How to assess the efficacy of myopia control treatments

Authors: Noel A. Brennan (1), Youssef M. Toubouti (1), Xu Cheng (1), Mark A. Bullimore (2)

1. Johnson and Johnson Vision, 7500 Centurion Pkwy, Jacksonville, FL, 32256, USA
2. University of Houston, USA

Date: November 2020

Reference: Progress in Retinal and Eye Research. 2020 [Link to open access paper]

There has been an exponential rise in the volume of myopia control research published in the past decade. However, despite the immense interest in the efficacy of treatment modalities, no standardised approach to reporting efficacy has been adopted.¹  Studies report results of efficacy in various formats; refractive shift (D), axial length (mm), or both. The inconsistency in reporting hinders direct comparison of the efficacy of treatment modalities and complicates Eye practitioners' ability to confidently recommend the most efficacious intervention to patients. 

This paper examines the theory underlying the reporting of myopia control efficacy and the sequelae of such investigation. The authors propose an alternate method of reporting efficacy; Cumulative Absolute Reduction in Axial Elongation (CARE), which conveys the benefit that a child receiving a specified treatment might expect, independent of age, progression rate, refractive error and ethnicity over a stated time period.¹ The authors provide Eye care practitioners with the tools to make efficacy evaluations about myopia control treatments in a considered and cautious manner.

The paper reports numerous conclusions, many of which have clinical implications for Eye care practitioners. The (7) principal interpretations of this study will be discussed individually below. 

1. Axial elongation is the preferred method for assessing myopic progression.
Clinical Relevance: While it is ideal that all practitioners engaging in myopia control have access to optical biometry equipment, lack of access should not impede or deter engagement with practising myopia control

• Practitioners without access to ocular biometry should strive to complete autorefraction with cycloplegia at least once yearly to monitor patients. Auto-refraction is advantageous as it avoids examiner bias and is more repeatable than subjective refraction.²
• Eye care practitioners should remain aware of the limitations of subjective refraction measurement. Variability in refraction results is 50% higher when cycloplegia is not utilised.¹

Limitations and further research: As the superiority of ocular biometry in assessing myopic progression is increasingly reported, investigations should be directed towards generating inexpensive equipment with such capabilities.¹ This development would augment the widespread adoption and implementation of such equipment into practice.

2. There is insufficient evidence to suggest that faster progressors (or younger myopes), experience greater treatment efficacy.

Clinical Relevance: Data suggests that an intervention provides a treatment effect that is, on average, comparable in absolute terms across progression, age and refractive error  

• Eye care practitioners should remain aware of the reduction in myopia progression that can be realistically expected
• Efficacy projections for early onset myopes are usually substantially less than those provided by percentage calculations, such as BHVI Myopia Calculator.¹ This is due to a reduction in annual treatment effect size over time and uniformity of absolute treatment effect across progression range. 
• See Kate's report from IMC 2019 for more info on why caution is needed when interpreting results from Myopia Calculators

Further research: Further research is needed to establish predictive markers to identify those patients that are most likely to progress at a fast rate and treatment options that will benefit them the greatest.

3. The initial rate of reduction of axial elongation by myopia control treatments is not sustained.

Clinical Relevance: Both the absolute efficacy and percentage efficacy of treatment decreases with time

• It cannot be assumed that results obtained from limited term clinical studies can be applied across a longer duration of treatment. It is inappropriate to extrapolate the treatment effect observed in the first 6-12 months to estimate the likely further benefit of treatment.³
• Despite markedly varied efficacies in the first year of treatment, interventions to slow progression have provided notably similar treatment effect sizes in the second and third years of treatment 
• Eye care practitioners should anticipate that the greatest treatment effect will likely be observed in the first year of treatment

Limitations and Further Research: Further research is required to characterise the exact nature of treatment vs time relationship and determine the mechanisms underlying this phenomenon. The authors of this article suspect that treatment efficacy is greatest in the first year due to the witnessed "shrinkage phase" of some patients' eyes, which eventually passes and is followed by a constant proportional growth rate that reduces treatment efficacy. This theory is discussed further below.

4. Current reporting styles of myopia treatment efficacy are misleading, and a superior, evidence-based method of assessing efficacy of myopia treatment must be established.

