There  are  many  possible  visual  endpoints  that  examine  safety,  and  benefit;  their  reliability,  and feasibility in terms of what patients can tolerate, and what is a proper target of functional testing have to be taken into account.  The discussion featured an overview of retinal structure and function, the relationship between structure and function in addition to measures in psychophysics, electrophysics, imaging  and  the  importance  of  assessing  activities  of  daily  living  and  assessing  patient  reported outcomes for visual function.

The overview of retinal structure and function underscores the complexity of the system and the need for understanding of the disease, and the potential therapeutic mechanism in order to be able to target the appropriate endpoint. For assessment of distance visual acuity, EDTRS is now standard; Freiburg visual acuity testing is also useful in assessing visual function in patients with low vision. This is semi- automated even down to hand movements and counting fingers, a numeric value can be assessed which correlated with EDTRS, and is not influenced by investigators.

Apart from clinical  history  and  the  standard  clinical  eye  examination,  additional  assessments  can include colour vision assessment, reading speed, dark adaptation, visual field, and electrophysiological assessments. Various options for colour vision testing (Lanthony Panel D-15 Test, Roth 28-hue Test, Farnsworth-Munsell  28  or  100  Test  and  Anomaloscopy),  contrast  sensitivity  (Pelli-Robson  Chart, Mesoptometer-With and without glare and Hamilton Veale Test) and visual field (static and kinetic) testing  are  available.     Microperimetry  may  be  helpful  for  example  in  central  visual  function assessments; for example in AMD, is the area of geographic atrophy increasing?   Eye  movement compensation is very valuable. The possibilities for dark adaptation (Adaptometer) and pupillometry (AMTECH Pupillograph) to aid understanding are highlighted.

For electrophysiology, the International Society of Clinical  Electrophysiology of Vision  (ISCEV)  has determined  the  relevant  standards  and  these  are  available  on  their   website.  Options  include Electroretinogram (ERG), Visually evoked potential (VEP), Multifocal ERG (mfERG), Pattern ERG (PERG) and  Electrooculogram  (EOG).  Specialised  ERGs  exists  if  necessary.  ERG  is  not  just  the  5  basic responses  (Isolated  rod  responses  ,  Rod  and  cone  Maximum  Responses,  Inner  Retina  Oscillatory Potentials, Isolated Cone Responses and Cone flicker Responses) but much more and the choice of test depends on understanding the putative action of a drug and exact question to be asked, in order to be able to select the correct test.

Imaging methods are also very useful including autoflourescence, and OCT, with Multimodal Mapping (Structure-function  correlation)  offering  new  perspectives.     Patient  Reported  Outcomes  are  very important; as scored directly by patients, these are free of interpretation by the physician or observer, and should give an account of how the patient functions or feels relative to a health condition or therapy. Good measurements should have unidimensionality, hierarchical order, and equal interval spacing. A PRO would measure any of the following: Symptoms, Symptom impact and functioning, Disability or handicap, Adverse events, Treatment tolerability, Treatment satisfaction or Health-related quality of life. A number of instruments are available. (Activities of Daily Living Scale (ADVS)-Reading, orientation/mobility,  finding  objects,  social  participation,  financial  handling….-,  Daily  Living  Tasks Dependent  on Vision  (DLTV),  Impact  of  Vision  Impairment  (IVI),  Macular  Disease  Quality  of  Life Questionnaire,  NEI-VFQ  25  (most  common,  well-equipped),  Visual  Function  Index  (VF-14),  Low- Luminance Questionnaire (LLQ), Miedziak's instrument, Vision-specific sickness impact profile (SIPV), Turano's instrument, Vision-Related Quality of Life Questionnaire, Retinopathy-Dependent QOL).  An example is given of an on-going trial in legally blind patients where the primary outcome measures comprises daily living tasks, recognition tasks, mobility, or a combination thereof.  Secondary outcome measures include visual acuity/light-perception and/or object-recognition, measured with tests such as Freiburg acuity, BaLM (“Basic Light and Motion Test”), BaGA (recognition of stripe pattern), VFQ-25, and patient long term safety.

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 ongoing studies have developed novel tests in order to monitor ultra-low vision changes including activities of daily living, which, however, are not yet validated.

