Survival benefit constitutes the primary pillar of therapeutic efficacy in oncology. However, the survival benefits observed in registrational trials broadly range from significant to marginal, even for US Food and Drug Administration (FDA)-approved drugs. This study explores the association between survival benefits and the likelihood of FDA approval and estimates the boundary effect size that distinguishes FDA-approved from non-approved drugs. We screened 3463 phase 3 trials initiated between 1990 and 2021 on ClinicalTrials.gov. Eligibility was restricted to randomized phase 3 trials for novel anticancer agents with overall survival (OS) as a primary or co-primary endpoint. Included trials required published results, including the OS hazard ratio (HR) and 95

Regional differences in approved drug dosages and administration are shaped by complex factors, including clinical data, prior regulatory decisions, and region-specific considerations. This study investigated how such factors are associated with variations in approved doses across the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) in the context of recent global regulatory practices. We analyzed 111 new molecular entities approved in the United States and Japan from 2017 to 2023, incorporating EMA data where available. Dose concordance, defined as agreement between regions on the labeled approved dosing regimen for the same indication, was observed in 77% between PMDA and FDA and 84% between EMA and FDA, higher than rates reported in earlier studies. Nevertheless, significant regional differences remain. Qualitative analysis suggested that discordance in approved doses was associated with a small number of high-level factors, including differences in benefit-risk perspectives, approaches to dose determination, population-related considerations. Quantitative analysis indicated associations with trial design and submission timing. In a subset of 11 products in which FDA approval preceded approvals by other agencies and involved FDA-led dose modifications, patterns were observed that were consistent with potential interdependence in regulatory decision making, while sponsor-driven harmonization and shared evidence bases may also underlie these patterns. These findings suggest that early regulatory engagement and international coordination may support efficient dose selection, although attention must be paid to differing benefit-risk assessment considerations across regions.

Drug dose appropriateness is one of the most discussed issues in regulatory reviews. We analyzed dose determinations during Food and Drug Administration (FDA) drug reviews to determine whether there were changes between the proposed and approved doses of new molecular entities (NMEs), including cases where postmarketing dose‐finding studies were requested, and explored the factors associated with these decisions. Of the 218 eligible NMEs approved between 2018 and 2022, 28 drugs (13%) had modifications to the proposed dose or requested additional postmarketing assessments, 20 of which were to a lower dose (“downward,” 9.2%) and five were to a higher dose (“upward,” 2.3%). Multinomial logistic regression analysis suggested that products that used the Accelerated Approval program were more likely to undergo downward modification (relative risk ratio (RRR) = 5.73). In addition, the fact that a dose/exposure–response relationship was observed for safety, but not efficacy, was associated with an increased probability of downward modifications (RRR: 4.27). In contrast, the use of pharmacodynamic biomarkers for dose setting and designation of Priority Review was associated with decreased probabilities of downward change (RRR: 0.405 and 0.195, respectively). Infectious disease drugs went through more upward modifications than those in the other therapeutic categories. This study revealed that dose “optimization” occurs during the FDA's review for drug approval and that not only product characteristics but also factors related to the drug review and approval process are associated with the decisions to modify or question the dose, suggesting considerations for the presence of compelling evidence and restrictions in data availabilities.

The number of pharmaceutical companies developing cell and gene therapy (CGT) products, categorized into cell therapy products (CTPs) and gene therapy products (GTPs), has increased, expanding patient access to approved treatments. Compared to conventional modalities, such as chemical compounds and biopharmaceuticals, both CTPs and GTPs pose significant challenges in their development. This study analyzed the characteristics of pharmaceutical companies associated with entry into CGT product development. Focusing on 309 pharmaceutical companies worldwide with marketed products, we analyzed entry into development and the numbers of CTPs and GTPs. We explored firm characteristics associated with entry into CTP and GTP development, as well as their respective proportions within company pipelines, using multiple regression models. Approximately 30

