Abstract
A large majority of Phase III, large scale, clinical trials will fail, including gene therapy trials. This paper attempts to address some of the causes that may have inadvertently led to such a high failure rate. After briefly reviewing the detailed and high quality work that goes both into the preparation and conduct of such large Phase III clinical trials, and the preclinical science that is used to support and originate such trials, this paper proposes a novel approach to translational medicine which would increase the predictability of success of Phase III clinical trials. We propose that a likely cause of such failures is the lack of “robustness” in the preclinical science underpinning the Phase I/II and III clinical trials. Robustness is defined as stability/reproducibility in the face of challenges. Many times preclinical experiments are tested in a very narrow set of experimental conditions. Thus, when such approaches are finally tested in the context of human disease, the challenge provided by the varied age of patients, the complex genetic makeup of human populations, and the complexities of the diseases to be treated provide challenges which were never tested or modeled. We believe that the introduction of revised approaches to preclinical science, including the use of the latest developments in statistical, scientific, mathematical, and biological models, ought to lead to more robust preclinical experimentation with its subsequent translation, to more robust Phase III clinical trials.
Keywords: Glioblastoma multiforme, phase III clinical trials, bayesian statistics, effect size, gene therapy, cancer
Current Gene Therapy
Title: Uncertainty in the Translation of Preclinical Experiments to Clinical Trials. Why do Most Phase III Clinical Trials Fail?
Volume: 9 Issue: 5
Author(s): Pedro R. Lowenstein and Maria G. Castro
Affiliation:
Keywords: Glioblastoma multiforme, phase III clinical trials, bayesian statistics, effect size, gene therapy, cancer
Abstract: A large majority of Phase III, large scale, clinical trials will fail, including gene therapy trials. This paper attempts to address some of the causes that may have inadvertently led to such a high failure rate. After briefly reviewing the detailed and high quality work that goes both into the preparation and conduct of such large Phase III clinical trials, and the preclinical science that is used to support and originate such trials, this paper proposes a novel approach to translational medicine which would increase the predictability of success of Phase III clinical trials. We propose that a likely cause of such failures is the lack of “robustness” in the preclinical science underpinning the Phase I/II and III clinical trials. Robustness is defined as stability/reproducibility in the face of challenges. Many times preclinical experiments are tested in a very narrow set of experimental conditions. Thus, when such approaches are finally tested in the context of human disease, the challenge provided by the varied age of patients, the complex genetic makeup of human populations, and the complexities of the diseases to be treated provide challenges which were never tested or modeled. We believe that the introduction of revised approaches to preclinical science, including the use of the latest developments in statistical, scientific, mathematical, and biological models, ought to lead to more robust preclinical experimentation with its subsequent translation, to more robust Phase III clinical trials.
Export Options
About this article
Cite this article as:
Lowenstein R. Pedro and Castro G. Maria, Uncertainty in the Translation of Preclinical Experiments to Clinical Trials. Why do Most Phase III Clinical Trials Fail?, Current Gene Therapy 2009; 9 (5) . https://dx.doi.org/10.2174/156652309789753392
DOI https://dx.doi.org/10.2174/156652309789753392 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
Call for Papers in Thematic Issues
Advances in CAR-T Cell Therapy and CRISP combination
CAR-T cell therapy is a groundbreaking immunotherapy that has transformed cancer treatment, particularly in hematological malignancies like leukemia and lymphoma. It involves engineering a patient’s own T cells to express chimeric antigen receptors (CARs) that target and destroy cancer cells. The therapy has demonstrated remarkable success, achieving durable remissions in ...read more
Melatonin Signaling in Health and Disease
Melatonin regulates a multitude of physiological functions, including circadian rhythms, acting as a scavenger of free radicals, an anti-inflammatory agent, a modulator of mitochondrial homeostasis, an antioxidant, and an enhancer of nitric oxide bioavailability. AANAT is the rate-limiting enzyme responsible for converting serotonin to NAS, which is further converted to ...read more
Programmed Cell Death Genes in Oncology: Pioneering Therapeutic and Diagnostic Frontiers.
Programmed cell death (PCD) is recognized as a pivotal biological mechanism with far-reaching effects in the realm of cancer therapy. This complex process encompasses a variety of cell death modalities, including apoptosis, autophagic cell death, pyroptosis, and ferroptosis, each of which contributes to the intricate landscape of cancer development and ...read more
The now and future of gene transfer technologies
Gene and cell therapies rely on a gene delivery system which is safe and effective. Both viral and non-viral vector systems are available with specific pros and cons. The choice of a vector system is largely dependent on the application which is a balance between target tissue/disease and safety, efficacy ...read more
Related Journals

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Oncolytic Viruses: The Best is Yet to Come
Current Cancer Drug Targets Targeting Protein-Protein and Protein-Nucleic Acid Interactions for Anti-HIV Therapy
Current Pharmaceutical Design Diagnostic and Therapeutic Applications of Recombinant Antibodies:Targeting the Extra-Domain B of Fibronectin, A Marker of Tumor Angiogenesis
Current Pharmaceutical Design Antineoplastic Potential of Medicinal Plants
Recent Patents on Biotechnology Editorial [ The Role of Epidermal Growth Factor Receptor (EGFR) Targeting Drugs in the Treatment of Cancer Guest Editor: Fortunato Ciardiello ]
Current Cancer Therapy Reviews Molecular Mechanisms of Action of Gas1 and its Possible Therapeutic Applications
Current Signal Transduction Therapy The Emerging Role of Stereotactic Radiosurgery in the Treatment of Glioblastoma Multiforme
Current Radiopharmaceuticals Advances Towards The Discovery of GPR55 Ligands
Current Medicinal Chemistry Development of Crystalline Cellulosic Fibres for Sustained Release of Drug
Current Topics in Medicinal Chemistry SnoN: Bridging Neurobiology and Cancer Biology
Current Molecular Medicine EGFR(s) in Aging and Carcinogenesis of the Gastrointestinal Tract
Current Protein & Peptide Science Role of Cardiolipin in Mitochondrial Diseases and Apoptosis
Current Medicinal Chemistry Targeting Glioblastoma: The Current State of Different Therapeutic Approaches
Current Neuropharmacology Epidermal Growth Factor Receptor as a Target for Anti-Cancer Agent Design
Anti-Cancer Agents in Medicinal Chemistry Dynamic Contrast-Enhanced MRI in Oncology Drug Development
Current Clinical Pharmacology Alpha-Crystallins and Tumorigenesis
Current Molecular Medicine Classical and Non-Classical Thyroid Hormone Intracellular Pathways Involved in T Lymphoma Growth
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Perfusion Computed Tomography and its Application in Oncologic Practice
Current Molecular Imaging (Discontinued) Renal Cell Carcinoma Cancer Stem Cells as Therapeutic Targets
Current Signal Transduction Therapy The Recent Progresses on The Improved Therapy of Melanoma by Novel Drug Delivery Systems
Current Drug Targets