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«31 August 2012 EMA/450332/2012 Human Medicines Development and Evaluation EU Regulatory Workshop – Ophthalmology – Summary and Report Clinical ...»

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31 August 2012

EMA/450332/2012

Human Medicines Development and Evaluation

EU Regulatory Workshop – Ophthalmology – Summary

and Report

Clinical Development, Scientific Advice and Paediatric Investigation Plans

The opinions, including any regulatory views, expressed in this report are personal ones,

which cannot be taken to reflect those of the European Medicines Agency (EMA), any of its

working groups or committees. This report should not be taken as regulatory guidance.

Summary The workshop aimed to share experience and get an update on existing and upcoming pharmacological treatments in eye disease. The focus was set on clinical development and methodological issues, including the choice of outcome measures, evolving towards a common understanding among regulators, academia and industry.

Visual Function Endpoints in Clinical Trials Clinical Academic View: Eberhart Zrenner Retinal structure and function is complex. Understanding of the disease, and the potential therapeutic mechanism is essential in order to target the appropriate endpoint. Patient reported outcomes are very important; as scored directly by patients, these are free of interpretation by the observer. Monitoring of visual function for safety and efficacy in very low and ultra-low vision patients is difficult; some of the on-going studies have developed novel tests in order to monitor ultra-low vision changes including activities of daily living, which, however, are not yet validated.

Industry View: Gabriela Burian Different stakeholders have different expectations of what an endpoint can provide; satisfying all objectives in a single trial/ endpoint can be challenging. Evaluation of the treatment benefit overtime (mean average VA change), offers an overall more comprehensive assessment immediately after treatment initiation. Improvement in VA is the new aim particularly for macular diseases, but the relevant benefit that can be translated to the individual patient level needs to be established.

Measurement of poor vision and vision in children remains a challenge. Open questions are the added value and clinical relevance of using co-endpoints with supportive surrogate markers, how best to demonstrate the correlation between function and anatomy, the use of other visual function assessments, and the future regulatory use for VF PROs?

Regulatory View: Jane Moseley Demonstration of a clinically relevant benefit is essential in order to be able to make a judgment on risk and benefit; thus visual function endpoints are fundamental to the assessment of ophthalmological products. The limitations of conventional visual acuity assessments are understood. There is scope for widening and deepening the range of visual function and functional vision endpoints that can considered in the regulatory context that are of clinical relevance to the patient. Prospective 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United

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© European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.

discussions with regulators are possible, and welcome regarding (non-)product specific advice on qualification of surrogate endpoints and novel approaches.

Advanced Therapy in Retinal Disease Regulatory View Committee for Advanced therapies: Lennart Åkerblom Information was provided on the regulatory framework, consistency in production, biodistribution, specific challenges with ATMPS, proof of concept, tumourigenicity, risk-based approach, and combined ATMPs.

Regulatory View Committee for Orphan Medicinal Products: Stylianos Tsigkos The Committee of orphan medicinal products acts as a gate opener for orphan products. Sponsors considering to apply are advised to start with a letter of intent to the orphan section of EMA and a subsequent presubmission meeting.

Clinical Academic View: Anthony Moore Inherited retinal disorders represent a unmet need with no effective treatments. Advances in molecular genetics will lead to identification of causative genes; there is much to be learned about mechanisms of photoreceptor cell death, and multiple strategies of research are needed; patient selection is very important, and determining the treatment effect will be major challenge.

Industry View: Matthew Campbell, Paul Williamson Advanced therapy products are complex with many challenges in the quality, nonclinical and clinical development. Examples are given. Early discussion with regulators is essential.

Macular Oedema Clinical Academic View: José Cunha-Vaz An overview of classification, frequency, characterisation, possible biomarkers, pathogenesis and treatment was given for macular oedema.

