Female representation in clinical trials leading to FDA cancer drug approvals for gastrointestinal (GI) cancers between 2008 to 2018.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 809-809 ◽  
Author(s):  
Shehara Ramyalini Mendis ◽  
Seerat Anand ◽  
Arvind Dasari ◽  
Joseph M. Unger ◽  
Anirudh Gothwal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Incidence ◽  
Drug Approval ◽  
Cancer Drug ◽  
Representation Of Women ◽  
Gi Cancer ◽  
Enrollment Rates ◽  
Gi Cancers ◽  
Drug Approvals ◽  
The U.S

809 Background: Proportionate representation of women in health research is an area for improvement. This study aims to assess the representation of women in gastrointestinal (GI) cancer clinical trials leading to FDA cancer drug approvals over the past 10 years. Methods: FDA cancer drug approvals between 07/2008-06/2018 were identified and trial reports supporting approvals sourced. The ratio of female to male (F:M) enrollment was compared with F:M cancer incidence in the U.S., and U.S. cancer prevalence and mortality. Results: Although F:M enrollment for all 229 trials leading to FDA cancer drug approvals in this period was similar to overall F:M cancer incidence in the U.S. (0.89 vs 0.86; Odds Ratio for female enrollment (OR) 1.05, 95% Confidence Interval (CI) 1.03-1.06, P<0.0001), in 17 trials that led to drug approvals in GI cancers there was lower F:M trial enrollment compared to cumulative U.S. incidence at those tumor sites (0.55 vs 0.79, OR 0.71, 95% CI 0.68-0.74, P<0.0001). F:M enrollment and U.S. incidence by the main GI tumor sites where approvals occurred is shown in Table. Female enrollment rates were also lower than U.S. female cancer mortality and prevalence rates in these tumor sites (P<0.0001 for all). Female enrollment in GI trials fell between 2008-2013 and 2014-2018 (38 vs 33%, OR 0.80, 95% CI 0.74-0.87, P<0.0001). Conclusions: Although disparity in female enrollment may be improving across combined FDA cancer drug approval trials, underrepresentation of females has persisted in GI cancer trials when compared to F:M cancer incidence, prevalence and mortality in the U.S. More work is required to determine the drivers of this disparity, in order to mitigate it. [Table: see text]

scholarly journals Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018

JAMA Oncology ◽  
2019 ◽  
Vol 5 (10) ◽  
pp. e191870 ◽  
Author(s):  
Jonathan M. Loree ◽  
Seerat Anand ◽  
Arvind Dasari ◽  
Joseph M. Unger ◽  
Anirudh Gothwal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Drug ◽  
Drug Approvals

Trend of Drug Approval on Hematological Malignancies in the U.S. and Japan.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3120-3120
Author(s):  
Fumitaka Nagamura ◽  
Arinobu Tojo ◽  
Tokiko Nagamura-Inoue ◽  
Aikichi Iwamoto
Keyword(s):  
Clinical Trials ◽  
Hematological Malignancies ◽  
Drug Evaluation ◽  
Geographical Location ◽  
Drug Approval ◽  
New Concepts ◽  
The Us ◽  
Accelerated Approval ◽  
Outstanding Result ◽  
The U.S

