Regular Approval Research Articles

Sotorasib Treatment Could Worsen the Prognosis of Advanced KRASG12C-Mutated Non-Small Cell Lung Cancer

Sotorasib, the first RAS inhibitor FDA-approved drug for advanced, KRASG12C-mutated non-small cell lung cancer (NSCLC), was approved in May 2021 under the FDA-Accelerated Approval program. This commentary critically reviews the results on progression-free survival (PFS) and overall survival (OS) of the CodeBreaK 200 trial, a randomized, open-label, phase 3 trial published in The Lancet in 2023. The study reported increased PFS with sotorasib based on a reduced hazard ratio (HR). Despite the FDA's rejection of regular approval for sotorasib in October 2023, the accelerated approval status is maintained pending further confirmatory trials. We stress the crucial role of journal editors in ensuring the comprehensive reporting of statistical analyses in RCTs, particularly for publications in highly-ranked journals like The Lancet, which can heavily influence the clinical practice of oncology. Their role in upholding the highest scientific integrity and transparency standards is essential for informing oncologists, patients, and decision-makers of public health systems.

FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

Accelerated Approval for Cancer Drugs in the United States and the Clinical Evidence Required for Conversion to Regular Approval

PurposeOncology products often leverage accelerated approval program to seek earlier launches in the United States. Little is known about how the Food and Drug Administration (FDA) has been balancing evidence and access, and the factors that may characterize post-accelerated approval requirements. The present study aimed to obtain insights on how accelerated approval is determined by investigating the balance between pre-accelerated approval and supplemental clinical evidence required for future regular approval.MethodsThe product properties, pre-accelerated approval evidence, rationale, post-accelerated approval requirements, and prior regulatory designations for oncology accelerated approvals were summarized based on public databases. Regression analyses were performed to investigate factors that may have been associated with the post-accelerated approval requirements.ResultsHundred fifty-seven accelerated approvals were granted between 1992 and 2021. An increase in the number of pre-accelerated approval trials by one trial resulted in a 20% decrease in supplemental trials. The endpoint for the post-accelerated approval trial tended to be more robust when products were indicated for common cancers, while less robust when products had been used to treat fewer subjects, when products were indicated for respiratory and skin cancers, or when less malignant cancers were targeted.ConclusionsAccelerated approvals for oncology products were often based on the response rate of a noncomparative trial. However, considerable variation was observed in the post-accelerated approval requirements. Factors such as the quality and quantity of pre-accelerated approval evidence, regulatory designations, and operational feasibility may have been considered when determining the accelerated approvals and post-accelerated approval requirements.

Characteristics of Clinical Trials for the US Food and Drug Administration Accelerated Approval and Subsequent Confirmatory Trials: Implications for Drug Approval in Japan.

The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.

A seamless phase II/III design with dose optimization for oncology drug development.

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Post-market study requirements and associations with timely submission and regulatory action for oncology drugs receiving accelerated approval, 2011-2023.

