Approved Oncology Drugs Research Articles

Impact of expediting formulary oncology drug approvals at a tertiary care safety net hospital.

410 Background: Advances in drug development and novel clinical trials have resulted in accelerated FDA approvals for oncology agents. These approvals often outpace the speed at which these agents are made “formulary” by hospitals. Non-formulary agents at most organizations need to undergo rigorous regulatory processes before their use and even after the approval for use, ordering them in the EMR poses a significant burden to both providers and pharmacists. Providers need to manually create treatment plans consisting of labs, medications, diluents, and infusion rates for non-formulary agents, consuming valuable time and leaving room for errors requiring extensive pharmacy review. Oncology agents can be considered non-formulary for at least 1 year post-FDA approval before they are approved by the pharmacy and therapeutics (P & T) committee and only 1 agent is approved per meeting. To expedite the formulary approval of oncology drugs, the 1 drug approval per meeting and 1 year post-FDA approval time limit rules were lifted within our institution. Methods: In September 2023, 8 oncology drugs were approved for formulary use by the P & T committee and their pre-built drug templates were established in the EMR. We obtained baseline data to order such non-formulary drugs through EMR prior to formulary approval and when drug templates were not pre-built, requiring manual order entry by providers and review by pharmacists. Baseline data was compared with data obtained post formulary approval and implementation of the pre-builtdrug template. We also created a process map to identify workflow inefficiencies in the formulary drug approval process for further optimization. Results: After the implementation of the pre-built oncology drug templatesand 8 simultaneous formulary drug approvals, the average total time required by physicians and pharmacists was reduced from 97 minutes to 12 minutes per order. The average number of edits made by pharmacists during order review changed from 21 to 4 per treatment order (Table). The use of pre-built drug templates resulted in an 87% reduction in time spent ordering and reviewing agents and an 81% reduction in edits made per drug order. Conclusions: Integration of treatment protocol building quickly into EMR by expediting formulary drug approval significantly reduced physician and staff burden in oncology care at a safety net hospital. Health systems should adopt innovative processes to streamline the formulary approval process and use pre-built drug templates, minimizing staff fatigue and increasing patient safety. Breakdown for provider order entry and pharmacist review with and without drug template. Manual Entry During Non-Formulary Period Template Entry after Formulary Approval Average provider order entry time (mins) 75 6 Average pharmacist review time (mins) 22 6 Average total time taken per order (mins) 97 12 Average edits/order by pharmacist 21 4 mins=time in minutes.

Expedited program and utilization for anticancer drug approval in China and the United States

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Is Canada Moving towards a More Agile Regulatory Approval and Reimbursement Process with a Shifting Role for Real-World Evidence (RWE) for Oncology Drugs?

Canada is known to have a complex pathway for new drug approval and reimbursement, resulting in delayed access for patients with serious and life-threatening diseases, such as cancer. Several recent publications from key stakeholders, including patients, physicians and policymakers, highlight patient helplessness, physician frustrations and policymakers entangled in a massive network of bureaucracy unable to make headway. Several quantitative and qualitative assessments using time from regulatory approvals to successful reimbursements confirm long review times and high rejection rates for oncology drugs, especially those receiving conditional approvals. A consensus forum of 18 Canadian oncology clinicians recently voiced frustration with the process and inability to deliver guideline-supported efficacious therapies to their patients. This manuscript compares data extracted from publicly available data sources from 2019 to June 2024 to previous publications. Methods: Public databases from Health Canada, the Canadian Agency for Drugs and Technologies in Health (CADTH), which is in the process of changing to Canada's Drug Agency, and the pan-Canadian Pharmaceutical Alliance (pCPA) were reviewed and the data collected were analyzed with descriptive statistics. Results: From the data, three trends emerge, (i) an increasing number of oncology drugs are receiving conditional approvals from Health Canada, (ii) the percentage of conditionally approved oncology drugs receiving positive reimbursement recommendations from CADTH is still low but appears to be improving, but delays in access are now contingent upon pCPA deciding whether to negotiate price and then the duration of any negotiation, and (iii) real-world evidence is no longer part of the decision-making for conditional approvals. A slight increase in the positive endorsement of RWE used to support CADTH recommendations was observed. Conclusions: The lack of timely access to oncology drugs hurts Canadian patients. While a small trend of improvement appears to be emerging, longer-term data collection is required to ensure sustained patient benefits.

