Accelerated Approval Pathway Research Articles

Accelerated approvals: Early-phase success or premature authorization?

We compare the clinical trial success rates of products receiving US Food and Drug Administration (FDA) accelerated approval (AA) to those approved without using this pathway. Our findings raise important questions about how the AA pathway can best optimize early access to therapeutics that are ultimately proven safe and effective.

Quality risk management and data integrity in R&D laboratories supporting CMC lifecycle of biological products

The development of pharmaceutical products is the critical bridge that moves a potential new medicine from academic discovery to applied treatment of patients. It translates an idea for a new drug to bench-level research on how it can be manufactured, formulated, characterized and controlled for use in non-clinical and early clinical trials.From pre-clinical R&D discovery work through the commercial launch, substantial R&D CMC data is generated to develop and optimize cGMP manufacturing and testing operations, while also supporting product comparability, elucidating product / impurity structures, assessing critical quality attributes, developing the drug delivery mode, and developing the product formulation for long-term stability. Significant R&D CMC work continues post-approval to support continuous improvement and market expansion of the commercial product. These activities are crucial elements of Product Lifecycle Management, and taken together, they comprise Pharmaceutical Quality or Chemistry, Manufacturing and Controls (CMC). The objective of this paper is to mitigate the regulatory ambiguity of R&D quality systems with practical, risk-based examples and recommendations when conducting supportive CMC studies for biological products.Making sound strategic CMC decisions under any circumstances assumes data from R&D studies are reliable, traceable, and complete. While there are specific regulatory guidelines on phase-appropriate cGMP activities, none exist for quality practices in R&D CMC laboratories conducting non-cGMP studies. Hindsight is not the time to discover that R&D studies lack key elements that would otherwise have allowed the data to be directly presented to regulators, if needed. There is a strong prospective business interest in protecting considerable investments made for CMC R&D studies. Therefore, establishment of a robust and stage-appropriate R&D laboratory quality system is essential for companies seeking to capitalize on prior knowledge, protect investments, and be prepared for accelerated approval pathways.

Analysis of cancer drugs receiving FDA’s Accelerated Approval between 1992 and 2021

Abstract Objectives This cross-sectional study examines the Food and Drug Administration (FDA)’s Accelerated Approval (AA) pathway for cancer drugs from 1992 to 2021, which expedites the development and approval of new drugs, including biologics, for severe or life-threatening conditions such as cancers. Methods Based on the ‘CDER Drug and Biologic AAs Based on a Surrogate Endpoint’ report, the number of indications where anticancer agents received AA and the conversion rates to Full Approval (FA) were analysed. Outcome measures used in phase II and phase III trials for these drugs were obtained from US National Library of Medicine for comparison. Key findings Of the 278 AA-granted indications, 67% were for anticancer agents. Lymphoma, leukemia, and lung cancer had the highest number of AA indications among all cancer types. The conversion rates to FA varied among periods: Early (1995–2003), Middle (2004–2012), and Late (2013–2021). The conversion rates for drugs were 82%, 79%, and 31%, while biologics exhibited rates of 100%, 78%, and 27%, respectively. The overall response rate was often the primary outcome measure in phase II trials, whereas overall survival and progression-free survival were the common outcome measures in phase III trials. Secondary outcome measures included disease control rate and duration of response. Conclusions This study provides valuable insights for stakeholders seeking to understand the approval criteria and processes for cancer drugs via the AA pathway. However, limitations in data availability, phase-specific variations in drug doses and combinations, and the inability to manage uncertain data should be acknowledged. Research on the AA program to non-cancer drugs is also required.

