Biomarkers and Surrogate Endpoints in Drug Development: a European Regulatory View

Special Issue Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View

Kerstin Wickstr¨om1 and Jane Moseley2

1Medical Products Agency, Uppsala, Sweden 2European Medicines Agency, London, United Kingdom

Correspondence: Kerstin PURPOSE. To give a European regulatory overview of the requirements on and the use of Wickström, Medical Products Agen- biomarkers or surrogate endpoints in the development of drugs for ocular disease. cy, Dag Hammarskjölds väg 42, 752 37 Uppsala, Sweden; METHODS. Definitions, methods to validate new markers, and circumstances where surrogate [email protected]. endpoints can be appropriate are summarized. Submitted: March 1, 2017 RESULTS. The key endpoints that have been used in registration studies so far are based on Accepted: March 27, 2017 visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, Citation: Wickström K, Moseley J. established outcome measures such as those based on visual acuity or visual field are not Biomarkers and surrogate endpoints feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual in drug development: a European acuity may be preserved even though the patient is legally blind owing to a severely restricted regulatory view. Invest Ophthalmol visual field, or vice versa). Vis Sci. 2017;58:BIO27–BIO33. DOI: 10.1167/iovs.17-21778 CONCLUSIONS. There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged. Keywords: regulatory, clinical research, biomarker, validation, drug development

hilst regulators are open to engaging on a broad range of and a focus on precision or personalized medicines. Efficient W novel approaches, in this article we focus on biomarkers. streamlined drug development programs could avoid rising We define these as measures of clinical, pathologic, or medicine costs stemming from wasteful approaches. Adopting physiological processes. These can be imaging, bioanalytic, or novel approaches in drug development is not without risks to other methods. Some biomarkers could evolve to act as the developer if decision makers such as regulators do not agree surrogate endpoints where appropriate (see below) and may with the approach taken. How can such risks be managed and be used in therapeutic trials, substituting for the clinical minimized yet retain the potential advantages of surrogate endpoint. A clinical endpoint is one that is of a direct importance endpoints or biomarkers, such as earlier readouts of efficacy or for the patient with an ocular disease, that is, one that evaluates better detection of the optimum dose and safety, and at the end how the patient functions or feels (see European Medicines of the day, speed up patient access to new medicines? Agency [EMA]: EU Regulatory Workshop – Ophthalmology1)and This article will stress the importance of the proposed should reflect the accepted norms and standards in the relevant regulatory ‘‘context of use’’ of the biomarker. There will be a field of research. Clinical relevance of primary and secondary discussion of the process for gaining regulatory acceptance for efficacy endpoints must be justified. Such empirical endpoints such methods, the scientific expectations in terms of validation, are based on, for example, visual acuity, while the more the European conditional marketing regulatory framework subjective endpoints include patient-reported outcomes (PROs) wherein biomarkers or surrogate endpoints could be accepted and recording of symptoms. In this article, we will discuss how in lieu of clinical outcome measures, and current and future use biomarkers can be used to shorten or optimize drug develop- of biomarkers in drug development. Medical devices (including ment in a way that is acceptable to drug regulators, as well as those for diagnostics) in Europe are subject to a separate legal other related questions, taking the European drug regulatory framework and thus out of scope for this article. landscape into account. This information is aimed at academics, pharmaceutical companies both large and small, health care professionals, and patients. Such questions are increasingly CONTEXT OF USE relevant and important with increasing demand for earlier access to new, safe, and effective medicines, particularly for diseases When proposing a biomarker in drug development, the starting with unmet treatment needs. Ophthalmology has many such point is the context of use—whether intended as a surrogate indications for which there are no satisfactory methods for endpoint for clinical efficacy or otherwise. The nature, treatment or prevention of disease. There are also a number of purpose, and techniques must be clearly defined. There are slowly progressing ocular diseases for which markers of disease several common themes for biomarker use: it could aim to progression would be more or less necessary for the conduct of a substitute for established visual function measures (visual field clinical trial within a reasonable time frame. Other factors that or visual acuity) or for functional vision (e.g., reading or make surrogates or biomarkers relevant in drug development are navigation). Biomarkers could be used to identify a specific pressure on health care budgets, increasing costs of medicines, patient population or a subset of this population, for example,

