Regulatory Considerations for the Use of Biomarkers and Personalized Medicine in CNS Drug Development: A European Perspective

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19 Regulatory Considerations for the Use of Biomarkers and Personalized Medicine in CNS Drug Development: A European Perspective Eamon O’Loinsigh, Anjana Bose Synchrogenix, A Certara Company, Delaware Corporate Center, Wilmington, DE, United States

I INTRODUCTION The lack of effective treatments for central nervous system (CNS) disorders represents an area of major unmet medical need. The growing economic burden associated with an aging population more prone to developing neurodegenerative and psychiatric diseases poses a unique challenge (GBD 2015 Neurological Disorders Collaborator Group, 2017; Millan, Goodwin, Meyer€ Lindenberg, & Ogren, 2015). Neurology is an area in which few new effective treatments for severe debilitating diseases, such as stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD), have been successfully developed in recent decades. In psychiatry, there is a need to develop more effective therapeutic interventions with improved efficacy to manage mood disorders and reduce the rates of suicide attributable to diseases such as major depression and schizophrenia. Regulatory agencies have recognized the urgent need for treatments of rare disorders that are serious but neglected, given the multiple challenges with development and market access (e.g., difficulties in performing clinical trials in smaller patient populations, pricing to recuperate the research, and development costs). The increased awareness was in part driven by a patientcentric movement and greater involvement of multiple patient groups and caregivers who are seeking solutions. Much progress has occurred in the area of oncology, and approaches developed for oncology are gradually spreading to other disease areas including neurological disorders that often have complex genetic roots and may benefit from targeted (or personalized) approaches to therapeutic interventions. Technological innovations

Translational Medicine in CNS Drug Development, Volume 29 ISSN: 1569-7339 https://doi.org/10.1016/B978-0-12-803161-2.00019-9

coupled with novel methodologies that are supported by regulatory agencies have led to multiple new initiatives to drive new approaches to address these needs. Personalized medicine (PM) is a new paradigm that represents a shift from the traditional medicine approach, which applies the same treatment regimen to all patients affected by a disease regardless of phenotype. Personalized medicine capitalizes on known variability in gene expression that results in differences in susceptibility to diseases and responses to medicines. Genetic data are combined with environment and lifestyle data to group patients according to their likely response to a specific intervention to better target treatment and prevention (World Health Organization, 2017). This chapter will summarize the European regulatory system that is embracing new technologies and research approaches in support of the development and approval of PMs for CNS disorders.

II THE EUROPEAN REGULATORY NETWORK AND APPROACH TO PERSONALIZED MEDICINE European pharmaceutical legislation facilitates the creation of a single market for pharmaceuticals in the European Union (EU). The European Medicines Agency (EMA) is a decentralized agency responsible for the scientific evaluation, supervision, and safety monitoring of medicines in the EU (EMA, 2016a, 2017a). It oversees a network of individual national Regulatory Agencies in the EU member states (e.g., Medicines Evaluation Board in the Netherlands and Medical Products Agency in Sweden).

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The EMA is a major contributor to international regulatory science (Hemmings, Germain, & Warner, 2018), and over the last two years, the EMA has initiated a new agenda focused on innovation and greater patient access, leading to increasing collaboration with other global regulatory authorities including the US Food and Drug Administration (FDA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) to determine new regulatory approaches for novel methodologies in drug development research including PM. A primary responsibility of the EMA is the evaluation of marketing authorization applications (MAAs) submitted through the centralized procedure leading to a single EU-wide approval with identical approved indications and conditions of use in all member states including the prescribing information (summary of product characteristics [SmPC]). The centralized procedure is compulsory for certain types of new medicines including those used to treat neurodegenerative disorders, medicines for rare diseases (orphan drugs), medicines derived from biotechnology products, and advanced therapy medicinal products (ATMPs), such as gene therapy, somatic cell therapy, and tissue-engineered medicines. The inclusion of neurodegenerative diseases, including AD, PD, and multiple sclerosis (MS), within the mandatory scope of the centralized procedure acknowledges the major unmet medical need in this therapeutic area and ensures that any new treatments will be made available to all EU citizens upon approval. There is also increased cooperation with notified bodies and other groups responsible for the development and approval of medical devices (e.g., in vitro diagnostic devices), because many PM approaches are dependent on the codevelopment and approval of companion diagnostics (CDx) in identifying patient subgroups likely to benefit from the treatment (EMA, 2017e, 2017h, 2018b). The EMA is committed to innovation in drug development, and its strategic plan acknowledges the need to strengthen regulatory capability across the EU regulatory network to address new areas, such as PMs, and ensure that it has the capability to adequately assess, regulate, and monitor novel products of the future as well as provide access to patients without delay (EMA, 2015i, 2017h, 2018f). The EMA’s Innovation Task Force (ITF) aims to facilitate the development of innovative medicines by addressing gaps in regulatory support for products in early development. The scope of ITF activities encompasses emerging therapies (e.g., gene therapy, cellular therapy, and engineered tissues), technologies (e.g., genomics or proteomics surrogates), and new methods of defining target populations (e.g., pharmacogenomics [PGx]) (EMA, 2014c). While there is no universally accepted definition of PM, the following definition adopted by the European Council is now widely accepted in Europe:

A medical model using characterisation of individuals’ phenotypes and genotypes (e.g., molecular profiling, medical imaging, lifestyle data) for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease and/or to deliver timely and targeted prevention. Personalised medicine relates to the broader concept of patient-centred care, which takes into account that, in general, healthcare systems need to better respond to patient needs. (Council of the European Union, 2015, p. C421/3)