11028 Background: For oncology drugs receiving accelerated approval (AA), the Food and Drug Administration (FDA) enforces Postmarketing Requirements (PMRs) to verify clinical benefit prior to regular approval. Although previous work has characterized the rigor and timeliness of confirmatory studies, the association between specificity and scope of PMR statements and the timeliness of PMR submission and ultimate approval status is not well understood. Methods: We identified 161 oncology indications granted AA between January 2011 and July 2023 using FDA’s Cancer AA database. We linked indications to 181 corresponding PMR statements using the Drugs@FDA database. We analyzed PMR statement scope and specificity based on the presence or requirement of eight characteristics: target population, comparator (active or placebo-controlled), randomization, multicenter trial, blinding (double-blind or open-label), enrollment target, follow-up duration, and endpoints. We used chi-square and t-tests to analyze associations between PMR characteristics and two primary outcomes: indication approval status (regular vs. withdrawn) and PMR timeliness (on time vs. late). We defined “late” submissions as PMRs submitted or withdrawals occurring after an expected PMR Final Report submission date. Ongoing PMRs were excluded from the timeliness analysis unless expected dates occurred before August 2023. Results: Among 181PMR statements, 98% percent specified target population, 81% endpoint (44% overall survival), 63% use of randomization, 54% comparator (40% active; 14% placebo-controlled), 30% follow-up duration 26% enrollment targets, 24% multicenter trial, and 13% double-blinding (and 8% open-label). Among AAs converted to regular approval, 82% of PMRs were submitted on time vs. 24% on-time for withdrawn AAs (p=0.001). Regular approval PMRs were submitted 10.2 months ahead of expected dates, whereas withdrawn AAs were submitted 14.5 months behind expected dates (p<0.001). Compared late PMR submissions, on-time PMR submissions had lower enrollment (400 vs. 665, p=0.01), less blinding (19% vs. 40%, p=0.03), more frequent use of a single trial for both AA and PMR (38% vs. 8%, p=0.001), and primary endpoints other than overall or progression-free survival (36% vs. 5%, p<0.001). Compared to late PMR submissions, on-time PMR submissions more often followed PMR statements that specified follow-up duration (39% vs. 13%, p=0.006) and non-survival primary endpoints (30% vs. 8%, p=0.01). Conclusions: There is marked variability in the contents of PMR statements for oncology AA drugs. Several characteristics of PMRs – including smaller enrollment size, surrogate endpoints, and single trials for AA and PMR – are associated with timely submission. These findings inform the specificity and scope of future FDA PMRs for oncology AA indications.

Discrepancies in therapeutic indications for the same oncology drugs among FDA, EMA, and Brazilian agency.

e23035 Background: Divergent marketing approvals for oncology drugs among prominent agencies can prompt questions, especially when they are grounded in the same evidence. The aim of this study was to evaluate and compare the assessment and approval processes for novel products and indications by the FDA, EMA, and the Brazilian Health Regulatory Agency (ANVISA). Methods: Therapeutic indications for FDA-approved anticancer drugs from January 2019 to December 2023 were identified. Data, including approval dates, details on authorization procedures and evidence presented, were extracted from the databases of the FDA, EMA, and ANVISA. Only approvals for non-hematologic solid tumors were considered. All data were publicly available, and ethical approval was not required. No patient involvement occurred in this study. Results: Between 2019 and 2023, the FDA granted approval for 154 therapeutic indications for marketing authorization, resulting from 148 pivotal trials. The predominant cancer types during this period were non-small cell lung cancer (31 approvals [20.1%]). Most trials were in phase III (66.8%) and randomized (68.1%). Additionally, 41 (26.6%) received accelerated approvals, with 6 subsequently obtaining regular approvals. Among the therapies, 66 trials (42.8%) involved active comparators, while 53 (34.4%) and 35 (22.7%) were single-arm and placebo-controlled trials, respectively. Approximately half (74 [48%]) of the therapies were approved for metastatic first-line treatment, 54 (35%) for second-line treatment, and the rest for neoadjuvant and/or adjuvant treatment. Regarding endpoint characteristics supporting approval, the most prevalent was a combination of objective response rate (ORR) + duration of response (DoR) (38 [24.6%]), followed by progression-free survival (PFS) + overall survival (OS) (31 [20.1%]). When comparing the 154 FDA-approved indications, 50 (32.4%) were not approved by EMA, and 60 (38.9%) were not approved by ANVISA. Furthermore, in 33 cases (21.4%), there were disparities in clinical indications between the FDA and EMA, primarily related to the target population specification, with 10 cases (6.4%) attributed to programmed death ligand-1 (PD-L1) expression. Notably, in these instances, the FDA approved the drug regardless of PD-L1 expression, while the EMA required a percentage of cells with PD-L1 expression. In all these cases, ANVISA aligned with the FDA's assessment. Conclusions: Significant clinical disparities were identified in the outcomes of the approval process for oncology products among the FDA, EMA, and ANVISA. Additional efforts are needed to standardize decision-making across regulatory systems.

Biomarkers for Precision Patient Selection in Cancer Therapy Approvals in the US, from 2011 to 2023.