Abstract Introduction: Characteristics on hematological malignancies, e.g., many of them arise from one chromosomal abnormality and there are many molecules discriminating malignancies from normal cells, have recently played very important role on the development of novel therapeutic options. Molecular-targeted therapies, such as antibodies and signal inhibitors, are good examples. On the other hand, drug evaluation and approval methods have been suffered from the difficulties in fastening approval periods and evaluating efficacies and safeties more precisely, especially in the case of these entirely new concepts of drugs. In this study, we clarified the trends of drug approval on hematological malignancies in the U.S. and Japan. By the comparison, the trends were made more clearly. Methods: Drugs for hematological malignancies, including CMPDs, which approved by December 2004 in the US or Japan were eligible. Supportive drugs, immunomodulators, biochemical modulators, and “off-label use” were excluded. Package inserts, reviews by agencies, publications on clinical trials were examined. The geographical analysis on clinical trials of oncologic drugs was based on the previous report (Proc ASCO2003; 22:534a). Results: Forty-six drugs were approved in the U.S., and 43 were in Japan. Twenty-seven drugs were approved in both countries. Twenty-two of 27 drugs were approved earlier in the U.S., and the dates of approval were considerably earlier in the U.S. (median: 46.0 Mo, mean: 54.7 Mo). These differences have not been shorten when compared in every 10-year period. Eight drugs were approved as “Accelerated Approval”, which stated in CFRs as “Subpart H”. Seven of eight “accelerated approval” drugs were approved only in the U.S. Furthermore, around one-thirds of drugs (7/19: 36.8%) approved only in the U.S. were based on “accelerated approval”. However, one drug approved as “accelerated approval” could have shown its clinical benefit in the designated clinical trial. Among the drugs approve only in the U.S., the number of drugs for “first line”, “second line or thereafter”, and “not specified” were 2, 13, 4, respectively. The geographical comparison of clinical trials was summarized in the Table below. The ratio of non-U.S. studies was considerably low in hematological malignancies. In Japan, the data on clinical trials exclusively performed in Japan was generally stated. Five drugs approved only in Japan were approved in the US for diseases other than hematological malignancies, while no drug was approved in the reverse case. Conclusion: “Accelerated approval” is useful for fastening the period until the approval, although the problem whether “surrogate markers” leads to “survival and/or QOL benefit” has not been clarified, yet. The outstanding result that most of pivotal/supportive studies were not “non-U.S.” studies may be caused by the superiority of drug development, especially in new concepts of drugs for hematological malignancies and the ability to conduct appropriate clinical trials in the U.S. On the contrary, the expansion of the indication would be the problem in the U.S. to be considered. Geographical Location of Studies U.S. only U.S. & Canada U.S. & Europe Non-U.S. Total All oncology drugs (1986.1–2002.9) 77 (43.5%) 23 (13.0%) 35 (19.8%) 42 (23.7%) 177 studies Hematological malignancies (1986.1–2004.12) 27 (62.8%) 4 (9.3%) 9 (20.9%) 3 (7.0%) 42 studies

Utility of circulating tumor DNA (ctDNA) versus tumor tissue clinical sequencing for enrolling patients (pts) with advanced non-colorectal (non-CRC) gastrointestinal (GI) cancer to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3516-3516
Author(s):  
Akihiro Ohba ◽  
Yoshiaki Nakamura ◽  
Hiroya Taniguchi ◽  
Masafumi Ikeda ◽  
Hideaki Bando ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Tumor Tissue ◽  
Cancer Type ◽  
Combined Analysis ◽  
Clinical Sequencing ◽  
Upper Gi ◽  
Gi Cancer ◽  
Wide Range ◽  
Gi Cancers

3516 Background: We recently reported that clinical assessment of genomic biomarkers using ctDNA had advantages over tumor tissue-based sequencing for enrollment into matched clinical trials across a wide range of GI cancers. Herein we investigated the utility of ctDNA in non-CRC cancers in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue samples of pts with non-CRC were analyzed by a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay, since Feb 2015. In GOZILA, plasma samples of non-CRC pts were analyzed by an NGS-based ctDNA assay, Guardant360, since Feb 2018. Results: As of Apr 2019, 2,952 pts in GI-SCREEN and 633 pts in GOZILA were enrolled. Baseline characteristics between the groups were well matched except that GOZILA included more pancreatic (P < 0.0001) and liver cancers (P = 0.016) but fewer gastric cancers (P < 0.0001) and GIST (P = 0.020) than GI-SCREEN. The success rates of the tests were 86.6% in GI-SCREEN and 87.3% in GOZILA (P = 0.649). Median turnaround time (TAT) was 37 days in GI-SCREEN and 12 days in GOZILA (P < 0.0001). The proportion of cases with actionable alterations detected (tissue vs blood; 29.8% vs 46.8%, P < 0.0001) and enrolled into matched clinical trials (4.8% vs 6.5%, P = 0.286) for each group by cancer type are shown in the Table. Pts with upper GI cancers, especially those in GOZILA, were more often enrolled into matched trials; trial enrollment for those with hepatobiliary and pancreatic (HBP) or other cancers was similar regardless of testing method. Median time from GI-SCREEN or GOZILA enrollment to clinical trial enrollment was 5.0 and 1.0 months (mo), respectively (P < 0.0001). Objective response rates (ORR) and progression-free survival (PFS) were not significantly different (tissue vs. blood; ORR: 14.6 vs. 26.3%, P = 0.30: median PFS: 3.3 vs. 2.6 mo, P = 0.71). Conclusions: Clinical sequencing of ctDNA, with its shorter TAT, contributed to rapid enrollment of non-CRC pts into matched clinical trials compared to those tested by tumor tissue sequencing, particularly for those with upper GI cancer, without compromising efficacy. Clinical trial information: UMIN000029315 . [Table: see text]

scholarly journals Cross-comparison of cancer drug approvals at three international regulatory agencies