The EMA notes that related terms include precision medicine and stratified medicine. Precision medicine is used as a synonym for personalized medicine, although some reserve it for targeted treatment guided by biomarkers (BMs). Alternatively, stratified medicine refers more specifically to the process of using genetic and physical characteristics to identify the right therapeutic strategy for subsets of patients. These concepts differ from the concept of individualized medicine, which refers to a tailor-made medical treatment (e.g., products based on a patient’s own cells) (EMA, 2017c). In March 2017 the EMA convened a workshop on PMs to gather the perspectives of various stakeholders responsible for overseeing the development, approval, reimbursement, and delivery of health care in Europe on aspects and challenges of developing PMs (EMA, 2017b, 2017c). The various EMA groups represented included the Committee for Medicinal Products for Human Use (CHMP), Pharmacovigilance Risk Assessment Committee (PRAC), Committee for Orphan Medicinal Products (COMP), Committee for Advanced Therapies (CAT), Pediatric Committee, and Scientific Advice Working Party (SAWP). The workshop also included representatives from health technology appraisal agencies, who are responsible for assessing the clinical effectiveness and cost-effectiveness of new treatments, and patient groups in recognition of the fact that regulatory approval is only one component of providing access to innovative new treatments. A key message from the workshop was that PM requires a major change in the way medicines are tested and evaluated and must bring together all stakeholders. Changes in the way health care is delivered and how health-care systems are structured must also occur. Widespread implementation of PM will require improving patients’ health literacy to allow them to become the center of health care. Educating health-care professionals to enable interpretation of the new types of data will also be beneficial. Certain PM approaches require the use of extensive individual patient- and population-based data, which raises challenges for the integration and communication of those data into clinical practice. Finally the growth of PMs creates additional challenges in terms of data protection and patient privacy, particularly given the increased focus on transparency and disclosure of clinical trial data

III CNS DISEASES AND PERSONALIZED MEDICINE

(e.g., EMA Policy 0070) and increasingly stringent EU data protection requirements (e.g., the new EU General Data Protection Regulation [GDPR]) (EMA, 2014d; EU General Data Protection Regulation, 2018). This manuscript will discuss ongoing application of PM approaches in CNS drug development (Section III). The different mechanisms and regulatory pathways by which the EMA can facilitate the development of PMs are also discussed, including PGx, genetic BMs, CDx, and rare diseases/orphan drugs (Section IV); novel methodologies and innovative clinical trial designs (Section V); development of ATMPs, including gene therapies, somatic cell therapies, and tissue-engineered medicines (Section VI); and miscellaneous other approaches including public-private research partnerships (Section VII).

III CNS DISEASES AND PERSONALIZED MEDICINE In recent decades, there have been few major advances in the development of new medicines to treat major neurological and psychiatric diseases despite the enormous resources devoted to this area by the pharmaceutical industry and academia. However, there are multiple ongoing initiatives to improve the diagnosis and classification of CNS disorders; develop a deeper knowledge of underlying risk factors; improve the design and outcome of clinical trials; develop reliable BMs to identify patient subgroups and predict medication efficacy; and promote collaborative approaches to innovation by uniting regulators, industry, academia, and patients (Arneric, Kern, & Stephenson, 2018; EMA, 2013a, 2014a; Gooch, Pracht, & Borenstein, 2017; Insel & Cuthbert, 2015; Millan et al., 2015). An aging population, improved diagnostic capabilities, innovative research, and rising health-care costs have led to greater awareness of the detection and treatment of rare and chronic progressive neurological conditions. The primary focus has been on improving quality of life with improved social and occupational functioning by early detection and developing treatments that reduce the severity of the diseases, reduce the rate of progression, and prevent relapses. Regulatory agencies have opened new avenues for designing and executing studies, thus setting the stage for new treatment approvals focused on specific patient groups in rare disease areas (Arneric et al., 2018; Council of the European Union, 2016; National Institutes of Health, n.d.). Significant inroads have been made in oncology through precision medicine, leading to many innovative therapies targeting specific genetic markers. In many other disease areas, although considerable efforts have been made to identify specific genotypes linked to a specific disorder, establishing a direct correlation remains

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an elusive goal due to the complex interplays of the hundreds of genes, each with a small contribution. As the diagnoses of many mental disorders are built on signs and symptoms derived from self-reports or observations from family members/caregivers rather than underlying biology, establishing the diagnostic validity for promising targets identified in preclinical studies and bringing them to studies in patients continue to be challenging. Research is ongoing to obtain a better understanding of brain function and to integrate the learnings with behavioral components to move from “symptom-based categories” to “data-driven categories” (Insel & Cuthbert, 2015; Schizophrenia Working Group of the Psychiatric Genomic Consortium, 2014; Venigalla et al., 2017). The US National Institute of Mental Health (NIMH)’s “precision medicine for mental disorders project,” known as the Research Domain Criteria (RDoC) initiative, is a prominent example of an attempt to rethink psychopathology by building a framework beyond basic symptomatology that includes genetic, behavioral, and self-reported aspects (Cuthbert & Insel, 2013; Insel et al., 2010; Insel & Cuthbert, 2015). This approach considers how personalized (or precision) medicine could deconstruct traditional symptom-based disease categories by studying patients with a range of mood disorders across several analytical platforms (e.g., genetic risk, brain activity, and physiology) to parse current heterogeneous symptoms into more discrete homogeneous clusters. It is noted that the RDoC initiative has served as a catalyst for other efforts to transform the diagnostic process outside the United States including the EU-funded Roadmap for Mental Health Research and the CNS projects funded by the EU Innovative Medicines Initiative (IMI) (see Section VII) to link clinical neuropsychiatry and quantitative neurobiology (Insel & Cuthbert, 2015; Millan et al., 2015). Identification of newly defined homogeneous data-driven patient clusters will require prospective replication and stratified clinical trials to validate these new clinical constructs and the ability of therapeutic interventions to improve clinical outcomes for these patient groups. It should be noted that using a variety of data sources (e.g., combining PGx signatures with brain imaging and life experiences) to identify new patient clusters and demonstrate therapeutic effects in clinical trials may raise practical challenges in identifying the same patient groups in a real-world clinical setting and may require changes to the education of health-care professionals and to the use of new diagnostic tools (e.g., beyond clinical interview for affective and other neuropsychiatric disorders). Central nervous system disorders with a genetic basis are an area where a PM approach can be effectively leveraged through identification of patients with an underlying genetic mutation responsible for the disease