Clinical Relevance: Using percentage reduction in progression as an index to describe treatment effect can be misleading

The most common reporting of efficacy in clinical reviews comparing different treatment options is relative reduction of progression, expressed as a percentage. This reporting relies on the assumption that relative treatment efficacy applies across the progression range (ie fast vs slow progressors) and is consistent across treatment (ie same effect in the first vs third year). However, neither of these assumptions have been proven and the reporting of a relative treatment effect has been commonly criticised.⁴ The authors provide a strong and robust argument that privies the reader to the pitfalls of reporting percentage efficacy.  

• To provide an example, the authors observe that expression of treatment as a percentage suggests a 1-1.5mm (approximately 3-4D) reduction in myopia progression might be achievable over a period of time. However, consistency of treatment effect across the progression range and reduction of treatment effect over time indicate there is only sufficient evidence for long-term mean efficacy of less than 0.5mm (approx 1D).
• Furthermore, re-analysis of the data from Cheng et al (2016) illustrated the misgivings of percentage efficacy, as it suggests that an 8-year old could expect 20% reduction in progression in 12 months of treatment, while an 11-year old at 6 months derives a 75% benefit, both with the same intervention. This analysis is helpful for Eye care practitioners as it unmistakably highlights the problem with utilising percentage efficacy and that caution is required when interpreting these results.
• It should be noted that not all studies report percentage reduction as their marker of efficacy. A recent Cochrane review⁵ reports mean reduction in axial elongation (with confidence intervals) in a time dependent manner. For example, when reporting results from a 3-year randomised control trial, authors reported mean difference in axial elongation from baseline to Year 1, baseline to Year 2 and baseline to year 3. This solves the authors concerns regarding reporting.

In response to the misleading utilisation of percentage reduction in progression, the authors of the paper propose Cumulative Absolute Reduction in axial Elongation (CARE) as a preferred efficacy metric. It is empirically determined and describes an effect size that is independent of patient age and incorporates reduction of efficacy over time

The authors determine the CARE value from numerous studies and establish the maximum CARE reported to date is 0.44mm (equates to approximately 1D) over 7 years and achieved via orthokeratology.⁶ While this result may appear modest, a reduction of myopia should reduce the risk of myopia macular degeneration by 40%, regardless of race or degree of myopia.⁷

 Limitations and future research: Two limitations of CARE can be observed. 

1. It is not independent of time, and hence must be expressed with reference to the time scale
2. In the reporting of CARE, the authors importantly do not include a measure variability around the mean (no confidence intervals). This is significant for two reasons. Firstly, readers are unable to determine if the reported result is statistically significant. Secondly, a gauge of precision is unable to be obtained

Future research should focus on the creation of a model that can predict future efficacy based on short term data.

5. There is no apparent superior method of treatment for myopia control. While different treatment methods have shown varying efficacies in the first year, they have shown only small differences after this.

• However, these are some treatments (PAL's, 0.01% atropine and soft multifocal contact lenses that prioritise clear vision) that may provide inferior treatment effects 
• Eye care practitioner should choose treatment based on numerous considerations, including their skill set, preferences of parents and children, ability of child to adapt to the treatment, availability of product and regulatory considerations

6. Rebound should be assumed until proven otherwise, and is a threat to the overall viability of myopia control treatment.

• Rebound has been observed with atropine and to some extent orthokeratology, and should be assumed with all treatment until proven otherwise
• Eye care practitioners and researchers should consider whether continuing treatment into teenage years or beyond can reduce rebound effect

7. All young myopes (less than 12 years of age) should be recommended treatment. 

Clinical Relevance: Eye care practitioners should not be hesitant in implementing myopia control treatment. The most efficacious treatments should be utilised, in combination with behavioural modifications at an early age and over extended periods of time.

• Decision to treat should be based on age of onset (or refraction at a given age), not past progression. Consideration may be given to ethnicity and parental myopia 
• Use of prior axial elongation is a superior method of predicting future progression

To conduct a thorough review and analysis of the concept of efficacy in myopia control, using accumulated information available in the scientific literature as well as the authors own studies. The authors aim to establish an evidence based approach to assessing efficacy of interventions to slow myopic progression and explore resultant implications.

