Friday, 23 May 2014

Failure to translate


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.
There is an increasing set of people criticising animal studies, but the failure to deliver drugs for MS may have as much to do with human activity as problems with the animals. Whilst many neurologists have been happy to bash animal studies for many years, it is important that they too become self critical so that they can take their share of responsibility in the failure to translate.
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Potential Reasons or Failures in the Drug Development Process
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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.
Pharmaceutical Science
  • 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 
Clinical Science
  • 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
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Can you come up with examples for eachpoint...I can.

CoI Members of Team G are authors of this paper.

3 comments:

  1. Prof mouse,

    You were never going to conclude that EAE was pants - it would be like turkeys voting for christmas. Prof g thinks that ebv might be the trigger. I don't believe mice get ebv. Some researchers think vit d is the issue - I've never seen a mouse on a sunbed. Mice can be cured of EAE, humans can't be cured of MS. No researcher knows what causes MS, whether inflammation causes damage or vice versa. So, given this big gap in our knowledge, any model is going to be guesswork at best. EAE has not led to the development of effective treatments for MS. I think EAE is an easy option for PHD students. Bad model/s which has resulted in poor results for MSers. But you're a nice guy.

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    Replies
    1. You are right why would I conclude pants....EAE is not MS. It is a tool that allows you to ask questions.....I would question you about effect treatments not coming from EAE work...tysabri is one of the most effective treatments.

      Mice can be cured of EAE because we are good at what we do...many people claim of a cure in EAE is probably about a couple of weeks from failure, but people don't check to see what would happen after stopping treatment. Disease will invariably return ....we have to try and develop these approaches into humans. Do nothing and wait to find the cause.....then Neuros will learn to commonly say "There, there I'll get a nice wheelchair for you". Doing nothing is not the option. However if people acknowledge the limitations of their EAE and did more translation and more robust experiment there would be less false hope.

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