizations for LVAD implantations, 57.6% of index hospitalizations were during the pre-HM3 era (mean age= 56 years, men= 77.2%), and 42.4% were during the HM3 era (mean age= 56 years, men= 76.6%). Hazards of 30-day all-cause readmissions were similar in the two eras (Figure 1 Panel A) . LVAD implantation in the HM3 era was associated with lower risks of 30-day readmission with a gastrointestinal (GI) bleed or pump thrombosis and a higher risk of 30-day readmission with an acute kidney injury (AKI) compared to the pre-HM3 era ( Figure 1 Panel B). Conclusion: There was no significant difference in risk of 30-day all-cause readmission after LVAD implantation in the HM 3 and Pre-HM 3 eras. However, implant in the HM3 era was associated with lower risk of readmission with GI bleed and pump thrombosis and higher risk of readmission with AKI.

United States regulatory approval of medical devices used for endovascular neurosurgery: A two-decade review of FDA regulatory files

BackgroundThe evolution of neuroendovascular technologies has progressed substantially. Over the last two decades, the introduction of new endovascular devices has facilitated treatment for more patients, and as a result, the...

The Real-World Outcomes of Ponatinib in 724 Patients with CML and Ph + ALL : A Post-Marketing Surveillance Study with a Special Interest in Arterial Occlusive Events in Japan

Introduction Ponatinib inhibits the BCR::ABL1 kinase, including a variant with threonine-to-isoleucine at position 315 (T315I) (Cortes et al. N Eng J Med. 2013; 369:1783-96); however, it has been reported that ponatinib is associated with a higher risk of major arterial events than other TKIs among patients with CML, those with a resistance/intolerance (r/i) to prior TKIs, and with patients with relapsed/refractory (r/r) Ph + ALL. ( Leuk Lymphoma. 2016; 57(6):1300-10.) Owing to the low prevalence of this disease (Ning et al. Exp Hematol Oncol 2020; 9 (29)), SEER Cancer Statistics Review 1975-2018. National Cancer Institute 2021, Ching-Hong et al. N Engl J Med 2004; 350:1535-48), the amount of data concerning patients treated with ponatinib is limited, indicating that the safety and efficacy of ponatinib require further evaluation. Therefore, we conducted a post-marketing surveillance (PMS) study to assess the safety and efficacy of ponatinib, focusing on arterial occlusive events (AOEs), to optimize its use in clinical practice in Japan. Methods This PMS study investigated the safety and efficacy of ponatinib (ICLUSIG ®, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) in patients with r/i CML who have been treated with TKIs and patients with r/r Ph + ALL. We collected clinical data from all patients in Japan who started ponatinib administration between November 21, 2016, and June 30, 2018. The observation period was two years (or until the end of ponatinib administration). AEs and ADRs were classified using the Medical Dictionary of Regulatory Affairs (MedDRA) version 25.0. Surveillance was conducted in accordance with the Japanese Ministerial Ordinance on Good Post-Marketing Study Practice for Drugs. Results A total of 807 patients were enrolled from 334 facilities. Safety analysis was conducted for all 724 patients; 421 (58.1%) participants were males with a sample median age of 62.0 years. The median (range) follow-up duration was 258.0 (1-1,436) days for the overall population, 729.5 (7-1,436) days for patients with CML-CP, and 168.0 (1-1,254) days for patients with Ph + ALL. As for safety data, adverse reactions (ADRs) were observed in 58.29% (422/724) of participants. The most common ADRs included platelet count decreases (8.15% - 59/724), hypertension (7.73% - 56/724), rash (5.56% - 41/724), decreased neutrophil count (4.83% - 35/724), and abnormal hepatic function (4.28% - 31/724). The most common serious ADR was a 2.49% (18/724) decrease in the platelet count. The incidence of AOEs was 6.49% (47/724) among the overall population, 6.22% (12/193) among patients with CML-CP, and 5.90% (23/390) among patients with Ph + ALL. The incidence of AOEs per 100 person-year was 6.8 events in total, 4.5 events in CML-CP, and 7.1 events in Ph + ALL. The incidence of cerebrovascular events was higher than that of cardiovascular events and peripheral vascular events in patients with CML-CP; there were no deaths related to AOEs in patients with CML-CP during the follow-up duration of PMS. Univariate logistic regression analysis revealed significant associations between AOEs and age (OR 1.039, 95% CI 1.017-1.062), hypertension (OR 2.137, 95% CI 1.169-3.907), and diabetes (OR 1.950, 95% CI 1.026-3.707). Regarding efficacy data, among the 89 patients with CML-CP who had not achieved MMR (MMR; BCR-ABL1transcripts [IS] ≤ 0.1%) before treatment with ponatinib, the cumulative MMR rates at weeks 12, 24, 52, and 104 were 22.8%, 36.9%, 58.8%, and 67.2%, respectively. Among the 19 patients with the BCR::ABL1 T315I mutation, the cumulative MMR rates at 12, 24, 52, and 104 weeks were 42.1%, 47.4%, 75.3%, and 75.3%, respectively. In patients with Ph + ALL, the CCyR rates at weeks 0, 12, 24, 52, and 104 were 35.4% (51/144), 77.1% (108/140), 73.6% (53/72), 83.6% (46/55), and 80.0% (36/45), respectively. Conclusions This two-year post-marketing surveillance of patients with r/i CML and r/r Ph+ ALL has demonstrated the general favorable safety and efficacy of ponatinib to patients in Japan. The main adverse reactions were those events reported in the clinical trials up until the time of approval. Furthermore, regarding AOE, no expression levels exceeding the results of the clinical trial were confirmed. However, patients with advanced age and who have predisposing factors for AOEs should be closely monitored for possible adverse vascular events.

