Anticancer Drug Approval in China: From Acceleration of Access to Certainty of Benefits

A surrogate end point (SEP) is an end point used in clinical trials as an alternative for measuring the true clinical benefit. The use of SEPs in trials shortens their duration. To investigate the use of SEPs in clinical trials to support the approval of anticancer drugs and to determine whether confirmatory studies that use overall survival (OS) as an end point are being conducted in Japan. In this cross-sectional study, drug approvals and background information were obtained from publicly available information, such as the Pharmaceuticals and Medical Devices Agency website, for anticancer drugs approved in Japan from January 2001 to December 2020. Data analysis was performed from September 2021 to March 2022. Characteristics of approved oncology drugs in Japan, end points for pivotal clinical trials, and outcomes of confirmatory trials using OS as an end point following drug approval. There were 299 anticancer drugs approved in Japan during the study period. Of these, 142 (47.5%) were molecular-targeted drugs, the most common of which targeted non-small cell lung cancer. There were 111 (37.1%) anticancer drugs with orphan designation. From 2001 to 2005, OS was used as an end point in 1 approval (3.6%); however, from 2006 to 2020, OS was used in 86 approvals (31.7%). Of the 212 anticancer drugs approved on the basis of SEPs, confirmatory studies with OS as the end point were conducted for only 37 approvals (17.5%); for the remaining 175 approvals, studies are under way for 35 approvals (16.5%), were waivered for 75 approvals (35.4%), and were not conducted for 65 approvals (30.7%). Furthermore, in 20 drug approvals (9.4%), the conducted confirmatory studies were not effective in determining the OS, but the drugs were approved following re-examination. The findings of this study suggest that starting from 2005, the use of OS as an end point has increased in studies supporting the approval of anticancer drugs in Japan. However, even after 2005, approximately two-thirds of these approvals were SEP based. Postmarketing surveillance studies of the true end points are necessary to validate the use of SEPs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16weeks-of 34% in 215treated patients, comprising 136patients who received targeted therapies and 79patients who received immunotherapy. The overall median duration of clinical benefit was 9months (95% confidence interval of 8-11months), including 26patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

To date, an empirical evaluation of the quality of control arms in randomized clinical trials (RCTs) leading to anticancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken. We sought to estimate the percentage of RCTs that used a control arm deemed suboptimal and led to FDA approval of anticancer drugs from January 1, 2013, to July 31, 2018. This quality improvement study included 143 anticancer drug approvals granted by the FDA from January 1, 2013, to July 31, 2018. All approvals based on single-arm studies (48 approvals) were excluded. Approvals based on RCTs were further investigated and each trial was analyzed for design, time of patient accrual, control arm, and primary end point. Standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of trial enrollment. The percentage of approvals based on RCTs that used suboptimal control arms was then calculated. The quality of the control arm was deemed suboptimal if the choice of control agent was restricted to exclude a recommended agent, the control arm was specified but the recommended agent was unspecified, and if prior RCT data had demonstrated that the control agent was inferior to an available alternative. Estimated percentage of RCTs that used suboptimal control arms that led to FDA approval of anticancer agents between January 1, 2013, to July 31, 2018. A total of 145 studies that led to 143 drug approvals between January 1, 2013, and July 31, 2018, were included. Of these studies, 48 single-arm studies were excluded. The remaining 97 studies led to 95 drug approvals. Of these 95 approvals, 16 (17%) were based on RCTs with suboptimal control arms; 15 were international trials, and 1 was conducted in the United States. The type of approval was regular in 15 trials and accelerated in 1 trial. When categorized by the nature of suboptimal control, 4 (25%) trials omitted active treatment in control arm by limiting investigator's choice, 11 (63%) trials omitted active treatment in the control arm by using a control agent known to be inferior to other available agents or not allowing combinations, and 1 (13%) trial used a previously used treatment in the control arm with a known lack of benefit associated with reexposure. Although anticancer drug approvals are increasing, a proportion of these drugs are reaching the market without proven superiority to what is considered the standard of care at the time of patient enrollment in pivotal trials. The choice of control arm should be optimized to ensure that new anticancer agents being marketed are truly superior to what most clinicians would prescribe outside a clinical trial setting.

Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anticancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Therefore, we initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anticancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. We use a stepwise approach per cohort of first 8 patients, and when at least one patient experienced clinical benefit that cohort expands to 24 patients. Presently, we have reviewed >1,100 submitted patient cases and included and treated >500 patients. We found an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 29% although the formal analysis is per cohort. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab or durvalumab, and tumors with HRD treated with olaparib. Our results have led to a personalized reimbursement model for nivolumab in patients with MSI tumors that is supported by all regulatory parties. The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Citation Format: Emile E. Voest. The Drug Rediscovery Protocol: Getting the most out of approved drugs [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr IA19.