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TABLE 1. Principles for Validation of a Surrogate Marker of Visual Function

Plausibility The marker should be mechanistically and/or biologically plausible. Credible mechanisms connect the marker, the pathogenesis of the disease, and the mode of action of the intervention. Construct validity Method for test and scoring must distinguish subject with normal visual function from those with impaired visual function. The marker should be able to measure seriousness in subjects with impaired vision and distinguish higher from lower performers. Reliability Performance of the marker should be evaluated. Interobserver, test–retest, and intraobserver reproducibility should be demonstrated. Content validity The marker should directly represent aspects of visual function (visual acuity, visual field, contrast sensitivity, color vision, dark adaptation), functional vision (e.g., reading, orientation mobility, activities of daily living, visual communication, and visual job skills), or vision-related quality of life. Responsiveness/ The marker should have the ability to detect a change. It should identify differences in scores over time in subjects predictability whose visual function has changed and remain stable in subjects with a stable visual function. When aiming to substitute for an effect on visual function, the marker should be able to predict a future clinical outcome. Change to intervention The marker should demonstrate a change in response to the intervention in parallel with a defined visual function outcome.

to enrich a patient population likely to be more responsive to If the above principles have been appropriately investigated treatment, or one expected to progress faster, to limit the and demonstrated, the marker may be accepted to support number of study subjects or the duration of a trial. Other regulatory decisions in the approval of a new drug. For a fully markers could measure disease activity, to detect the intended validated endpoint as a primary endpoint in a confirmatory pharmacologic activity of a drug (e.g., for proof-of-concept or trial, it must finally be demonstrated that the change can be to aid in dose selection), or to identify a risk for potential concluded to represent or predict a clinical benefit across trials adverse drug reactions or patients at high risk of drug toxicity. with other interventions. Safety markers can in addition be developed already at the preclinical stage of drug development to better predict Conditional Marketing Authorization and Use of potential clinical safety issues. Biomarkers as Surrogate Endpoints As part of the context-of-use definition, the population (specific disease, stage/severity), phase (exploratory or confir- At the time of the marketing authorization application (MAA) matory trial), and importance (primary, secondary, or explor- in Europe, regulators expect that the dossier should contain a atory measure) should also be defined. thorough justification of the validity of the primary endpoint. The level of evidence required to support the intended use However, the MAA could be based on surrogate endpoints that of the marker depends on its context of use. If aimed as a are reasonably likely to translate into a clinical benefit, but do preliminary efficacy outcome measure in early drug develop- not directly measure it. The suitability of the surrogate, ability ment, for example, in proof-of-concept or dose selection, to predict the clinical outcome, the level of certainty, and the regulatory requirements are less strict. Nevertheless, the use of evidence need to be discussed in the MAA submission. If the these markers can provide timely support for development and evidence fully supports the surrogate endpoint, then a full inform designs of later confirmatory trials. In confirmatory license, all other standards being met, would be expected. trials, for lower-ranked outcome measures or subgroup From an ophthalmic perspective, we would want to know, markers, regulatory requirements may also be limited but will for example, how the proposed surrogate endpoint translates depend on the label claims associated with the marker. Where into a delay to significant visual impairment or into a direct intended as a primary (or key secondary) endpoint in a pivotal treatment effect. clinical trial to support a full approval of a new drug (see also Under the European regulatory framework, a conditional Conditional Marketing Authorization below), the measure marketing authorization (CMA) could be possible when a needs to be validated, that is, there must be evidence that biomarker shows, with reasonable certainty, benefits that demonstrates that the surrogate endpoint captures the outweigh remaining uncertainties about the extent to which treatment’s effect on the clinically relevant outcome. Biomark- the marker translates into a clinical benefit (as well as the ers can be diagnostic (determine the presence and type of risks). Thus, marketing is conditional on confirmation of the disease), prognostic (indicate the likely outcome of disease), or clinical benefits through specific obligations post authoriza- predictive (provide information on the effect of treatment).2 tion. In other words, the benefit to public health of the The regulatory considerations for other biomarker contexts of medicinal product’s immediate availability on the market use are discussed below. outweighs the risks due to need for further data. The EMA guidance provides further information on the CMA eligibility criteria (e.g., aimed at treating, preventing, or diagnosing VALIDATION OF A SURROGATE ENDPOINT seriously debilitating or life-threatening diseases, emergency situations, or medicines for rare diseases).3 Validation of a surrogate endpoint requires that the link to and relevance between marker and the clinical outcome be established. Although a correlation between the clinical TODAY outcome and the surrogate could indicate the potential to predict the clinical benefit, for example, in terms of preserving Among the ophthalmology drugs approved through the or improving visual function, correlation alone is insufficient. centralized procedure in the European Union (EU), surrogate The marker should also be mechanistically or biologically endpoints or biomarkers based on signs, pharmacodynamics, plausible, and measurement properties (construct validity, or disease processes—such as intraocular pressure (IOP), reliability, content validity, and responsiveness) need to be corneal stains, and vitreous haze—have been frequently used investigated (Table 1). If aiming to substitute for a future effect and accepted by regulators. Below (Table 2) is a summary of on visual function, its predictability needs to be demonstrated. the approved indications and the bases for evaluation of