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(e.g., Friedreich’s ataxia and Huntington’s disease), genetic risk factors (e.g., the presence of apolipoprotein E4 [APOE4] in AD), or deterministic genes (e.g., presenilin1/2 in AD and mutated dystrophin gene in Duchenne muscular dystrophy [DMD]). Other areas include developing therapies to target genetic disorders (e.g., eteplirsen for treatment of DMD and cerliponase alfa for treatment of neuronal ceroid lipofuscinosis type 2 disease [CLN2]). European regulatory considerations for the development of various PM approaches are discussed further in the following sections.

IV BIOMARKERS, PGx, CDx, AND RARE DISEASES Biomarkers can be defined as characteristics (e.g., a molecular, histologic, radiographic, or physiologic characteristic) that are measured as indicators of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions (Daniel, McClellan, Richardson, & Nosair, 2016). This definition broadly captures a variety of BMs that serve several important functions in the nonclinical and clinical settings of medical product development and clinical practice. These include utilization of BMs as measurable indicators to identify patients at risk of disease (e.g., with genetic signatures for diagnosis of genetically based diseases), for enrichment of trials (e.g., patient subgroups with a common disease risk factor or higher likelihood of response to drug therapy), or as surrogate endpoints in predicting clinical outcomes once validated during development. Biomarkers are becoming increasingly prevalent in drug developments, and both the EMA and FDA are fostering collaboration and providing new guidance, encouraging use of innovative clinical trial designs and endpoints, and offering increased opportunity for agency interactions throughout development. Genetic BMs, including PGx, are discussed in Section A, and nongenetic BMs are addressed in Section V.

A Genetic Biomarkers and Pharmacogenomics An area where a PM approach to drug development has been very successful is the use of PGx, defined as how the variability of the expression of genes between people leads to differences in susceptibility to diseases and responses to medicines. PGx are instrumental in the development and life cycle management of targeted therapies for PM. An increasing number of large prospective randomized studies incorporating PGx-BMs have allowed the identification of closely defined patient populations for therapeutic intervention, most notably in the oncology therapy area.

The CHMP has adopted a series of guidance documents (EMA, 2012a) to assist drug developers in regard to good PGx and genomics BM practices, methodological considerations, pharmacokinetic evaluation, and pharmacovigilance (EMA, 2007, 2011a, 2015c, 2016b). The CHMP’s multidisciplinary PGx Working Party (PgWP) (EMA, 2018k) oversees matters relating directly or indirectly to PGx, including preparing guidelines for the preparation and assessment of the PGx sections of regulatory submissions, providing advice to the CHMP on general and product-specific matters relating to PGx, and supporting educational efforts in this developing area. Sponsors can arrange informal (i.e., nonbinding) briefing meetings with PgWP to discuss technical, scientific, and regulatory issues that may arise due to the inclusion of PGx in the development strategy and to assess their potential implications for the regulatory process (EMA, 2006, 2018k). Such interactions allow for information exchange, can minimize development risks associated with using PGx, and can inform future scientific advice and MAA submissions for both the sponsor and the agency. There is also an avenue for joint FDA-EMA voluntary genomic data submissions to allow the agencies to develop a better understanding of new genomic data.

B Companion Diagnostics (CDx) and Use of PGx to Optimize Drug Therapy Orchestrating an individualized therapeutic regimen based on the individual’s characteristics, genetic makeup, and the mechanism of action of the treatment inherently relies on the development of BMs. The assay used to measure the BM is considered a CDx. The EMA defines a CDx as a device that is used to identify patients who are most likely to benefit from or to identify patients who are likely to be at increased risk for serious adverse reactions as a result of treatment with the corresponding medicinal product; therefore CDx is essential to the safe and effective use of the corresponding medicinal product (EMA, 2017f). The inclusion of PGx information in a drug’s labeling can contribute to an improved benefit/risk balance through optimization of the target population and dosing recommendations potentially resulting in improved efficacy and safety including minimization of adverse drug reactions. The EU SmPC guideline (European Commission, 2009) contains specific recommendations on how PGx information should be presented in the label, and the EMA has created training materials to guide incorporation of PGx information into drug labeling. A 2015 paper by the EMA summarized all PGx-related information mentioned in EU product labels and classified it according to its main effect and function on drug