Use of Geriatric Assessment and Genetic Profiling to Personalize Selection of Intensive Versus Low Intensity Chemotherapy in Older Adults with Acute Myeloid Leukemia (AML): Final Results of a Phase II Trial

Introduction: Geriatric assessment can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories are associated with survival following intensive chemotherapy in AML. Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative precision medicine approach to personalize therapy selection in older adults with AML. We report final results of a pragmatic phase II trial using such strategy, aiming to reduce early mortality (NCT03226418). Methods: Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for intensive chemotherapy (Table 1). Additional assessment included Karnofsky Performance Scale (KPS), Patient Health Questionnaire-9 (PHQ-9), and Mini Nutritional Assessment-Short Form (MNA). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 European LeukemiaNet criteria. While available mutation test results were incorporated to risk stratify, the study did not require waiting for the results prior to therapy initiation, given an anticipated turnaround time of 1-2 weeks for mutation test results. Therapy selection followed the algorithm in Figure 1. Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit. Patients with high-risk AML received low-intensity chemotherapy such as a hypomethylating agent with or without venetoclax or novel drugs (based on timing of FDA approval of these drugs), or CPX 351 if they were fit and met the FDA-approved indications. Patients with organ dysfunction (e.g. creatinine ≥2 mg/dl) and those requiring chemotherapy for other malignancy were eligible for low-intensity chemotherapy. Chemotherapy could be administered in community oncology settings. Patients were followed for quality of life assessments, as well as functional and oncologic outcomes. Results: Between July 2017-October 2022, 75 patients were consented; 2 patients were considered screen failure. Baseline characteristics of 73 eligible patients included a median age of 69 years (range 60-87 years), 49% female, 92% white, and a median KPS of 80 (range 60-100). As presented in Table 1, most had ≥3 comorbidities (55%), impaired physical function measured by Short Physical Performance Battery (70% had a score of 9 or less) and impaired cognition measured by Montreal Cognitive Assessment (64% had a score of 25 or less). Genetic risk categories included adverse (62%), intermediate (22%), and good-risk AML (16%). Patients had one or more of the following mutations: TET2 (26%), NPM1 (22%), RUNX1 (19%), ASXL1 (19%), TP53 (19%), DNMT3A (16%), IDH2 (15%), IDH1 (11%), FLT3 ITD (10%), FLT3 TKD (10%), biallelic CEBPA (4%), EZH2 (2%). Seven patients (10%) received intensive chemotherapy; CPX 351 (n=4) or 7+3 based regimen (n=3). Other patients received low-intensity chemotherapy: azacitidine or decitabine and venetoclax (n=43, 59%), decitabine or azacitidine alone (n=18, 24%) prior to approval of venetoclax, and other (n=5, 7%). The median time from diagnosis to therapy initiation was 6 days and from enrollment to therapy initiation was 1 day (range 0-13). Mortality at 30 days from diagnosis was 6.8% (95% confidence interval, CI 3.0-15.1%) and at 90 days was 21.9% (95% CI 14.0-32.7%). Mortality compared favorably to an unmatched historical cohort of patients ≥60 years treated at our center between 2011-2016, where 30-day mortality was 30% (95% CI 22-40%) and 90-day was 41% (95% CI 32-52%) (Future Oncol. 2019;15:1989-95). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 1 day following enrollment. Pragmatic aspects of the trial included broad eligibility criteria and co-management of patients with community oncologists. The results from our final analysis appear promising with lower rates of early mortality compared to unmatched historical controls.