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TABLE 2. Primary Efﬁcacy Outcome Measures Used in Pivotal Studies for Ophthalmology Products Approved in the EU Between 1999 and 2016

Name of First EU Primary Endpoint Based on Indication (Abbreviated) Product Active Substance Approval, y

BCVA Neovascular AMD, RVO, DME, myopic CNV Eylea Aflibercept 2012 Neovascular AMD, RVO, DME, CNV Lucentis Ranibizumab 2007 Neovascular AMD Macugen Pegaptanib 2006 Visual impairment in LHON Raxone Idebenone 2015 Neovascular AMD (predominantly classic Visudyne Verteporfin 2000 CNV), myopic CNV BCVA, vitreous haze RVO, DME (second line), noninfectious Ozurdex Dexamethasone 2010 uveitis involving the posterior segment Corneal cystine crystals Corneal cystine deposits Cystadrops Mercaptamine 2017 Corneal epithelial defects and Severe limbal stem cell deficiency Holoclar Ex vivo expanded autologous 2015 corneal neovascularisation human corneal epithelial cells containing stem cells Inflammatory lesions, vitreous haze, Noninfectious uveitis involving the Humira Adalimumab 2003 anterior chamber cells, BCVA posterior segment IOP Open-angle glaucoma or ocular Izba Travoprost 2014 hypertension Lumigan Bimatoprost 2002 Travatan Travoprost 2001 IOP Open-angle glaucoma or ocular Azarga Brinzolamide/timolol 2008 hypertension (second line) Azopt Brinzolamide 2000 DuoTrav Travoprost/timolol 2006 Ganfort Bimatoprost/timolol 2006 Simbrinza Brinzolamide/brimonidine 2014 Ocular itching and redness Symptomatic treatment of seasonal allergic Emadine Emedastine 1999 conjunctivitis Postoperative inflammation Post–cataract surgery pain and Nevanac Nepafenac 2007 (aqueous cells and flare), macular inflammation, risk reduction of edema postoperative DME Postoperative inflammation Post–cataract surgery inflammation Yellox Bromfenac 2011 (aqueous cells and flare) Pupil diameter during cataract Maintenance of mydriasis and prevention Omidria Ketorolac/phenylephrine 2015 surgery of miosis during surgery, acute postoperative pain Signs (corneal staining) and Severe keratitis in patients with dry eye Ikervis Ciclosporin 2015 symptoms disease Signs (redness) and symptoms Signs and symptoms of seasonal allergic Opatanol Olopatadine 2002 (itching) conjunctivitis Vitreomacular adhesion Vitreomacular traction Jetrea Ocriplasmin 2013 The approved indications and the bases for the evaluation of primary efficacy are summarized in the above table. For further details see Summary of Product Characteristics (SmPC) and European Public Assessment Reports (EPAR) from the EMA website (http://www.ema.europa.eu; in the pubic domain). CNV, choroidal neovascularization; DME, diabetic macular edema; LHON, Leber’s hereditary optic neuropathy; RVO, retinal vein occlusion. primary efficacy for products centrally approved (1999–2016) Glaucoma for various ocular conditions in the EU. Owing to the generally slowly progressing visual field loss in As seen in the table, in pivotal registration trials, the glaucoma, a reduction in IOP has been the established efficacy evaluation of primary efficacy has been based on symptomatic measure in this therapeutic area for decades—even though the improvement in allergic and dry eye conditions; however, so far, association between an IOP reduction in terms of visual field the only clinical primary endpoint that addresses visual function progression was not known. The work of Heijl and coworkers5 has been the evaluation of best corrected visual acuity (BCVA). in 2002, later confirmed by Garway-Heath et al.,6 nevertheless Other functional measures such as visual field, contrast presented epidemiologic evidence demonstrating that a sensitivity, and photophobia were used as supportive endpoints reduction of the IOP reduces the risk for a future visual field in these studies. However, since generally accepted anchors loss. Even though IOP is a key risk factor for glaucoma, some (with exception of visual field where some consensus has been glaucoma patients still progress to vision loss despite low IOP; reached) to define relevant changes are not yet in place, their there is thus a need for alternative treatment strategies ranking as secondary or exploratory outcomes are appropriate. intervening at the level of retinal ganglion cells or the optic nerve. Consequently, there is a need to develop new surrogate In addition, there is some experience with the evaluation of markers for efficacy, but none is yet established. New structural diabetic retinopathy (DR) by use of the Early Treatment and functional endpoints were discussed in a symposium Diabetic Retinopathy Study (ETDRS) DR severity scale and this gathering of the glaucoma research community and the United is briefly addressed in the label for Eylea (Bayer Pharma AG, States Food and Drug Administration (FDA).7 Also from an EU Berlin, Germany). DR is also accepted as an outcome for perspective, stakeholders are encouraged to bring forward microvascular complications in diabetes research in general proposals, for example, as requests for qualification advices for (see EMA Guideline CPMP/EWP/1080/00 Rev. 1).4 new markers (see below).