During the period of 2011-2023, the US Food and Drug Administration (US FDA) granted 139 accelerated and 329 regular approvals for 86 and 152 cancer therapeutic products, respectively. The percentage of approvals for a biomarker-defined population was numerically higher in accelerated approvals in comparison to regular approvals, that is, 48% vs. 40%. From 2011-2016 to 2017-2023, there was an increasing number of approvals with biomarker-defined populations in lung and breast cancers, serving as the primary driver for the overall increase in the percentage of approvals for biomarker-defined populations in solid tumors relative to hematological malignancies. Over the years, approvals were incorporating a more diverse collection of distinct biomarkers, from 3 in 2011 to 16 in 2022. Overall, HER2, hormone receptor (HR), EGFR, ALK, BRAF, and PD-L1-defined populations received the highest numbers of approvals. The FDA decision on approving a biomarker-defined or an all-comers population may depend on a number of factors and may evolve over time based on emerging evidence. The review discusses selected FDA approvals where a pivotal trial enrolled an all-comers population but the approved indication was restricted to a biomarker-defined population, as well as challenges in clinical trial design in the context of precision medicine. The prominent role of biomarkers in optimizing trial design and identifying a population most likely to benefit from treatment underlines the significance of a comprehensive understanding of disease biology and drug mechanisms. Our review illustrates that biomarker-driven approaches enhance the likelihood of identifying optimal patient populations, potentially streamlining trials through accelerated approval pathways for cancer drug development.

Comparison Table: Some Topical Drugs for Rosacea.

The FDA has granted regular approval to the oral kinase inhibitor tepotinib (Tepmetko – EMD Serono) for treatment of adults with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval

The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit. To determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit and to evaluate the basis of conversion to regular approval. In this cohort study, publicly available FDA data were used to identify cancer drugs granted accelerated approval from 2013 to 2023. Demonstrated improvement in quality of life or overall survival in accelerated approvals with more than 5 years of follow-up, as well as confirmatory trial end points and time to conversion for drug-indication pairs converted to regular approval. A total of 129 cancer drug-indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with more than 5 years of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years. Fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. Time to withdrawal decreased from 9.9 years to 3.6 years, and time to regular approval increased from 1.6 years to 3.6 years. Among 48 drug-indication pairs converted to regular approval, 19 (40%) were converted based on overall survival, 21 (44%) on progression-free survival, 5 (10%) on response rate plus duration of response, 2 (4%) on response rate, and 1 (2%) despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 of 48 (38%) were unchanged, while 30 of 48 (63%) had different indications (eg, earlier line of therapy). Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes.

Abstract 923: Biomarker use in oncology approvals in the US

Abstract Introduction: Precision medicine through the use of biomarkers has revolutionized the way we understand and combat cancer. We are summarizing the current state and challenges of biomarker use in the context of cancer therapeutic products approved by the United States Food and Drug Administration (FDA). Methods: We curated a dataset of oncology therapeutic products approved by the FDA through the regular and accelerated pathways from 2011 to 2022, based on publicly available FDA database, approval letters and reviews, prescribing information, publications, and clinicaltrial.gov. Results: During the period of 2011 to 2022, the FDA granted 132 accelerated and 331 regular approvals for 80 and 144 oncology therapeutic products with 133 and 340 new indications, respectively. The percentage of approvals for a biomarker-defined population was higher in accelerated approvals in comparison to regular approvals (i.e., 51% vs. 39%). The five disease sites with the highest number of approved indications were leukemia, lung, non-Hodgkin lymphoma, breast, and skin. The vast majority of lung and breast cancer indications were approved in a biomarker-defined population through a range of different biomarkers. Overall, HER2-, EGFR-, BRAF-, HR-, and ALK-defined populations received the highest numbers of approvals. The most common biomarkers linked to the approval of a specific cancer type include Philadelphia chromosome for leukemia, EGFR/ALK for lung cancer, HER2/HR for breast cancer, BRAF for skin cancer, and BRCA for ovarian cancer. Multiple myeloma, kidney cancer, and Hodgkin lymphoma did not have any approval with a biomarker-defined population. Non-Hodgkin lymphoma had a large number of approvals, but the percentage approved for a biomarker-defined population was small. dMMR, MSI-H or dMMR, BRAF mutation, NTRK fusions, TMB H, and RET fusions are biomarkers linked to tissue-agnostic indications approved for solid tumors only through the accelerated pathway. Conclusion: To the best our knowledge, the analysis represents the most comprehensive overview of the current landscape on integration of biomarker in oncology therapeutic products approved by the FDA through both the accelerated and regular pathways. Our analysis shows that the FDA has increasingly approved indications based on biomarkers, particularly through the accelerated approval pathway. Biomarkers are reshaping cancer therapy under an evolving regulatory landscape with a growing emphasis on precision medicine that promises continued progress in personalized cancer care. Citation Format: Yannan Nancy Dou, Christian Grimstein, Jian Wang, Jacques Mascaro. Biomarker use in oncology approvals in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 923.

