Comment from M Simunovic

Dear Sir/Madam,<br/><br/>I am a vitreoretinal surgeon and Professor of Ophthalmology &amp; Visual Science at the University of Sydney with a clinical and research focus on inherited retinal diseases (IRDs), retinal gene therapy, retinal prostheses and visual function assessment. I have participated in clinical trials of novel therapies for inherited retinal disease and have a longstanding interest in psychophysics and the measurement of visual function.<br/><br/>I am writing in support of the Haystack Project&#39;s Petition for Rulemaking regarding the evaluation of whether clinical investigations in rare diseases should be considered &ldquo;well-controlled&rdquo; within the context of the disease under study.<br/><br/>In inherited retinal diseases, clinically meaningful impairment is often poorly captured by traditional visual acuity measures. Patients may experience substantial deficits in visual fields, dark adaptation, colour discrimination, contrast sensitivity and mobility despite relatively preserved central acuity. Conversely, treatments may provide meaningful improvements in functional vision without producing large changes in visual acuity.<br/><br/>For this reason, regulatory frameworks should retain flexibility regarding outcome measures. Depending on the disease and intervention, validated psychophysical assessments such as full-field stimulus testing (FST), visual fields, microperimetry, dark adaptation testing, colour vision testing and patient-reported outcomes may provide highly relevant evidence of treatment benefit.<br/><br/>The development of voretigene neparvovec provides an instructive example. Multi-luminance mobility testing (MLMT) was accepted by the FDA as a pivotal endpoint and demonstrated clinically meaningful benefit. However, improvements in MLMT performance were accompanied by improvements in full-field stimulus threshold testing, supporting the biological relevance of psychophysical measures of visual sensitivity as indicators of functional vision. While MLMT is a valuable assessment, requiring the development of bespoke mobility platforms for every programme may substantially increase cost and complexity without necessarily improving the quality of evidence when validated psychophysical measures are available.<br/><br/>This principle is supported by decades of visual science research. Classical work by Pirenne, Marriott and O&#39;Doherty demonstrated a close relationship between absolute visual sensitivity and performance under low-light conditions (Pirenne MH, Marriott FHC, O&#39;Doherty EF. Individual Differences in Night-Vision Efficiency. Medical Research Council Special Report Series No. 299. London: HMSO, 1957). The relationship between visual threshold and real-world visual function is therefore not a novel concept but a longstanding observation in visual science.<br/><br/>In rare retinal disease research, validated psychophysical endpoints should be considered acceptable when supported by biological plausibility, clinical relevance and empirical evidence. Regulatory frameworks should permit scientifically justified flexibility in endpoint selection rather than implicitly encouraging the repeated development of complex surrogate functional assessments where simpler validated measures may provide equivalent or complementary information.<br/><br/>Yours sincerely,<br/><br/>Professor Matthew Simunovic MB BChir PhD FRANZCO<br/>Professor of Ophthalmology &amp; Visual Science<br/>University of Sydney<br/>Vitreoretinal Surgeon, Sydney Eye Hospital<br/>