scholarly journals Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Samer Al Hadidi ◽  
Carlos A. Ramos
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Hematological Malignancies ◽  
Phase Iii ◽  
Clinical Activity ◽  
Level Of Evidence ◽  
Phase Iii Clinical Trials ◽  
Early Phase Trials ◽  
Phase Iii Trials ◽  
Drug Approvals

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

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 JAK Inhibitors: Treatment Efficacy and Safety Profile in Patients with Psoriasis

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Leeyen Hsu ◽  
April W. Armstrong
Keyword(s):  
Clinical Trials ◽  
Clinical Symptoms ◽  
Treatment Options ◽  
Janus Kinase ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Psoriasis Treatment ◽  
Jak2 Inhibitor ◽  
Early Phase Trials ◽  
Phase Iii Trials

Janus kinase (JAK) pathways are key mediators in the immunopathogenesis of psoriasis. Psoriasis treatment has evolved with the advent of targeted therapies, which inhibit specific components of the psoriasis proinflammatory cascade. JAK inhibitors have been studied in early phase trials for psoriasis patients, and the data are promising for these agents as potential treatment options. Tofacitinib, an oral or topically administered JAK1 and JAK3 inhibitor, and ruxolitinib, a topical JAK1 and JAK2 inhibitor, have been most extensively studied in psoriasis, and both improved clinical symptoms of psoriasis. Additional JAK1 or JAK3 inhibitors are being studied in clinical trials. In phase III trials for rheumatoid arthritis, tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors, methotrexate monotherapy, or disease-modifying antirheumatic drugs. The results of phase III trials are pending for these therapies in psoriasis, and these agents may represent important alternatives for patients with inadequate responses to currently available agents. Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population.

scholarly journals Experiences of establishing an academic early phase clinical trials unit

2017 ◽  
Vol 14 (4) ◽  
pp. 349-356 ◽  
Author(s):  
Sarah R Brown ◽  
Debbie Sherratt ◽  
Gill Booth ◽  
Julia Brown ◽  
Fiona Collinson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Late Phase ◽  
Knowledge Retention ◽  
Lessons Learned ◽  
Phase Iii ◽  
Trial Management ◽  
Early Phase Trials ◽  
Early Phase Trial ◽  
Phase Trial

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely, and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This article describes an approach to establishing an academically led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009, the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focussing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article.

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.

Characteristics of a phase II study that predict for a positive phase III trial—A study of 383 clinical trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6604-6604
Author(s):  
S. M. Ueda ◽  
V. E. Sugiyama ◽  
C. Stave ◽  
J. Y. Shin ◽  
B. J. Monk ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Predictive Factors ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Iii Trial ◽  
Phase Iii Clinical Trials ◽  
Phase Ii Studies ◽  
Phase Iii Trials

6604 Background: To identify the characteristics of a phase II study that predict for a subsequent positive phase III trial. Methods: All phase II studies and subsequent phase III clinical trials on biologics in advanced cancers published from 1985 to 2005 were extracted. Chi-square test and logistic regression models were used for analyses. Results: 383 phase III clinical trials and their preceding phase II studies were identified. 183 (47.8%) phase III trials were “positive” and 200 (52.2%) were negative. 220 trials (57.4%) used biologics alone and 162 (42.3%) used a combination of biologics and chemotherapy. Over the study periods 1985–1990, 1991–1995, 1996–2000, 2001–2005, the percentage of phase II studies that led to positive phase III trials increased from 37.7% to 33.3% to 56.0% to 76.8% (p<0.001). The interval between the publication of phase II and III studies, 0.5–5, 6–10, 11–15, and 16–20 years were also associated with the success of phase III trial, 55.6%, 42.2%, 32.6%, and 10.0%, respectively (p<0.001). Phase II studies from multiple rather than single institutions were more likely to have a successful trial (60.4% vs. 39.4%; p<0.001). The percent of successful trials from pharmaceutical companies was significantly higher compared to academic, cooperative groups, and research institutes (89.5% vs. 44.2%, 45.2%, 46.3%; p=0.002). The publication of the phase II studies in journals with an impact factor of 8 or greater compared to those less than 8 was also predictive (44.1% vs. 58.0%; p=0.024). Phase II studies with a lower attrition rate were also associated with a positive phase III trial (61.1% vs. 41.8%; p=0.025). On multivariable analysis, all factors, except for journal impact factor, were independent predictive factors for a positive phase III trial. Conclusions: In phase II biologic studies, characteristics such as larger number of patients, more recent year of study, multiple vs. single institution participation, shorter time period between publication of phase II to phase III trial, and lower rate of attrition were predictive factors of success in a phase III trial. Investigators need to be cognizant of these phase II study characteristics before designing phase III trials. No significant financial relationships to disclose.