2016 ◽  
Vol 23 (5) ◽  
pp. 454 ◽  
Author(s):  
N. Samuel ◽  
S. Verma
Keyword(s):  
Antineoplastic Agents ◽  
Drug Product ◽  
Drug Approval ◽  
Primary Objective ◽  
Cancer Drug ◽  
European Medicines Agency ◽  
Cancer Drugs ◽  
Regulatory Bodies ◽  
Drug Approvals ◽  
Health Canada

Background The primary objective of the present study was to examine the drug approval process and the time to approval (tta) for cancer drugs by 3 major international regulatory bodies—Health Canada, the U.S. Food and Drug Administration (fda), and the European Medicines Agency (ema)—and to explore differences in the drug approval processes that might contribute to any disparities.Methods The publicly available Health Canada Drug Product Database was surveyed for all marketed antineoplastic agents approved between 1 January 2005 and 1 June 2013. For the resulting set of cancer drugs, public records of sponsor submission and approval dates by Health Canada, the fda, and the ema were obtained.Results Overall, the tta for the 37 antineoplastic agents that met the study criteria was significantly less for the fda than for the ema (X̄ = 6.7 months, p < 0.001) or for Health Canada (X̄ = 6.4 months, p < 0.001). The tta was not significantly different for Health Canada and the ema (X̄ = 0.65 months, p = 0.89). An analysis of the review processes demonstrated that the primary reason for the identified discrepancies in tta was the disparate use of accelerated approval mechanisms.Summary In the present study, we systematically compared cancer drug approvals at 3 international regulatory bodies. The differences in tta reflect several important considerations in the regulatory framework of cancer drug approvals. Those findings warrant an enhanced dialogue between clinicians and government agencies to understand opportunities and challenges in the current approval processes and to work toward balancing drug safety with timely access

scholarly journals Sex Representation in Clinical Trials Associated with FDA Cancer Drug Approvals Differs Between Solid and Hematologic Malignancies

2020 ◽  
Author(s):  
Shehara Mendis ◽  
Seerat Anand ◽  
Joanna M. Karasinska ◽  
Arvind Dasari ◽  
Joseph M. Unger ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hematologic Malignancies ◽  
Cancer Drug ◽  
Drug Approvals

scholarly journals Landmark Cancer Clinical Trials and Real-World Patient Populations: Examining Race and Age Reporting

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5770
Author(s):  
Thejus Jayakrishnan ◽  
Sonikpreet Aulakh ◽  
Mizba Baksh ◽  
Kianna Nguyen ◽  
Meghna Ailawadhi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Real World ◽  
Age Distribution ◽  
Mean Difference ◽  
Cancer Drug ◽  
P Value ◽  
World Population ◽  
Drug Approvals ◽  
Age Disparity

Background: Concern exists that the clinical trial populations differ from respective cancer populations in terms of their age distribution affecting the generalizability of the results, especially in underrepresented minorities. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity. Methods: Food and Drug Administration (FDA) drug approvals from July 2007 to June 2019 were reviewed to identify oncology approvals, and trials with age details were selected. The outcomes studied were the weighted mean difference in age between the clinical trial population and real-world population for various cancers, the prevalence of race reporting and association of age and race reporting with each other. Results: Of the 261 trials, race was reported in 223 (85.4%) of the trials, while 38 trials (14.6%) had no mention of race. Race reporting improved minimally over time: 29 (85.3%) in 2007–2010 vs. 49 (80.3%) in 2011–2014 vs. 145 (85.4%) during the period 2015–2019 (p-value = 0.41). Age discrepancy between the clinical trial population and the real-world population was higher for studies that did not report race (mean difference −8.8 years (95% CI −12.6 to −5.0 years)) vs. studies that did report it (mean difference −5.1 years, (95% CI −6.4 to −3.7 years), p-value = 0.04). Conclusion: The study demonstrates that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations, and that the two factors may be interrelated. We recommend continued efforts to recruit diverse populations.

scholarly journals Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects

2021 ◽  
Vol 13 ◽  
pp. 175883592110595
Author(s):  
María Gion ◽  
José Manuel Pérez-García ◽  
Antonio Llombart-Cussac ◽  
Miguel Sampayo-Cordero ◽  
Javier Cortés ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Drug Development ◽  
Hormone Receptor ◽  
Early Stage ◽  
Drug Approval ◽  
Cancer Drug ◽  
Surrogate Endpoints ◽  
Long Term Outcomes

Drug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy–based trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance.

