Heterogeneity of Clinical Trials for Antihypertensive Drugs in Japan: Exploratory Analysis of Confirmatory Phase III Trials Used for Marketing Approval

2017 ◽  
Vol 104 (1) ◽  
pp. 120-129 ◽  
Author(s):  
Reina Kaneko ◽  
Kota Sano ◽  
Shunsuke Ono
Keyword(s):  
Clinical Trials ◽  
Antihypertensive Drugs ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Marketing Approval ◽  
Phase Iii Trials ◽  
Confirmatory Phase

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.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

scholarly journals Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jiali Du ◽  
Jichun Gu ◽  
Ji Li
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Solid Tumours ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Iii Trials ◽  
Exploitation And Exploration ◽  
Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

Trial design from a clinical perspective

ESC CardioMed ◽  
2018 ◽  
pp. 3067-3071
Author(s):  
John G. F. Cleland ◽  
Ian Ford
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Trial Design ◽  
Statistical Significance ◽  
Well Being ◽  
Phase Iii ◽  
Practical Significance ◽  
Commercial Company ◽  
Phase Iii Trials ◽  
General Guidance

This chapter is written primarily from the perspective of investigators with limited resources designing clinical trials to assess the effects of interventions on patient well-being and outcomes with the hope that the results might influence clinical practice and guidelines. Other perspectives should be taken into account. The advice may be less applicable when resources are abundant (e.g. phase III trials sponsored by a large commercial company). Much research is funded by commercial companies hoping for a return on investment; they will design clinical trials to increase the chance of a statistically positive result. Many investigators will do the same although their motivation may differ. However, practising clinicians, patients, and health services want trials that help inform their daily clinical practice rather than merely achieving statistical significance. Large studies may be statistically positive but of dubious practical significance. This chapter gives some general guidance on selecting patients, comparators, endpoints, and study design.

scholarly journals A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion

2018 ◽  
Vol 38 (12) ◽  
pp. 2073-2091 ◽  
Author(s):  
Ligen Shi ◽  
Marcelo Rocha ◽  
Rehana K Leak ◽  
Jingyan Zhao ◽  
Tarun N Bhatia ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Cell Types ◽  
Phase Iii ◽  
Preclinical Studies ◽  
New Era ◽  
Stroke Research ◽  
Neuroprotective Strategies ◽  
Neurovascular Protection ◽  
Phase Iii Trials

Recent advances in stroke reperfusion therapies have led to remarkable improvement in clinical outcomes, but many patients remain severely disabled, due in part to the lack of effective neuroprotective strategies. In this review, we show that 95% of published preclinical studies on “neuroprotectants” (1990–2018) reported positive outcomes in animal models of ischemic stroke, while none translated to successful Phase III trials. There are many complex reasons for this failure in translational research, including that the majority of clinical trials did not test early delivery of neuroprotectants in combination with successful reperfusion. In contrast to the clinical trials, >80% of recent preclinical studies examined the neuroprotectant in animal models of transient ischemia with complete reperfusion. Furthermore, only a small fraction of preclinical studies included long-term functional assessments, aged animals of both genders, and models with stroke comorbidities. Recent clinical trials demonstrate that 70%–80% of patients treated with endovascular thrombectomy achieve successful reperfusion. These successes revive the opportunity to retest previously failed approaches, including cocktail drugs that target multiple injury phases and different cell types. It is our hope that neurovascular protectants can be retested in future stroke research studies with specific criteria outlined in this review to increase translational successes.

scholarly journals Chronic lymphocytic leukemia paradigm continues to be refined: news from the American Society of Hematology 2018 annual meeting

2019 ◽  
Vol 8 (2) ◽  
pp. IJH14
Author(s):  
Stefano Molica
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Standard Of Care ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Prospective Phase ◽  
American Society ◽  
Anti Cd20

There were a number of important updates and advances presented at the 2018 Annual American Society of Hematology meeting. With respect to the treatment of chronic lymphocytic leukemia, the American Society of Hematology 2018 was notable for an improved understanding of ibrutinib-based therapies. In fact, three prospective Phase III trials presented at the meeting indicate, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard of care for chronic lymphocytic leukemia. However, additional clinical trials comparing chemo-immunotherapy with ibrutinib alone or in association with an anti-CD20 monoclonal antibody remain a reasonable avenue to complete results of these large studies.

scholarly journals Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials

2019 ◽  
Vol 10 (4) ◽  
pp. 425-436 ◽  
Author(s):  
Sinje Gehr ◽  
Thomas Kaiser ◽  
Reinhold Kreutz ◽  
Wolf-Dieter Ludwig ◽  
Friedemann Paul
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Patient Reported Outcomes ◽  
Progressive Multiple Sclerosis ◽  
Phase Iii ◽  
Primary Progressive Multiple Sclerosis ◽  
Systematic Overview ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
Secondary Endpoints

AbstractThis manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere “relapse-prevention” approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants.

Sign in / Sign up

Export Citation Format

Share Document