The regulatory perspective on visual function endpoints, based upon previous regulatory experience with  scientific  advice,  and  centralised  marketing  authorisation  procedures  for  ophthalmological products. This was considered on a background of globalisation and increasing needs to address health technology assessments and use of novel methods and biomarkers. There are no European guidelines dedicated to the development of ophthalmology products; some references are made in the rhino- conjunctivitis  guideline.  Never  the  less,  general  guidelines  relating  one  pivotal  study,  small populations, adaptive designs, missing data, control groups, and general principles of clinical trials are important and need to be highlighted.   Focussing on  phase III confirmatory studies and endpoints, attention is drawn to important principles outlined in ICH E8 and 9; the primary endpoint should reflect clinically relevant and important treatment effects based on the primary objective of the study. The CHMP generally interprets this as measuring how a patient feels or functions. Secondary endpoints should also be seen to be supportive. Surrogate endpoints, if used, should be reliable predictors of clinical outcomes. In Alzheimer’s disease, the concepts of symptomatic progression as opposed to disease modification are distinguished where in the latter the changes in the clinical outcome are supported by changes in a fully qualified pathological biomarker.  It is useful to consider as a frame of reference, measurements assessing the organ structure, organ function in an experimental setting such as visual acuity, visual field, contrast sensitivity and colour vision, to integrated functional vision such as reading ability, orientation and mobility, and lastly and more complex still, measurements relating to vision related quality of life.

CHMP  Scientific  advice  is  a  voluntary  non-binding  procedure,  based  on  the  European  network  of experts/working  parties  and  committees.  CHMP  advice  has  been  given  on  approximately  100 ophthalmology products, a large proportion of which are rare diseases.

Visual fields have rarely been proposed as a primary or co-primary endpoint, although this has been accepted as such in particular contexts with caveats such as the need to be supported by data such as test/retest  reliability,  sensitivity,  and  feasibility  in  the  actual  patient  group,  the  definition  of responders,  and  progression  rate  /  linearity  and  information  to  support  the  clinical  relevance  of possible effect sizes.

When  considering  primary  endpoints,  the  emphasis  is  frequently  on  visual  acuity  and  on  clinical relevance, and that the quantification of the primary endpoint will need to be translated into clinical benefit. For best-corrected visual acuity (BCVA) as a primary endpoint, EU regulators have variably commented in different contexts; - the percentage of patients who gained more than 15 letters of best-corrected ETDRS visual acuity (BCVA) from baseline to 12 months   is acceptable. - Additional efficacy analyses, allowing for repeated measurements over time, up to 12 months should be provided, assessing the sustained effect on change on BCVA over time. - It is essential that a clinically relevant treatment effect is also prespecified and justified in terms of the treatment effect on ‘change in BCVA from baseline’ and in difference in proportions with visual acuity (VA) categories of gain/ loss/ no change. -The minimally clinically relevant improvement (perceived as such by patients) in this disease is around 10 letters. The improvement of at least 15 letters (responders) should be a key secondary endpoint.    EU  regulators  have  also  accepted  mean  change  in  visual  acuity,  however,  secondary responder analyses have been considered helpful.   Indeed  Visual  acuity scores  determined at one single time-point might be questionable, and a “mean VA score” over a longer period of time for example the last six months before study end may be more appropriate in certain contexts. In the setting of non-inferiority studies, a single time point was preferred over mean average over multiple time points to allow better discrimination between treatments.

The  correct  handling  of  missing  data  is  essential;   it  is  important  that  approaches  taken  are conservative, allow sensitivity analysis, are pre-planned and that trials are designed in such a way as to minimise the impact of missing data. Findings should be robust to different approaches, particularly when there are extensive missing data and rescue treatments. The European guideline on missing data is recommended.

Patients with very low vision: Limited numbers of development programs with such populations have been  presented  for  scientific  advice.  Possible  approaches  include:  Attributing   scores  to   semi- quantitative acuity in patients with very poor vision, Using best recovery of visual acuity per eye over baseline, Using best visual acuity per patient vs. baseline; Enrolling the better eye, or both eyes (as a Cluster or Average).

In  the  context  of  attributing  scores  to  semi-quantitative  acuity,  it  is  essential  that  the  study  is controlled, and masking is strictly maintained, the rationale for the difference between categories would need to be justified at the time of submission including a full literature review demonstrating that the numbers proposed above are indicative of current clinical thinking: The allocation of "light perception" category  to  the  scale  at all  requires particular justification.  Consider a  "worst  case" evaluation, overemphasis of improvements at the lower end of the scale should be avoided, a range of sensitivity analyses should be provided using different values for the categories. The main difficulty will be defining what constitutes a clinically relevant difference with the proposed scale. Some form of responder analysis (with an clinically relevant definition of ‘responder’) would be of help. Clinical global impression (CGI), could well be of importance (again provided that there is certainty on the blinding) to demonstrate that the magnitude of the statistical significance does not depend on the numerical values assigned.