The reliability of evidential pluralism in drug regulation

The aim of this paper is to shed light on and critically evaluate the potential impact of evidential pluralism in the realm of pharmaceutical regulation. In the complex landscape of drug evaluation and approval, the role of evidence is pivotal. Firstly, we delve into the role of evidence of mechanisms within drug regulation, with a particular focus on the Accelerated Approval pathway administered by the US Food and Drug Administration. Our analysis reveals that this program, in practice, closely resembles a pluralistic approach to evidence. Secondly, we undertake a thorough examination of the reliability of evidential pluralism within the context of drug regulation. We dissect and discuss the open-cases approach recently put forth by Sung and Holman. While acknowledging its potential merits, we also identify and articulate significant limitations inherent in this approach. Finally, we propose an alternative empirical approach that centres on the real-world outcomes of regulatory programs.

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.

Commercial health plan spending on oncology drugs approved via the accelerated approval pathway and later withdrawn from the market.

11134 Background: The U.S. Food and Drug Administration (FDA) introduced the Accelerated Approval Program in 1992 to expedite the approval of drugs that can be used to treat certain conditions and fill an unmet medical need. Clinical trials conducted to achieve accelerated approval status often use surrogate outcomes as primary endpoints to reduce the time it takes to get FDA approval. Drug manufacturers must conduct further research to verify and report the projected clinical benefit and safety. The FDA may issue traditional approval to previously accelerated approved drug or may request the manufacturer to withdraw a drug from the market based on the clinical benefit and/or safety demonstrated in the confirmatory trial(s). We report members impacted, total drug claims, and total drug cost incurred by a commercial health plan associated with the coverage of oncology drugs approved by the FDA and later withdrawn from the market between 2020 to 2023. Methods: Fifteen unique indications associated with oncology drugs that received accelerated approval and later withdrawn by the FDA were identified between 2020 to 2023. A cohort of patients enrolled in commercial health plan was further identified using the ICD-10 code related to the drug indication being withdrawn. To calculate total paid amount for drugs, de-identified administrative claims data submitted on behalf of this cohort were sorted and summed in this time period using either J-code for drugs covered under medical benefits or national drug code (NDC) for drugs covered under pharmacy benefits. Results: Between 2020 to 2023, 8 oncology drugs were withdrawn because of later failing to demonstrate clinical benefit in the confirmatory trials, 2 drugs were withdrawn due to safety concerns, and 5 drugs were withdrawn due to drug manufacturer unable to complete a confirmatory trial. In this population, we identified 18,430 unique members with 103,743 administrative claims. The total paid amount was $1,392,553,995 in this time period. The average drug cost per administrative claim was $13,423 and the average drug cost per member was $75,559. Conclusions: Drug costs established by manufacturers are not differentiated based on the approval status - accelerated or regular. While drugs approved via accelerated approval pathway may provide benefit to certain patient population, the cost associated with accelerated approved drugs needs more attention. Indication-specific pricing model may help alleviate the cost burden associated with drugs approved via accelerated approval pathway. [Table: see text]

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.

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.

The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women

BackgroundMakena (17-hydroxyprogesterone caproate) was FDA approved for prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway but fundamental pharmacokinetic or pharmacodynamic (phase1 and phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data questions whether the dosing regimen for 17-hydroxyprogesterone caproate was optimized. ObjectiveThe purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing three data sets that evaluated 17-hydroxyprogesterone caproate pharmacology: the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. Study DesignData from the Omega 3 study were utilized to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. ResultsAnalysis of the Omega 3 dataset indicated that the risk of spontaneous preterm birth decreased as the log of 17-hydroxyprogesterone caproate increased [odds ratio (95%CI) 0.04 (0.00 - 0.90)]. A steady state concentration> 9 ng/ml (equivalent to > 8 ng/ml at 25-28 weeks) was associated with the lowest risk of spontaneous preterm birth [hazard ratio (95%CI) 0.52 (0.27-0.98, p=0.04)]; this concentration was not achieved in 25% of subjects receiving the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and IQR) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, > 5 weekly injections were required to reach the 9 ng/ml target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/ml concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/ml concentration within two weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/ml target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects receiving a weekly dose of 500 mg exceeded the 9 ng/ml steady state. ConclusionsThe dosing regimen for 17-hydoxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. Risk is lowest when concentration exceeds 9 ng/ml but 25% of women receiving the 250 mg weekly dose will never reach and maintain this concentration. The drug’s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

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.