IV BIOMARKERS, PGx, CDx, AND RARE DISEASES

treatment. As reported in the paper, approximately 15% of all EMA-evaluated medicines (i.e., those that have been centrally authorized in the EU) contain PGx information in the SmPC in the indications, posology, contraindications, warnings, or clinical trial (pharmacodynamics) sections, all of which directly impact patient treatment (EMA, 2018j). The PGx-BM information was related to 48 different genes of which 14 encode for drug targets or other gene variations having predictive information regarding the drug treatment outcome, while the rest of the genes were related to drug metabolism and transport. Examples include the need to use a CDx for selection of patients as defined in the therapeutic indication (e.g., HER-2 testing for trastuzumab and EGFR testing for cetuximab), use of CDx screening prior to treatment (e.g., the presence of HLA-B*5701 allele before the use of abacavir), or potential use of CDx testing to inform dosing or metabolism (e.g., dose adjustment of clopidogrel in poor CYP2C19 metabolizers) (ERBITUX, 2017; HERCEPTIN, 2017; PLAVIX, 2018; ZIAGEN, 2017). A recent example of an FDA approval based on genetic information is Kalydeco (ivacaftor) for the treatment of cystic fibrosis (CF) in patients with at least one mutation in their CF gene, which expanded the use from 10 to 33 mutations (KALYDECO, 2017). The extended approval was based on laboratory data that identified patients with certain rare gene mutations who are likely to respond to this treatment, and this development was a close collaboration with the Cystic Fibrosis Foundation (US FDA, 2017b). Thus PGx information in the drug label has an impact on appropriate prescribing (and, by extension, the reimbursement) of the drug as well as the associated CDx. The 2015 EMA paper (Ehmann et al., 2015) notes that several alleles act as pharmacogenetic BMs for more than one drug (e.g., the HER-2 allele responsible for encoding the human epidermal growth factor receptor 2 present in a subset of breast cancer patients) or more than one indication (e.g., HER-2 presence in certain stomach or pancreatic neoplasms). The identification of specific groups of patients who will benefit from targeted therapy, even across different indications, is a key principle of a PM approach. Analyses of the patient population noted by the therapeutic indication section of the SmPC (Section 4.1) demonstrated that 19 out of 30 products were only tested in the BM-selected patient population and 10 out of 30 products included BM-positive and BM-negative patients in their pivotal clinical trials and that some inclusions of PGx information were based on retrospective analyses as distinct from prospectively designed clinical trials. These observations indicate that there is inherent flexibility in the European regulatory approach to the assessment and approval of drugs that rely on PGx-BMs or other PM methodologies. Additional examples of utilization of PGx markers include physiologically based pharmacokinetic modeling

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and simulation using the Virtual Twin technology developed by Certara. This technology enables the creation of a computer-simulated model for each patient using the patient’s various attributes (e.g., age, sex, race, and genetics of drug metabolizing enzymes) that can be used to evaluate a drug’s effect on the patient as well as the optimal drug-dosing regimen. Two recently completed proof-of-concept studies using this technology include prediction of olanzapine (an antipsychotic) exposure in individual patients (Polasek et al., 2018) and prediction of the likely occurrence of cardiotoxic events with citalopram (an antidepressant) (Patel, Wisniowska, Jamei, & Polak, 2018).

C Rare Diseases Many rare and orphan diseases are associated with heritable mutations, and therefore genetic approaches to patient characterization are featured prominently in the development of orphan drugs for these diseases. Orphan designation can be granted in Europe for drugs meeting the following criteria (EMA, 2018h): • Intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating. • The prevalence of the condition in the EU must not be more than 5 in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development. • No satisfactory method of diagnosis, prevention, or treatment of the condition concerned can be authorized, or if such a method exists, the medicine must be of significant benefit to those affected by the condition. The EMA has established COMP as a specialist committee to oversee the development of orphan drugs. This committee assigns orphan designation early in the drug’s development and assesses whether the drug constitutes a significant benefit over existing therapies. It also performs an orphan maintenance assessment to confirm orphan designation at the time of market authorization. Drugs that qualify for orphan designation can receive incentives for development such as reduced fees for regulatory activities, MAAs, inspections, and postauthorization changes (EMA, 2018d, 2018g, 2018i). Orphan drugs authorized for marketing also benefit from 10 years of protection from market competition from other approved drugs with similar indications. This period of protection can be extended by two years for medicines that have completed agreed-upon pediatric investigation plans. Because rare diseases are a global issue, the EMA works closely with its international counterparts,

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in particular, the FDA, on the designation and assessment of orphan drugs. This includes sharing information on orphan drugs, developing common procedures for applying for orphan designation, and submitting annual reports on the status of development of designated orphan drugs. In addition, the EMA and FDA set up a new “cluster” in September 2016 to work jointly on advanced treatments for patients with rare diseases with the goal of expediting the review and approval of treatments for rare diseases (EMA, 2016g). The EMA also works with organizations representing patients with rare diseases through the European Organization for Rare Diseases (EURORDIS). Within CNS drug development the implementation of PGx approaches has been slow due to difficulty in establishing a correlation between diagnostic BMs and drug response despite considerable progress in genomic research and disease pathology. Other impediments include difficulties in implementing PGx in large randomized clinical trials. However, examples of drug approvals relying on PGx for rare CNS diseases include the following: • Translarna (ataluren) approved in the EU only for treatment of patients aged 5 years and older with DMD who are able to walk. Translarna is for use in patients whose disease is due to the presence of certain defects (called nonsense mutations) in the dystrophin gene, which prematurely stop the production of a normal dystrophin protein, leading to a shortened dystrophin protein that does not function properly (EMA, 2017i). Translarna works in these patients by enabling the protein-making apparatus in cells to move past the defect, allowing the cells to produce a functional dystrophin protein. • The EMA and FDA approval of Spinraza (nusinersen), a survival motor neuron-2-directed antisense oligonucleotide, indicated for the treatment of 5q spinal muscular atrophy (SMA) in children and adults. Spinal muscular atrophy is a rare and fatal genetic disease affecting muscle strength and movement (EMA, 2017d). The efficacy of Spinraza was demonstrated in a clinical trial of 121 patients with infantile-onset SMA who were less than 7 months old at the time of their first dose. • The EMA and FDA approval of Brineura (cerliponase alfa) for treatment of a specific form of Batten disease (to slow the loss of ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal CLN2, also known as tripeptidyl peptidase-1 deficiency (EMA, 2018n). Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). The efficacy of Brineura was established in a nonrandomized, single-arm, dose-escalation