Licensing experience and visual function outcomes; A list of European centralised licensing procedures for ophthalmological products is presented; the overall success rate for ophthalmology products is approximately  70%  and  is  comparable  to  other  published  data  on  overall  rates  of  success.  The centralised procedure provides a simultaneous marketing authorisation in all 27 European Member states.  Other  EU  licensing  procedures  (mutual  recognition,  decentralised  or  National  licensing procedure) are  not  considered  in  this analysis.  Based  on the  Centralised  licensing  experience  for ophthalmological products- examples of major objections raised during the marketing authorisation procedure  in  relation  to  visual  function  endpoints  are  provided:  The  foremost  issue  is  the demonstration  of  clinical  relevance.  Amongst  examples  examined  was  a  change  to  the  primary endpoint  after  the  study  start.  This  is  a  particularly  high  risk  strategy  and  would  be  actively discouraged.  Additional issues related to the strength and consistency of evidence provided in relation to efficacy and safety.

Examples of Other Concerns relating to visual endpoints were floor effects, the absence of other tests of visual function (such as contrast sensitivity, visual fields, automatic perimetry, ERG), the distinction between patients where the active disease was in the eye with the best visual acuity or the eye with the poorest visual acuity (patients with active disease in their best eye actively learn to compensate by developing extrafoveal fixation and improved abilities to scan their defective visual field over a visual target), the need for patients' evaluation of subjective qualities of vision that are difficult or impossible to assess qualitatively (such as metamorphopsia, relative central scotoma, binocular function, etc), the use of LOCF, the validation status of the various scales used in the studies, the provision of Health- related quality of life (HQL) results, the provision of plots (with confidence intervals) of visual acuity over time from pivotal clinical studies, and absence of re-estimation of sample size/power calculations.

Health technology assessment

A significant challenge today is that all new medicines are not potentially accessible by all patients in need, and at there are diverging development requirements for the Reimbursement/ health technology assessment perspective and the Licensing viewpoint. The EMA has a pilot process for multi-stakeholder involvement in early-stage drug development to improve clarity, provide input and alignment among the  stakeholders  regarding  what  constitutes  a   medicine’s  value   and  the   evidence  required  to demonstrate that value most effectively.

EMA FDA parallel advice

Another parallel Agency procedure provides for increased dialogue between Agencies and sponsors from early stages of development with the aim to exchange views, share expertise, optimise and facilitate global development, whilst meeting both agencies’ requirements.

Biomarkers:  There  are   2   new   regulatory   procedures   focused   on   the   qualification   of   novel methodologies or biomarkers. A CHMP Qualification Advice provides input on future protocols and methods for further method development aiming towards qualification, based on the evaluation of the scientific  rationale and on  preliminary data submitted  (confidential). A  CHMP Qualification Opinion pronounces on the acceptability of a specific use of the proposed method (e.g. use of a biomarker) in a R&D context (non-clinical or clinical), based on the assessment of data, which is not product-specific and involves a qualification team, peer review, public consultation, and is ultimately published.

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 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 framework for ATMPs

Annex I of Directive 2001/83/EC, revised through directive 2009/120/EC, introduces new definitions for somatic cell therapy and gene therapy Medicinal products. Also, the technical requirements are updated. The basic requirements for tissues and cells are outlined in Directive 2004/23/EC and its technical  directives.  Specific  guidelines  as  well  as  general  information  for  cell  and  gene  therapy products  can  be  found  on  EMAs  website.    There  are  three  types  of  products  defined  within  the regulation  of  ATMPs.  Cell  and  gene  therapy  products  have   been  regulated  since  2003.  Tissue engineered products were introduced into the legislation by the Regulation of ATMPs.  The Regulation on Advanced Therapies (1394/2007/EC) introduces the certification procedure for Quality and Non- clinical data. With this  Regulation follows also some  incentives for SMEs, e.g. 90 %  reduction on scientific advice fee. Furthermore, it is also possible to have the product classified whether or not it is an ATMP.

Consistency in production

The main objective should be to document the quality profile and consistency of both the product and the production process, using generated data and supportive data to justify the development strategy and the current set of specifications proposed including control of the process and stability data. The cellular  starting  materials  should  comply  with  the  requirements  of  Dir.  2004/23/EC  and  the corresponding technical directives. The manufacturing process should be validated to ensure product consistency. Also, the manufacturing process should comply with the technical requirements defined in dir. 2009120/EC. The manufacture of drug substance and drug product is performed in compliance with GMP requirements. The Control strategy for the manufacturing process for the drug substance and the drug product is mainly based on characterisation data.

