TABLE 2.

Reasons for termination and suggested solutions.

Reasons for termination	Suggested solutions
1. Discrepancy in results between preclinical and clinical research Leung et al. (2014); Victor et al. (2017); Rybalka et al. (2020); Wagner. (2020); Soblechero‐Martín et al. (2021)	Larger animals with no difficulties to breed Larcher et al. (2014)
	Animal models representative of the human disease Larcher et al. (2014)
	Less inter-animal variability Larcher et al. (2014)
2. Disease rarity: insufficient sample sizes and insufficient exposure time Goemans et al. (2018); Finkel et al. (2021b)	Sensitive and objective outcome measures Hogrel et al., (2016); Lilien et al. (2019); Ropars et al. (2020)
	Digital or lab-based biomarkers Haberkamp et al. (2019); Lilien et al. (2019)
	Sharing of placebo data Goemans et al. (2020a)
	Enrichment of placebo arms with data from natural history studies Mercuri et al. (2020)
3. Disease heterogeneity: non-linear disease progression and variability in response Ricotti et al. (2016); Goemans et al. (2018); Finkel et al. (2021b)	Disease modeling and use of Bayesian statistical design of clinical trials Rooney et al. (2014); Fouarge et al. (2021)
	Stratification of patients by disease trajectory Mercuri et al. (2016); Muntoni et al. (2019b); Goemans et al. (2020b)
	Normalisation of data based on growth and developmental stage Goemans et al. (2013); Poleur et al. (2021)
	Refinement of inclusion criteria based on predictors of disease trajectory Mercuri et al. (2016)
4. Insufficient characterisation of surrogate endpoints Servais et al. (2019)	Characterisation of relationships between surrogate endpoints and functional outcomes Le Guiner et al. (2017); de Feraudy et al. (2021)
	Characterisation of time needed between observed differences in surrogate endpoints and observed differences in functional outcomes Servais et al. (2019); Servais et al.
5. Variability between investigation sites Goemans et al. (2018)	Evaluator training and strict protocols for procedures Mazzone et al. (2009)
	Objective and investigator-independent outcome measures Hogrel et al. (2016); Lilien et al. (2019); Ropars et al. (2020)