clinical trial in 23 symptomatic pediatric patients with CLN2 disease who were at least 3 years of age and had motor or language symptoms. • The FDA approval of EXONDYS 51 (eteplirsen) injection for treatment of DMD for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping (US FDA, 2018b). The approval was based on three small clinical trials using a surrogate endpoint of dystrophin increase in skeletal muscle predictive of reasonable clinical benefit with the confirmed mutation. The EU MAA for EXONDYS 51 is currently under review by the EMA, and a decision is expected by the first half of 2018. In addition, there are NDA and MAA applications under review for cannabidiol for Dravet syndrome (severe myoclonic epilepsy of infancy) and LennoxGastaut syndrome (pediatric epilepsy) as of March 2018 (GW Pharmaceuticals, 2017; GW Pharmaceuticals, 2018). There are also numerous other CNS drugs with orphan designation currently in the preauthorization development stage (European Commission, 2018).

D PGx Approaches in Nonrare Diseases In addition to PGx-BMs being used to diagnose diseases such as DMD and Huntington’s disease, there is ongoing research into the genetic bases for various psychiatric disorders through the use of genome-wide association studies including major depression and schizophrenia (Allardyce et al., 2018; Ledford, 2015; Power et al., 2017; Schizophrenia Working Group of the Psychiatric Genomic Consortium, 2014). Other approaches include PGx profiling of samples collected during previously completed drug trials to retroactively identify subgroups of patients who demonstrated an increased drug response and/or improved safety profile (Li & Lu, 2012). Such approaches may lead to improved identification of more homogeneous patient subgroups and optimized drug labeling. Using PGx to identify subsets of patients within otherwise nonrare conditions with the intent of filing an orphan application can be a challenging issue for COMP. This issue is of importance in cases when BMs redefine the classification of medical diseases or syndromes. Reclassification based on BMs necessitates the validation of the link between the BM and the condition in question and must exclude effects outside the BM-defined subset to secure orphan designation (Tsigkos et al., 2014). Validated PGx-BMs may ultimately be able to identify new homogenous target populations and distinguish them from a broader patient group defined by a symptomatology-based classification. Specific identification of new patient populations with shared prognostic indicators or genomic signatures could be used for enrichment of clinical trial populations and may lead to differential treatment effects for these populations.

V NONGENETIC BMs AND NOVEL METHODOLOGIES, NEW CLINICAL TRIAL DESIGNS, PATIENT-REPORTED OUTCOMES (PROs)

Finally the availability of new CDx capable of identifying specific patient populations may guide the choice of therapeutic interventions in CNS disorders in the future.

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A Qualification of BMs and Diagnostics for Medicine Development

offers scientific advice to support the qualification of innovative development methods for a specific intended use in the context of research and development into pharmaceuticals and has issued a guidance that addresses the essential considerations for successful qualification of novel methodologies (EMA, 2017m). The CHMP can issue a qualification opinion on the acceptability of a specific use of a method, such as use of a novel methodology or an imaging method in nonclinical or clinical trials, and its application as a novel BM. In addition, the CHMP can issue qualification advice on protocols and methods that are intended to develop a novel method with the aim of moving towards qualification. Based on qualification advice the EMA may propose a letter of support as an option when the novel methodology under evaluation cannot yet be qualified but has promising preliminary data. The letter of support is intended to encourage data sharing and to facilitate further studies aimed at eventual qualification for the novel methodology under evaluation. The EMA’s commitment to regulatory convergence in drug development is demonstrated through the availability of a joint letter of intent template from the EMA and FDA intended to facilitate parallel submissions for qualification to both agencies. The intent is to promote the sharing of scientific perspectives and advice and to provide coordinated responses to applicants where feasible. To date, BMs have been used frequently for patient enrichment of CNS trials; however, none have been qualified for use as a diagnostic tool or as an outcome measure in CNS clinical trials (Arneric et al., 2018). Diseases with significant ongoing work in BMs include AD, amyotrophic lateral sclerosis (ALS), autism spectrum disorders (ASD), major depressive disorder, Huntington’s disease, MS, PD, schizophrenia, traumatic brain injury (TBI), and rare CNS diseases. The recently published 2018 EMA guideline on the clinical investigation of medicines for the treatment of AD notes that BMs in AD clinical trials can be separated according to their potential context of use as diagnostic (for determining diagnosis), enrichment (for selecting populations), prognostic (for determining course of illness), predictive (for predicting a future clinical response to therapy and for safety assessment), and pharmacodynamic (for determination of intended or unintended activities) (EMA, 2018b). This new AD guideline clarifies that qualification of BMs for any of these uses will require testing in both BM-positive and BM-negative AD patients. The CHMP has granted a qualification opinion for the following novel methodologies in CNS disorders:

The EMA has established a regulatory pathway for the qualification of novel methodologies and innovative approaches to drug development similar to the clinical outcome assessment qualification program implemented by the FDA (EMA, 2018m; US FDA, 2018e). The EMA