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Uveitis disruption in patients with RP. EZ measurements have been investigated in RP patients and it has been shown that the Also in uveitis, where the ultimate aim is to preserve vision, measure is robust and that it changes over time, at least in cells and flare for anterior uveitis, or vitreous haze for uveitis subjects with X-linked RP.8,9 involving the posterior segment has been the basis of the Other studies have been performed to correlate EZ license in registration trials. From an EU regulatory view, measurements with visual field measurements,10,11 and it reassurance also in terms of preserving or (potentially) appears that the area around the edge of the EZ width improving visual acuity is needed, but it is recognized that represents the part of the retina that undergoes the most rapid the evaluation of BCVA is too insensitive and not relevant for all rate of visual field loss.10,12 Thus, there is scientific support for patients. It is thus not regarded as an appropriate primary the concept of developing the EZ measurement as an endpoint efficacy endpoint. Vitreous haze is associated with the for use in drug development. However, besides some concerns inflammatory process and therefore served as a primary regarding the manual procedure to identify the zone and its endpoint; however, in intermediate or posterior uveitis, the fuzzy borders, there is yet insufficient information to conclude degree of vitreous haze does not necessarily correlate with whether the EZ is a suitable endpoint to demonstrate efficacy inflammatory activity over the severity spectrum of the disease. in RP patients. For a fully validated endpoint with the context Therefore, we encourage alternative approaches. While a final of use as a primary endpoint in a confirmatory trial, it decision on the benefits of a new drug for the treatment of ultimately needs to be demonstrated that the EZ predicts uveitis includes evaluations also of secondary endpoints that change with the intervention and that this change can be are expected to address other aspects of inflammation, a concluded to represent a clinical benefit. composite endpoint including such aspects as structural In 2016, the Innovative Medicines Initiative 2 (IMI2) changes (e.g., macular edema, retinal vascular inflammatory decided to support the Macustar project, a project that aims changes) and patient’s symptoms may be useful for a more to identify and validate functional, structural, and patient- robust evaluation of a treatment effect in this rather limited, reported endpoints for use in drug development in patients but highly heterogeneous, population. In this regard, the with intermediate AMD, that is, in subjects with impaired low- multicomponent strategy for primary efficacy (i.e., inclusion contrast and low-luminance vision, but not yet late-stage AMD also of retinal inflammatory lesions and BCVA) used in the with GA or neovascular disease. The project is still in an early registration trials for Humira (AbbVie Ltd, Maidenhead, United phase, but future interactions with regulators are foreseen and Kingdom) in uveitis are acknowledged. As for glaucoma, EMA welcomed. welcomes proposals for discussion on more optimized Measuring not only visual function, but also functional endpoints in uveitis. vision, has an important place in drug development to evaluate or refine the risk/benefit ratio of intervention in patients with Retinal Degeneration impaired vision. For example, in 2016 EMA published a letter of support for the development of reading speed and In slowly progressing diseases such as dry age-related macular Functional Reading Independence (FRI) Index in patients with degeneration (AMD), retinitis pigmentosa (RP), or other