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

e23022 Background: Overall survival (OS) is commonly used as a primary endpoint in phase III oncology trials in the United States, serving as direct evidence of clinical benefit and as an objective outcome measure. Other endpoints such as progression-free survival (PFS) and objective response rate (ORR) are also utilized. Factors such as a cancer type and treatment line are considered important for primary endpoint selection, however, the fundamental factor influencing primary endpoint selection across various cancer types or treatment lines remains unclear. I hypothesize that the prognosis of the target patient population is one of the key fundamental factors across any groups in primary endpoint selection. This study aims to investigate the associations between the prognosis and the type of primary endpoint. Methods: All phase 3 clinical trials conducted in the US, focusing on drug therapies for cancer, between January 1, 2015 and Dec 31, 2022 were included. Multinomial logistic regression was utilized to assess the relationships between prognosis, indicated by the median overall survival of the control arm, and the type primary endpoint among OS, non-OS time-to-event endpoints (Other TTE), and response or remission rate (RR). Models were adjusted for cancer type, treatment line, the primary endpoint of the previous clinical study for the same target patient population, monotherapy, mechanism of action (MOA), biomarker for the drug, orphan drug designation (ODD), and accelerated approval (AA) before regulatory approval. Results: Out of 5,877 phase 3 clinical trials, 151 studies and 167 evaluation sets were included in the analysis. When the prognosis and the type of primary endpoint were tested, this factor demonstrated a statistically significant difference with a positive coefficient for Other TTE, RR, and a co-primary endpoint of OS and Other TTE compared to OS. The prognosis, the median OS of the control arm, was 10.5 months (95% CI 5.00-16.6) for OS, 18.5 months (95% CI 7.50-34.3) for Other TTE, 32.9 months for RR, and 13.6 months (95% CI 8.7-46.6) for the co-primary endpoint of OS and Other TTE respectively. No effect modification was observed for Other TTE and the co-primary endpoint of OS and Other TTE. Conclusions: A better prognosis is associated with the selection of surrogate endpoints in phase 3 oncology trials among many factors. The associations between the prognosis and the type of primary endpoint were observed for Other TTE and a co-primary endpoint of OS and Other TTE. These findings elucidate one of the fundamental factors for primary endpoint selection and emphasize the importance of prognosis in selecting a primary endpoint in phase 3 clinical trial in oncology in the US. However, further study is required to comprehensively understand the impact of RR on primary endpoint selection, as this analysis was limited by the lack of median OS data for RR.

Pharmaceutical companies have adopted biomarker-based enrichment (personalized) strategies to improve research and development productivity. We explored the background in which personalized strategies are adopted and examined whether their adoption is linked to improved efficacy of new drugs approved for non-small cell lung cancer (NSCLC) by US Food and Drug Administration (FDA). We extracted data from the first labels of drugs approved for NSCLC between May 2003 and February 2021, and performed a qualitative comparative analysis and meta-analysis. Personalized strategies were adopted in more than half of the trials (16/27) and were often used in trials aimed at obtaining first-line indications and in drugs that were not first-in-class. The meta-analysis showed that personalized trials had significantly improved progression-free survival (PFS) hazard ratio (HR) than trials without personalization but not for relative response rate ratio (RRR) or overall survival (OS) HR. Trials in which PFS HR was the primary endpoint tended to have improved PFS HR, and trials in which OS HR was the primary endpoint had worse PFS HR. The efficacy endpoints that are substantially affected by personalized strategies appear to differ, especially for new drugs with novel mechanism of action (MOA), because trial designs are employed to validate drug-specific advantages.

Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: -29.907, P < .001), and the age of control drugs in the market followed (coefficient: -2.581, P = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the P-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA.

Survival benefit is a fundamental property of anticancer drugs for cancer patients. However, the survival benefits observed in registrational trials broadly ranged from significant to marginal, even for US Food and Drug Administration (FDA)-approved drugs. This study explores the boundary of survival benefits between FDA-approved and non-approved drugs. We screened 3,463 phase 3 investigational studies initiated from January 1990 to January 2021 with survival measurement on ClinicalTrial.gov and identified 208 randomized controlled registrational trials for anticancer drugs with overall survival (OS) measurement. Among 208 studies, 79 (38%) were conducted for FDA-approved, and 129 (62%) were for FDA-non-approved drugs. The pooled mean risk reduction of death across FDA-approved drugs was 29% (Hazard ratio (HR) 0.71), whereas FDA-non-approved drugs exhibited only a 6% risk reduction in OS (HR 0.94). The probability of FDA approval showed a sharp sensitivity to the HR for OS in the logistic regression model. A boundary was observed ranging from 0.74 to 0.86 in the HR for OS, with a 50% probability of FDA approval at HR 0.80. Our findings delineate the required survival benefits for new anticancer drugs based on the clinical and regulatory outcomes over 20 years.