• Cerebrospinal fluid protein levels (containing both low Aβ1-42 and high T-tau proteins) and/or positron emission tomography amyloid imaging (positive/ negative) as BMs for enrichment of clinical trial populations with mild to moderate AD who are at

V NONGENETIC BMs AND NOVEL METHODOLOGIES, NEW CLINICAL TRIAL DESIGNS, PATIENT-REPORTED OUTCOMES (PROs), AND DIGITAL/ WEARABLE TECHNOLOGIES In addition to PGx approaches, there are ongoing efforts to validate other novel methodologies and innovative approaches for drug development and PM in CNS disorders. These include the development of new (nongenetic) BMs to identify more tightly defined patient groups to enrich clinical trial populations or for diagnostic purposes (e.g., AD and PD). Other BMs under development include more sophisticated tools that capture patient-reported outcomes (PROs), which can be used to identify patients sharing common features or more prominent impairments within a disease (e.g., ataxia subtypes and tremor types [essential, cerebellar, and psychogenic]) or patients with PD with differing impairments of motor function or can provide more sensitive and/or specific measures of drug effects (e.g., new clinical outcome measures for prodromal AD). For many neurological diseases, caregiver input provides useful data to assess the environmental impacts and sociodynamics, which are hard to derive from physiological or clinical assessments and could further inform PM approaches. New approaches to clinical trial design (e.g., basket, master, and umbrella designs) using enriched patient populations or novel methods of patient selection based on BMs (e.g., new modalities such as brain imaging, common symptom clusters, and genetics) are being used to investigate new PM approaches that embody many of the concepts proposed by RDoC and related initiatives to redefine CNS drug development (see Section III). These approaches have led to a notable shift on the part of the regulatory agencies through new guidance documents embracing the changes and establishing pathways for increased dialogue with various stakeholders to encourage the development of new tools and diagnostics, the use of alternative study designs and endpoints, and options for accelerated approval pathways.

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increased risk of having an underlying AD neuropathology. Both were qualified for trial enrichment only and not as a diagnostic tool or outcome measure (EMA, 2012b). • Low hippocampal volume (atrophy) as measured by magnetic resonance imaging as a marker of progression to dementia in patients with cognitive deficit compatible with the predementia stage of AD for enrichment of clinical trial populations (EMA, 2011b). • A novel data-driven model of disease progression and trial evaluation in mild and moderate AD to provide a quantitative rationale for selection of study design and inclusion criteria (EMA, 2013b). There is also an ongoing open consultation as of March 2018 on the qualification of molecular neuroimaging of the dopamine transporter as an enrichment BM in clinical trials to identify patients with early-manifest Parkinsonism in PD (EMA, 2017l). Both EMA and FDA encourage the use of diagnostic tests for early detection and measurement. The FDA recently granted an approval of the Banyan Brain Trauma Indicator, a blood test measuring two proteins (UCH-L1 and GFAP) that are released into the bloodstream following a head injury to evaluate mild TBI. This test means that health-care professionals can assess the need for a computed tomography scan, thereby reducing costs and risks of unnecessary scans and radiation exposure (US FDA, 2018f). In addition to qualified methodologies, the EMA has issued many letters of support to promote the development of BMs, novel methodologies, and PRO measures evaluated directly from the patient (see also Section C). These include a patient data platform for capturing PRO measures in Dravet syndrome, which facilitates data capture and supports longitudinal tracking of patient symptoms and multiple letters of support for developments in ASD, including new methods for stratifying populations and measuring impairments or clinical outcomes (EMA, 2015d, 2015e, 2015f, 2015g, 2015h, 2016c). These ongoing research efforts are expected to facilitate successful development of new PMs for CNS disorders.

B Innovative Study Designs and New Clinical Guidelines In recent years, increased participation by dedicated patient groups (including caregivers) has resulted in an urgency to seek and utilize new pathways to accelerate availability of treatment options for patients with serious diseases with unmet need and with rare disorders. Because of small patient populations in rare diseases, traditional randomized controlled trials may not be feasible to establish the effectiveness of the medicinal product.

Trials using newer approaches (e.g., adaptive trials, basket trials, platform trials, and observational trials) that have been used in other disease areas are being explored for use in trials focused on CNS disorders. The EMA has adopted multiple new guidelines to assist drug developers investigating new therapies for AD (EMA, 2018o), ASD (EMA, 2017k), ALS (EMA, 2015b), DMD and Becker muscular dystrophy (EMA, 2015j), and MS (EMA, 2015a). In February 2018 the FDA released a batch of new guidance documents (US FDA, 2018d) for treatment of neurological disorders to encourage drug development for AD, DMD, ALS, migraine, and pediatric epilepsy. These guidelines redefine primary endpoints, diagnostic criteria, the use of BMs for early detection of disease, and the use of new PROs. Of particular note is the incorporation of patient input into these new FDA guidance documents, specifically the new DMD guidance (US FDA, 2018c), which was preceded by a pioneering effort from Parent Project Muscular Dystrophy, which submitted their own independent proposed draft guidance in 2014. This independently authored draft guidance provided important scientific and patient input from the DMD community and stimulated the production of the new FDA guidance (US FDA, 2014). Similarly the new draft of the ALS-related guidance (US FDA, 2018a) was influenced by a comprehensive proposed draft guidance from the ALS Association (US FDA, 2017c). In the EU the revised EMA guidelines on AD and MS were preceded by workshops involving multiple stakeholders including patient representatives (EMA, 2013a, 2014a). The development history of these guidelines highlights the increasing importance placed by the regulatory authorities on patients’ perspectives in the development of CNS drugs and PMs. Master protocols are innovative study designs used to evaluate targeted therapies in rare disorders using PGx-BMs and include the evaluation of more than one treatment within the same trial. These protocols include multiple trials that share key design components and operational aspects. Use of master protocols (e.g., umbrella or basket trials) is common in oncology and is designed to evaluate multiple therapies for a single disease or single targeted therapy for multiple disease subtypes (Woodcock & LaVange, 2017). Examples include the B2225 master protocol investigating a common BM in multiple treatment combination and the National Cancer Institute’s Molecular Analysis for Therapy Choice master protocol evaluating multiple genetic markers and associated targeted therapies for cancers that carry the targeted mutation. Another innovative dynamic design concept includes platform trials, an extension of the umbrella trial type that utilizes a decision algorithm to allow therapies to enter or leave the platform. Examples include I-SPY-2, an exploratory-phase platform trial (12 therapies from nine sponsors as of March 2017), and