Real-World Incidence, Characteristics and Management of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cell Therapy across Hematologic Malignancies

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. CRS occurs with varying frequency and severity, depending on the underlying disease and immunotherapy used, such as chimeric antigen receptor T-cell (CAR-T) therapy or off-the-shelf T-cell engaging bispecific antibodies. Limited research exists on the diagnosis and management of CRS in the real world. This study describes the real-world incidence, severity and clinical management of CRS induced by commercially available CAR-T therapies for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and multiple myeloma (MM). Methods: Real-world data (RWD) were obtained from the Flatiron Health, US, nationwide electronic health record (EHR)-derived, de-identified database of cancer patients within a network comprised primarily of community cancer practices. The Flatiron Health network also includes practices designated as academic sites by the National Cancer Institute; however, relative proportions of community/academic practices may vary depending on the study cohort. Data as of August 31, 2022, on CAR-T therapy, clinical characteristics and disease outcomes specific to CAR-T therapy, as well as CRS and its clinical management, were abstracted from unstructured documents in EHRs (in addition to routinely available structured data), in a cohort of patients receiving commercial CAR-T therapy. Specifically, data for CRS including treatments and resolution were abstracted based on explicit mention of and attribution to CRS in charts. Results: Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (&amp;lt;15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL. Highest incidence of Grade ≥2 CRS was observed among MCL patients, whereas Grade ≥3 CRS was most commonly observed among FL patients. Time to onset of CRS ranged from 0 to 16 days, with median onset between 3-4 days among lymphoma patients and earlier median onset of 1 day for MM patients. Median time to CRS resolution ranged from 2 to 6 days across indications. While 81-95% of patients received CAR-T therapy at an academic center, 5-14% received CAR-T therapy at a community center. Tocilizumab and corticosteroids were the most commonly used treatments for CRS, including 37-48% use of tocilizumab for Grade 1 CRS (Table 2). Discussion: This study uniquely summarizes RWD on CRS following the use of commercially available CAR-T therapies across multiple hematologic malignancies, based on information from clinical notes abstracted retrospectively from EHRs. Consistent with the timing of approval of commercially available CAR-T therapies, the sample size for MM was limited compared with other malignancies. Safety events are typically under-reported in RWD sources, specifically for CRS when relying on information documented in patients' EHRs, compared with other published literature. In accordance with other RWD on CRS, grading criteria for CRS as well as vasopressor and oxygen use were not consistently reported in patients' EHRs. CAR-T treatments were predominantly administered in academic centers. Limited use in community practices was also observed; however, further information to accurately characterize the size and capabilities of community centers was not available in this database. Data also showed considerable use of tocilizumab to treat low-grade CRS, suggesting the need for additional evidence on its role to treat CRS beyond its current regulatory approval. Increased evidence generation, specifically from usual clinical practice, can contribute to increased awareness and knowledge about CRS diagnosis and management, and in turn realize the maximum potential of T-cell therapeutics.

Sustainability pathways in European waste management for meeting circular economy goals

This study explores trends in recycling rates and municipal solid waste landfilling to construct a circularity index (CI) forecasted up to 2035. This projection is contrasted with the pathways that countries must adopt to attain set targets. We further estimate the impact of the CI on factors such as sustainability performance, innovation, commodity trade balance, and waste reduction. Moreover, we provide policy implications useful for designing industrial and environmental strategies, including accelerating permit approval times for waste treatment facilities, introducing more flexibility in state aid rules, empowering service users or waste generators, implementing tax credits, and leveraging specialized funds. These strategies are aimed at supporting the recycling industry to stimulate convergence and achieve circular economy objectives.