Two key sources of information were utilised in the paper. Firstly, a set of reanalyses of data from the authors' clinical studies. Secondly, a set of key papers that describe clinical trials of myopia control. Inclusion criteria included a treatment modality with demonstrated efficacy, statistical significance and an effect size of 0.1mm reduction in axial length elongation at any timepoint during follow-up. Both masked and non-masked studies were included. It is interesting to note that no studies involving 0.01% atropine satisfied the threshold for inclusion in this analysis due to the lack of efficacy in reducing axial length elongation.

Axial Elongation is the preferred method for assessing myopic progression Traditionally, refractive error measurement has been used to monitor myopia progression. However, widespread use of ocular biometry potentially challenges this dominion. This section of the paper discusses advantages and disadvantages of using axial elongation versus refractive error change as the primary endpoint. 

In order to establish the presence of myopia, refractive error (preferably measured with cycloplegic autorefraction) is clearly preferred. However, once myopia is detected and the requirement is to monitor progression, measurement of axial length emerges as the superior method for numerous reasons.

Firstly, inhibition of axial elongation is considered the primary means of minimising risk of myopia associated pathologies.⁸ Secondly, the authors report that ocular biometry is the only method of accurately assessing progression with orthokeratology and atropine treatments. Both orthokeratology and atropine treatments induce changes in the refracting components of the eye which renders change in refractive error ineffective in determining treatment effect. Lastly, the authors assessed the repeatability of refractive error measurements by autorefraction and ocular biometry. The results demonstrated that ocular biometry displays superior sensitivity and is 3x more repeatable than cycloplegic autorefraction.

Assessing integrity of absolute and relative measures of axial length

The authors implemented 4 strategies to investigate the advantages and disadvantages of absolute and relative measures of axial length.

Firstly, an investigation of standard distributions of progression from a previously published study (Cheng et al, 2016).⁹ The aim was to examine the validity of expression of myopia control as a percentage. The authors concluded that reporting of relative (percentage) efficacy is misleading and only applies to a specific sample population in the progression spectrum.   

Secondly, a reanalysis of published results of a contralateral eye study. The hypothesis that progression in eyes treated for myopia control is a fixed proportion of progression in untreated contralateral eyes was tested. The authors applied Deming regression to a clinical trial where myopia control intervention was applied monocularly¹⁰ to test the hypothesis that increasing treatment efficacy will be observed across the progression range. The authors reported a negative result (not statistically significant) and hence the null hypothesis was not able to be rejected. However, the author's noted considerable variance in apparent treatment efficacy across the progression rang^e. 

Thirdly, an analysis of the impact of age on treatment efficacy using data from the study of Cheng et al, 2016⁹ was conducted. The authors reported a non-significant trend towards greater, rather than smaller, treatment effect with increasing age. 

Lastly, a meta-analysis of standard deviations from aggregate trial data was conducted, to test the hypothesis that frequency distributions are consistent with the concept of relative treatment effect. The results indicated a significant difference in means but not significant difference in standard deviations.

Treatment efficacy across time  

This section of the paper aimed to investigate changes in treatment efficacy with time. A meta-regression using a weighted inverse variance linear mixed model with random intercept and slope was conducted, to model the difference in axial elongation between treated and untreated groups over time. Results demonstrated an initial "burst" of efficacy, with some 31-40% of the projected 4-year treatment efficacy occuring in the first 6 months and 46-54% occurring in the first year. The authors concluded that both absolute and percentage efficacy decrease with time. The suggested theory to explain this centres on the initial shrinkage phase of the eye, which provides a one-time boost to efficacy. Once the shrinkage phase has passed, a constant proportional growth rate occurs in treated compared to untreated eyes. The authors suggest the percentage treatment effect in the second and third years of treatment might be constant. The authors acknowledge that there is insufficient data available at present to test this hypothesis and further research is indicated to characterise the exact nature of treatment versus time relationship. 

Proposal of CARE (Cumulative Absolute Reduction in axial Elongation)

CARE is an empirically determined, evidence based articulation of myopia control effect. It communicates the benefit that a child receiving a specified treatment might expect independently of age, progression rate, refractive error and ethnicity over a stated time period. CARE was developed in order to overcome the weaknesses associated with reporting efficacy as a percentage reduction in axial length. The authors report CARE as an improved outcome measure of efficacy; however, it is dependent on time and requires reporting of 95% confidence intervals to determine both statistical significance and precision of outcome.