We analyzed factors shaping the choice of the lead indication (i.e., cancer type) in the first clinical development projects of new oncological drugs in the United States (US), and how the type of pharmaceutical company is related to this choice. We selected 576 new clinical development projects in the US since 2000 for analysis. These projects were characterized according to three potential perspectives detected by multiple correspondence analysis: the morbidity of the cancer type which corresponds to market size of each cancer type, the company’s previous experience with the cancer type, and the company’s attitude to development risks. Mega firms tend to choose cancer types with higher morbidity (and large-market), previously experienced cancer types, while diverse small firms choose both major and rare cancers and both high- and low-risk projects, indicating that different sizes of firms utilize different development entry patterns. Common tendencies concerning the choice of lead indication were found across all companies. Cancer types the company had developed and launched in the past were more likely to be chosen; cancer types with high five-year survival rates and those with high competition were less likely to be chosen. The study showed that pharmaceutical companies seem to enter clinical development from cancer types where they can demonstrate their strengths and advantages through experience, depending on each cancer type’s different market sizes and development difficulties. The results could provide clues for considering what support measures and incentives are appropriate to balance the efficiency of industrial development and the fulfillment of society’s unmet medical needs.

BACKGROUND:This study aimed to demonstrate the differences in the way cell and gene therapy (CGT) products have been developed and reviewed for approval in Japan, the USA, and the EU by comparing regulations and successfully launched products in each region, and to examine the background to such differences.METHODS:Information on relevant regulations and approved CGT products were collected from the public source and compared by region.RESULTS:While regulations on CGT products are largely consistent among these regions, some differences could have a substantial impact on the practices defining CGT products, the timing of responses required to comply with the regulations for handling gene-modified organisms, and the acceptable validation processes under good manufacturing practice regulations. Although CGT products are given some preferential status in all regions, the preferential treatment given to CGT products varies across regions. The CGT products launched in each region also differ significantly in type, indications, the nature of the developers, and the clinical evidence submitted. While all the cellular products launched in Japan were approved based on small uncontrolled trials, most cellular products in the USA and EU were approved based on controlled studies. A trend was observed for companies to enter their home markets.CONCLUSION:Our study showed differences of regulations on CGT products and of features in approved products as well as the trend of their home market entries, which may have been driven by a different context than that of traditional pharmaceuticals.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

Our study objective was to determine lung cancer chemotherapy attributes that are important to patients in Japan. A discrete choice experiment survey in an anonymous web-based questionnaire format with a reward was completed by 200 lung cancer patients in Japan from November 25, 2019, to November 27, 2019. The relative importance of patient preferences for each attribute was estimated using a conditional logit model. A hierarchical Bayesian logit model was also used to estimate the impact of each demographic characteristic on the relative importance of each attribute. Of the 200 respondents, 191 with consistent responses were included in the analysis. In their preference, overall survival was the most important, followed by diarrhea, nausea, rash, bone marrow suppression (BMS), progression-free survival, fatigue, interstitial lung disease, frequency of administration, and duration of administration. The preferences were influenced by demographic characteristics (e.g., gender and age) and disease background (e.g., cancer type and stage). Interestingly, the experience of cancer drug therapies and adverse events had a substantial impact on the hypothetical drug preferences. For the Japanese lung cancer patients, improved survival was the most important attribute that influenced their preference for chemotherapy, followed by adverse events, including diarrhea, nausea, rash, and BMS. The preferences varied depending on the patient's demographic and experience. As drug attributes can affect patient preferences, pharmaceutical companies should be aware of the patient preferences and develop drugs that respond to segmented market needs.

Since the adoption of the E5 guideline, “Ethnic Factors in the Acceptability of Foreign Clinical Data,” at the International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use in 1998, one of the several methods used for drug development is a bridging strategy in Japan or Asia.1–7 One of the purposes of a bridging strategy is to minimize the duplication of clinical data and facilitate the acceptance of foreign clinical data. Shimazawa et al7 reported examples of new drugs approved through a bridging strategy. Figure 1 provides an overview of the most typical bridging strategy considered when drug companies aim to obtain a manufacturing and marketing approval in Japan. When planning a bridging strategy, it is necessary to consider which clinical studies in the foreign clinical data package are intended to be bridged or extrapolated. Subsequently, the bridging study should be performed in Japan by the same design or similar design to that of the counterpart study. Counterpart studies have been mainly performed in the United States and/or Europe Union. In Figure 1, the study to be bridged is a foreign dose-response study, and the study to be extrapolated is a foreign confirmatory study in the foreign clinical data. If dose-response relationships and safety profiles between the Japanese dose-response study (bridging study) and the foreign dose-response study (the study to be bridged) are found to be similar, the foundation of the bridge between these studies is acknowledged. Furthermore, the results of the foreign confirmatory study could be extrapolated as confirmatory trial results in the Japanese clinical data package without performing a confirmatory study in Japan. One of the merits of a bridging strategy is that there is no need to repeat confirmatory studies in Japan. At present, global drug development is actively promoted; thus, multiregional clinical trials (MRCTs) are an efficient drug development strategy. Therefore, regulatory authorities encourage pharmaceutical companies to conduct such trials.1–4 As a result, the drug lag, namely, the approval lag for new drugs between Japan and the United States/European Union, has reduced.8–10 However, it has been reported that the approval lag still exists in some therapeutic areas.10–13 Shortening the development start lag is important for reducing a large approval lag.14 In Japan, drug development may be pursued using bridging strategies if