Abstract 173: A Case Series of Basilar Tip Aneurysm Endovascular Treatment – The Barrow Neurological Institute Experience

Introduction Basilar‐tip aneurysm (BTA) is the most common aneurysm found in the posterior circulation, representing 5–8% of total intracranial aneurysms. Endovascular techniques are first‐line for treatment of the vast majority of posterior circulation artery aneurysms because of their deep location and the high mortality and morbidity associated with microsurgical clipping. Coil embolization (CE) is safer and more efficacious in the treatment of BTAs compared to open surgery but has increased rate of recanalization. Two adjunctive modifications of CE ‐ balloon remodeling techniques (BRT) and stent‐assisted coiling (SAC) ‐ have been utilized to facilitate occlusion of BTAs of variable anatomies/morphologies, sizes, and rupture status. We aimed to compare the clinical utility, safety and efficacy of these adjuvant therapies for treating BTAs. Methods A retrospective secondary analysis of a prospectively collected database at our institution was performed, including all patients with endovascularly treated basilar tip aneurysms database from January 1996 through January 2019 (n=121; CE=26; BRT=51; SAC=44). This project was approved by the local institutional review board. Patient data on demographics, aneurysmal characteristics and management, post‐operative outcomes, ICU management, and withdrawal of care were abstracted from the medical record of eligible patients. Univariate statistics used Welch’s two‐sample t‐test for continuous data and chi‐squared test for frequency‐based variables. Multivariate analysis used multivariate Poisson and Firth’s logistic regression. Results Aneurysms treated with CE were found to be smaller compared to BAC and SAC, with a median difference of 4 mm. For ruptured aneurysms, Adjuvant therapy (BAC or SAC) was used to treat larger dimension aneurysms compared to CE (p = 0.046). Adjusted for other factors, aneurysm dimension was an independent factor influencing recanalization or recurrence (OR = 1.16, p = 0.006), retreatment (OR = 1.165, p = 0.005), and obliteration (Raymond Roy Grade, continuous, β = 0.033, p = 0.043). Ruptured aneurysms were most frequently treated with CE (80.8%), followed by BAC (47.1%), and least frequently with SAC (6.8%) (p &lt; 0.001). We also found an association with time of approval to retreatment. Stents approved by FDA after 2014 (used in 13 cases) had a greater rate of retreatment (46.2% vs. 10.7%). Adjusted for other factors, BAC had 3 times greater odds of recanalization or recurrence compared to SAC. CE demonstrated a 1.19‐month greater time to retreatment than BAC and a 1.89‐month longer time to retreatment than SAC. Overall, CE had a 1.28‐month greater time to retreatment than adjuvant therapy (SAC or BAC). Conclusion CE and its adjuvant therapies have similar safety profile but pose variable efficacy in terms of obliteration, recurrence, retreatment, and durability over time. This study represents one of the largest data sets on endovascular adjuvant therapy of BTAs and has the potential to inform clinical decision making when considering CE with BRT vs. SAC for BTA of specific size and morphology. In the future, inclusion of BTAs treated with WEB device and more novel flow divertor devices in this data set can further inform clinical decision making.

Impact of the COVID pandemic on functioning of the institutional ethics committee: A comparison study.

In COVID 19 pandemic, it was essential to document the functioning of the institutional ethics committee (IEC), how the organization adapted and faced challenges posed, thus forming the rationale behind this particular audit. The objectives were to assess the impact of the pandemic on the structure, review process, outcomes, and administration of IEC and to compare the same during its functioning in the prepandemic stage. The study was conducted as a retrospective audit. After exemption from ethics review, the data were collected from the IEC office situated in KEM Hospital and were segregated into four domains: structure, review process, outcomes, and administration. The data were analyzed using descriptive statistics. Mann-Whitney U-test was used to compare the turnover time for approval of projects between the two study periods at 5% level of significance. SPSS software version 22 was used to analyze the data. Constitution changed , more protocols pertaining to COVID 19 studies were reviewed, meetings frequency doubled, and Standard Operating Procedures was amended to incorporate the changes faced during pandemic. Significant decrease in turnover time was noticed with respect to submission to query letter and study completion. There were more protocol deviations. Financial burden and expenditure decreased due to less paperwork and meetings being held online. The ethics committee infrastructure and functioning had to undergo a paradigm shift to adapt to the various changes and overcome the various hurdles occurring during the COVID-19 pandemic.