Index of application status transparency and availability of public information for Project Orbis agencies

The purpose of this paper is to provide a guideline for understanding and comparing the regulatory framework of Project Orbis Partners (POPs) and Project Orbis observers, with a focus on their approaches to drug approvals, rejections, and withdrawals. While each agency has its own regulatory framework and guidance, there are some similarities and differences between the language used to describe drug approvals, rejections, withdrawals, and the public availability of these decisions. Project Orbis is an international partnership of regulatory agency, led by the U.S. Food and Drug Administration (FDA), aimed at streamlining the submission and review processes to expedite the global availability of oncology medications for patients. Since its inception, Australia’s Therapeutic Goods Administration (TGA), Brazil’s National Health Surveillance Agency (ANVISA), Canada’s Health Canada (HC), Israel’s Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, Singapore’s Health Sciences Authority (HSA), Switzerland’s Swissmedic (SMC), and United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) have joined and become POPs. Other international agencies such as, the European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) are currently observing Project Orbis, as of late 2023. They are not full Project Orbis partners but work closely with the FDA to facilitate oncology drug approval through international collaboration. Running Title: An Index of the FDA and international regulators involved in Project Orbis looking at the similarities and differences between approval, rejection, and withdrawal characteristics of applications and public transparency of actions.

Commercial markups on pediatric oncology drugs at 340B pediatric hospitals.

Eligible pediatric hospitals can purchase clinician-administered drugs at discounted rates through the 340B Drug Pricing Program and charge payers prices exceeding drug acquisition costs, but the magnitude of these markups is not known. In a study of newly approved oncology drugs at pediatric 340B hospitals, median negotiated prices ranged from 102% (interquartile range [IQR]: 91%-156%) of average sales price (ASP) at Phoenix Children's Hospital to 630% (IQR: 526%-630%) at Driscoll Children's Hospital. Pediatric hospitals participating in the federal 340B Drug Pricing Program can extract steep payments on new drugs from commercial insurers, though with wide variation between and within hospitals.

Analysis of post-marketing requirements for oncology drug conditional approvals in the United States and China

BackgroundConditional approvals, also known as accelerated approvals, have been introduced by many pharmaceutical regulators around the world, allowing innovative drugs to enter the market earlier on the basis of limited evidence. This research aims to systematically analyze and compare the post-marketing requirements for conditional approvals of oncology drugs in China and the United States. By collecting and categorizing different types of post-marketing requirements, this study seeks to elucidate how these requirements are proposed and discern the underlying logic and patterns. MethodsThis study delved into oncology drug approvals, encompassing FDA accelerated approvals (up to December 31, 2022) and NMPA conditional approvals (from 2017 to December 31, 2022). Leveraging review documents from FDA and NMPA, comprehensive data on product characteristics, all post-marketing commitments and requirements, and especially those related to confirmatory requirements were extracted. The analysis incorporated descriptive statistics, visualizations such as Upset plots, and thorough examination of confirmatory requirement timeframes. FindingsThis study examined 168 FDA accelerated approvals and 41 NMPA conditional approvals for oncology indications. Post-marketing requirements displayed diversity: FDA emphasized confirmatory studies, clinical pharmacology studies, and more, while NMPA predominantly focused on confirmatory studies. Confirmatory requirement timeframes indicated higher FDA-required completion times for new confirmatory trials compared to continued completion of original pivotal trials. In contrast, NMPA's requirement patterns were comparatively singular, with relatively fixed timeframes. FDA's evolving trend showed decreasing timeframes over time, suggesting an increasing demand for timely confirmatory data. InterpretationConditional approvals offer a unique approach to bring potentially life-saving drugs to the market faster, despite limited supporting evidence. Our analysis of oncology drug conditional approvals in the U.S. and China reveals diverse post-marketing requirement patterns. This study provides valuable insights for regulatory decision-making in a dynamic pharmaceutical landscape. Balancing the risks and rewards of conditional approvals is crucial in ensuring both patient safety and timely access to innovative treatments.

An Evaluation of Novel Oncology Approvals with a PMR/C for Assessing Data in Racial and Ethnic Populations Underrepresented in Premarket Clinical Trials.

Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Recent policies have focused on ensuring premarket clinical trials are more inclusive and representative of racial and ethnic diversity in the general U.S. population or intended patient population; however, recent U.S. Food and Drug Administration (FDA) guidance on postmarketing approaches to collecting data in underrepresented populations demonstrates that, in certain circumstances, postmarketing requirements and/or commitments (PMR/Cs) may be issued to conduct more representative studies if there are remaining questions about safety or efficacy. This analysis demonstrates that prior to 2020, no drugs had PMR/Cs to further characterize use in a more representative population, and in the last 3 years, more than half of novel oncology approvals have had such a PMR/C (21/40, 53%). In addition, this analysis helps to identify characteristics, such as single-arm pivotal trial design, U.S. enrollment, and results of safety subgroup analyses based on race and ethnicity, that may contribute to decisions to issue a PMR/C to conduct a study that is more representative of the racial and ethnic diversity of the U.S. or intended patient population. These results can inform efforts to improve premarket clinical trials to ensure they are representative and able to characterize use in any patient who may need the drug.

Reflections and Roadmaps: Career Development beyond the FDA-AACR Oncology Educational Fellowship.

In 2020, the FDA's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This article reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.

Targeting of human cancer stem cells predicts efficacy and toxicity of FDA-approved oncology drugs

Cancer remains the leading cause of death worldwide with approved oncology drugs continuing to have heterogenous patient responses and accompanied adverse effects (AEs) that limits effectiveness. Here, we examined >100 FDA-approved oncology drugs in the context of stemness using a surrogate model of transformed human pluripotent cancer stem cells (CSCs) vs. healthy stem cells (hSCs) capable of distinguishing abnormal self-renewal and differentiation. Although a proportion of these drugs had no effects (inactive), a larger portion affected CSCs (active), and a unique subset preferentially affected CSCs over hSCs (selective). Single cell gene expression and protein profiling of each drug's FDA recognized target provided a molecular correlation of responses in CSCs vs. hSCs. Uniquely, drugs selective for CSCs demonstrated clinical efficacy, measured by overall survival, and reduced AEs. Our findings reveal that while unintentional, half of anticancer drugs are active against CSCs and associated with improved clinical outcomes. Based on these findings, we suggest ability to target CSC targeting should be included as a property of early onco-therapeutic development.

US Food and Drug Administration Approval Summary: Eflornithine for High-Risk Neuroblastoma After Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the US Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, study 3(b), compared with an external control (EC) derived from a National Cancer Institute/Children's Oncology Group-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival hazard ratio (HR) was 0.48 (95% CI, 0.27 to 0.85) and overall survival HR was 0.32 (95% CI, 0.15 to 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable EC data set with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

Quantifying clinical actionability of updated tumor profiling reports through electronic health record (EHR)-enabled, on-demand ordering and resulting.

e13621 Background: Next-generation sequencing reports provide matched therapies and clinical trials based on genomic alterations to drive therapeutic decisions in clinical practice. Biomarker-matched oncology drug approvals and trials have grown tremendously over the past decade. From January 2000 to October 2022 alone, a total of 573 agents were approved for various oncology indications, with nearly half being targeted therapies. While matched therapies and clinical trials are current at time of issue, updated variant classification, changes in FDA approvals, and trials available are not reflected in static reports. It is not always practical nor feasible to provide a new biopsy specimen. To address this gap in clinical care, we piloted Tempus Refresh, an on-demand informatics service that provides clinicians with refreshed therapy and trial matches from prior molecular reports directly through the EHR. Here we quantify the clinical actionability of Refresh reports. Methods: TriHealth piloted the Tempus Refresh orderable through the Epic EHR at the treating physician’s discretion. The clinical team specified prior DNA molecular reports (tissue or blood) to update. Orders were transmitted to Tempus through an HL7 interface. All alterations provided on the prior report were updated for therapeutic and trial matches through existing workflows. An updated structured report was then delivered to the TriHealth Epic EHR linked in the lab tab. Results: From 2/2023 to 11/2023, 10 TriHealth providers participated. A total of 35 unique Refresh orders were placed via custom HL7 Epic order, of which 3 were canceled due to orders outside of pilot parameters. Of the 32 Refresh reports, 34% (11/32) contained new FDA-approved therapies (OncoKB Level 1 or 2), and 78% (25/32) were annotated with new clinical trials. The average elapsed time from original date of report issuance to Refresh order delivery was 14.5 months (range 1 month to 45 months). The mean turnaround time for issuance of a Refresh report was 29 hours (range 5 hours to 53 hours). Conclusions: These results demonstrate that on-demand report updates increase the availability of tumor biomarker-matched therapies and trials. Furthermore, the study exhibits the feasibility of integrating updates directly into the standard EHR clinical workflow. This service provides visibility across teams and can support specialty pharmacists in therapy authorization. Considering the success of this pilot, future studies will assess the expansion of Tempus Refresh to additional sites.