The value of the accelerated approval pathway: real-world outcomes associated with reducing the time between innovations.

Aim: We investigated the effect of shortening time between innovations with the accelerated approval (AA) pathway on patient outcomes for three solid tumors. Methods: This real-world analysis evaluated patients receiving sequential AA pathway-approved innovations after initial treatment with existing therapies in three solid tumor case studies. Outcomes attributable to AA were estimated and assumed approval occurred at the time of conversion to approval and extrapolated to the US population. Results: Survival gains from accessing innovative therapies were 2.3-3.8-times higher when using the AA pathway. At the US population level, AA was associated with ∼8000 life-years gained across all three tumor case studies. Conclusion: In areas of rapid clinical development, the value of existing therapies can be enhanced by earlier access to AA pathway innovations and should be considered when evaluating the AA program.

Development of a Comprehensive Regulatory Model for Medical Devices

Abstract Background: The development of a comprehensive regulatory model for medical devices is essential to ensure the safety, efficacy, and quality of medical devices throughout their lifecycle, from design and development to post-market surveillance. This paper outlines a robust framework for such a regulatory model, detailing key components and processes necessary for effective regulation. Methods: The data and literature were collected from various databases including Springer, Science Direct, Taylor and Francis, Wiley, Bentham Science, and websites of different regulatory agencies. The collected data were utilized in the research work to formulate the new regulatory model. Results: Different guidelines represent acceptable regulatory practices for all medical items. There are four risk classification levels of the medical devices (class I–IV, based on the risk level). For every country, the regulatory requirements are different. Global regulations for medical device approval are essential to guaranteeing their quality, safety, efficacy, and performance before they can be put on the market to safeguard, prevent, enhance, and maintain public health. Different classes have different regulatory steps for approval of the devices, which varies from region to region. The World Health Organization’s Department of Essential Health Technologies’ Diagnostic Imaging and Medical Devices team has developed and implemented the Baseline Country Survey on Medical Devices. The proposed model includes the establishment of a clear legislative and regulatory framework, featuring a risk-based classification system aligned with international standards. It emphasizes rigorous pre-market requirements, including design controls, clinical evaluation, quality management systems, and technical documentation. Market authorization processes are described, highlighting pathways such as Premarket Notification (510(k)), Premarket Approval (PMA), and De Novo Classification, supported by thorough scientific review and expert advisory panels. The present study is all about the global requirements of the regulation of the medical devices and it was concluded that overall, a global comprehensive regulatory model for medical devices aims to strike a balance between ensuring patient safety, facilitating innovation, and enabling timely access to life-saving medical technologies around the world. Conclusion: The model advocates for international harmonization and collaboration, promoting regulatory convergence and the adoption of global standards. It also supports innovation through accelerated approval pathways and regulatory sandboxes, alongside continuous improvement driven by regulatory science research and stakeholder engagement. By integrating these elements, the comprehensive regulatory model aims to protect public health while fostering medical device innovation and ensuring global regulatory compatibility.

Subcutaneous (SC) lecanemab is predicted to achieve comparable efficacy and improved safety compared to lecanemab IV in early Alzheimer’s disease (AD)