Rehabilitation for Post-COVID Syndrome covered by the German Pension Insurance in 2021

The present work is intended to give an overview of rehabilitation of patients with post COVID-19 condition covered by the German Pension Insurance in 2021. Cross-sectional analysis of medical rehabilitation completed in 2021, in which COVID-19 sequelae were coded in first or second place in the uniform discharge report according to the International Statistical Classification of Diseases and Related Health Problems was carried out. The codes U08(.9), U09(.9) and U10(.9) as well as the corresponding codes from 2020 were taken into the evaluation as COVID-19-related diseases. Children's rehabilitation and oncological rehabilitation for pensioners and their relatives were excluded. Statistically, relative and absolute frequencies are given for nominal and ordinal variables, and median and quartiles for continuous, skewed distributed variables. 9,666 rehabilitations with one of the codes mentioned in first or second place remained. 54.8% of the patients were women and 43.2% men. The median age was 54 and 55 years (women/men). In all, 64.4% of the rehabilitations were carried out in the pulmonary medicine department. Owing to somatic indications, almost 50% of these patients in rehabilitation remained in the clinic beyond the regular approval period. The most common other diagnoses were diseases of the respiratory system. In 80.7% of those affected, the treating physicians considered the post-COVID-19 condition-associated symptoms as improved through rehabilitation. Furthermore, employment was subject to social security contributions for 88.0% of these patients, and 30.5% were employed in the fields of health, social affairs, teaching, and education. Of those affected, 63.8% were on sick leave when they were admitted, 63.0% when they were discharged. With regard to performance in the last job or on the general job market, over 90.0% received a prognosis for 6 hours and more. The importance of post-COVID-19 condition in the context of medical rehabilitation increased significantly over the course of 2021. The disease causes long periods of disability. With regard to performance, the available analyses give a positive picture; only 6.5% of those individuals undergoing rehabilitation were assessed as having a reduced capacity to earn of less than 3 hours on the general labor market.

National Comprehensive Cancer Network Guideline Recommendations of Cancer Drugs With Accelerated Approval

Many cancer drugs are approved under the US Food and Drug Administration (FDA) accelerated approval pathway based on preliminary evidence. It is unclear how this limited evidence is integrated into the National Comprehensive Cancer Network (NCCN) guidelines, which are common references for clinicians and are used by public and private payers to determine reimbursement for oncology treatments. To analyze the NCCN guidelines' assessments for cancer drug indications that received FDA accelerated approval compared with cancer drug indications that received FDA regular approval. This cross-sectional study analyzes FDA-approved indications for cancer drugs that were granted accelerated approval from program inception in 1992 to June 30, 2022. For each drug, the FDA-approved labeling was reviewed to identify all indications. All analyses were performed at the drug-indication level. The exposure was FDA regulatory status as of October 2022, including regular approval, accelerated approval, accelerated approval converted to regular approval, and withdrawn accelerated approval. The level of evidence and consensus (category 1, 2A, 2B, and 3) and treatment preference (preferred, alternative preferred, other recommended, and useful in certain circumstances) ratings assigned by NCCN committees as of February 2023. A total of 315 oncology indications for 100 drugs were analyzed. These indications included 156 (50%) with regular approval, 60 (38%) with accelerated approval, 78 (49%) with accelerated approval that was converted to regular approval, and 21 (13%) with withdrawn accelerated approvals. Among all indications, 105 (33%) were rated by the NCCN as having category 1 evidence, 185 (59%) with category 2A, 6 (2%) with category 2B, and 2 (1%) with category 3 evidence. Compared with indications with regular approval, those with accelerated approval were less frequently assigned category 1 evidence (47% vs 3%; P < .001) and were less often listed as preferred treatment options (58% vs 40%; P = .008). Among the 21 withdrawn accelerated approval indications, 8 (38%) remained in the NCCN guidelines, with most having level 2A evidence ratings. This study found that cancer drug indications with accelerated approval were less likely to be assigned high-level evidence ratings and preferred status in the NCCN guidelines compared with indications with regular approval; most accelerated and regular approval drugs had low-quality evidence ratings but high levels of consensus among oncologists on NCCN committees. Greater clarity on the thresholds and definitions of evidence levels would make the NCCN guidelines more useful to clinicians, patients, and payers.

