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Review
. 2020 Feb 7;13(2):dmm042903.
doi: 10.1242/dmm.042903.

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

Raffaella Willmann  1 , Joanne Lee  2 , Cathy Turner  2 , Kanneboyina Nagaraju  3 , Annemieke Aartsma-Rus  2   4 , Dominic J Wells  5 , Kathryn R Wagner  6 , Cristina Csimma  7 , Volker Straub  2 , Miranda D Grounds  8 , Annamaria De Luca  9
Affiliations
Review

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

Raffaella Willmann et al. Dis Model Mech. .

Abstract

Clinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any clinical trial must be carefully pondered in order to minimize the risk of clinical trial withdrawal or failure. A rigorous distinction between proof-of-concept and preclinical efficacy studies using animal models is key to support the rationale of a clinical trial involving patients. This Review evaluates the experience accumulated by the TREAT-NMD Advisory Committee for Therapeutics, which provides detailed constructive feedback on clinical proposals for neuromuscular diseases submitted by researchers in both academia and industry, and emphasizes that a timely critical review of preclinical efficacy data from animal models, including biomarkers for specific diseases, combined with adherence to existing guidelines and standard protocols, can significantly help to de-risk clinical programs and prevent disappointments and costly engagement.

Keywords: Animal models; Clinical trial; Efficacy studies; Guidelines; Neuromuscular; Preclinical; Standard protocols.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Recommendations on preclinical data given to TACT applicants. The x-axis shows the number of items of TACT advice (see Table 1) given to applicants in relation to the development phase of the research program at the application date. For example, 61% of programs submitted at the preclinical phase were given between one and three items of TACT advice.
Fig. 2.
Fig. 2.
Distribution of TACT advice according to applicant type. The x-axis shows the percentage of programs for which TACT identified pre-clinical issues. For example, in 61% of the programs coming from academia, TACT provided one to three items of advice in the preclinical assessments.
Fig. 3.
Fig. 3.
Clinical trial status in 2019 related to stage of development at the TACT submission date. (A) Clinical trial status in 2019 related to stage of development at the TACT submission date 2010-2019. Programs that were submitted at their preclinical phase have not yet resulted in a clinical trial in 70% of the cases (blue bar), whereas 30% (orange and gray bars) resulted in trials that are still ongoing or completed. (B) Clinical trial status in 2019 related to stage of development at the TACT submission date 2010-2017. Considering programs submitted until spring 2017, the rate of continuing into clinical trials slightly increases.
Fig. 4.
Fig. 4.
Clinical trial status in 2019 related to applicant type, 2010-2017. Programs submitted before spring 2017 developed into a clinical trial in ∼50% of the cases (orange and gray bars).
Fig. 5.
Fig. 5.
Status of clinical trials in 2019 for DMD programs. (A) Status of clinical trial in 2019 for DMD programs submitted to TACT 2010-2017. (B) Status of all DMD clinical trials in 2019 registered on clinicaltrials.gov 2010-2017. Almost 30% of the DMD trials needed to be stopped ahead of completion, indicating a high rate of failure that could probably be reduced by a careful evaluation of the preclinical evidence and its readiness for translation to the clinical setting.
See this image and copyright information in PMC

References

    1. Bøtker H. E., Hausenloy D., Andreadou I., Antonucci S., Boengler K., Davidson S. M., Deshwal S., Devaux Y., Di Lisa F., Di Sante M. et al. (2018). Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res. Cardiol. 113, 39 10.1007/s00395-018-0696-8 - DOI - PMC - PubMed
    1. Capogrosso R. F., Mantuano P., Uaesoontrachoon K., Cozzoli A., Giustino A., Dow T., Srinivassane S., Filipovic M., Bell C., Vandermeulen J. et al. (2018). Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy. FASEB J. 32, 1025-1043. 10.1096/fj.201700182RRR - DOI - PMC - PubMed
    1. Conwit R. A., Bhanushali M. J., Porter J. D., Kaufmann P. and Gutmann L. (2011). Adding more muscle and nerve to clinical trials. Muscle Nerve 44, 695-702. 10.1002/mus.22130 - DOI - PubMed
    1. Ferreira G. S., Veening-Griffioen D. H., Boon W. P. C., Moors E. H. M., Gispen-de Wied C. C., Schellekens H. and van Meer P. J. K. (2019). Correction: a standardised framework to identify optimal animal models for efficacy assessment in drug development. PLoS ONE 14, e0220325 10.1371/journal.pone.0220325 - DOI - PMC - PubMed
    1. George Carlson C., Bruemmer K., Sesti J., Stefanski C., Curtis H., Ucran J., Lachey J. and Seehra J. S. (2011). Soluble activin receptor type IIB increases forward pulling tension in the mdx mouse. Muscle Nerve 43, 694-699. 10.1002/mus.21944 - DOI - PMC - PubMed

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