Atropine and the Goldilocks problem

Ian Flitcroft and Corrina McElduff provide an update on UK approval for atropine

A tropine has been on our collective radar for myopia control for a long time. I am sure many people are wondering, ‘Why is it taking so long?’  

A few years back, when the first studies came out of Singapore (including the ground-breaking Atom2 study), it seemed that low-dose atropine was going to be the game-changer for myopia. At a dose of 0.01%, atropine offered the prospect of good efficacy at slowing myopia progression with few side effects and no rebound.  

The logical next step was to conduct trials in Western populations to confirm that it also worked in our patients. It was also important to show that low dose atropine would be acceptable to kids in this part of the world, who are not famed for their love of eye drops. Our group at the Centre for Eye Research Ireland and several others started planning just that sort of trial in 2018-19. 

The challenge with any trial involving a pharmacological agent and children is that there are many regulatory and safety checks required to start the trial.

And once under way, the results are only available when the last enrolled subject has completed their two or three-year check-up. And rather like buses, having waited for ages, three turn up all at the same time. 

The results of the three biggest trials (our Mosaic trial, the Champ trial based in the US and Europe, and the US-based MTS1 trial from the PEDIG group) have all been announced over the past three months in online publications. 


Mixed results 

The results from these trials have raised almost as many questions as they have solved. From a safety and tolerability perspective, the trials all agree that once-a-day eye drops are acceptable and have an excellent safety profile with no serious adverse events. From an efficacy point of view, the results are more mixed.  

The Champ study showed efficacy for both refractive change and axial length over three years for 0.01%. This trial also tested a higher dose, 0.02%, which showed an effect on axial length but the impact on refraction was not statistically significant.  

Our Mosaic study, based in Ireland, found significant effects on refraction and axial length in subjects of white ethnicity, but not in non-white participants.

We also found an apparent strong impact of Covid, with participants who were subject to school closures and the several lockdowns showing no effect, but those recruited once those measures were lifted showed a strong effect of 0.01% atropine on both refraction and axial length.  

This suggests that the extra screen time and lack of time outdoors our children experienced during Covid can counteract the impact of atropine, emphasising the need for advice for optimising behaviour as well as providing myopia interventions.

The online paper describing the smallest of these three trials (MTS1) was released on July 13 and shows no benefit from 0.01% on either refraction or axial length. 


Atropine’s Goldilocks problem

So, where does that leave us? The variability of these results suggests that a fully approved and licensed preparation of low dose atropine may still be some way off. While we have known for many years that 0.5% or 1% atropine has a strong effect on myopia progression, it has a lot of side effects when used on a daily basis at those concentrations.  

Currently, that leaves us with a Goldilocks problem. If some people feel 0.01% is too low a dose and different people think that 0.5% or 1% is too high, then the answer must surely be somewhere in the middle.  

Studies from Hong Kong have favoured 0.05%, but we are still waiting for the first results in European children. The Mosaic trial will be reporting results on that concentration later this year.

In the meantime, we have no licensed preparations in the ‘just-right’ Goldilocks zone and may be waiting several years for such approvals.  

In the UK, some hospital pharmacies are compounding low dose atropine and there are also ‘grey market’ products being imported from other countries. Some of these products have a very low pH (4.0 to 4.5) and are preserved with agents, such as benzalkonium chloride, which creates concerns regarding long term use.  

A few ophthalmologists are certainly starting to use unlicensed low dose atropine on a ‘no-label’ basis and licensed 0.5% and 1% are also used on an ‘off-label’ basis. Nevertheless, without an approved, licensed product, it would seem unlikely that low dose atropine will be widely adopted in the UK in the next few years.  

Such approval would also be required, under current regulations, to allow eye care professionals (ECP) with an independent prescribing qualification to prescribe low dose atropine.  

Following Brexit, the UK now has its own approval body (the Medicines and Healthcare products Regulatory Agency, MHRA) but there are no signs that the approval process for new drugs is any faster under the new regime.  


‘The first shall be last, and the last shall be first’ 

Long term, we have no doubts that atropine will become an established part of myopia management, but the immediate future of myopia management is most definitely optical.  

Soft contact lens, spectacle lens and orthokeratology solutions have now overtaken atropine in the race to achieve approved status.  

This reflects both the success of the clinical trials for optical interventions and the different regulatory pathways for drugs compared to medical devices, which is the category that contact lenses and glasses fall under.  

The current availability of optical solutions should help speed up the adoption of myopia management. In the UK, dispensing opticians and optometrists outnumber ophthalmologists by 10 to one, and they are the practitioners best placed to provide optical-based myopia management solutions. 

While we may be waiting several more years for licensed low dose atropine products, there is no reason to sit on the fence when it comes to getting involved in myopia management. Indeed, the professional bodies are now encouraging UK ECPs to discuss myopia management with their patients and offer guidelines as how to approach this new area.  

To adapt an old Chinese proverb: ‘The best time to start myopia control is before your patient becomes myopic, the second best time is now.’  

  • Professor Ian Flitcroft is an ophthalmologist and the founder of Ocumetra.
  • Corrina McElduff is an optometrist and director of professional affairs at Ocumetra.