Single-arm trials for domestic oncology drug approvals in China.
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC10690876 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Single-arm trials for domestic oncology drug approvals in China.
Zhang Hong H Liu Sen S Ge Chenghao C Liu Xiaozhen X Liu Yang Y Yin Chen C Li Yi Y An Jing J Yan Zhongtian Z Chen Xiaoyuan X
Cancer biology & medicine 20231101 11
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Project description: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.
| S-EPMC11336774 | biostudies-literature
Project description:Often, single-arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of 'insufficient drug activity' is rejected, the next step could be a randomised two-arm trial. However, single-arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single-arm trials followed by randomised two-arm trials with stand-alone single-stage or group sequential randomised two-arm trials. Through this, we are able to investigate the utility of single-arm trials and determine the most efficient drug development plans, setting our work in the context of a published single-arm non-small-cell lung cancer trial. Reference priors, reflecting the opinions of 'sceptical' and 'enthusiastic' investigators, are used to quantify and guide the suitability of single-arm trials in this setting. We observe that the explored development plans incorporating single-arm trials are often non-optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single-arm trials avoided, for the non-small-cell lung cancer treatment through direct progression to a group sequential randomised two-arm trial. Careful consideration should thus be given to the use of single-arm trials in oncological drug development when a randomised trial will follow.
| S-EPMC4855632 | biostudies-literature
Project description:ImportanceThe growth of cancer drug spending in the US has outpaced spending in nearly all other sectors, and an increasing proportion of the drug development pipeline is devoted to oncology. In 2018, there was a record number of drugs entering the US market.ObjectiveTo estimate the number of patients with cancer who are eligible for the newly approved drug-indication pairs, and project potential spending and use of the approvals in the US.Design, setting, participantsThis is a retrospective review of 2018 US Food and Drug Administration (FDA) oncology drug approvals with estimation of the eligible population. The cost of new therapy was estimated, and savings from displaced therapies were subtracted. Two-way sensitivity analysis explored uncertainty in pricing and market diffusion. Data were collected between March 1, 2019, and September 30, 2019.ExposuresData related to the cancer drug approval (ie, indications, approval pathway, basis for approval), cancer incidence, and drug price were extracted from publicly available sources, including the FDA, National Cancer Institute, and American Cancer Society websites, as well as the RED BOOK database.Main outcomes and measuresThe primary outcome was the projected net expenditure in the US associated with the new therapies. The secondary outcome described how variable market diffusion and pricing permit expected levels of spending.ResultsA total of 46 oncology approvals were included in the analysis, with 17 novel drugs and 29 new indications. The average price per patient per treatment course was $150 384. From a national perspective and with 100% market diffusion, the projected net expenditure for newly approved drugs was $39.5 billion per year. To maintain the recent trend of cancer drug spending, the 2018 cancer drug approvals need to be used in fewer than 20% of eligible patients.Conclusions and relevanceNew cancer drugs approved by the FDA in 2018 would drastically increase cancer drug spending in the US if used widely. Alternatively, only low-level use of the new drugs is consistent with market forecasting.
| S-EPMC7653539 | biostudies-literature
Project description:BackgroundIn the past decade, the Chinese drug regulatory system has undergone many changes. A major reform starting in 2015 has significantly reshaped the regulatory processes. It was important to assess the impact of the reform on new drug approvals in China.MethodWe analyzed the temporal trends of regulatory characteristics of the new drugs approved by the Chinese regulatory agency from 2011 to 2021, using data collected in the Pharmcube database.ResultsA total of 353 new drugs were approved, including 220 small molecule drugs, 86 biological products and 47 vaccines. The annual number of new drug approvals increased dramatically since 2017, reaching a record high of 70 in 2021. The median NDA approval time was 15.4 months in 2017-2021, the shortest in the decade, and was significantly shorter than that in the pre-reform period. The newly instituted expedited pathways such as priority review (PR) and accelerated approval for urgently needed overseas drugs (UNOD) significantly reduced new drug application (NDA) approval times compared with standard review. For imported drugs, in 2017-2021, the median time difference between the first approval in the world and the approval in China was 5 years, representing significant "drug lag". However, the proportion of the imported drugs approved in China within 3 years of its first foreign approval has increased to 24.4% in 2017-2021.ConclusionThe regulatory reform has produced significant, positive immediate outcomes in several metrics of drug regulatory approval. China's regulatory system will continue to evolve as there still are many areas requiring further reform and improvement.
| S-EPMC9628473 | biostudies-literature
Project description:BackgroundDrug-drug interactions (DDIs) in subjects enrolling in clinical trials can impact not only safety of the patient but also study drug outcomes and data validity. This makes it critical to adequately screen and manage DDIs. The study objective was to determine the prevalence of DDIs involving study medications in subjects enrolling in National Clinical Trials Network (NCTN) clinical trials at a single institution. DDIs were evaluated based on study protocol recommendations for concomitant medication use (i.e. exclude, avoid or use caution), screening via DDI tool, and pharmacist review.MethodsSubjects enrolled in NCTN trials of commercially available agents between January 2013 and August 2017 were included if a complete medication list was available. Complete medication lists were collected from the date of enrollment or the next available date then screened utilizing protocol guidance and the DDI screening tool, Lexicomp® Drug Interactions (Wolters Kluwer, Hudson, OH). Interactions were reviewed for clinical relevance: defined as a DDI that would require a medication change to ensure study agent safety and efficacy at enrollment.ResultsOne hundred and twenty-eight subjects enrolled in 35 clinical trials were included. Protocol guidance detected 15 unique DDI pairs that should be avoided or used with caution in 10.2% (13/128) of subjects. The majority of these subjects did not have a clinically relevant DDI (69.2%, 9/13) based on pharmacist review. Lexicomp® detected moderate to major DDIs in 24.2% (31/128) of subjects, with 9.4% (12/128) having a clinically relevant DDI.ConclusionsThis study confirms a high prevalence of DDIs present in subjects enrolling in oncology clinical trials. Further efforts should be made to improve methods to detect and manage DDIs in patients enrolling on clinical trials to ensure patient safety and trial data validity.
