Baker D & Amor S. Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. MSARD Epub
Although multiple sclerosis is a uniquely human disease, many pathological features can be induced in experimental autoimmune encephalomyelitis (EAE) models following induction of central nervous system-directed autoimmunity. Whilst it is an imperfect set of models, EAE can be used to identify pathogenic mechanisms and therapeutics. However, the failure to translate many treatments from EAE into human benefit has led some to question the validity of the EAE model. Whilst differences in biology between humans and other species may account for this, it is suggested here that the failure to translate may be considerably influenced by human activity. Basic science contributes to failings in aspects of experimental design and over-interpretation of results and lack of transparency and reproducibility of the studies. Importantly issues in trial design by neurologists and other actions of the pharmaceutical industry destine therapeutics to failure and terminate basic science projects. However animal, particularly mechanism-orientated, studies have increasingly identified useful treatments and provided mechanistic ideas on which most hypothesis-led clinical research is based. Without EAE and other animal studies, clinical investigations will continue to be “look-see” exercises, which will most likely provide more misses than hits and will fail the people with MS that they aim to serve.
Potential Reasons or Failures in the Drug Development Process
Basic (Pre-clinical) Science
- EAE/Strain model does not reflect human biology in PwMS.
- Drug does not target biology relevant to MS.
- Drugs are not used in a way appropriate to use in PwMS.
- Drug doses are not in physiological human dose range.
- Overstating drug effect as model optimised to overestimate effect.
- Overstating drug effect because of biases in experimental design.
- Studies are not reproducible in EAE/Lack transparency.
- Insufficient resource of develop and licence drug.
- Drug pharmacokinetic/formulation issues in animal/humans
- Drug toxicological issues in animals/humans
- Perceived risk-benefit concerns
- Lack of effective patent protection/Commercial opportunities
- Competition in the target indication
- Regulatory Restrictions
- Commercial interest and changing focus/interests of companies
- Insufficient resource of incentive to develop and licence drug
- Lack of clear understanding of MS biology,
- Experimental Biology is wrong or drug does not work
- Over-interpretation of significance of pre-clinical studies
- Drug dose is too low, compared to studies used to justify trial
- Insufficient appreciation of drug pharmacokinetics/
- Insufficient appreciation of drug CNS penetration
- Study underpowered due to unrealistic expectation of efficacy
- Study underpowered as test population not responding as predicted
- Study underpowered because the study too short to observe effect
- Measurement instrument/outcome is inadequate/non-responsive
- Wrong group of patients are studied (Disease stage may be beyond therapeutic intervention)
- Side-effects in PwMS prevented optimal response
- Side-effects in PwMS meant people stopped taking the drug.
- Side-effects in PwMS terminate drug development.
- Insufficient resource for adequate studies and drug development
Can you come up with examples for eachpoint...I can.
CoI Members of Team G are authors of this paper.