AbstractBackgroundLecanemab is an anti‐amyloid antibody that has been approved by the United States FDA for treatment of early AD under the accelerated approval pathway. Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously (IV) was shown in the CLARITY‐AD trial to slow the progression of AD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady‐state concentrations (Cav,ss) are associated with amyloid plaque lowering and efficacy, while maximum steady‐state concentrations (Cmax,ss) are correlated with the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). SC lecanemab is being developed to improve patient convenience and safety profile by lowering the rate of ARIA‐E.MethodTwo single‐dose studies (NCT05045716 and NCT05533801) were conducted in healthy subjects to establish absolute bioavailability of a drug‐in‐vial (SC vial) formulation and to compare PK of SC vial and autoinjector (AI). In the first study, subjects were administered 10 mg/kg IV Q2W or 700 mg SC vial once‐weekly (QW) lecanemab (n = 30/arm). In the second study, subjects were administered 720 mg SC vial or 720 mg AI lecanemab (n = 80/arm). Serum lecanemab concentrations were measured for 50 days, and noncompartmental PK parameters were calculated.ResultThe absolute bioavailability of SC vial was 49.7% (90%CI:43.5‐56.8). Cmax following SC vial was 22.8% of IV (59.8 vs 262 µg/mL). AI had 20% higher AUC than SC vial (20900 vs 17400 µg.h/mL). PK modeling demonstrated that Cav,ss following 720 mg QW, administered by SC vial or AI, is similar to 10 mg/kg IV lecanemab. Cmax,ss following SC vial or AI will be approximately half that of IV. Based on these results, exposure‐response models predict similar amyloid plaque lowering and efficacy for IV, SC vial and AI. ARIA‐E rates are expected to be reduced with SC formulations (APOE4 carriers, IV:14.0%, SC Vial:4.8%, AI:5.6%; APOE4 noncarriers, IV:5.4%, SC Vial:1.7%, AI:2.0%).Conclusion720mg QW using SC vial or AI results in comparable Cav,ss to 10 mg/kg Q2W IV lecanemab and is expected to have similar amyloid plaque lowering and efficacy. SC lecanemab has the potential to substantially lower incidence of ARIA‐E compared to IV. Ongoing studies will confirm the safety and efficacy profiles of SC lecanemab.

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.

Who goes first? Patterns of cancer drug approvals across four major regulatory authorities: EMA, FDA, Health Canada, and PMDA.

149 Background: New anticancer therapies have led to substantial improvements in prognosis across many cancers. Commercial access to a drug is not possible until the drug has received regional regulatory authority market authorization. In prior work (1), we found that European Medicines Agency (EMA) drug approvals frequently lagged US Food and Drug Administration (FDA) approvals from 2010-2019. Here, we expand the analytic time period to 2004-2023 and include two additional regulatory agencies – Health Canada (HC) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Methods: Drugs with an anticancer indication and first global approval from 2004-2023 were preliminarily identified. Only drugs with an approval by all 4 regulators were included. For each drug, the first and last regulator’s initial approval dates were determined, and the interval between first and last approval was calculated. For drugs approved by all 4 regulators within 1 year (y), it was further determined whether they were considered first-in-class. Results: 209 drugs met the preliminary criteria, and 98 (47%) had approvals by all 4 regulators. The FDA was most commonly the first to approve (84 drugs), followed by PMDA (9 drugs), then EMA (5 drugs); HC was never first to approve. 43 of the FDA-first approvals (51%) were by the accelerated approval (AA) pathway; none of the EMA-first approvals were on the conditional marketing pathway. PMDA was most commonly the last to approve (62 drugs), followed by HC (21 drugs), the EMA (14 drugs), then the FDA (1 drug). The median (IQR) time between first and last regulator’s first approval was 2.4 y (1.3-3.5 y). Some drugs had &gt;5 y between first and last regulator’s approval (Table 1). Conversely, only 16 drugs were approved by all regulators within 1 y, and only 1 drug (isatuximab) was approved by all within 6 months. Of the 16 drugs approved within 1 y by all regulators, 6 (37.5%) were first-in-class: asciminib, elotuzumab, idecabtagene vicleucel, inotuzumab ozogamicin, sotorasib, and trastuzumab emtansine. Conclusions: This study shows that patients with cancer in the US usually have access to new cancer drugs earlier than those in Europe, Japan, and Canada, at least in part due to AA pathways. Less than 8% of newly approved cancer therapies are approved by all 4 regulatory agencies within 1 y of first approval, with a lengthy median first-to-last delay that could exceed the life expectancy of many patients with advanced cancer. Greater global regulatory collaboration in the approval of new anticancer drugs is essential to ensure patients have aligned and coordinated access. (1) Lythgoe et al. JAMA Network Open 2022.[Table: see text]