scholarly journals Dissemination of trial results to participants in phase III pragmatic clinical trials: an audit of trial investigators intentions

BMJ Open ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. e035730
Author(s):  
M Zulfiqar Raza ◽  
Hanne Bruhn ◽  
Katie Gillies
Keyword(s):  
Clinical Trials ◽  
Ethics Committees ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Integrated Research ◽  
Pragmatic Clinical Trials ◽  
Phase Iii Trials ◽  
The Uk ◽  
Dissemination Of Results ◽  
Trial Participants

ObjectiveTo determine the proportion of Phase III clinical trials given a favourable opinion by a research ethics committee in the UK that provided trial results to those who participated.DesignAudit of records.SettingPhase III clinical trials registered on the UK’s research permissions system (Integrated Research Application System) between the 1 January 2012 to 31 December 2017.Main outcome measuresProportion of trial investigators that intended to provide results to trial participants compared against what trials reported to ethics committees at the end of study.ResultsOut of 1404 Phase III trials, 87.7% (n=1231) trials stated they intended to disseminate results to participants while 12.3% (n=173) trials stated they would not. Out of these 1231 trials, 18.8% (n=231) trials intended to actively communicate trial results or a means of accessing results to their participants, a further 80.5% (n=991) reported passive intention to disseminate and for the remainder (n=9) the process was unclear. Of the 370 End of Study reports (30% of all included studies) that could be accessed 10 (2.7%) explicitly mentioned activities related to dissemination of findings to participants with the majority (74.9%) having no mention and a further 22.4% of reports not being accessible. Of the 10 which did report dissemination of results to participants the majority (n=6) were through a lay summary or letter.ConclusionsReported intention to disseminate results to trial participants among trial investigators is high, however, reporting of feedback methods is lacking. In addition, mechanisms to ensure intentions to disseminate trial results are translated into actual behaviour need to be put in place to ensure those who participate in trials have the opportunity to find out about the results.

scholarly journals Efficacy and Safety of COVID-19 Vaccines in Phase III Trials: A Meta-Analysis

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 582
Author(s):  
Haoyue Cheng ◽  
Zhicheng Peng ◽  
Wenliang Luo ◽  
Shuting Si ◽  
Minjia Mo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Phase Iii ◽  
Cochrane Library ◽  
Efficacy And Safety ◽  
Common People ◽  
Random Effects Models ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials

Nowadays, the vaccination with COVID-19 vaccines is being promoted worldwide, professionals and common people are very concerned about the efficacy and safety of COVID-19 vaccines. No published systematic review and meta-analysis has assessed the efficacy and safety of the COVID-19 vaccines based on data from phase III clinical trials. Therefore, this study has estimated the efficacy and safety of COVID-19 vaccines and the differences between vaccine types. PubMed, Embase, the Cochrane Library, CNKI, Wanfang, medRxiv databases and two websites were used to retrieve the studies. Random-effects models were used to estimate the pooled efficacy and safety with risk ratio (RR). A total of eight studies, seven COVID-19 vaccines and 158,204 subjects were included in the meta-analysis. All the vaccines had a good preventive effect on COVID-19 (RR = 0.17, 95% CI: 0.09–0.32), and the mRNA vaccine (RR = 0.05, 95% CI: 0.03–0.09) was the most effective against COVID-19, while the inactivated vaccine (RR = 0.32, 95% CI: 0.19–0.54) was the least. In terms of safety, the risk of overall adverse events showed an increase in the vaccine group after the first (RR = 1.46, 95% CI: 1.03–2.05) or second (RR = 1.52, 95% CI: 1.04–2.20) injection. However, compared with the first injection, the risk of local (RR = 2.64, 95% CI: 1.02–6.83 vs. RR = 2.25, 95% CI: 0.52–9.75) and systemic (RR = 1.33, 95% CI: 1.21–1.46 vs. RR = 1.59, 95% CI: 0.84–3.01) adverse events decreased after the second injection. As for the mRNA vaccine, the risk of overall adverse events increased significantly, compared with the placebo, no matter whether it was the first (RR = 1.83, 95% CI = 1.80–1.86) or the second (RR = 2.16, 95% CI = 2.11–2.20) injection. All the COVID-19 vaccines that have published the data of phase III clinical trials have excellent efficacy, and the risk of adverse events is acceptable. The mRNA vaccines were the most effective against COVID-19, meanwhile the risk and grade of adverse events was minimal, compared to that of severe symptoms induced by COVID-19.