Oncology Drug Approvals Under Health Canada’s Notice of Compliance With Conditions Policy: A Retrospective Cohort Analysis

Health Canada’s Notice of Compliance with conditions (NOC/c) policy provides expedited access to promising new therapies for serious conditions. This retrospective cohort analysis sought to examine the use of the NOC/c policy for oncology drugs, to determine whether confirmatory studies are aligned with the approved indication, and to assess the impact of the NOC/c policy by quantifying the number of oncology drugs approved under this policy that become the standard of care treatment for their respective indications. The findings suggest that Health Canada’s NOC/c policy has been successful in providing expedited access to promising new therapies. However, ensuring that confirmatory trials are under way at the time of NOC/c issuance may provide assurance that studies addressing the uncertainty associated with NOC/c will not be unnecessarily prolonged. The inclusion of real-world evidence (RWE) as part of confirmatory evidence may help fill gaps.

Viewpoint: Reflections on an Analysis of Health Canada’s NOC/c Policy for Oncology Drug Approvals

This project provided an opportunity to examine the data and nuances of oncology submissions processed under Health Canada’s Notice of Compliance With Conditions (NOC/c) policy. While Health Canada's transparency mechanisms typically focus on individual submissions, our examination across all submissions over time provided us with a comprehensive resource. This allowed us not only to observe the extent to which confirmatory studies align with approved indications, but also to understand the impact of our decisions under the NOC/c policy. Looking ahead, this study underscores the importance of maintaining mechanisms for reviewing promising new medications and emphasizes the significance of confirmatory trials. Real-world evidence may play an important role in supplementing confirmatory studies and providing additional support for the use of these products.

Abstract B011: Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer

Abstract Objective: Combination drug regimens have changed the treatment landscape of metastatic urothelial cancer (mUC) and other cancers and are integrated into routine clinical practice. Combination drug regimens may impact cancer outcomes via three major pharmacologic principles: less-than-additive, additive, or more-than-additive efficacy (i.e., synergy). Despite the profound implications of these types of interactions on future drug and biomarker development, as well as on treatment sequencing, these principles have been underexplored in contemporary clinical trials. Here we analyze recent phase 3 trials in locally advanced or metastatic UC to assess whether progression-free survival (PFS) distributions of combination therapies with immune checkpoint inhibitors (ICIs) are lesser than, greater than, or equal to the additive effect expected based on single-agent efficacies. Methods: We analyzed phase 3 trials in locally advanced or metastatic UC including EV302, CheckMate 901, KEYNOTE-361, DANUBE, and IMvigor130. When one monotherapy was not included as an arm in the phase 3 trial, we utilized monotherapy PFS distributions from trials in patients with metastatic UC including EV103, KEYNOTE-045, CheckMate 275, and HCRN-GU17-294. The expected additive effect of a drug combination was calculated by adding the PFS durations of individual drugs, sampled from monotherapy distributions, as recently described for other approved oncology drug combinations (Hwangbo et al, Nature Cancer, 2023). Results: Combination therapies with ICIs were as clinically effective as predicted by additivity, or less so in one case. Specifically, Pembrolizumab plus Enfortumab vedotin (EV302), Nivolumab plus Gemcitabine/Cisplatin (CheckMate 901), Pembrolizumab plus chemotherapy (KEYNOTE-361), and Durvalumab plus Tremelimumab (DANUBE) each exhibited PFS distributions that were statistically indistinguishable from PFS predicted by the additivity model (Cox Proportional Hazards). Atezolizumab plus chemotherapy (IMvigor130) was inferior to additivity. Subgroup analyses by PD-L1 expression and by cisplatin versus carboplatin will be presented. Conclusions: Life-prolonging treatments for mUC have been the result of additive combination therapies, wherein the efficacy of the drug combination is quantitatively explained by the individual efficacies of the component drugs. Additivity in this setting has several potential implications: (1) when a single-agent is principally active in a biomarker-defined subpopulation, the use of that agent in a combination will also principally improve outcomes in that subpopulation; (2) net duration of disease control may be similar between up-front combination and sequential use of the same drugs; assuming that the biology of disease at progression does not preclude the ability to receive subsequent lines of therapy, and (3) future drug development should prioritize combinations based on highly active single agents rather than solely based on hypothesized mechanistic rationale. Citation Format: Noah M. Schlachter, Eric J. Miller, Jonathan F. Anker, Matthew D. Galsky, Adam C. Palmer. Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B011.

