Core limitations in clinical trials leading to anticancer drug approvals by the U.S. Food and Drug Administration.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2057-2057
Author(s):  
Talal Hilal ◽  
Miguel Gonzalez-Velez ◽  
Vinay Prasad
Keyword(s):  
Clinical Trial ◽  
Optimal Control ◽  
Overall Survival ◽  
Clinical Trials ◽  
Drug Administration ◽  
Randomized Trials ◽  
Food And Drug Administration ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Drug Approvals

2057 Background: To date, a comprehensive evaluation of core limitations in clinical trials leading to anti-cancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken.The aim of this analysis was to assess the percentage of clinical trials with core limitations, defined as lack of randomization, lack of overall survival data, inappropriate use of crossover, and use of sub-optimal control arms that led to FDA approvals from 2014 to 2019. Methods: This observational analysis included all approved anti-cancer drug indications by the FDA from July 2014 through July 2019. All indications were investigated and each clinical trial evaluated for design, enrollment period, primary endpoints, and presence of core limitations. The standard of care therapy was determined by evaluating the literature and published guidelines 1-year prior to start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. We then calculated the percentage of approvals based on clinical trials with any or all core limitations. Results: A total of 187 anti-cancer approvals were evaluated. The number of anti-cancer drug approvals doubled over time with 68 in first half of study period (June 2014 to December 2016) to 119 in second half of study period (January 2017 to July 2019). Of those, 125 (67%) were based on a clinical trial with at least one core limitation. 64 (34%) approvals were based on a single-arm clinical trial. Of the remaining 123 approvals based on randomized trials, 60 (32%) had a core limitation. Of all randomized trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a sub-optimal control, and 17 (14%) used crossover inappropriately. Conclusions: The majority of cancer drugs are approved based on clinical trials with core limitations. Efforts to minimize core limitations at the time of clinical trial design are essential to ensure that new anti-cancer drugs being marketed truly improve patient outcomes over current standards.

Enrollment of Elderly Patients in Clinical Trials for Cancer Drug Registration: A 7-Year Experience by the US Food and Drug Administration

2004 ◽  
Vol 22 (22) ◽  
pp. 4626-4631 ◽  
Author(s):  
Lilia Talarico ◽  
Gang Chen ◽  
Richard Pazdur
Keyword(s):  
Clinical Trials ◽  
Cancer Patients ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
The Elderly ◽  
New Drugs ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Age Related ◽  
The Us

Purpose To analyze the age-related enrollment of cancer patients onto registration trials of new drugs or new indications approved by the US Food and Drug Administration from 1995 to 2002. Patients and Methods This study involved retrospective analyses of demographic data of cancer patients enrolled onto registration trials. The data on 28,766 cancer patients from 55 registration trials were analyzed according to age distributions of ≥ 65, ≥ 70, and ≥ 75 years. The rates of enrollment in each age group for each cancer were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the period 1995 to 1999 based on the 2000 US Census. Results The proportions of the overall patient populations aged ≥ 65, ≥ 70, and ≥ 75 years were 36%, 20%, and 9% compared with 60%, 46%, and 31%, respectively, in the US cancer population. Statistically significant under-representation of the elderly (P < .001) was noted in registration trials for all cancer treatment except for breast cancer hormonal therapies. Patients aged ≥ 70 years accounted for most of the under-representation. Conclusion Elderly were under-represented in the registration trials of new cancer therapies. Various strategies may be needed to evaluate cancer therapies for the elderly in prospective clinical trials and to improve cancer care in the elderly population.

Timing of US Food and Drug Administration (FDA) cancer drug approvals relative to publication of clinical trial results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2071-2071 ◽  
Author(s):  
Ali Raza Khaki ◽  
Aakash Desai ◽  
Martin W. Schoen ◽  
Bishal Gyawali ◽  
Eddy J. Chen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Cancer Treatments ◽  
Fda Approval ◽  
Anti Cancer ◽  
Accelerated Approval ◽  
Drug Approvals ◽  
Clinical Trial Results ◽  
Careful Assessment

