scholarly journals Surveys/Research Exploring Japanese Phase I Studies in Global Drug Development: Are They Necessary Prior to Joining Global Clinical Trials?

2021 ◽  
Author(s):  
Masaru Hirano ◽  
Masanori Yamada ◽  
Toshiaki Tanaka ◽  
Toshiko Koue ◽  
Tomohisa Saito ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Phase I Studies ◽  
Global Drug Development

scholarly journals Prediction of Drug Approval After Phase I Clinical Trials in Oncology: RESOLVED2

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Guillaume Beinse ◽  
Virgile Tellier ◽  
Valentin Charvet ◽  
Eric Deutsch ◽  
Isabelle Borget ◽  
...  
Keyword(s):  
Machine Learning ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Attrition Rate ◽  
Phase I Clinical Trials ◽  
Test Set ◽  
Free Survival ◽  
Fda Approval ◽  
Independent Test

PURPOSE Drug development in oncology currently is facing a conjunction of an increasing number of antineoplastic agents (ANAs) candidate for phase I clinical trials (P1CTs) and an important attrition rate for final approval. We aimed to develop a machine learning algorithm (RESOLVED2) to predict drug development outcome, which could support early go/no-go decisions after P1CTs by better selection of drugs suitable for further development. METHODS PubMed abstracts of P1CTs reporting on ANAs were used together with pharmacologic data from the DrugBank5.0 database to model time to US Food and Drug Administration (FDA) approval (FDA approval-free survival) since the first P1CT publication. The RESOLVED2 model was trained with machine learning methods. Its performance was evaluated on an independent test set with weighted concordance index (IPCW). RESULTS We identified 462 ANAs from PubMed that matched with DrugBank5.0 (P1CT publication dates 1972 to 2017). Among 1,411 variables, 28 were used by RESOLVED2 to model the FDA approval-free survival, with an IPCW of 0.89 on the independent test set. RESOLVED2 outperformed a model that was based on efficacy/toxicity (IPCW, 0.69). In the test set at 6 years of follow-up, 73% (95% CI, 49% to 86%) of drugs predicted to be approved were approved, whereas 92% (95% CI, 87% to 98%) of drugs predicted to be nonapproved were still not approved (log-rank P < .001). A predicted approved drug was 16 times more likely to be approved than a predicted nonapproved drug (hazard ratio, 16.4; 95% CI, 8.40 to 32.2). CONCLUSION As soon as P1CT completion, RESOLVED2 can predict accurately the time to FDA approval. We provide the proof of concept that drug development outcome can be predicted by machine learning strategies.

Analysis of renal function in patients entered onto CTEP-sponsored phase I studies since 1979

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2519-2519 ◽  
Author(s):  
W. M. McHayleh ◽  
R. Sehgal ◽  
D. M. Potter ◽  
R. B. Royds ◽  
T. G. Nekrassova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Renal Function ◽  
Phase I ◽  
Creatinine Clearance ◽  
Renal Dysfunction ◽  
Antineoplastic Agents ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Phase I Studies ◽  
Administration Methods

2519 Background: The NCI and FDA utilize different criteria for classifying renal dysfunction. We analyzed renal function in all patients entered onto CTEP-sponsored phase I clinical trials since 1979 to evaluate the percentage of patients with acceptable renal function according to criteria utilized by the National Cancer Institute, as compared with those advocated by the Food and Drug Administration. Methods: Data from 12575 patients entered onto CTEP-sponsored phase I studies since 1979 were evaluated. Renal function was characterized by calculating creatinine clearance (CrCl) by three different formulae (Cockroft-Gault, Jelliffe, and Levey), as well as GFR according to MDRD. Results: Of the 12,575 patients, data were available to calculate renal function with all the 4 formulae in 5,177. Distributions of CrCl and GFR were defined, and patients were classified as having normal renal function or severe, moderate, or mild renal dysfunction according to FDA or NCI criteria. The resulting distributions are indicated in the table below. Conclusions: Approximately 40% of patients entered into CTEP-sponsored phase I trials have mild renal dysfunction according to FDA criteria and approximately 95% have CrCls > 50 ml/min. These data imply that moderate and severe are the only renal dysfunction categories that need to be evaluated in renal dysfunction studies of novel antineoplastic agents and that FDA guidelines should be applicable. Whether patients in the NCI database with CrCls of 50–80 ml/min experience more toxicities than those with creatinine clearances > 80 ml/min is undergoing evaluation. [Table: see text] [Table: see text]