This study examined the outcomes of recent confirmatory randomized controlled trials (RCTs) in phase III that were initiated between 2005 and 2017 for oncologic drugs in the United States and identified several factors that were associated with the success of RCTs. Our regression analysis showed that studies with progression‐free survival or response rate as primary end point were more likely to succeed than studies with overall survival (odds ratio (OR) = 2.94 and 6.23, respectively). The status of development was also linked with success rates. Studies for non‐lead indication tended to have lower success rates than studies for lead indication (OR = 0.68). Studies for first‐line therapy were observed to have low success rates compared with studies for post second‐line therapies (OR = 0.37). Studies for which strong prior evidence was not listed in their publication tended to be more successful than studies that followed rigorous RCTs or single arm studies for the indication. These results suggest that historical success rates may reflect not only the important features of trials, which can be observed directly from study design and results, but also the background status of trials in clinical development pathways.

BACKGROUND:Regulatory agencies as well as private organizations pursue programs that advocate patient centricity and emphasize the importance of dialog with patients. Various methods are applied to elicit the preferences of patients regarding the aspects of treatment they lend more importance to. Decisions on treatment choices are critical to patients with lung cancer because of their poor prognosis and the serious trade-off between safety and efficacy in traditional cytotoxic chemotherapy.METHODS:We conducted a systematic literature review of quantitative patient preference studies of patients with lung cancer. Our exhaustive search of MEDLINE, CINAHL, EMBASE, PLOS, and SpringerLink identified 15 relevant studies published from January 2000 to April 2020 that enabled us to assess the relative importance of treatment attributes according to lung cancer patients' perspective.RESULTS:The literature review revealed that patients with lung cancer tend to place a higher weight on efficacy and quality of life (QoL) attributes than on other attributes. Overall survival was found to be the most important among the efficacy attributes. The consequences of adverse events seemed less important than the possible efficacy from therapies. The clinical utility of treatment, such as the route of administration, was generally not considered important. It remains inconclusive whether sociodemographic factors and/or medical history affect the relative importance of a patient's preference.CONCLUSION:Our systematic review clarified that patients generally prefer a better efficacy profile to a better safety profile, which underscores the importance of improved benefits in anti-lung cancer drug development.

As the drug development landscape becomes more globalized, the trade-off between global and local development pathways has become an increasingly important issue. Trade-offs are observed in a variety of consequences, including the resources and time required for development and the impact on patient health. From a public health perspective, studies suggest that the choice of global development pathways for new drugs by pharmaceutical companies may have a significant impact on drug efficacy and safety in Japan. In particular, the fact that dose-finding or confirmatory Phase III studies in Japan have led to improved post-marketing safety demonstrates the potential value of collecting local evidence. The global vs. local trade-off has been overlooked because we lack the concepts and tools to discuss it rigorously in the current drug evaluation science. We need to build a framework for drug evaluation science for a new generation.

WHAT IS KNOWN AND OBJECTIVE:The objectives of this study were to explore completeness of direct adverse event (AE) reports from consumers and healthcare professionals (HCPs), and to discuss the reasons completeness varied among reporters with different occupations.METHODS:We used a total of 5475 direct AE reports to the United States (US) Food and Drug Administration (FDA) from the first and second quarters of 2016 and assessed completeness of basic information (eg, patient sex, age, weight) and information relevant to AEs (eg, suspect and concomitant drugs). Logistic regression analysis was conducted to evaluate the associations between report completeness and reporting backgrounds.RESULTS AND DISCUSSION:The completeness of AE reports from consumers was generally greater than that of reports from HCPs. Completeness of specific items varied among different occupations, which may reflect accessibility to, and/or availability of, relevant information for each type of reporter. There was a clear association between the proportion of 'known' ADRs in a report and completeness, suggesting that consumers and HCPs are likely to consult labelling information when reporting AEs.WHAT IS NEW AND CONCLUSION:The quality of AE reports seemed to depend on information costs accrued to potential reporters. Researchers should consider the impact of database heterogeneity and possible sample selection bias when using spontaneous AE reports as a sample of events in the United States.