Industry View: Yehia Hashad Regulatory guidance is sought on a range of issues: flexibility in the design of the clinical studies, target population definitions (baseline acuity, OCT types, duration of MO, sub-populations (e.g., focal vs. diffuse or ischemic vs. non ischemic), prior laser), optimum endpoints (as specific time points or mean change over time, reduction in treatment burden), calculation of non-inferiority margins, the role for laser or sham treatment as comparators, duration of trials, combination therapy, and addressing BRVO and CRVO as a single pivotal or separate studies.

Regulatory View: David Silverman Factors dictating the expected duration of safety and efficacy data requirements are discussed including the existing knowledge and safety database with a product, the intended duration of treatment, unmet medical needs, the natural history of the disease, and formulation/implant release factors. If studies enrol both BRVO & CRVO patients, results for each condition need to be considered separately. The chosen primary endpoint needs to reflect clinically relevant effects of treatment;





situations where mean BCVA at an single time-point, mean average and responder are useful are discussed. The choice of comparator varies with existence of licensed alternatives and disease related factors. Non-inferiority studies against a licensed alternative must demonstrate assay sensitivity, with the choice of the non-inferiority margin also considering the maximum difference between treatments that can be considered clinically irrelevant. Companies should consider how they will advise clinicians on concomitant use of their product with laser and how these data will be generated given the timing of combination and delayed effects on efficacy.

Dry Age-related Macular Degeneration Clinical Academic View: Adnan Tufail Dry AMD is a major public health issue because it is the most common cause of legal blindness in the developed world and will become more prevalent with the expected increase of population aged over 80 years of age. Moreover, no effective treatment is currently available for dry AMD. A very important issue is how to measure disease progression in clinical studies. The standard endpoint of high contrast visual acuity might be problematic: there are structural and functional markers. Colour Fundus Photos (CFP), OCT, low luminance visual acuity, reading speed, microperimetry, dark adaptation, contrast sensitivity and quality of life questionnaires, and their limitations are discussed.

EU Regulatory Workshop – Ophthalmology – Summary and Report EMA/450332/2012 Page 2/39 Industry View: Oliver Zeitz It could be argued that visual acuity is not the preferred outcome measure for clinical development in dry AMD. Morphological parameters have been developed recently and are under evaluation and could be utilised as outcome variables soon.

Regulatory View: Marco Coassin No surrogate primary outcome for efficacy has yet been validated for this condition in a licensing procedure. Best corrected distance visual acuity may not be sensitive enough to assess disease progression within a reasonable time frame. Relevant secondary clinical/functional outcomes should be looked at closely in order to generate supportive evidence complementing the chosen primary endpoint. The clinical meaningfulness of the chosen endpoint should be justified. It might be possible to plan a trial with a suitable functional visual loss parameter as a primary outcome in an enriched population with greater risk of GA progression; implications for generalisabilty should be considered.

Uveitis Clinical Academic View: Manfred Zierhut Uveitis is a heterogeneous group of diseases making trials difficult. There is a need for better definition of entities and further validation of endpoints, and more randomised controlled trials with well-defined uveitis entities and specific endpoints dependent on aetiology. Longer follow up in studies is needed (recurrences: 1 year). Children with uveitis should also be involved in studies. Damage tends to develop with inflammatory activity; control of this inflammatory activity is the most important goal of treatment. Endpoints should reflect activity of inflammation as visual acuity is not always a good primary endpoint.

Industry View: Robert Kim In developing trial designs for uveitis, heterogeneity in uveitis syndromes, the lack of accepted standard of care, and knowledge gaps in understanding the biology represent significant challenges.

Regulatory View: Karl-Heinz Huemer Different trial design proposals might be considered as valid, depending on the exact disease definition and the claim targeted. This has consequences with regard to endpoints, treatment duration, acceptable controls, and inclusion/exclusion criteria. Many parameters could be justified case by case.