Post-hoc power of clinical trials supporting anticancer drug approval by FDA.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
Michelle Nadler ◽  
Alexandra Desnoyers ◽  
Ramy Saleh ◽  
Eitan Amir
Keyword(s):  
Effect Size ◽  
Statistical Significance ◽  
Drug Approval ◽  
Cancer Drug ◽  
Large Sample Size ◽  
Expected Effect ◽  
Anti Cancer ◽  
Drug Approvals ◽  
Post Hoc

2018 Background: Regulatory approval of drugs is based typically on randomized control trials (RCTs) observing statistically significant superiority of an experimental agent over a prior standard. Statistical significance can result from large effect size and/or over-sampling (as a result of large sample size or long follow-up). Here we explore the source(s) of statistically significant results in trials supporting anti-cancer drug approval by the FDA. Methods: We searched Drugs@FDA to identify anti-cancer drug approvals for solid tumors (excluding lymphoma) from 2015-2019. We retrieved corresponding manuscripts and associated appendices and extracted data on study characteristics, statistical plan, primary outcomes and accrual and follow-up times. Post-hoc power was calculated based on observed results and was compared to expected effect size and power in the statistical plan. We explored associations with higher than expected power resulting from over-sampling using binary logistic regression. Results: We identified 75 unique drug-approvals reporting 94 endpoints. The most common tumour types were lung, breast, melanoma, and renal cell carcinoma. The most common endpoints were progression free survival and overall survival (OS). In 74 endpoints (79%), observed power was greater than expected power. The magnitude of higher than expected power ranged from 0.1 to > 20%. Of these, 59 (80%) had an effect size greater than predicted in the statistical plan. In 44/74 over-powered endpoints (60%), post-trial power was 100%. When post-hoc power was calculated based on expected effect size rather than observed effect size, 50 endpoints (85%) remained over-powered. Higher than expected power resulting from over-sampling was associated with OS compared to other endpoints (OR 3.03), with targeted agents compared to immunotherapy (OR 1.63) and inversely associated with year of approval (OR 0.57). Conclusions: Most cancer drug approvals result from statistically significant studies which are over-powered due to greater than anticipated effect size. Approximately 1 in 5 studies are over-powered likely due to over-sampling. In this setting, benefit observed in RCTs may not translate to the real-world setting.

Trends in PRO reporting in clinical trials leading to GU cancer drug approvals from 2007 to 2018.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 641-641
Author(s):  
Monica Tamil ◽  
Houssein Safa ◽  
Adele Semaan ◽  
Jad Chahoud
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Standards Of Care ◽  
Cancer Drug ◽  
Type I ◽  
Cancer Drugs ◽  
Urological Cancer ◽  
Quality Reporting ◽  
Patient Reported ◽  
Drug Approvals

641 Background: Having standardized and high quality reporting of patient reported outcomes (PRO), especially in clinical trials that establish standards of care in oncology is important for patient centered care. This study assessed the status of reporting and quality of analysis of PROs in FDA approved drugs for genitourinary malignancies. Methods: We conducted a systematic review of the FDA archives to identify urological cancer drugs approved between 2007-2018. We retrieved the clinical trials that led to these drug approvals from ClinicalTrials.gov and PubMed. We systematically screened for PROs and reviewed their analytic tools and interpretation methods reported in their published manuscripts and study protocols. A clinical trial was considered to include PROs if they were reported in either the primary or a subsequent manuscript. Results: We identified 22 clinical trials leading to FDA approval of urological cancer drugs between 2007-2018. Only 63% of trials had published PROs. PROs were reported in the primary clinical trial manuscripts for two drugs (9%), and in a secondary PRO manuscript for 12 drugs (54%). The median time between the primary and secondary papers was 12 months (IQR:7.5-26 months). Among the 14 published PRO papers, the hypothesis was broad in 79%, and not reported in 21%. PROs were never included as a primary endpoint of a study. Instead, PROs were reported as secondary endpoints in 5 (36%) and as exploratory endpoints in 7 (50%) studies, while two papers (14%) did not mention PRO reporting in their endpoints. The most common PRO instruments were EQ-5D (64%) and FACT-P (50%). In 92% of PRO papers, statistical analyses were conducted to account for missing data. Control for type I error was needed but not done in 57% of the trials. Conclusions: Delays in publication of PROs occur regularly in trials leading to drug approval in GU malignancies. Our study highlights the need to enhance standardization of the analysis and interpretation of PROs to maximize the value of this data for drug development and approval.

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