slowly GA (Table 3). progressing inherited retinal diseases, clinical endpoints such With the ongoing research progress, for example, in gene as BCVA and visual field have clear limitations. These endpoints and cell therapy, there is need for further development of are recognized as not being sufficiently sensitive and thus not markers for efficacy, and there is promising work in progress. appropriate for evaluating efficacy, as the long duration of the To capture aspects also of functional vision, mobility testing trials and/or the high number of patients to be included could under well-defined and standardized conditions has the risk making the trial unfeasible. As discussed below, potentially, potential to serve as a future highly ranked endpoint in certain populations may be enriched to obtain more timely relevant settings, but there is currently insufficient regulatory evaluations of a treatment effect. experience; thus, it is premature to draw any conclusion on In dry AMD with geographic atrophy (GA), there has been the adequacy of mobility testing for decision making with focus on anatomic markers as surrogates for clinical endpoints regard to patient benefit. for some years. Structural markers include, for example, evaluations of the change in area of the GA or the volume of Patient-Reported Outcomes drusen. In several of the currently ongoing phase II/III interventional trials for GA, progression of the area of the Although clinical endpoints, new PROs, generally in the form atrophic lesion is assigned the primary outcome measure. of questionnaires, provide a direct report from the patient From the EU regulatory perspective, the use of GA area as a without interpretation by the clinician, and they could also be primary efficacy variable could in principle be acceptable. considered novel methods that need validation. The specific However, no primary outcome for efficacy has yet been validation methods for PROs require separate detailed consid- validated for this condition in a licensing procedure and eration and are not addressed here, but some regulatory therefore, it needs to be justified that the marker represents a considerations are worth mentioning. The National Eye valid surrogate measure for visual function. Such justification Institute Visual Function Questionnaire-25 (NEI VFQ-25), a could be based partly on literature demonstrating the broad measure of visual functioning and quality of life, is the prognostic value of GA area on visual function, but there most commonly used PRO for ophthalmology and low vision would also be a need for support by evidence from the patients.14 It is a generic instrument widely used in several registration studies showing at least a trend of a positive effect ocular conditions. While the NEI VFQ-25 has been shown to be of treatment on functional parameters. Secondary clinical relevant and appropriate for use in patients with a number of meaningful outcome measures might include BCVA, contrast conditions, it has also been criticized, for example, for floor sensitivity, reading speed, perimetric measures, and PROs, and ceiling effects, and for not being appropriate in certain among others. Importantly, the clinical meaningfulness of a indications.15,16 It is also not disease specific. There are several change in the rate of progression of the lesion size in terms of additional ocular-specific PROs validated to a greater or lesser delay to significant visual impairment remains to be justified. extent, but only occasionally seen in applications for approval Other structural markers under development include of drugs in the EU. In addition to the FRI discussed above, measurement of the ellipsoid zone (EZ) width or area additional instruments are under development. From the EU