Use of Single-Arm Trials in FDA Approvals of Treatments in Relapsed or Refractory B-Cell Lymphoma

Background: Single-arm trials are commonly used to evaluate therapies targeting life-threatening or rare diseases (e.g., late-stage cancers that are relapsed or refractory to prior interventions). A number of oncology products supported by single-arm trials have been approved by the United States Food and Drug Administration (FDA). The draft guidance issued by the FDA on 24 March 2023 recommended key considerations for trial design and analysis when a single-arm trial is considered appropriate to support accelerated approval. The objective of this study was to assess how often anticancer drugs approved by the FDA were based on single-arm trials in a typical relapsed or refractory indication and to evaluate the quality of trial design and data leading to approvals. Methods: We reviewed past approvals between 2006 and 2023 listed on the FDA website, focusing on the indication of relapsed or refractory B-cell lymphoma. Of 11 approvals identified, eight were supported by single-arm trials and three were based on randomized controlled trials. Approvals based on single-arm trials were further investigated, and each trial was analyzed for the following criteria as recommended by the draft FDA guidance: 1) if the endpoint was based on response rate assessed using appropriate criteria; 2) if the sample size was sufficient to provide robust estimates of efficacy and safety profile; and 3) if the magnitude and duration of response were adequate. Results: Among the eight approvals based on single-arm trials, one was approved in 2017, one in 2018, and two each in 2020, 2021, and 2023. Three were chimeric antigen receptor T-cell (CAR-T) therapies and were granted regular approval; the other five were non-CAR-T therapies which were granted accelerated approval. The primary endpoints adopted by all the trials were overall response rates (defined as complete and partial responders) and duration of response determined by an independent review committee. The magnitude of overall response rates reported by most trials ranged from 48% to 72% (with more than 50% of them with a complete response); one trial reported an overall response rate of 29% with complete response rate of 13%. A minimal median follow-up of six months after response was achieved in all trials. The estimated median duration of response varied from 10.3 to 21.7 months, with three trials reporting medians not reached. Based on the trial description, the analysis population was pre-specified for the evaluation of efficacy, ranging from 68 to 192 participants. Conclusion: Submissions based on single-arm trials for oncology therapies in the relapsed and refractory setting tended to be well accepted by FDA for accelerated and regular approval when the key criteria of trial design and data quality were adequately met.

Evaluation of Alectinib Metabolic Stability in HLMs Using Fast LC-MS/MS Method: In Silico ADME Profile, P450 Metabolic Lability, and Toxic Alerts Screening.