LBA27 - Drug Rediscovery Protocol: Expanded use of existing anticancer drugs

A critique of the fragility index - Authors' reply.

A critique of the fragility index.

The approval of anticancer drugs in Japan has increased to meet high medical demand. To maximize the benefits of anticancer drugs, adverse drug reactions (ADRs) must be properly managed. However, in some cases, clinically significant safety issues are detected after launch, and safety-related regulatory actions (SRRAs) are implemented. We aimed to determine the characteristics of SRRAs for anticancer drugs approved in Japan and to identify factors related to the drug development and regulatory approval process associated with the occurrence of an SRRA. We defined an SRRA as the issuance of a 'Yellow Letter', 'Blue Letter', or an official notification by the Ministry of Health, Labor and Welfare. Anticancer drugs approved in Japan as new active ingredients from April 2004 to July 2016 were analyzed using publicly available information. The Kaplan-Meier survival curve was plotted to estimate the probability of the occurrence of an SRRA, and the Cox proportional hazards model was used to identify risk factors associated with the occurrence of an SRRA. Independent variables were selected using backward/forward stepwise selection according to Akaike's Information Criterion. An SRRA was implemented for 38 of 63 anticancer drugs. Approximately 70% of SRRAs occurred within 2years after approval, and the median time between approval and the occurrence of an SRRA was 1.6years (interquartile range 0.94-2.4). No Yellow Letter was issued during the follow-up period; however, one Blue Letter was issued for 'acute lung injury and interstitial pneumonia' for sorafenib. According to official notifications, 'clinically significant adverse reactions' was the most revised section of package inserts (62%). The probability of an SRRA at the 1-, 2- and 3-year follow-up was 15.9% (95% confidence interval [CI] 6.4-24.4%), 41.3% (95% CI 27.8-52.3%), and 56.8% (95% CI 41.8-68.0%), respectively. Monoclonal antibodies were associated with a low risk of occurrence of an SRRA (hazard ratio [HR] 0.29, p = 0.019), while the large number of patients in pivotal studies (per 100 patients) was associated with a high risk of occurrence (HR 1.07, p = 0.012). The high-risk period for the occurrence of an SRRA for anticancer drugs in Japan was within 2years after approval. Among the factors related to the drug development and regulatory approval process, anticancer drugs in the form of non-monoclonal antibodies, and whose pivotal studies included a large number of patients, were more likely to be associated with an SRRA. Postmarketing follow-up should therefore be carefully performed, especially in the first 2years after approval and for non-monoclonal antibody anticancer drugs. Moreover, postmarketing follow-up is crucial, even if large-scale pivotal studies for regulatory approval have already been performed.

The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281.0days [interquartile range, 263.3-336.0]; 222.5 patients [66.0-454.3]) were significantly lower than those on non-orphan drugs (353.0days [277.0-535.5]; 521.0 patients [303.5-814.5], respectively) (P < 0.001). Phase II, non-randomized and non-controlled designs were more frequently used in pivotal studies on orphan anticancer drugs (45.9%, 41.9% and 43.2%) than non-orphan drugs (17.2%, 14.1% and 14.1%, respectively). Response rate was more commonly used as a primary endpoint in pivotal studies on orphan anticancer drugs (48.6%) than non-orphan drugs (17.2%). Indications limited by molecular features, second or later treatment line, and accelerated approval in the United States were associated with the use of response rate in orphan anticancer drug studies. In conclusion, we demonstrated that orphan anticancer drugs in Japan have unique characteristics compared to non-orphan drugs: shorter regulatory review and pivotal studies frequently using phase II, non-randomized, or non-controlled designs and response rate as a primary endpoint, with fewer patients.

There are many steps on the road from discovery of an anticancer drug to securing its final approval by the Food and Drug Administration. In this thoroughly updated and expanded second edition of the Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, leading investigators synthesize an invaluable overview of the experimental and clinical processes of anticancer drug development, creating a single indispensable reference that covers all the steps from the identification of cancer-specific molecular targets to screening techniques and the development and validation of bioanalytical methods to clinical trial design and all phases of clinical trials. The authors have included new material on phase 0 trials in oncology, organ dysfunction trials, drug formulations and their impact on anticancer drug PK/PD including strategies to improve drug delivery, pharmacogenomics and cancer therapy, high throughput platforms in drug metabolism and transport pharmacogenetics, imaging in drug development and nanotechnology in cancer. Authoritative and up-to-date, Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, 2nd Edition provides in one comprehensive and highly practical volume a detailed step-by-step guide to the successful design and approval of anticancer drugs. Road map to anticancer drug development from discovery to NDA submission Discussion of molecular targets and preclinical screening Development and validation of bioanalytical methods Chapters on clinical trial design and phase 0, I, II, III clinical trials Pharmacokinetics, pharmacodynamics, pharmacogenomics, and pharmacogenetics of anticancer agents Review of the drug development process from both laboratory and clinical perspectives New technological advances in imaging, high throughput platforms, and nanotechnology in anticancer drug development