Impact of Early Access Reform on Oncology Innovation in France: Approvals, Patients, and Costs.

An ambitious reform of the early access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access to innovative drugs. This study analyzes the characteristics of oncology drug approvals through the EA process and its impact on real-life data for oncology patients. The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS, Haute Autorité de Santé) were reviewed until 31 December 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between 1 January 2019 and 31 December 2022 was also performed using the French nationwide claims database (Systeme National des Données de Santé [SNDS]) to assess the impact of the reform on the number of indications and patients, and the costs. Among 110 published decisions, the HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomized (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EAs. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3137 patients in 2019 to 18,341 in 2022 (+ 484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n=17), lung (n=12), digestive (n=9) and breast cancer (n=9). Reimbursement costs for EA treatments surged from €42 to €526 million (+ 1159%). The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments.

An empirical analysis of overall survival in drug approvals by the US FDA (2006-2023).

The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

US FDA's Dose Optimization Postmarketing Requirements and Commitments of Oncology Approvals and the Impact on Product Labels from 2010 to 2022: An Emerging Landscape from Traditional to Novel Therapies.

Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA's Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs. Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010-2015 and 2016-2022) due to differences in available information. From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes. Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA's Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting.

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.

Abstract A167: Cellular fitness of MYC-driven cancer cells to genetic and pharmacologic perturbations in normoxia, hypoxia and 3D culture

Abstract MYC and hypoxia gene clusters are two most commonly recurring transcriptional programs in a heterogenous tumor. Understanding the cellular fitness of MYC-driven cancer cells in normoxia and hypoxia may lead to identification of cancer cell vulnerabilities. Using genome-wide CRISPR screenings of MYC-driven liver cancer cells cultured in 21% and 1% oxygen in monolayer, and 21% oxygen in 3D spheroid over 4 weeks, we not only identify many targetable essential genes under all three conditions but also context-specific fitness genes and pathways. In parallel, we perform drug screening under three conditions. We find that cells respond to 125 FDA approved oncology drugs in different ways in normoxia, hypoxia and 3D. Our resource study highlights unique epigenetic and metabolic dependency of MYC-driven cancer cells in different tumor environments. Citation Format: Jun Yang. Cellular fitness of MYC-driven cancer cells to genetic and pharmacologic perturbations in normoxia, hypoxia and 3D culture [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A167.

The reimbursement decision speed for oncology new drugs in China and its determinant factors.

China has initiated national price negotiations to improve access to innovative drugs. Learning the factors that contributed to the time gap from marketing authorization to reimbursement leads to more clarity to decision-making, which remains under-researched in China. We collected new oncology drug approvals that were marketed before 30 Jun 2022, using the Listed Drug Database of the Chinese drug agency. Major information of each approval was obtained from the published review report, including the first approval region (China or the US) and the receipt of expedited review pathways (priority review and conditional approval). The reimbursement lists issued by China National Healthcare Security Administration from 2015 to 2023 were used to determine the reimbursement status of drugs. The duration from marketing authorization to reimbursement was defined as the reimbursement decision speed, and the Cox regression was performed to explore the underlying factors. A total of 186 oncology approvals were included. More than half of the approvals qualified for reimbursement (110[59.14%]), and the median reimbursement decision speed was accelerated from 540.5 days in the third-round negotiation to 448 days in the seventh-round. Domestic new drugs had a higher probability of being adopted by the Chinese payer than drugs developed by foreign companies (adjusted HR = 3.73, 95% CI 2.42 to 5.75; P < 0.001). Furthermore, new drug applications receiving the regular review pathway were more likely to be reimbursed (adjusted HR = 2.15, 95% CI 1.13 to 4.08; P = 0.020) compared to those approved under the conditional approval pathway. These findings indicate that the Chinese government is actively working toward improving access to new oncology drugs. The faster reimbursement decision speed for domestic drugs might be attributed to their pricing advantages and the regulator's efforts to stimulate innovation in the domestic pharmaceutical industry. However, concerns about the uncertainty in drug benefits can affect the reimbursement decision-making, which suggests the delicate tradeoff between drug accessibility and risk involved in the reimbursement process.