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clinical trials can be used to inform how preclinical assessments should beperformed

Our toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.

Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however, in many diseases an agent found successful in animal models does not show efficacy in human subjects. Our contention is that the approach of rigorous, clinical trials can be used to inform how preclinical assessments should be performed. Clinical trials in humans are carefully designed investigations executed with consideration of critical methodological issues, such as pre-specified entrance criteria and validated, outcome measures coupled with power analysis to identify sample size. Blinding of evaluators of subjective measures and randomization of subjects are also critical aspects of trial performance. Investigative agents are also tested in subjects with active disease, rather than prior to disease induction as in some pre-clinical assessments. Application of standard procedures, including uniform reporting standards, would likely assist in reproducibility of pre-clinical experiments. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use. Introduction The armamentarium of immune suppressive agents used in the treatment of autoimmune myasthenia gravis (MG) has largely emanated from the transplant literature and experience with the use of these drugs in the treatment of other autoimmune disorders. At first glance, this may seem surprising given that most common antigenic targets of the autoimmune response in MG are well known and the availability of a well-studied animal models of MG either experimental autoimmune myasthenia gravis (EAMG) produced by immunization with the acetylcholine receptor (AChR) or muscle specific tyrosine kinase (MuSK) or passive transfer of autoantibody (PTMG) . With the exception of the C5 complement inhibitor eculizumab, which was originally found to be effective in PTMG rat , none of the therapies currently used for treatment of MG emerged from pre-clinical work in animal models. Upon closer inspection, however, it is clear that there are limitations to EAMG as a tool for pre-clinical assessment of potential therapeutic agents, and these issues will be discussed in greater detail elsewhere in this special issue. Here we focus on how experience from clinical trials in patients with MG might be used to enhance the utility of the EAMG rodent models for pre-clinical evaluation of therapeutics prior to their advancement into human clinical trials. Trial design Human clinical trials are carefully designed experiments with significant attention to important methodological issues. For example, eligibility criteria are defined in order to yield an appropriate study population; treatment allocation is randomly assigned; primary and secondary outcome measures and endpoints are pre-specified; outcomes are assessed by an evaluator blinded to treatment assignment; and due consideration is given to the sample size needed to demonstrate the minimal clinically important difference in outcome in order to ensure that the trial has adequate power to detect the treatment effect of interest. The rigor of pre-clinical therapeutic studies in EAMG rodent models would benefit from attention to these methodological issues.

Phase III Preclinical Trials in Translational Stroke Research

The multicenter phase III preclinical trial concept is currently discussed to enhance the predictive value of preclinical stroke research. After public announcement, we collected a community feedback on the concept with emphasis on potential design features and guidelines by an anonymous survey. Response analysis was conducted after plausibility checks by applying qualitative and quantitative measures. Most respondents supported the concept, including the implementation of a centralized steering committee. Based on received feedback, we suggest careful, stepwise implementation and to leave selected competencies and endpoint analysis at the discretion of participating centers. Strict application of quality assurance methods is accepted, but should be harmonized. However, received responses also indicate that the application of particular quality assurance models may require more attention throughout the community. Interestingly, clear and pragmatic preferences were given regarding publication and financing, suggesting the establishing of writing committees similar to large-scale clinical trials and global funding resources for financial support. The broad acceptance among research community encourages phase III preclinical trial implementation.

The concept of multicenter ‘phase III’ preclinical trials (P3PT) for the evaluation of neuroprotective strategies is suggested to overcome the translational roadblock in stroke research . Importantly, it is not meant to replace exploratory scientific work as usually performed by individual laboratories (‘phases I and II’), but represents a type of confirmative research conducted by collaborating centers. P3PT should be performed prior to early stage clinical investigations and shall contribute to the strongly desired predictive value increase in stroke research.

Expert consortia are currently defining potential P3PT frameworks and guidelines, including ways for their future implementation. In parallel, a number of editorials, white papers, and commentaries have reviewed the concept. However, such publications exclusively represent statements by groups of selected experts or renowned individuals. While this provides well-thought through and highly relevant impulses expediting and refining the P3PT idea, it omits the chance to include ideas and feedback from a broader audience.

The first P3PT has recently been completed, but wider adoption and sustained utilization of the P3PT concept requires acceptance throughout the community down to its grassroots, i.e., junior investigators in smaller stroke research laboratories, as well as technicians and students conducting experiments everyday. Hence, the currently ongoing, expert consortia-based design of the P3PT framework might benefit from sensory input from a diverse audience representing the wider stroke research community without balancing towards a specific subgroup.

Collecting a Community Feedback on the P3PT Concept

We sought community feedback on the P3PT concept by a public call for an online questionnaire which was announced in a previous publication . The roster contained single (SA) and multiple answer (MA) questions plus five free text answers (see supplementary information). It was hosted by SoSci Survey (Munich, Germany) for 6 months. Answers were assessed for repeated access to avoid bias from counting multiple, but similar and potentially extreme statements. Received information was further subjected to a plausibility check to ensure information consistency (see supplementary material for details). Only those contributions addressing an a priori defined minimum of one survey section were included in the final analysis. An exception was a negative statement regarding general acceptance of the P3PT concept (first question), which was recorded even in case no further question was answered to prevent missing any potential negative statements on the concept. All survey questions, methodological details on the feedback acquisition strategy and data analysis are given in the supplementary material, which also contains complete collection of all free text answers.

Of note, the survey was designed as a completely anonymous platform and did not weight individual contributions by the responder’s level of responsibility, experience, or visibility in the field. Nevertheless, the feedback received on the free text answers suggests that a significant proportion of individuals responding to our call are experienced scientists, having profound experience with clinical research, and/or oversee a wide spectrum of research activities. A total of 93 contributions were considered for analysis based on aforementioned plausibility checks, with 81 individuals completing the entire survey.

Medicilon CEO

Chunlin Chen

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