Barriers to phase I clinical trial protocol IRB approval at KCI

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9080-9080
Author(s):  
D. Wang ◽  
E. Heath ◽  
A. Powell ◽  
T. Chaperon ◽  
F. LaGrone ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Median Time ◽  
Ethical Issues ◽  
Phase 1 ◽  
Cancer Drug ◽  
Final Approval ◽  
Standard Language ◽  
Molecular Therapeutics

9080 Phase I oncology clinical trials are critical in the oncology drug development process. To protect human subjects, every phase 1 protocol must be approved by an institutional review board (IRB) to assure safety before patient accrual. As the volume and complexity of phase 1 trials have increased, the amount of time spent on IRB protocol reviews have also increased for various reasons. Objectives: 1) Determine the average time spent on protocol approval by IRB at KCI/WSU; 2) Identify potential issues raised by IRB resulting in approval delays; 3) Identify the redundancies for which “standard language” implementation could facilitate future IRB applications thereby expediting approval. Methods: 96 Phase 1 research IRB applications at KCI/WSU between 8/1/2005 and 10/31/2006 were reviewed. These applications were stratified based on submission (new protocol versus amendment) and IRB approval (tabled, provisional or approved) status. Concerns frequently brought up by the IRB were identified. Results: The average and median time spent from initial submission to final approval of all 96 applications were 41.4 days and 43 days, respectively. Forty eight of 96 applications (50%) were provisionally approved from the initial review. Average and median time of obtaining final approval were 52.5 days and 52 days. Nine of 96 (9.4%) protocols were tabled with their average approval 83 days. The most common concerns raised by IRB were risks/benefit issues. These concerns were an even greater approval barrier when protocols involved specialized technologies of molecular therapeutics or complicated study designs. Regulatory policy changes issued by oversight organizations also required “real-time” updates into protocols and consent form amendments. Areas of “standard language” for future IRB applications are being compiled and will be discussed upon presentation. Conclusion: Phase 1 clinical trials are essential to anti-cancer drug development. The complicated ethical issues and science warrant an ongoing constructive collaboration of both parties. Identification of commonalities that delay IRB approval will lead to more expeditious IRB approval not only at our institution, but could also benefit other institutions. No significant financial relationships to disclose.

Informed consent in phase I clinical trials: Implications for trends in design.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14077-e14077
Author(s):  
Paul Henry Frankel ◽  
Susan G. Groshen
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Phase I ◽  
Dose Finding ◽  
Institutional Review Boards ◽  
Severe Toxicity ◽  
Phase I Clinical Trials ◽  
Traditional Use ◽  
Phase I Studies ◽  
Definition Of

e14077 Background: Informed Consent (IC) is a critical aspect of human subjects protection. Institutional Review Boards are tasked with insuring proper IC as one aspect of protecting participants in clinical trials. Phase I trials in oncology present special issues with IC, as often neither the risks nor the benefits are well-known. This has resulted in carefully worded IC templates for Phase I studies based on the traditional use of dose-finding designs that are geared towards finding the “Maximum Tolerated Dose (MTD)”. As the definition of this term varies by study, the implication for patient risk and informed consent are rarely discussed. Methods: We reviewed Phase I designs to present options for improving the informed consent process for Phase I oncology trials. Results: Phase I studies have seen an increase in designs based on work from the early 1990s seeking a dose that results in a targeted percent of patients experiencing a “Dose Limiting Toxicity (DLT)” to define the MTD. The most common definition of a DLT is a treatment-related toxicity that results in a particularly concerning severe toxicity (grade 3 or higher) in the first cycle of therapy and the most common rate targeted (in designs that define toxicity as a goal) is 25%. In that setting, while lower doses may have a lower likelihood of DLT, higher doses or the expansion cohort are likely to have a 25% chance of DLT if the target is pursued. This information is rarely quantitatively communicated in the informed consent. Conclusions: IRBs and investigators should consider communicating through informed consent the quantitative summary of goals of the study and related risk. For example, transparency suggests conveying when the goal (target) of the study is to find the dose where there is a one in four chance of experiencing a severe adverse event in the first cycle.

