April 3, 2023
By Dwight Akerman, OD, MBA, FAAO, FBCLA, FIACLE
Eye care practitioners can prescribe several therapies for slowing progression in children and adolescents. Currently, no monotherapy has been shown in randomized controlled trials (RCTs) to stop myopia progression completely. Therefore, research continues to discover more efficacious interventions.
The complexity, length, and cost of myopia clinical trials for regulatory approval can be challenging, especially for start-up companies. The U.S. Food and Drug Administration (FDA) currently requires a three-year RCT. However, the regulatory bar appears more reasonable in other markets such as the European Union, Canada, and Australia/New Zealand. An interesting complication for myopia control is that both medical devices and pharmacological treatments slow the progression of childhood myopia. It remains uncertain how the FDA will approach comparisons of myopic control devices and myopia control pharmacological interventions as different groups currently review them within the FDA.
As the regulatory pathway to obtain the coveted “myopia progression control” labeling indication can be lengthy, some treatments have entered clinical practice before regulatory approval through peer-reviewed papers of academic investigator-led trials. The availability of on-label and off-label myopia control therapies creates challenges for conducting placebo-controlled RCTs, including ethics, recruitment, retention, selective loss of faster progressors, and non-protocol treatments.
The authors propose that future myopia control clinical trials may adopt one of the following designs:
- non-inferiority trials
- short-term conventional efficacy trials
- virtual control group trials
- short-term control data from a cohort
- time-to-treatment-failure trials
The authors conclude that the failure to rethink the design of myopia control clinical trials may impede innovation and, ultimately, patient care.
The Future of Clinical Trials of Myopia Control
Mark A Bullimore, Noel A Brennan, Daniel Ian Flitcroft
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, randomized clinical trials, including ethics, recruitment, retention, selective loss of faster progressors, and non-protocol treatments:
- Ethics: It is valid to question whether withholding treatment in control subjects is ethical.
- Recruitment: Availability of treatments is making recruitment into clinical trials more difficult.
- Retention: If masking is not possible, parents may immediately withdraw their child if randomized to no treatment.
- Selective loss: Withdrawal of fast progressors in the control group leading to a control group biased towards low progression.
- 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:
- 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.
- 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.
- Virtual control group trials based on data relating to axial elongation, myopia progression or both, accounting for subject’s age and race.
- Short-term control data from a cohort, for example, one year or less, and applying an appropriate, proportional annual reduction in axial elongation to that population and extrapolating to subsequent years.
- 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.
Bullimore MA, Brennan NA, Flitcroft DI. The future of clinical trials of myopia control. Ophthalmic Physiol Opt. 2023 Mar 10. Epub ahead of print.