Waiting for Godot: the true story behind why we need Phase III trials for cancer drugs

2011 ◽  
Vol 8 (1) ◽  
pp. 6
Author(s):  
Mikkael A Sekeres
Keyword(s):  
Phase Iii ◽  
Cancer Drugs ◽  
True Story ◽  
Waiting For Godot ◽  
Phase Iii Trials

Public Availability of Results of Trials Assessing Cancer Drugs in the United States

2013 ◽  
Vol 31 (24) ◽  
pp. 2998-3003 ◽  
Author(s):  
Thi-Anh-Hoa Nguyen ◽  
Agnes Dechartres ◽  
Soraya Belgherbi ◽  
Philippe Ravaud
Keyword(s):  
United States ◽  
The United States ◽  
Phase Iii ◽  
Cancer Drugs ◽  
Randomized Controlled ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Completion Date ◽  
Public Availability ◽  
Over Time

Purpose To evaluate to what extent results of completed trials of cancer drugs conducted in the United States are publicly available at ClinicalTrials.gov, as required by the Food and Drug Administration Amendments Act (FDAAA), or are published in journals. Methods We searched ClinicalTrials.gov for cancer trials governed by the FDAAA: phase II to IV trials assessing drugs in the United States with a primary completion date between December 26, 2007, and May 31, 2010. For each trial, we also searched PubMed to identify the publication of results. We assessed the cumulative percentages of posted or published results over time by using the Kaplan-Meier method. Results We identified 646 trials, including 209 randomized controlled trials (RCTs). At 12 months after completion of the trials, the cumulative percentages of trials with results posted at ClinicalTrials.gov, published in journals, and available either at ClinicalTrials.gov or in journals were 9% (95% CI, 7% to 11%), 12% (95% CI, 10% to 15%), and 20% (95% CI, 17% to 23%), respectively, and for RCTs, the percentages were 12% (95% CI, 8% to 16%), 5% (95% CI, 2% to 8%), and 17% (95% CI, 12% to 22%), respectively. At 36 months, these percentages were 31% (95% CI, 28% to 35%), 35% (95% CI, 31% to 39%), and 55% (95% CI, 51% to 59%), respectively, and for RCTs, they were 38% (95% CI, 31% to 45%), 32% (95% CI, 25% to 39%), and 56% (95% CI, 48% to 62%), respectively. Public availability of phase III trials was 15% (95% CI, 7% to 23%) at 12 months, 39% (95% CI, 27% to 49%) at 24 months, and 64% (95% CI, 50% to 73%) at 36 months. Conclusion Despite the FDAAA, results for nearly half the trials of cancer drugs in the United States were not publicly available 3 years after completion of the trials.

scholarly journals Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

2009 ◽  
Vol 27 (26) ◽  
pp. 4398-4405 ◽  
Author(s):  
Elizabeth A. Richey ◽  
E. Alison Lyons ◽  
Jonathan R. Nebeker ◽  
Veena Shankaran ◽  
June M. McKoy ◽  
...  
Keyword(s):  
Orphan Drug ◽  
Phase Ii ◽  
Phase Iii ◽  
Drug Status ◽  
Cancer Drugs ◽  
Phase Ii Trials ◽  
Development Times ◽  
Phase Iii Trials ◽  
Accelerated Approval ◽  
Confirmatory Trials

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

scholarly journals Assessing Population Diversity in Phase III Trials of Cancer Drugs Supporting FDA Approval in Solid Tumors

2021 ◽  
Author(s):  
Emre Yekedüz ◽  
Dario Trapani ◽  
Wenxin Xu ◽  
Elisabeth GE Vries ◽  
Chris Labaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Population Diversity ◽  
Phase Iii ◽  
Cancer Drugs ◽  
Fda Approval ◽  
Phase Iii Trials

Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6026-6026 ◽  
Author(s):  
A. J. Lurie ◽  
B. Djulbegovic ◽  
J. R. Nebeker ◽  
C. Angelotta ◽  
L. I. Gordon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Necessary Condition ◽  
Marketing Approval ◽  
The Novel ◽  
Cancer Drugs ◽  
Novel Therapy ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials ◽  
Accelerated Approval

6026 Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs. No significant financial relationships to disclose.

Clinical implications and outcomes of the ORION Phase III trials

2020 ◽  
Author(s):  
Julia Brandts ◽  
Kausik K Ray
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phase Iii ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Clinical Safety ◽  
Phase Iii Trials ◽  
Phase Ii And Iii ◽  
Ongoing Phase

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran’s efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran’s impact on cardiovascular outcomes.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

Sign in / Sign up

Export Citation Format

Share Document