scholarly journals Research biopsies in the context of early phase oncology studies: clinical and ethical considerations

2013 ◽  
Vol 7 (1) ◽  
pp. 5 ◽  
Author(s):  
Matilde Saggese ◽  
Divyanshu Dua ◽  
Emily Simmons ◽  
Charlotte Lemech ◽  
Hendrik-Tobias Arkenau
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Tumor Biology ◽  
Biological Response ◽  
Resistance Mechanisms ◽  
Dose Finding ◽  
Direct Result ◽  
Phase I Studies ◽  
Increasing Demand ◽  
Tumor Biopsies

The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

Phase I clinical trials in patients with advanced non-small cell lung cancer treated within a Drug Development Unit: What have we learnt?

Lung Cancer ◽  
2017 ◽  
Vol 111 ◽  
pp. 6-11 ◽  
Author(s):  
Marta Capelan ◽  
Desamparados Roda ◽  
Elena Geuna ◽  
Karim Rihawi ◽  
Shankar Bodla ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Phase I Clinical Trials ◽  
Small Cell Lung ◽  
Development Unit

scholarly journals Dose–Response Relationship in Phase I Clinical Trials: A European Drug Development Network (EDDN) Collaboration Study

2014 ◽  
Vol 20 (22) ◽  
pp. 5663-5671 ◽  
Author(s):  
Victor Moreno García ◽  
David Olmos ◽  
Carlos Gomez-Roca ◽  
Philippe A. Cassier ◽  
Rafael Morales-Barrera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Dose Response ◽  
Response Relationship ◽  
Phase I Clinical Trials ◽  
Dose Response Relationship ◽  
Development Network

scholarly journals Research biopsies in the context of early phase oncology studies: clinical and ethical considerations

2013 ◽  
pp. e5 ◽  
Author(s):  
Matilde Saggese ◽  
Divyanshu Dua ◽  
Emily Simmons ◽  
Charlotte Lemech ◽  
Hendrik-Tobias Arkenau
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Tumor Biology ◽  
Biological Response ◽  
Resistance Mechanisms ◽  
Dose Finding ◽  
Direct Result ◽  
Phase I Studies ◽  
Increasing Demand ◽  
Tumor Biopsies

The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

NEW ORIGINAL DRUG ROSEOFUNGIN-AS, OINTMENT 2%

2021 ◽  
pp. 55-64
Author(s):  
А.К. САДАНОВ ◽  
В.Э. БЕРЕЗИН ◽  
И.Р. КУЛМАГАМБЕТОВ ◽  
Л.П. ТРЕНОЖНИКОВА ◽  
А.С. БАЛГИМБАЕВА
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Physicochemical Properties ◽  
Phase I ◽  
Mechanism Of Action ◽  
Chemical Structure ◽  
Antifungal Drug ◽  
Polyene Antibiotic

В статье приводятся сведения о разработке нового отечественного противогрибкового препарата «Розеофунгин-АС, мазь 2%» для наружного применения на основе оригинального природного полиенового антибиотика розеофунгина. Приводятся данные о продуценте антибиотика, процессе его биосинтеза и получения, его физико-химических свойствах и химической структуре, рассматриваются его антифунгальные и антивирусные свойства, механизм его действия, а также основные этапы разработки противогрибкового препарата - доклинические и I, II и III фазы клинических исследований. This paper provides the information on the development of new domestic antifungal drug Roseofungin-AS, ointment 2% for external use based on the original natural polyene antibiotic roseofungin. Data on the antibiotic producer, the process of its biosynthesis and production, its physicochemical properties and chemical structure are presented, its antifungal and antiviral properties, the mechanism of action as well as the main stages of the antifungal drug development including preclinical and phase I, II, III clinical trials are discussed.

Global drug development in cancer: A cross-sectional study of clinical trial registries

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2520-2520
Author(s):  
P. Hertz ◽  
B. Seruga ◽  
L. W. Le ◽  
I. F. Tannock
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase Ii ◽  
New Drugs ◽  
Phase Iii ◽  
Cancer Site ◽  
Cancer Type ◽  
Clinical Trial Registries ◽  
Global Drug Development

2520 Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research. [Table: see text] No significant financial relationships to disclose.

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