| S-EPMC6249716 | biostudies-literature
Project description:ImportanceWhile there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain.ObjectiveTo assess the percentage of clinical trials with limitations in 4 domains-lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms-that led to FDA approvals from June 30, 2014, to July 31, 2019.Design, setting, and participantsThis observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated.Main outcomes and measuresEstimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA.ResultsA total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately.Conclusions and relevanceTwo-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards.
| S-EPMC7296449 | biostudies-literature
Project description:BackgroundDespite the interest from the scientific community and regulatory agencies, limited data are available on the association between health-related quality-of-life (QoL) results, outcome of efficacy and drug approvals.Materials and methodsWe updated the previously published meta-research study of phase III clinical trials in patients with solid tumours treated with systemic treatments, published from 2012 to 2021 in 11 selected journals. For the present analysis, we focused on studies conducted in the advanced setting. The primary outcome was the association of global QoL results with study primary endpoints (EP1), overall survival (OS) and progression-free survival (PFS), while a secondary outcome was the frequency of positive global QoL results among treatments approved by regulatory agencies [European Medicines Agency (EMA)/Food and Drug Administration (FDA)]. A descriptive analysis was carried out and the association between QoL results and characteristics of studies and of publications was tested.ResultsFive hundred and ninety-two eligible publications were identified from 2012 to 2021. The primary endpoint was OS in 298 clinical trials (50.3%) and PFS in 304 clinical trials (51.4%). A positive result in EP1 analysis was reported in 124 trials (41.6%) with OS as EP1 and in 182 trials (59.5%) with PFS as EP1. Among studies with positive OS and PFS, global QoL results were positive in 39 (31.5%) and 45 studies (24.7%), respectively. FDA and EMA approvals were available for 143 (24.2%) and 142 studies (24%), respectively. Among these, global QoL results were positive in 55 (38.5%) and 56 studies (39.4%), respectively. QoL results were available for most drugs approved by regulatory agencies, but the proportion of approvals with positive global QoL results was not significantly increased from 2012-2016 to 2017-2021.ConclusionsDespite QoL data being available for most cancer treatments recently approved by regulatory agencies, QoL improvement has been demonstrated in a minority of studies with positive results in the primary endpoint.
| S-EPMC11410715 | biostudies-literature
Project description:Despite increasing utilization of real-world data (RWD)/real-world evidence (RWE) in regulatory submissions, their application to oncology drug approvals has seen limited success. Real-world data is most commonly summarized as a benchmark control for a single arm study or used to augment the concurrent control in a randomized clinical trial (RCT). While there has been substantial research on usage of RWD/RWE, our goal is to provide a comprehensive overview of their use in oncology drug approval submissions to inform future RWD/RWE study design. We will review examples of applications and summarize the strengths and weaknesses of each example identified by regulatory agencies. A few noteworthy case studies will be reviewed in detail. Operational aspects of RWD/RWE study design/analysis will be also discussed.
| S-EPMC10276785 | biostudies-literature
Project description:(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We performed a review of the literature and reported the trials that led to the approval of tissue-agnostic treatments and ongoing clinical trials currently investigating novel biomarker-based approaches. (3) Results: We discussed the approval of agnostic treatments: pembrolizumab and dostarlimab for MMRd/MSI-H, pembrolizumab for TMB-H, larotrectinib and entrectinib for NTRK-fusions, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusions. In addition, we reported novel clinical trials of biomarker-based approaches, including ALK, HER2, FGFR, and NRG1. (4) Conclusions: Precision medicine is constantly evolving, and with the improvement of diagnostic tools that allow a wider genomic definition of the tumor, tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved survival outcomes.
| S-EPMC10144220 | biostudies-literature
Project description:For regulatory approval of a new medicine, the gold standard for demonstration of efficacy has traditionally been a minimum of two positive, adequate, and well-controlled clinical trials. Nevertheless, drugs to treat cancer and rare diseases are usually approved based on a single and often uncontrolled pivotal trial. In contrast, little is known about single pivotal trial approvals for non-orphan, non-oncology drugs. Between 2012 and 2016, 23 novel therapeutic drugs were approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for 27 non-orphan, non-oncology indications each based on a single pivotal trial. Although there was considerable variation in the nature and strength of the efficacy evidence supporting these drug approvals, the majority (85%) of the pivotal trials were randomized and controlled. For all superiority trials, the primary outcome was met with a statistical significance of P ≤ 0.005. Most approvals were supported by additional efficacy data from nonpivotal studies.
| S-EPMC6662549 | biostudies-literature