V NONGENETIC BMs AND NOVEL METHODOLOGIES, NEW CLINICAL TRIAL DESIGNS, PATIENT-REPORTED OUTCOMES (PROs)

Lung-MAP, a phase 2–3 master protocol evaluating multiple targeted therapies independently of others based on genetic subgroups in advanced squamous non-smallcell lung cancer. The recent FDA approval of Keytruda (pembrolizumab) for all solid tumors with a specific genetic signature regardless of where in the body the cancer started was based on novel trial designs and has led to the approval of a tumor-type agnostic indication (KEYTRUDA, 2017). Early notable examples of master trials in CNS disorders in the United States sponsored by the NIH include the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which compared various atypical antipsychotic drugs for the treatment of schizophrenia, and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, which compared various antidepressants in patients diagnosed with major depressive disorder (Lieberman et al., 2005; Rush, Lavori, Trivedi, Sackeim, et al., 2004). Examples of ongoing platform trials in CNS include the Dominantly Inherited Alzheimer Network Trial (DIAN-TU) trial, which tests multiple drugs to slow or prevent the progression of AD in autosomal dominant AD (ADAD) caused by genetic mutations (Washington University School of Medicine, n.d.; Bateman et al., 2017). The first trial in this platform was launched in 2012, a placebo-controlled, two-year BM trial involving two drugs, solanezumab and gantenerumab, and then transitioned to a phase 3 cognitive endpoint trial in 2014. The earlier examples highlight the potential of innovative trial designs to lead the identification of new patient groups, leading ultimately to the approval of new therapies for CNS disorders. This could include testing multiple new therapies for a CNS disorder within a single trial or, alternatively, enrolment of different patient populations in a single interventional trial to demonstrate safety and efficacy across multiple indications.

C PROs, Wearable Technologies, and Real-World Data Other avenues under consideration in the expanded approach to CNS drug development include the use of electronic health records, registries, wearable devices, and the use of PROs to ensure greater involvement of patients in the decision-making process and to obtain access to observational and real-world data that could be used for regulatory decision-making (GetReal Initiative, 2018). Technological advances have led to novel solutions such as extracting critical information from unstructured notes included in patient records for use by clinicians and researchers without conducting a clinical trial (e.g., Flatiron Health) (Flatiron, n.d.). A PRO measures the patient’s symptoms or the effect of a medical condition on a patient’s functioning. These

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are reported by or measured directly in the patient and include observations recorded in diaries or other tracking devices (e.g., pain intensity scales, seizure episodes, and sleep diaries). The use of PROs as primary or secondary endpoints in clinical trials is gaining momentum and is encouraged by regulatory agencies (DeMuro et al., 2013; EMA, 2014b; Gnanasakthy & De Muro, 2016; Gnanasakthy, Mordin, Evans, Doward, & DeMuro, 2017; Storf, 2013; US FDA, 2017a; Venkatesan, 2016). A specific PRO measure utilized in CNS trials and often mentioned in product labeling is quality of life, which covers physical and cognitive functioning. Other measures include activities of daily living, motor function, somatic symptoms (e.g., pain intensity and degree of impairment), and assessment of seizure severity (rufinamide for seizures associated with Lennox-Gastaut syndrome) (AMPYRA, 2017; DeMuro et al., 2013; Gnanasakthy et al., 2012; NUCYNTA, 2017; SAVELLA, 2016; VYVANSE, 2017). Use of disease-specific PROs in pivotal clinical trials allows for more relevant and patient-centric treatment effects to be considered in regulatory decision-making. Wearable devices using sensors are being introduced in clinical trials utilizing data science technologies to gain understanding of the underlying symptoms, disease progression, and drug effects. A recent 2017 paper from the Critical Path Institute’s Electronic Patient-Reported Outcome Consortium has proposed recommendations regarding the selection and evaluation of wearable devices and their measurement for use in regulatory trials and to support labeling claims (Byrom et al., 2017). The data collected by wearable devices provide an alternative to traditional PRO measures, because the data can be collected without the patient or clinician actively recording the information. These devices have potential for tracking longitudinal data without long-term extension trials. Recent examples include (i) a wearable device used in a pilot study of an experimental drug in patients with PD to track data on movement and effect of medication, (ii) use of Fitbit monitors in MS studies to track patient movements in real time, and (iii) a 3-year study using wearable devices and other technology to assess potential physical changes that could be associated with cognitive decline (Evans Center Affinity Research Collaborative, n.d.; Bachlin et al., 2010; Balto, KinnettHopkins, & Motl, 2016). Other data sources potentially contributing to the development of PM include technological advances in procuring and organizing “big data” obtained from alternative data sources, bioinformatics, and large national health databases (e.g., UK Clinical Practice Research Datalink collates data from the entire UK National Health Service) (Clinical Practice Research Datalink, 2018). The extensive use of patient- and population-based data raises challenges for integration and analyses, implementation in

