Guidance for future myopia control research

Paper title: The future of clinical trials of myopia control

Authors: Bullimore, Mark A (1), Brennan, Noel A 92), Flitcroft, Daniel Ian (3,4)

1. College of Optometry, University of Houston, Texas, USA
2. Johnson & Johnson Vision, Jacksonville, Florida, USA
3. Centre for Eye Research Ireland, Environmental Sustainability and Health Institute, Technological University, Dublin, Ireland
4. Department of Ophthalmology, Children’s University Hospital, Dublin, Ireland

Date: May 2023

Reference: Bullimore MA, Brennan NA, Flitcroft DI. The future of clinical trials of myopia control. Ophthalmic Physiol Opt. 2023 May;43(3):525-533. [Link to abstract]

This article considered ongoing and emerging obstacles experienced by researchers using placebo-controlled, randomised clinical trials to investigate and develop myopia control therapies.

These included challenges with participant recruitment and retention (including due to selective loss and non-protocol treatments) and ethical considerations.

The authors made suggestions as to how clinical trials may be adapted to navigate these issues.

Participant recruitment

• Parents of myopic children with awareness of myopia and knowledge of currently available myopia control therapies may be wary of enrolling their child in a long-term masked clinical trial if their child has only a 50% chance of receiving the treatment option.
• Families finding myopia control cost prohibitive may be attracted to a clinical trial. However, this can introduce a risk of inclusion bias within the study population and affect generalisability of the results. Some studies have shown that lower income families may actually be less likely to participate.^1,2

Participant retention

• Withdrawal from clinical trials is typically greater in the control or placebo group and can occur at any time. It may be immediate if it has not been possible to mask the trial treatment (orthokeratology or bifocal spectacle lenses, for example).
• Despite most trials offering intervention at no cost to the patient, parents may still withdraw from a study if they suspect their child is not receiving the intervention, they are concerned about increasing myopia or they are offered an established option outside of the study.
• Differential loss to follow-up can occur if faster progressors withdraw from a trial control group. This can artificially inflate the numbers of slower progressors and skew the findings.^3,4 It may also occur with non-tolerance of an intervention, with potential for poor compliance or loss to follow-up in the treatment group.⁵

 Ethical considerations

The authors suggest that with the increasing evidence for the risk of visual impairment from high myopia, using a non-intervention approach in a control group is harder to justify.

There is also an ethical question over re-randomising patients in long-term clinical trials, where an intervention is withdrawn from the patient.

 Suggested solutions

1. Adopting an asymmetrical randomisation ratio such as 2:1 treatment to control group may be a solution to recruitment and retention of study subject issues without losing statistical robustness. It would provide an increase in data on treatment acceptability and long-term safety, increased overall cohort size, give better odds for participants of being assigned the treatment and ultimately improve retention.
2. Non-inferiority trials which compare new interventions to treatments with previously established efficacy instead of a placebo or control group, have not been readily adopted in myopia control research. There are difficulties with this approach, including a current lack of a commonly accepted ‘gold standard’ treatment for comparison.
3. Short conventional efficacy trials may be used to determine long-term efficacy of new interventions. Clinical trial data has shown that treatment efficacy is greater within the first year of treatment.⁶ General predictions for subsequent years can be based on this data, meaning efficacy of novel treatments could be assessed in short-term trials.
4. Using virtual control groups based on historical data can provide age or ethnicity matched control groups. This would eliminate ethical concerns of withholding effective treatments from a control group. The authors recommend using data gathered from large meta-analyses of high-quality trials to minimise control group outliers and to avoid the limitations of comparing only to small cohorts or a single studies.
5. Adopting a short-term approach of following a control group for no more than a year before using progression modelling to estimate ongoing progression in subsequent years. This would give the benefit of establishing progression rates for specific populations. 
6. Time-to-treatment-failure trials (or survival analysis) considers the point at which a treatment stopped working and provides information on efficacy. Adopting this strategy includes data at all time points within a trial, including from trial participants lost to follow-up. Children progressing beyond a pre-determined cut-off value can be offered rescue treatment, avoiding ethical concerns and promoting trial recruitment and retention.

Where myopia control research has been rapidly evolving, the obstacles facing researchers have also increased. These need addressing to maintain meaningful, high-quality research and to avoid impeding patient care.

Although each of these proposals listed would provide both short and long-term benefits to clinical research, the authors advise on the need to apply them appropriately in order to benefit from their advantages.

At present, the FDA requires random controlled trials (RCTs) to complete a 3-yr cycle prior to approval. Although this requirements may vary between countries, myopia clinical trials can still be lengthy. Using shorter efficacy trials to gauge short-term efficacy could accelerate the availability of treatments to the market. Clinical trials featuring asymmetrical treatment-to-control ratios would benefit practitioners and patients by providing more data on efficacy and safety.

It is uncertain when the use of non-inferiority trials for myopia research may be possible. The timescale will rely on reclassification of the optical and pharmacological therapies currently available. A ‘gold standard’ intervention therapy also needs to be established before non-inferiority trials in myopia control research can commence.

Prevention of myopia onset remains an area where there is no definite therapy. Future research could ethically use placebo groups in order to assess effective delay or prevention of myopia onset in pre-myopes or utilise historical control data from cohort studies or school-based studies for comparisons

Title: The future of clinical trials of myopia control

Authors: Bullimore, Mark A; Brennan, Noel A; Flitcroft, Daniel Ian

Abstract: In the field of myopia control, effective optical or pharmaceutical therapies are now available to patients in many markets. This creates challenges for the conduct of placebo-controlled, randomised clinical trials, including ethics, recruitment, retention, selective loss of faster progressors and non-protocol treatments:

1. Ethics: It is valid to question whether withholding treatment in control subjects is ethical.
2. Recruitment: Availability of treatments is making recruitment into clinical trials more difficult.
3. Retention: If masking is not possible, parents may immediately withdraw their child if randomised to no treatment.
4. Selective loss: Withdrawal of fast progressors in the control group leading to a control group biased towards low progression.
5. Non-protocol treatment: Parents may access other myopia treatments in addition to those within the trial.

 We propose that future trials may adopt one of the following designs:

1. Non-inferiority trials using an approved drug or device as the control. The choice will depend on whether a regulatory agency has approved the drug or device.
2. Short conventional efficacy trials where data are subsequently entered into a model created from previous clinical trials, which allows robust prediction of long-term treatment efficacy from the initial efficacy.
3. Virtual control group trials based on data relating to axial elongation, myopia progression or both, accounting for subject's age and race.
4. Short-term control data from a cohort, for example, 1 year or less, and applying an appropriate, proportional annual reduction in axial elongation to that population and extrapolating to subsequent years.
5. Time-to- treatment- failure trials using survival analysis; once a treated or control subject progresses or elongates by a given amount, they exit the study and can be offered treatment.

In summary, the future development of new treatments in myopia control will be hampered if significant changes are not made to the design of clinical trials in this area.

 [Link to abstract]