Characterisation studies should involve methods that would be suitable to ensure consistency of the product. A validated potency assay based on the functional properties or mode of action of the product should be introduced. The product characterisation should provide information on critical parameters of the cells or the product. The tools for in–process controls and release and stability testing have to be qualified. Specific limits need to be defined and set for composition, dose and level of impurities. If changes  are  introduced  in  the  manufacturing  process  during  or  after  the  pivotal  clinical  studies, comparability of the product before and after the change(s) has to be demonstrated.  A draft guideline on  changes  during  development  of  GTMPs  has  been  elaborated.  The  consequences  of  changes introduced during development in terms of regulatory compliance may be complicated. An evaluation of the impact such changes might have on the safety and efficacy is therefore needed.

Potency of ATMPs

Bioassays  measure  potency  by  evaluating  a  product’s  active  ingredients  within  a  living  biological system. Bioassays can include in vivo animal studies or cell culture systems and should reflect the relevant biological attributes that are identified during development.    Analytical assays can  provide extensive  product  characterisation  data  by  evaluating  molecular  attributes  of  the  product.  These attributes may be used to demonstrate potency if the surrogate measurement(s) can be substantiated by correlation to a relevant product-specific biological activity. Clinical study results may be correlated to product´s potency. Therefore, clinical study results may be used to establish a correlation between the product´s clinical efficacy and a potency measurement.

Biodistribution

Biodistribution is a complex issue that relates to cell localisation and migration as well as survival and differentiation  status.  The  design  of  biodistribution  studies  conducted  in  animals  must  include  a consideration of multiple factors: The methods applied to cellular detection and their sensitivity. Is single species adequate? Will xenogenic cells (i.e. human cells) migrate in a relevant way in an animal model? Can a homologous model be used? What is the route of administration?  There is no single satisfactory method of tracking the fate of cells in vivo. It may be done through the use of reporter probes imaging. Cellular markers of phenotypic differentiation, and genetically modified tagging of cells may  allow  the  monitoring  of  CBMPs  –  methods  to  address  the  safety  concerns  related  to biodistribution.

Specific challenges with ATMPs

The need for biodistribution data will depend on the clinical evidence available. Since adequate cell tracing  is often difficult  in  humans,  non-clinical  data  may  become  necessary  in  a  suitable  animal model.  When  a  well-developed  animal  model  is  available,  evidence  for  robust  proof-of-concept preclinical test results is valuable and informative. Tumourigenicity studies are considered essential for products in which a tumourigenic potential of the cells cannot be ruled out, e.g. regarding  self-renewal of undifferentiated cells. Ectopic tissues formation and migration from the site of transplantation are also  concerns.  Control  of  cell  differentiation  should  be  highlighted.  Clinical  considerations  in  the establishment of the optimal effective dose should be addressed. The risk of transmission of infectious agents should also be investigated (e.g. use of material of animal origin).

There are several specific challenges with ATMPs as possibilities of masking and the feasibility of dose finding and biodistribution studies in humans.

Risk-based approach

The draft guideline presents the methodology of the risk-based approach and is intended to support the Applicant to identify the risks and associated risk factors, and to establish a risk profile of their ATMP under development. With the use of the identified risk profile the Applicant will be able to justify the  extent  of  data  to  be  included  in  the  MAA  dossier.  The  guidance  does  not  provide  a  rigid classification system of different  risks and  it  should therefore  be  distinguished from  Benefit/  Risk Assessment and Risk Management in the context of a marketing authorization application.

Combined ATMPs

Combined ATMPs means that they incorporate as an integral part of the product, one or more medical devices or one or more active implantable medical devices. Also, its cellular or tissue part must contain viable cells or tissues or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to.  If the Medical Device is already CE marked, Does the ATMPs incorporate as an integral part this MD? Where the medical device or active implantable medical device is combined with the cells at the time of the manufacture or administration of the finished products, they shall be considered as an integral part of the finished product. If the product contains a structural component that is not CE marked? The structural component can be an integral part of the finished product. It can also be considered as a support to contain or preserve biological characteristics and functional activities of the cells. The structural component should be inert.