Alectinib, also known as Alecensa®, is prescribed for the therapeutic treatment of individuals diagnosed with metastatic non-small cell lung cancer (NSCLC) who have a specific genetic mutation referred to as anaplastic lymphoma kinase (ALK) positivity. The Food and Drug Administration granted regular approval to alectinib, a drug developed by Hoffmann-La Roche, Inc. (Basel, Switzerland)/Genentech, Inc. (South San Francisco, CA, USA), on 6 November 2017. The screening of the metabolic stability and identification of hazardous alarms within the chemical structure of ALC was conducted using the StarDrop software package (version 6.6), which incorporates the P450 metabolic module and DEREK software (KB 2018 1.1). The primary aim of this investigation was to develop a high-throughput and accurate LC-MS/MS technique for the quantification of ALC in the metabolic matrix (human liver microsomes; HLMs). The aforementioned methodology was subsequently employed to assess the metabolic stability of ALC in HLMs through in vitro tests, with the obtained results further validated using in silico software. The calibration curve of the ALC showed a linear correlation that exists within the concentration range from 1 to 3000 ng/mL. The LC-MS/MS approach that was recommended exhibited accuracy and precision levels for both inter-day and intra-day measurements. Specifically, the accuracy values ranged from -2.56% to 3.45%, while the precision values ranged from -3.78% to 4.33%. The sensitivity of the established approach was proved by its ability to adhere to an LLOQ of 0.82 ng/mL. The half-life (t1/2) and intrinsic clearance (Clint) of ALC were estimated to be 22.28 min and 36.37 mL/min/kg, correspondingly, using in vitro experiments. The ALC exhibited a moderate extraction ratio. The metabolic stability and safety properties of newly created derivatives can be enhanced by making modest adjustments to the morpholine and piperidine rings or by substituting the substituent, as per computational software. In in silico ADME prediction, ALC was shown to have poor water solubility and high gastrointestinal absorption along with inhibition of some cytochrome P450s (CYP2C19 and CYP2C9) without inhibition of others (CYP1A2, CYP3A4, and CYP2D6) and P-glycoprotein substrate. The study design that involves using both laboratory experiments and different in silico software demonstrates a novel and groundbreaking approach in the establishment and uniformization of LC-MS/MS techniques for the estimation of ALC concentrations, identifying structural alerts and the assessment of its metabolic stability. The utilization of this study strategy has the potential to be employed in the screening and optimization of prospective compounds during the drug creation process. This strategy may also facilitate the development of novel derivatives of the medicine that maintain the same biological action by targeted structural modifications, based on an understanding of the structural alerts included within the chemical structure of ALC.

Impact of the US Accelerated Approval for New Anticancer Drugs on Time to Verification of Benefit and Regulatory Approval in the EU and Japan.

The accelerated approval (AA) program in the USA has succeeded in expediting the regulatory approval of new cancer drugs based on surrogate endpoint data. It is unclear whether the AA program promotes overall drug development, including verification of the clinical benefit, as the verification of drugs granted AA often takes long time. To determine the impact of the AA program on overall drug development, the time required for verification of clinical benefits was compared between anticancer drugs that initially received AA and those that received regular approval (RA). It was found that anticancer drugs that were approved under the AA program took longer time for verification, suggesting that the program may delay the start of a confirmatory study, and there may be room for speeding up the process. In addition, discordance was found in the pivotal study between the USA and the EU and the USA and Japan for obtaining the indication for which AA was granted in the USA and a delay in the start of the confirmatory study for the AA indication was considered to lead to a delay in approval in the EU and Japan. Early initiation of confirmatory studies for AA indications is recommended to reduce the time that patients receive drugs with unproven benefit in the USA, as well as to deliver innovative new drugs to patients earlier in the EU and Japan.

Framing the statistical criteria for accelerated approval of oncology drugs: A pathway for front runners

FDA has recently proposed a one-trial approach in Project FrontRunner for both accelerated approval and regular approval in the same trial. The goal of this short communication is to make the regulatory criteria for decision-making on accelerated approval based on the interim analysis more explicit. Two related high-level statistical issues are addressed under simplified yet representative scenarios. The first is at what Type I error level should the interim analysis be tested? To conform with the conventional two-trial approach, it may be tested at the 1.0% level without paying penalty for regular approval. This criterion is more relaxed than current practice. The second is what may be considered as adequate totality of evidence for accelerated approval. It turns out that, with the first criterion met, the observed treatment effect of the clinical endpoint intended for regular approval needs to be close to the target effect for the study. The criterion helps make the regulatory decision more transparent and objective.