Rebound

 In this section reports of rebound for studies involving atropine, orthokeratology, SMCL's and spectacles are analysed. The authors conclude that the data is insufficient to allow generalisation; however, rebound has been observed in atropine studies. As a general principle, rebound should not be ruled out and should be assumed until treatment-specific evidence to the contrary is obtained.

Illusion of inflated success

In this section the authors utilise Monte Carlo simulations to investigate potential erroneous interpretation of myopia control treatment effect. It is concluded that substantial over-estimation of treatment effect can arise when using past "measured" refractive progression as a basis to treat. Secondly, analysis of data from Cheng et al (2016⁹, 2019¹¹) demonstrated that it is not viable to predict progression using previous data. Only with greater than 1D of measured progression in the first year was there an appreciable increase in mean second year progression. The authors conclude that an illusion of inflated efficacy is created by measurement error in refraction, sample bias in only treating 'measured' fast progression and regression to the mean.

• The analysis does not include the utilised search criteria or study flow diagram for each separate meta-analysis conducted. Consequently, readers are unable to assess the volume of papers that were excluded from the analysis. 
• This is an industry sponsored review that makes recommendations that would typically be the result of endeavours such as a Cochrane review 
  • It proposes CARE as a superior method of reporting efficacy of myopia control treatment. However, as the authors did not report confidence intervals alongside CARE, valuable information is withheld

The aim of this paper was to conduct a thorough review and analysis of the concept of efficacy in myopia control. The results are immensely thought-provoking and have many clinical implications for Eye care practitioners. The introduction of a new method of assessing myopia control efficacy, CARE, is an honourable attempt by the authors to prevent the use of other misleading reporting styles of efficacy in the future. CARE is similar to reports of efficacy utilised in previous high quality papers, including Cochrane reviews. However, in order to be implemented and interpreted accurately, CARE must be accompanied by a measure of variability and a reference to a time scale. CARE can then be used to fully inform Eye care practitioners, and eventually patients, of the efficacy of various myopia control treatments. 

There is rapidly expanding interest in interventions to slow myopia progression in children and teenagers, with the intent of reducing risk of myopia-associated complications later in life. Despite many publications dedicated to the topic, little attention has been devoted to understanding 'efficacy' in myopia control and its application. Treatment effect has been expressed in multiple ways, making comparison between therapies and prognosis for an individual patient difficult. Available efficacy data are generally limited to two to three years making long-term treatment effect uncertain. From an evidence-based perspective, efficacy projection should be conservative and not extend beyond that which has been empirically established. Using this principle, review of the literature, data from our own clinical studies, assessment of demonstrated myopia control treatments and allowance for the limitations and context of available data, we arrive at the following important interpretations: (i) axial elongation is the preferred endpoint for assessing myopic progression; (ii) there is insufficient evidence to suggest that faster progressors, or younger myopes, derive greater benefit from treatment; (iii) the initial rate of reduction of axial elongation by myopia control treatments is not sustained; (iv) consequently, using percentage reduction in progression as an index to describe treatment effect can be very misleading and (v) cumulative absolute reduction in axial elongation (CARE) emerges as a preferred efficacy metric; (vi) maximum CARE that has been measured for existing myopia control treatments is 0.44 mm (which equates to about 1 D); (vii) there is no apparent superior method of treatment, although commonly prescribed therapies such as 0.01% atropine and progressive addition spectacles lenses have not consistently provided clinically important effects; (viii) while different treatments have shown divergent efficacy in the first year, they have shown only small differences after this; (ix) rebound should be assumed until proven otherwise; (x) an illusion of inflated efficacy is created by measurement error in refraction, sample bias in only treating 'measured' fast progressors and regression to the mean; (xi) decision to treat should be based on age of onset (or refraction at a given age), not past progression; (xii) the decreased risk of complications later in life provided by even modest reductions in progression suggest treatment is advised for all young myopes and, because of limitations of available interventions, should be aggressive.

[Link to open access paper]