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

The orphan framework has been put in place to provide incentives for the development and marketing of medicines intended for diagnosis, prevention or treatment of unprofitable medical conditions, such as rare diseases.  Criteria for orphan designation are defined in Regulation (EC)141/2000 and can be generally listed as: rarity/insufficient return of investment, severity of the target condition, significant benefit over satisfactory treatments (as well as the implicit criterion of medical plausibility).

There is an orphan designation/ authorisation gap that can be identified for ophthalmology: at the time of the ophthalmology workshop, no marketing authorisations for orphan medicinal products for eye disorders were granted, but 40 orphan designations have already been granted. Retinitis pigmentosa is the most frequently designated target condition.

Examples of the criteria for designation can be found in the following case studies:

1) An overview of the products designated for the treatment of RP reveals that most sponsors (6/8) presented preclinical data in relevant preclinical models to justify medical plausibility.

2) An overview of the products designated for the treatment of Uveitis revealed that with regards to significant benefit, most sponsors justified significant benefit on the grounds of a clinically relevant advantage, and  in  particular  with  regards  to  a  potential  for  improved  efficacy  over authorised counterparts. The fulfilment of significant benefit has to be reviewed at the Marketing authorisation stage. With regard to withdrawals during the evaluation stage, the applicants were considerably more successful compared to overall orphan procedures.

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

Professor Moore discussed the diagnosis of inherited retinal disorders, the molecular genetics, current treatments, strategies for developing new treatments, and assessment of treatment effects. There are many genetic retinal disorders; as a group, it is the 2nd  commonest cause of childhood blindness, and tends to affect adults of working age affecting 1/4000 of the population; 50% of cases have no family history. There are no available medicinal therapies.

These diseases are classified as diseases confined to eye- or associated with other systemic disorders. They can be stationary or progressive, and can also be classified by mode of inheritance, and site of dysfunction.  Most  progressive  dystrophies  affect  both  classes  of  photoreceptors;  patients  are interested  in  preservation  of  cone  function  which  is  the  challenge  for  treatment.  Classification  is increasingly  being  based  on  molecular  diagnosis.  Phenotypes  can  vary.  There  have  been  major advances  in  molecular  genetics  which  together  with  the  phenotype,  will  identify  subtypes.  The identification of genes helps with molecular diagnosis, improves genetic counselling, helps understand disease mechanisms, and improves prospects for treatment; either gene specific or generic such as based on growth factors. Knowing genotypes allows better evaluation and ability to stratify trials of treatment. There is  much genetic  heterogeneity. An interaction of rods with cones  has also  been identified for diseases with rod only genes affected. Many affected genes are not eye specific but because of high metabolic activity in eyes, this may lead to disease manifestation in eyes only.

Characterising retinal disorders also requires identifying the cells affected, and the pattern of disease on  electrophysiology,  imaging  and  psychophysical  testing.  Judicious  care  is  needed  in  selecting endpoints. Children present specific problems in this regard because, in many orphan retinal diseases, it is expected that treatment will work best early in disease, and therefore there is a need to test children and develop endpoints for use in children. This is an important area for development. The objective, if baseline vision is low, depends on whether the aim is to increase baseline vision or slow deterioration. Autofluorescence is mooted : can this be used to track cell death and to look at treatment response?  Adaptive optics is suggested as a possible way of selecting patients for treatment trials, e.g. cone function in choosing those with structurally normal retinas, or for assessment of treatment effects. There are new possibilities opening up for looking at effectiveness of treatments.

Is abnormal function due to cell death or dysfunction; if cells are dead, treatment strategies are different.   Are  the  photoreceptors  salvageable;  not  imaging  alone  but  also  psychophysics  may be needed for assessment.  The hyper-fluorescent ring  is proposed as a possible marker for residual outer segments; it is possible to plot the time course of shrinkage of the ring. Can this be an early surrogate marker for slowing degeneration? The challenge is to choose endpoints in clinical trials that tell us about slowing degeneration in visual acuity or visual fields. Surrogate markers are needed for early treatment effects. There is a need to be more imaginative and move away from visual acuity.

Inherited retinal disorders represent a major challenge with no effective treatments. The approaches to therapy depend on the disease and state of patients with the disease. With still healthy retina, and viable photoreceptors, gene replacement therapy is seen as a development option in addition to other strategies to protect photoreceptors (growth factors/ inhibition of apoptosis/ pharmacological agents). At the point of extreme photoreceptor loss, these strategies will not work, and there is a need for tissue replacement stem cell therapy such as, retinal or RPE replacement, or use of an artificial retina. There are a number of gene therapy trials on-going.

Inherited retinal disorders represent a major challenge with yet 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.