scholarly journals Efficacy and safety of new oral anticoagulants in prophylaxis and treatment of venous thromboembolism

2010 ◽  
Vol 1 (1) ◽  
pp. 7
Author(s):  
Luca Masotti
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Oral Anticoagulants ◽  
Clinical Development ◽  
Ease Of Use ◽  
New Oral Anticoagulants ◽  
Phase Iii ◽  
Thrombin Inhibitors ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials

One of the main innovation emerged in recent years in the field of venous thromboembolism (VTE) has been represented by the clinical development and marketing of new oral anticoagulant agents used for prophylaxis and acute treatment. These drugs are represented by direct thrombin inhibitors (anti-factor IIa) and the direct inhibitors of activated factor X (anti-Xa). The main achievementof these new agents is represented by their ease of use without laboratory monitoring or dose adjustment. Dabigatran (anti-factor IIa), rivaroxaban, and apixaban (anti-Xa) are in advanced phase of clinical development with concluded phase III trials. Up to now the results of efficacy and safetyof phase III clinical trials are available, while phase IV studies are currently ongoing. Overall, the phase III clinical trials showed the non inferiority of new oral anticoagulants in VTE prophylaxis of patients undergone to major orthopedic surgery, such as hip and knee arthroplasty, compared toconventional prophylaxis represented by subcutaneous low molecular weight heparin with similar safety. Moreover dabigatran has shown to be not inferior when compared to warfarin for the prevention of six months VTE recurrences, with a significative lower incidence of bleedings. Awaitingthe results of many other ongoing phase III trials, since now it is possible to think that, in the next future, new oral anticoagulants will be widely diffused in clinical practice for their ease of use and feasibility. In this review the Authors analyse the available results of phase III clinical trials for dabigatran, rivaroxaban and apixaban, focusing on the antithrombotic endpoints for prevention andtreatment of VTE and the bleeding risk. Moreover synthesis of ongoing trials will be displayed.

scholarly journals Efficacy and safety of new oral anticoagulants in prophylaxis and treatment of venous thromboembolism

2010 ◽  
Vol 1 (1) ◽  
pp. 7-26 ◽  
Author(s):  
Luca Masotti ◽  
Cecilia Becattini ◽  
Roberto Cappelli ◽  
Giancarlo Landini ◽  
Alessandro Pampana ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Oral Anticoagulants ◽  
Clinical Development ◽  
Ease Of Use ◽  
New Oral Anticoagulants ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Phase Iii Clinical Trials ◽  
Phase Iii Trials

One of the main innovation emerged in recent years in the field of venous thromboembolism (VTE) has been represented by the clinical development and marketing of new oral anticoagulant agents used for prophylaxis and acute treatment. These drugs are represented by direct thrombin inhibitors (anti-factor IIa) and the direct inhibitors of activated factor X (anti-Xa). The main achievement of these new agents is represented by their ease of use without laboratory monitoring or dose adjustment. Dabigatran (anti-factor IIa), rivaroxaban, and apixaban (anti-Xa) are in advanced phase of clinical development with concluded phase III trials. Up to now the results of efficacy and safety of phase III clinical trials are available, while phase IV studies are currently ongoing. Overall, the phase III clinical trials showed the non inferiority of new oral anticoagulants in VTE prophylaxis of patients undergone to major orthopedic surgery, such as hip and knee arthroplasty, compared to conventional prophylaxis represented by subcutaneous low molecular weight heparin with similar safety. Moreover dabigatran has shown to be not inferior when compared to warfarin for the prevention of six months VTE recurrences, with a significative lower incidence of bleedings. Awaiting the results of many other ongoing phase III trials, since now it is possible to think that, in the next future, new oral anticoagulants will be widely diffused in clinical practice for their ease of use and feasibility. In this review the Authors analyse the available results of phase III clinical trials for dabigatran, rivaroxaban and apixaban, focusing on the antithrombotic endpoints for prevention and treatment of VTE and the bleeding risk. Moreover synthesis of ongoing trials will be displayed.

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