Uncertainty in the Translation of Preclinical Experiments to Clinical Trials. Why do Most Phase III Clinical Trials Fail?

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.

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…This matches the so‐called lack of “robustness” seen with gene therapy in phase II and III clinical trials42 that has ultimately led to failure.…”

“…In the complete dataset, intracranial delivery (rather than intralesional) and multiple dosing (particularly four or more doses) were most effective. In contrast to the difficulties of transfecting tumours in humans with glioma, we were surprised that, taken together, systemic therapies were as efficacious as those delivered intracranially 42, 43. Over 90% of the thymidine kinase studies administered gene therapy intracranially with a single dose—analogous to clinical practice 16, 44, 45, 46…”

Preclinical Research: A Rise or Dawn

“…Arguments pertaining to the use of animals are strongly persisting [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] mentioning the harmful and non therapeutic experimentation if wrong on humans, applies same to that of …”

“…Subsequently, animal studies are justifiable if done in a way to minimize pain in animal models and wherever applicable alternative methods are explored and avoiding unnecessary cruel treatment to animals [5]. However, various reports have enforced on the failures of trails that has never capitalized after thorough observation of safety and efficacy in animal models which mainly portraits the requirement of robustness in preclinical studies [6][7][8][9][10]. For instance, reports say that, almost 95% of drugs that enter clinical trials related to stroke or septic shock do not get launched in the market though enormous expenditures have been dealt with the basic studies and drug discoveries [11] and similarly, the average success rate in clinical cancer trials is less than 8% after preclinical estimation [10].…”

The Early Career Researcher’s Toolkit: Translating Tissue Engineering, Regenerative Medicine and Cell Therapy Products

“…With this in mind however, substantial inertia must be overcome for flawed models to be abandoned. These limitations can be addressed by employing a robust range of models to identify weaknesses early on, reducing the likelihood of failure when facing the heterogeneity of human patients [30]. In particular, many clinical trials employ patient stratification, as safety and efficacy frequently vary with patient age, sex, co-morbidity, genetics etc [31].…”