1706P Time to full approval of novel anticancer medicines granted accelerated approval and implications for reform of the accelerated approval pathway

1706P Time to full approval of novel anticancer medicines granted accelerated approval and implications for reform of the accelerated approval pathway

Use of patient-reported outcome measures for oncology drugs receiving accelerated approval.

Patient-reported outcomes (PROs) represent an important evaluation of health-related quality of life that has become more commonly incorporated into oncology drug clinical trials. The frequency of PRO inclusion as an endpoint in oncology drug clinical trials leading to the initial accelerated approval of a new therapy is not yet known. We conducted a cross-sectional study evaluating all new drug applications submitted to the FDA over the past 10 years (2013-2022) that led to the initial approval of an oncology drug through the accelerated approval process. The objective was to assess whether the trials leading to such an approval included PROs. Between 2013 and 2022, the FDA approved 59 unique drugs for an oncology indication via the accelerated approval pathway, and 35 (59%) included a PRO assessment in the clinical trial. A median of 1 PRO measurement was used in each trial, with 23 different types of PRO assessment tools were used across the 59 new drug applications. In summary, we found that PRO measurements are inconsistently utilized in trials leading to initial accelerated approval of oncology drugs, and there seems to be a lack of harmonization of different PRO measurement tools used across trials.

The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence.

The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of a study of 12 boys. After a contentious review process and a high-profile meeting of an external advisory committee, FDA leaders concluded that very small increases in treated patients' levels of dystrophin, a muscle protein, were reasonably likely to predict clinical benefit. The eteplirsen approval, which was followed by approvals of other drugs in the same class via the same pathway, has been controversial because of the questionable evidence underlying these decisions, delays in mandated postapproval testing, and high U.S. prices. Questions remain about the effectiveness and long-term safety of these products. Although the FDA initially set a November 2020 deadline for eteplirsen's manufacturer to complete a clinical trial determining whether the drug has clinical benefit, the company will not complete the trial until 2024 or later. The relationship between levels of truncated dystrophin, the muscle protein studied in eteplirsen's pivotal trial, and clinical outcomes remains uncertain. Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.

Delandistrogene Moxeparvovec: First Approval.

Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS®) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138kDa) version of the dystrophin protein expressed in normal muscle cells (427kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4through 5years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 1014 vector genomes per kg of body weight or 10mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5years with DMD and a confirmed mutation in the DMD gene.

FDA approves Alzheimer's disease treatment

The U.S. Food and Drug Administration (FDA) on July 6 converted Leqembi (lecanemab‐irmb), indicated to treat adult patients with Alzheimer's disease, to traditional approval following a determination that a confirmatory trial verified clinical benefit, an FDA news released announced. Leqembi is the first amyloid beta‐directed antibody to be converted from an accelerated approval to a traditional approval for the treatment of Alzheimer's disease. The drug works by reducing amyloid plaques that form in the brain, a defining pathophysiological feature of the disease. Leqembi was approved in January under the FDA's Accelerated Approval pathway. This pathway allows the FDA to approve drugs for serious conditions where there is an unmet medical need, based on clinical data demonstrating the drug's effect on a surrogate endpoint — in the case of Leqembi, reducing amyloid plaques in the brain — that is reasonably likely to predict a clinical benefit to patients. As a post‐marketing requirement of the accelerated approval, the FDA required the applicant to conduct a clinical trial, often referred to as a confirmatory study, to verify the anticipated clinical benefit of Leqembi.