Biomarker qualifications procedures are recommended for novel methodologies. Open questions for guidance include: managing standard of care including off label use, and absence of a uniformly accepted SoC, population definitions, appropriate steroid sparing endpoints, the choice of comparator, the most clinically relevant endpoints, the role of macular oedema as an endpoint, continuous or dichotomous data for the primary analysis, handling of combination treatments and rescued patients.

Ocular Surface Restoration Clinical Academic View: Per Montan Unmet needs in restoration of the ocular surface include the best topical steroid regime for low-risk corneal grafts, the add-on value of topical immuno-suppressants and/or anti-angiogenic treatments, the value of systemic immunosuppression and HLA-matching in high-risk grafting and allogeneic stem cell transplants, and the development of gold standard cultivation of (limbal stem cells) LSCs. Potential clinical trial design parameters, including endpoints for high-risk corneal grafting and LSCs are proposed.

Industry View: Giovanni Milazzo Challenges for industry in the development of limbal stem cells are that the target disease is a rare condition, the severity grading of which is not established, that there is no suitable reference treatments, that the optimum approach to minimise the potential for bias remains to be established in addition to the most appropriate endpoint of efficacy.

Industry View: Claus Cursiefen There is an unmet medical need with no specific licensed medical treatment for corneal neovascularisation (CNV), particularly in the context of corneal transplantation. It is proposed that inhibition of CNV is the most relevant primary endpoint to demonstrate efficacy of anti-angiogenic agents in patients with proliferative corneal new vessels uncontrolled under the current best available therapy and furthermore that this supports benefits for the patient in preventing the need for a corneal graft, as well as improving graft survival if transplantation becomes necessary.

EU Regulatory Workshop – Ophthalmology – Summary and Report EMA/450332/2012 Page 3/39 Regulatory View: Gopalan Narayanan Open questions for guidance: the best methods to assess severity of limbal stem cell deficiency, and corneal surface restoration, and the duration of long term follow up needed. Also, the acceptability of corneal neovascularisation as an endpoint for primary or secondary prevention of rejection in corneal grafting or for angioregression is not yet established. Formal submission of biomarker qualification advice or opinion is recommended for novel methods such as corneal neovascularisation as an endpoint in confirmatory trials for corneal graft rejection, or methods to assess severity of limbal stem cell deficiency.

Dry Eye Disease and Meibomian Gland Dysfunction Clinical Academic View: David Sullivan, Kelly Nichols, Anthony Bron In the development of treatments for dry eye disease (DED), the common signs and symptoms do not correlate. New diagnostic approaches and outcome measures reflective of the disease are needed. We need rigorous criteria for each phenotype of dry eye. We need validated questionnaires and measures to quantify severity. We need to optimise tissue sampling and to select biomarker technology and associate those with clinical tests. Better tests to evaluate and grade Meibomian gland dysfunction (MGD) are needed. In MGD, there is a high need for additional randomised, controlled, double-masked treatment trials with clearly defined objectives, relevant outcome measures based on pathophysiology, and refined inclusion & exclusion criteria. There is a need to further characterise the natural history of MGD and to gain further understanding of the association with dry eye disease. A development and validation of a symptom questionnaire specific to MGD would be welcomed.

Industry View: Auli Ropo Dry Eye Disease (DED) is a heterogeneous condition and both diagnosis and endpoints for clinical trials are diverse. The Industry would welcome harmonisation of the diagnosis and measures / endpoints for clinical trials where possible. Since we currently are lacking those, the best approach for the industry would be to allow some flexibility in designing the protocols and endpoints. However, these endpoints should be very well justified and could be based on the mechanism of action of the study drug. The development and acceptability of reliable biomarkers would be helpful. The clinically relevant change of symptoms is not clear. Evaluating symptoms is difficult since variability can be high and repeatability is a problem. It is not clear what are the signs to be used as inclusion criteria and what is a clinically significant change. Development of new pharmaceutical therapies is hampered by the lack of objective tests for response outcomes.



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