2071 Background: Publication of clinical trial results in peer reviewed literature is essential to inform clinicians regarding the use of new anti-cancer treatments, which often have a low therapeutic ratio and require careful assessment of risks and benefits. Publication of registration trials should precede FDA approval to facilitate evaluation and implementation of new therapies. The timing of trial publication relative to FDA drug approvals has not been systematically investigated. Methods: We collected all FDA drug approvals for a cancer indication between 2000-19. Trials were identified using FDA labels as well as drugs and publications indexed on HemOnc.org. Approvals for generics/biosimilars, non-oncology indications and label revisions without supportive evidence were excluded. Dates of approval, the approval pathway, approval type (new vs expansion), and the first full publication related to the registration were recorded. Trials and approvals were matched using available metadata. We calculated the proportion of drugs approved prior to publication overall and for those receiving accelerated approval (AA). We used logistic regression to compare rates of pre-publication approval by approval pathway and by new vs expanded approval. Results: Among a total of 378 drug approvals, 139 (37%) had pre-publication approval. Of these, the median overall time from approval to publication was 140 days (IQR 64-281 days). For those with approval after publication, median time from publication to approval was 157 days (IQR 72-359 days). The number of drugs approved pre-publication rose by 27% between the first and last quarters of the study period, though, the proportion decreased as more anti-cancer drugs have been approved in recent years (Table). More drugs were approved pre-publication through AA than regular approval (46% vs 34%, OR 1.66 [95% CI 1.03-2.70], p=0.04) and as new approvals vs. expanded approvals (45% vs 32%, OR 1.76 [95% CI 1.15-2.70], p=0.01). Conclusions: A substantial minority of FDA approvals occur before trial results are published, with the odds being higher for drugs receiving AA and for new approvals. Since clinicians rely upon published results to inform risk/benefit decisions, efforts are needed to ensure trial results are published by the time of FDA approval of new cancer drugs and indications. [Table: see text]

scholarly journals Benefit, burden, and impact for a cohort of post-approval cancer combination trials

2019 ◽  
Vol 17 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Benjamin Gregory Carlisle ◽  
Adélaïde Doussau ◽  
Jonathan Kimmelman
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
National Comprehensive Cancer Network ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
Guideline Recommendation ◽  
Anti Cancer ◽  
Grade 3 ◽  
Cancer Network

Background: After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research. Methods: To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer “index” drugs first licensed 2005–2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration. Results: We captured 323 published post-approval trials exploring combinations, including 266 unique combination–indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3–4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33–1.79) and 1.51 (1.16–1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92–1.05) and 0.85 (0.79–0.93), respectively. None of the combination–indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up. Conclusion: Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.

New Drug Approvals by FDA: An Update

2018 ◽  
pp. 1-6
Keyword(s):  
Clinical Trials ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
New Products ◽  
New Therapies ◽  
New Drug ◽  
Arduous Task ◽  
Drug Approvals ◽  
Preclinical Safety

Bringing a drug into the market is an arduous task, and involved testing from preclinical safety to clinical trials. With its understanding of the science used to create new products, testing and manufacturing procedures, and the diseases and conditions that new products are designed to treat, FDA (U.S. Food and Drug Administration) provides scientific and regulatory advice needed to bring new therapies to market. This article provides an overview of the steps involved during development of a drug and its launch into the market.

scholarly journals Regulators, Pivotal Clinical Trials, and Drug Regulation in the Age of COVID-19

2020 ◽  
Vol 51 (1) ◽  
pp. 5-13
Author(s):  
Joel Lexchin ◽  
Janice Graham ◽  
Matthew Herder ◽  
Tom Jefferson ◽  
Trudo Lemmens
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
Drug Regulation ◽  
New Drugs ◽  
European Medicines Agency ◽  
Approval Process ◽  
Health Canada ◽  
Clinical Trial Information

Medicine regulators rely on pivotal clinical trials to make decisions about approving a new drug, but little is known about how they judge whether pivotal trials justify the approval of new drugs. We explore this issue by looking at the positions of 3 major regulators: the European Medicines Agency, Food and Drug Administration, and Health Canada. Here we report their views and the implications of those views for the approval process. On various points, the 3 regulators are ambiguous, consistent, and demonstrate flexibility. The range of views may well reflect different regulatory cultures. Although clinical trial information from pivotal trials is becoming more available, regulators are still reluctant to provide detailed information about how that information is interpreted. As medicines and vaccines come up for approval for treatment of COVID-19, transparency in how pivotal trials are interpreted will be critical in determining how these treatments should be used.

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.

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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