Celebrating 268 years of clinical trials

On the 20th May we celebrated international clinical trials day as well as research awareness week at Great Ormond Street Hospital (GOSH) so it seems particularly fitting this week to blog about research.

International clinical trials day commemorates the start of the first clinical trial by the British naval physician James Lind in 1747.  Lind noted in his 1753 publication, Treatise of the Scurvy, that:

 “Armies have been supposed to lose more men by sickness, than by the sword. But this observation has been much more verified in our fleets and squadrons; where the scurvy alone, during the last war, proved a more destructive enemy, and cut off more valuable lives, than the united efforts of the French and Spanish arms.”

Although the term scurvy was used to describe what we now know to be numerous ailments, there is no denying the impact a treatment for scurvy would have (and indeed did have) on society at the time Britain was fighting to rule the waves.

Serving as a surgeon on HMS Salisbury in 1747, Lind tested six different 14 day treatments for scurvy on groups of two patients each.  His 12 patient’s were “as similar as I could have them” i.e. living in the same quarters and on the same diet.  It was the group given two oranges and one lemon that showed “the most sudden and visible good effects” despite (due to insufficient supplies) their treatment only lasting for six days instead of the intended 14.  Lind’s study is widely acknowledged as the first documented ‘fair’ clinical trial.

Now lets fast forward 263 years to 2010 when I began to work on a clinical trial for Duchenne muscular dystrophy (DMD).  DMD is a fatal muscle disorder affecting approximately 1 in 4,000 male births and whilst it is classified as a rare disease, it is one of the most commonly diagnosed fatal genetic disorders in children.  DMD is characterised by progressive muscle weakness whereby patients usually lose the ability to walk in their early teens.  Under proper management, most patients will die from heart and breathing complications in their twenties.

Unlike scurvy in the 18th century, we know an awful lot about DMD today.  It is caused by DNA mutations in the Duchenne, or DMD, gene that lies on the X chromosome (males have only one copy which is why the overwhelming majority of patients are boys).  This gene holds the code for cells to make a protein called dystrophin and DMD-causing mutations result in the loss of dystrophin from muscle cells which ultimately leads to the loss of muscle function in DMD patients.

Keeping on with our nautical theme, dystrophin is like the chain that attaches a ship to its anchor.  In cells, dystrophin provides a mechanical link between the intracellular cytoskeleton and the extracellular matrix and without it muscle cells become unstable and suffer from the stress of muscle contraction.  An obvious therapeutic treatment is therefore to restore lost dystrophin.  My research, and the subject of several current clinical trials uses ‘molecular patches’ called antisense oligonucleotides to mask the effect of mutations at the molecular level.  We call this therapy exon skipping as the antisense oligonucleotide is designed to ‘skip’ regions of the code (exons) so that the message can be translated into a modified dystrophin protein.  It is important to note that this particular treatment could never be a cure but rather is designed to reduce the severity of the disease and improve the patient’s quality of life.  We aim to change the natural history of the disease; and have indeed observed dystrophin restoration in muscle cells from treated patients.  Several clinical trials are now fully evaluating the promising therapeutic potential of exon skipping for DMD.

Unlike Lind’s study, in clinical trials today we must use carefully defined outcome measures – that is a measure by which we can deem the treatment to be a success.  For DMD this has traditionally been the six minute walk test (how far patients can walk in six minutes); a significant improvement compared to a control group would indicate the treatment is successful.  Whilst the six minute walk test may be a reliable measure of disease progression, we are unsure as to the amount of dystrophin protein production that is required to produce a functional improvement in patients.  It therefore remains relevant to include biochemical outcome measures – a molecular measure of success which proves that the treatment is in fact restoring dystrophin protein production and to what extent.

Technical difficulties in measuring dystrophin have led to several competing methodologies and differing opinions on which is the most robust measure for clinical trials, so much so that regulatory bodies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) highlighted this lack of consensus as an obstacle to the field.  I am pleased to say that we are making great progress in validating biochemical outcome measures through multi-institution collaborations.  In fact, and in great contrast to Lind’s time, rare disease research is particularly collaborative in nature, something I have discussed in a previous post.

The results of the first proof-of-concept exon skipping clinical trial for DMD were published in 2009 and six years later this particular drug (eteplirsen) is now in the later stages of a phase III clinical trial and on track to be submitted as a new drug application to the FDA later this (2015) year.  The drug discovery road will always be too long for patients and their families; lets take a look at how long it took to get Lind’s reccomendations for scurvy translated into practice without our modern day regulatory hurdles.

Firstly, did Lind even recommend lemon juice?  The more I read about Lind the more I find that all is not quite as it seems (see Baron 2009 for a thorough reassessment of Lind):

  • Lind’s patients were not listed on the ship’s sick list bringing into question the timing of his study
  • Despite presenting conclusive evidence, Lind does not state that citrus juice is a cure for scurvy in his Treatise of the Scurvy publication and continued to recommend other remedies such as infusion of malt
  • Citrus juices were used at sea long before Lind’s study; the first surgeon  general of the East India Company, John Woodall recommended ships carry lemon juice in 1617 to which Lind makes no reference

Lind published Treatise of the Scurvy six years after his clinical trial and it was another 48 years (and countless lives) after that in 1795 when the Admiralty was finally persuaded to act. Whilst undoubtedly flawed by modern standards, his work is celebrated today as international clinical trials day to raise awareness and highlight the importance of research for improving public health.  Clinical trials provide vital hope for the DMD community and let me tell you now, in today’s world of patient advocacy we will not let 48 years go by before we decide if exon skipping is to become a recommended treatment for eligible patients!

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