Real-world use, dose intensity, and adherence to enfortumab vedotin (EV) in locally advanced or metastatic urothelial cancer (la/mUC).

e16567 Background: EV, the first antibody drug conjugate approved for la/mUC, received accelerated approval in the US in 2019 as later-line therapy (post-immunotherapy and platinum-chemotherapy) and regular approval in 2021 with label expansion to include earlier-line therapy (cisplatin-ineligible, ≥1 prior therapy). Because EV delivery per current labelling (1.25 mg/kg, D1, 8, 15 of a 28D cycle) may differ from routine practice, we examined real-world EV use, dose intensity and adherence across 280 US cancer clinics. Methods: This descriptive post-marketing retrospective cohort study used the Flatiron Health longitudinal database derived from EHR records of US patients with la/mUC initiating EV on or after December 19, 2019. We summarized EV use, including but not limited to: % cisplatin-ineligible, and median duration of use and number of cycles administered. We computed metrics of dose intensity: average treatment rate (mean number of treatments per patient-month), dosing frequency (mean number of treatments per cycle), dose (mean dose, mg/kg), and % change in dose (mg) from baseline (difference in dose between last recorded treatment in last cycle and first recorded treatment in first cycle). Finally, we measured treatment adherence, defined as % of cycles across all patients where a patient had &gt; 2 treatments per 28D cycle. Results: Among patients with la/mUC, we identified 416 EV users (mean [SD] age 71 [9] years, 27.4% female, 24.8% non-white, 70.2% prior smokers, 17.5% ECOG 2+, 81.5% from community sites). EV use, dose intensity, and adherence are shown (table). Most were cisplatin-ineligible (55%). Average dosing frequency (2.4 [0.5] treatments per cycle) and dose (1.1 [0.2] mg/kg) were lower than label indication guidelines; 58.8% received &gt; 2 treatments per 28D cycle. Conclusions: Among la/mUC patients treated with EV in contemporary practice, treatment frequency and dosing were lower than recommended in the product labelling. Further research is required to understand clinical factors and outcomes associated with the differences observed. [Table: see text]

Clinical practice guideline descriptions of oncologic drugs granted FDA accelerated approval: A cross-sectional study.

1590 Background: The Food and Drug Administration’s (FDA's) accelerated approval (AA) pathway allows drugs to be approved using surrogate endpoints, while requiring that sponsors complete postmarketing requirement (PMR) studies verifying clinical benefit. Subsequently, FDA determines whether AA can be converted to standard approval or be withdrawn. It is unclear whether clinical practice guidelines reflect PMR results or FDA regulatory decisions. As most drugs granted AA are cancer therapies, we investigated whether and how National Comprehensive Cancer Network (NCCN) guidelines reflect underlying evidence supporting AAs and subsequent FDA decisions. Methods: In this cross-sectional study, we used Drugs@FDA to identify drug indications granted AA by FDA for oncologic indications from 2016-2018, PMR status and results, and whether AA was converted to regular approval or withdrawn. We excluded pediatric and tumor-agnostic indications. PMR studies were classified as positive if the results from primary efficacy endpoint were statistically significant ( P&lt;0.05) favoring the drug. For each AA indication, we searched relevant NCCN guidelines for their recommendations and examined if AA status, PMR results, and updated FDA decisions were reflected. Results: Among 36 oncology drug indications granted AA from 2016 to 2018, 29 (81%) NCCN guidelines did not mention that the drug was approved via AA pathway or had not yet verified clinical benefit. For all 36 (100%) indications, NCCN guidelines did not state that approval was based on surrogate endpoints. As of December 31, 2022, among 16 drug indications that were converted to standard approval, 13 (81%) guidelines reflected FDA’s updated decisions. Among 8 indications withdrawn after AA, 5 (63%) guidelines reflected the withdrawn status. Of 6 drug indications with negative PMR study results that were withdrawn, 2 (33%) were still recommended in NCCN guidelines thereafter. Conclusions: NCCN guidelines do not consistently reflect FDA regulatory status or PMR study results, highlighting the need for more up-to-date and accurate information to guide clinical practice.[Table: see text]