Aim/Hypothesis: The complexity and heterogeneity of multiple pathological features make Alzheimer’s disease (AD) a major culprit to global health. Drug repurposing is an inexpensive and reliable approach to redirect the existing drugs for new indications. The current study aims to study the possibility of repurposing approved anticancer drugs for AD treatment. We proposed an in silico pipeline based on “omics” data mining that combines genomics, transcriptomics, and metabolomics studies. We aimed to validate the neuroprotective properties of repurposed drugs and to identify the possible mechanism of action of the proposed drugs in AD. Results: We generated a list of AD-related genes and then searched DrugBank database and Therapeutic Target Database to find anticancer drugs related to potential AD targets. Specifically, we researched the available approved anticancer drugs and excluded the information of investigational and experimental drugs. We developed a computational pipeline to prioritize the anticancer drugs having a close association with AD targets. From data mining, we generated a list of 2914 AD-related genes and obtained 49 potential druggable targets by functional enrichment analysis. The protein–protein interaction (PPI) studies for these genes revealed 641 interactions. We found that 15 AD risk/direct PPI genes were associated with 30 approved oncology drugs. The computational validation of candidate drug–target interactions, structural and functional analysis, investigation of related molecular mechanisms, and literature-based analysis resulted in four repurposing candidates, of which three drugs were epidermal growth factor receptor (EGFR) inhibitors. Conclusion: Our computational drug repurposing approach proposed EGFR inhibitors as potential repurposing drugs for AD. Consequently, our proposed framework could be used for drug repurposing for different indications in an economical and efficient way.

Medikamentöse Therapieinnovationen in der Onkologie werfen medizinische und ethische Fragestellungen auf. Die zunehmende Inzidenz und Prävalenz von Krebserkrankungen sowie die Zulassung neuer, in aller Regel kostspieliger Wirkstoffe sind mit steigenden Gesamtkosten für die Behandlung von Krebserkrankungen verbunden. Deshalb ist die Entwicklung von wissenschaftlich begründeten Strategien zur Nutzenbewertung neuer medikamentöser Therapieverfahren unentbehrlich. Im Mittelpunkt dieses Beitrags steht die Nutzen- beziehungsweise Nutzen-Risiko-Bewertung als Grundlage für Entscheidungen über die Priorisierung bei hämatologischen Neoplasien und soliden Tumoren. Zunächst werden regulatorische Anforderungen an die Zulassung und Defizite in klinischen Zulassungsstudien als Grund für die zum Zeitpunkt des Markteintritts häufig nicht mögliche Nutzenbewertung neuer Wirkstoffe in der Onkologie dargestellt. Anschließend werden mögliche Lösungsansätze zur Optimierung einer Nutzen- bzw. Kosten-Nutzen-Bewertung und Vorschläge zur Verbesserung der wissenschaftlichen Datenlage diskutiert.

Reports have indicated that approval lag for anticancer drugs between Japan and the United States has decreased. However, if this is also true for drugs used to treat minor cancers remains unknown. We analyzed the anticancer drugs approved in Japan from 2006 to 2016 to compare the drug approval lag based on cancer incidence (major vs. minor cancers) between Japan and the United States. The lag of anticancer drugs for minor cancers had not decreased relative to that a decade ago. Recently, development strategies resulting in longer approval lag were used by pharmaceutical companies more often for the development of drugs used to treat minor cancers than for drugs targeting major cancers, leading to significant differences in the approval lag time between drugs for major and minor cancers. Effective measures that expedite the development of drugs targeting minor cancers in Japan should, therefore, be implemented to shorten lag time.

Malignant tumors continue to threaten people’s lives, and the incidence and mortality of lung cancer are particularly high. Due to different ethnic and cultural backgrounds, China and the United States differ in the clinical treatment of lung cancer and related basic research. The discrepancies are mostly visible in the prevention of cancer, the approval of anticancer drugs, availability of medical insurance, structure of medical education, availability of research funds, and many other aspects By understanding these differences, China and the United States, as well as other nations, can learn from each other and make progress together, which will help to improve the outcomes of cancer therapy.

Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (Pobs) was calculated based on completed study characteristics and observed hazard ratio (HRobs). Studies were considered over-sampled if Pobs > expected with HRobs similar or worse than expected or if Pobs was similar to expected with HRobs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.