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TABLE 3. Letters of Support Issued by EMA for Surrogate Endpoints

Biomarker/Novel Method and Need EMA Review: Context of Use and Further Development Needs

Reading speed To provide information on the relationship Reading speed could be used as one tool to support the clinical impact of a treatment effect between GA lesion size and reading on GA area progression although further data are needed to address some remaining function, and to explore the potential uncertainties. What constitutes a clinically meaningful change, the impact of variability, effect of treatment on reading lesion location, confounding factors, potential learning effects, adequacy of standardization, consistency with other functional measures, and comparability of the different charts needs to be thoroughly explored.13 The Functional Reading Independence Index To provide information on the relationship This index may provide information on aspects of vision-related functioning that are not between GA lesion size and reading captured by other outcome measures. Further data will be needed to further support function, and to explore the potential sensitivity to change, to examine precision, and to explore the impact of the better-seeing effect of treatment on reading function eye.13

regulatory perspective, the development of disease-specific, To what extent the enrichment of a patient population will and of course, appropriately validated, PROs is encouraged. be described in the label depends on how representative the studied patient population is compared to the patient Enrichment of a Study Population population targeted in real life and whether there are scientifically sound reasons to make extrapolations across Biomarkers have a place in drug development to enrich a study subsets of patients. This will be subject to review of the actual population for purposes of identifying a patient population data once a file is submitted for registration. that may progress more rapidly (based on prognostic biomarkers), detecting a (larger) treatment effect (based on predictive biomarkers) with consequential impacts on trial THE FUTURE design. The evidence supporting such biomarkers will need to Ophthalmology represents a potential growth area for bio- address regulatory questions, which often involve the ratio- marker and novel method development. There are significant nale, the proposed cutoff points, the relationship with other indications with unmet need. If established outcome measures risk factors, and the handling of multiplicity. Furthermore, are not available or suitable for the targeted patient population, sponsors will be required to justify the choice of population, we encourage sponsors to pursue a qualification procedure for the endpoints used, and overall interpretation of findings regulatory acceptance for novel endpoints. Efficacy endpoints including replication. alone are not the only area for biomarker or method In GA, disease characteristics such as bilateral GA or development. Recently published scientific literature reviews neovascular disease in one eye,17 a baseline BCVA of 20/50 the current status and work in progress to investigate possible or better,18 and hyperautofluorescence adjacent to the GA19 novel methods with potential applications in ophthalmic drug have been associated with a more rapid progression to loss of development in various contexts of use such as detecting BCVA. When a population is enriched, the possibility of earlier stages of disease, classifying prognosis, or identifying detecting a relevant treatment effect within a clinical trial of a responders in indications ranging across retinal vascular and reasonable duration may thus increase. Other approaches in degenerative diseases,22–24 postsurgical fibrosis,25 ocular sur- GA as well as in other diseases include restricting or enriching face disease,26,27 ocular oncology,28 and uveitis.29 the patient population to one with certain gene mutations associated with risks for development or progression of AMD. For example, in the ongoing development described for the PROCESS FOR QUALIFICATION OF BIOMARKERS complement factor D inhibitor lampalizumab, which is There are two approaches to gaining regulatory acceptance for currently under evaluation in phase III clinical studies, the (to qualify) a new biomarker or novel method in Europe. The studies are enriched with ‘‘biomarker positive’’ subjects, that optimum approach is to seek first a qualification advice on is, subjects who are positive for complement factor I (e.g., how to gather and analyze the evidence needed to support the 20 EudraCT No. 2014-000106-35). marker, and subsequently, a qualification opinion. As summarized in Table 4, in 2015, the EMA published a letter of support for the development of microaneurysm Qualification Advice formation rate (MAFR) as a biomarker to enrich a type 2 diabetic clinical trial population with mild to moderate DR This involves submitting a dossier to the EMA outlining the with those at higher risk of developing clinically significant context of use, objective, studies, methods, and protocols. macular edema. Relevant EMA guidance is available on the undertaking of such

TABLE 4. Letter of Support Issued by EMA for a Biomarker for Enrichment

Biomarker/Novel Method and Need EMA Review: Context of Use and Further Development Needs

MAFR measured with MAFR seems to be a very promising biomarker for enriching a patient population at higher risk for the development a validated automated of CSMO. Additional data are needed given the low CSMO event rates in the validation studies, the highly variable method progression rates between subjects, and to enable evaluation independently of other risk factors.21 CSMO, clinically signiﬁcant macular edema.

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TABLE 5. Previous Qualiﬁcation Opinions

