An opinion paper authored by experts at the Medical Products Agency Uppsala, Sweden, and the European Medicines Agency, London, UK, has highlighted the need for new biomarker development to assist in accelerating the development of new treatments for a range of ocular disorders. The agencies comment that there are a significant number of ophthalmic indications with high unmet medical need for which biomarker assays may present useful tools to monitoring therapeutic affect and diagnostic accuracy. The paper was published in the journal of Investigative Ophthalmology & Visual Science (IOVS, 2017;58:BIO27–BIO33).
Biomarkers were defined in the publication as “measures of clinical, pathologic, or physiological processes” and, subject to regulatory oversight, may be used as surrogate endpoints in clinical trials. European drug regulators have identified a need for the development of such tools due to a number of factors including patient demand for earlier access to new medicines for disorders with no treatments available, the existence of slowly progressing ophthalmic diseases for which markers of disease progression would assist in accelerating new treatments, and as an innovation to help control the increasing cost of global health and drug development processes. Biomarkers may be employed in many different applications – to assist in selecting targeted patient populations that may respond optimally, or respond faster, to a new drug, or as measures of disease activity, disease progression, or to detect the beneficial activity of a given drug. The key of course is to ensure that such tools are adequately validated so that they are of proven clinical relevance and directed towards patient benefit.
The level of evidence required by regulators to validate biomarkers generally depends on the context in which they are used: therapeutic efficacy marker validation in early stage research may be somewhat less strict than that required for the use of a biomarker in a clinical trial study in which the biomarker is being presented as a primary endpoint outcome to secure marketing approval. In such an instance, the biomarker must clearly demonstrate efficacy of real clinical relevance above and beyond alternative available measures. Acceptance of such validation by regulators may be obtained if it can be demonstrated that the association between the biomarker and the clinically relevant outcome is demonstrably beyond correlation alone but is supported by clear mechanistic or biologically plausible properties with statistical under-pinning. Regulators will accept biomarker validation if sufficient evidence is presented that the surrogate endpoint is likely to predict clinical benefit, even if such benefit is not measured directly. To date, surrogate endpoints, or biomarkers, which have been employed in research studies include, for example, intraocular pressure (IOP) measurement in glaucoma, vitreous haze in uveitis, and changes in the area of geographic atrophy, or the volume of drusen, in dry age related macular degeneration. In terms of geographic atrophy, the EMA in 2016 announced support for the development of reading speed, and a Functional Reading Independence (FRI) Index as a valuable endpoint in ophthalmic studies. The commentary concludes by encouraging researchers to develop new and innovative biomarker technologies, stating: ”[I]f established outcome measures are not available or suitable for the targeted patient population, we encourage sponsors to pursue a qualification procedure for regulatory acceptance for novel endpoints.”