Broad Purpose Novel Method EMA Review: Regulatory Qualiﬁcation

Primary outcome measure The Paediatric Ulcerative Primary outcome measure in clinical trials of pediatric ulcerative colitis as a proxy Colitis Activity Index for endoscopic assessment when colonoscopy is waived with appropriate justification among other regulatory uses Prognostic biomarker Total kidney volume In combination with patient age and eGFR, as a prognostic biomarker for use in clinical trials evaluating patients with autosomal dominant polycystic kidney disease to identify patients likely to experience a progressive decline in renal function as characterized by a decline in eGFR or progression to end-stage renal disease Proof of concept, In vitro hollow fiber system In anti-TB drug development programs as an additional and complementary tool to selection of dose and model of TB existing methodology to inform selection of dose and treatment regimen, treatment regimen providing preliminary proof of concept for developing a specific drug or combination to treat TB, and selecting the pharmacodynamic endpoints Dose finding Model-based design and An efficient statistical methodology for model-based design and analysis of phase II analysis of dose finding dose finding studies Disease progression Novel data-driven model of As a longitudinal model for describing changes in cognition in patients with mild model disease progression and and moderate AD, and for use in assisting in trial designs in mild and moderate trial evaluation in mild AD, to simulate the natural progression of disease (without placebo or drug and moderate AD effect), to inform on the power of competing designs Enriching a clinical trial Cerebrospinal fluid biomarker To identify patients with clinical diagnosis of mild to moderate AD who are at population signature based on a low increased risk of having an underlying AD neuropathology, for the purposes of Ab1-42 and a high T-tau enriching a clinical trial population AD, Alzheimer’s disease; eGFR, estimated glomerular ﬁltration rate; TB, tuberculosis.

procedures,30 clinical development of diagnostic agents,31 and unmet medical need. To date, while a number of surrogates for various aspects of pharmacogenomics in drug development.32 efficacy have been accepted by European regulators, the only Any legal or natural person can apply, including consortia functional clinical primary endpoint used for registration trials composed of any or all of the following: academics, companies, in Europe has been based on visual acuity. This is an endpoint or patient organizations. We encourage such consortia to avoid recognized as not being feasible, for instance, in very slowly multiple and divergent duplication of possible new endpoints progressing diseases, or not even relevant for a number of and waste of resources. The outcome of the advice procedure conditions, and alternative endpoints are needed. Additionally, is an advice letter to the applicant(s) providing the regulators’ the use of new markers that, for example, capture a population opinion on the proposed plan. Obtaining such advice before that would respond better to treatment or one that responds embarking on a biomarker development plan and costly or sooner, is an area for further development. lengthy studies represents a risk management approach that To help speed up patient access to new medicines, there is might otherwise not meet regulators’ expectations. consequently a need to explore the use of novel methods, On the basis of the qualification advice, EMA may propose a biomarkers, and surrogate endpoints. However, the relevance letter of support as an option, when the novel methodology of these methods needs to be justified with data and under evaluation cannot yet be qualified but is shown to be scientifically substantiated arguments. There is some flexibility promising based on preliminary data. EMA will publish letters in the European regulatory system to give timely access to new of support on the EMA website, subject to sponsor’s agreement drugs for serious conditions for which there is a high unmet to encourage data sharing and to facilitate studies toward medical need; and a conditional marketing authorization based qualification for the novel methodology under evaluation (see on a biomarker could be justified when the benefits, with also Tables 3, 4). reasonable certainty, outweigh the remaining uncertainties about the extent the biomarker translates into a clinical benefit Qualification Opinion (and the corresponding risks). Independent of the route to approval of a new medicine, the benefit/risk evaluation is When sufficient information has been put together and the based on all available data. applicant considers that there is enough evidence to support There is an EU regulatory pathway for the qualification of the biomarker or surrogate endpoint for the intended context biomarkers or novel methods. A collaborative approach of use, then it is possible to submit the evidence dossier for including academia, clinicians, and industry is encouraged. regulatory acceptance in the process outlined in the above- After advice has been received and the marker/method has mentioned guidance. Following evaluation, the EMA, in been developed and validated, a qualification opinion could be agreement with the applicant, will publish a draft opinion for sought. A positive qualification opinion will give the applicant public consultation on the EMA website to engage with regulatory acceptance for use of the marker in a defined broader scientific discussion; after review and resolution of context. Further requests for qualification advices (as well as comments, EMA issues a final opinion on the novel method. opinions) in the field of ophthalmology with multiple Table 5 provides examples of novel methods that EMA has interactions and dialogue are welcomed. qualified for different contexts of use. Acknowledgments CONCLUSIONS The views expressed in this article are personal and not necessarily the views of the European Medicines Agency, the Committee for There is high activity in the development of drugs for ocular Medicinal Products for Human Use, or the Medical Products disease, an area with several conditions for which there is an Agency.

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