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clinical practice, and the education of health-care providers and patients themselves. These challenges, including the need to respect data protection and patient confidentiality, must be carefully considered to optimize the benefits and risks. Data collected using wearable technologies and other nontraditional sources are expected to provide meaningful input regarding patient characteristics, lifestyle, and other environmental factors and have the potential for further development as enrichment tools or diagnostic markers. The burgeoning data arising from many different sources present both great promise and challenges. An area of relevance is the field of quantitative science, which is evolving to incorporate data from adjacent disciplines and diverse technologies. New quantitative tools that can analyze, simulate, and present data in decisioninforming ways are being developed. One example of a relevant interdisciplinary quantitative science innovation is the pharmacology-to-payer platform developed in the infectious disease area, which links pharmacology, epidemiology, and health economics (Kamal et al., 2017). This platform can be applied to capture a patient journey for a new medicinal product and project health economic outcome or inform the target product profile of a new agent. These approaches could be applied to the CNS therapeutic area to provide better information regarding patientcentric decision-making. In summary the development of novel methodologies and BMs, new clinical trial design approaches, the use of new PROs and wearable technologies, and integration of multiple data sources all have potential utility in the development of new PMs for CNS diseases.

VI ADVANCED THERAPY MEDICINAL PRODUCTS AND PERSONALIZED MEDICINE Advanced therapy medicinal products include gene therapies, somatic cell therapies, and tissue-engineered medicines for rare diseases and other chronic disorders with limited treatment options (Council of the European Union, 2017). The EMA along with the European Commission’s Directorate General for Health and Food Safety works with competent authorities in member states to support the development and authorization of highquality, safe, and effective ATMPs. The CAT is the EMA committee responsible for assessing the quality, safety, and efficacy of ATMPs and for following scientific developments in the field (EMA, 2018a). The CAT provides scientific expertise related to the development of innovative medicines and therapies and provides scientific recommendations on the classification of ATMPs. It also contributes to the scientific advice in cooperation with the SAWP and participates in CHMP or PRAC

procedures delivering advice on the conduct of efficacy follow-up, pharmacovigilance, or risk-management systems for ATMPs (EMA, 2018c). The CAT has produced multiple guidelines that address developers of advanced therapies on quality, nonclinical, clinical, and risk-management aspects of these innovative new therapeutic interventions (EMA, 2008a, 2008b, 2011c, 2012c, 2016d, 2017j). A multistakeholder meeting was held on May 2016 to explore ways to foster ATMP development and to expand patient access to ATMPs (EMA, 2016d, 2017j). The areas covered included optimizing regulatory processes for ATMPs; facilitating research and development; improving funding, investment, and patient access; and moving from hospital exemption to marketing authorization. At an international level, a forum for dialogue was set up in October 2017 among the EMA, FDA, Health Canada, and PMDA to share experience on ATMPs (EMA, 2017j). To date, 18 MAAs for ATMPs have been submitted to the EMA, and 10 products have been approved. No ATMPs for CNS disorders have yet been approved. Examples of EMA-approved ATMPs include the following: • Spherox (spherical aggregates of ex vivo expanded autologous matrix-associated chondrocytes), an implant suspension to repair defects to the cartilage in the knee (EMA, 2017g) • Zalmoxis, genetically modified allogenic T cells for hematopoietic stem cell transplantation (EMA, 2016f) • Strimvelis, autologous CD34 + cells transduced with a retroviral vector that encodes for the human adenosine deaminase cDNA sequence for treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (EMA, 2016e) • Alofisel (darvadstrocel), which are expanded adiposederived stem cells for treatment of complex perianal fistulas in patients with Crohn’s disease (EMA, 2018p) The MAA review of the gene therapy Luxturna (voretigene neparvovec-rzyl) for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss is ongoing (Spark Therapeutics, 2017). Ongoing developments for ATMPs for CNS disorders include research into alternative treatment options in epilepsy and evaluating stem cell transplantation therapy using either autologous or allogeneic cell types. Autologous transplant approaches avoid controversial ethical concerns, because the donor is the host and potentially has reduced safety risks compared with allogeneic transplantations where the donor is not the same as the host but is a close match. Other avenues include induced pluripotent stem cells that are derived from adult stem cells and provide the promise of autologous cell replacement and gene therapy to reprogram cells (Rao, Mashkouri, Aum, Marcet, & Borlongan, 2017). Additional projects

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include the recent announcement of a strategic collaboration to develop a gene therapy platform to produce anti-tau antibodies within the brain to promote cellular stability and function in AD and other neurodegenerative diseases and stem cell transplantation for treatment of PD (AbbVie, 2018; Kegel, 2017). Making regenerative cellular therapies a reality for patients faces many challenges at all stages of development and post approval, including validation, large-scale manufacturing, and affordability (Corbett, Webster, Hawkins, & Woolacott, 2017). These therapies are expensive and require considerable support from health-care providers, and the long-term prospects are also yet to be worked out. Advanced therapies such as gene therapy and stem cells may eventually provide effective PM therapies for currently incurable neurodegenerative diseases.

VII MISCELLANEOUS Other European initiatives of relevance to PM in CNS include public-private partnerships such as the IMI, which is jointly funded and driven by the European Commission, pharmaceutical industry, and academia (European Federation of Pharmaceutical Industries and Associations, 2014). The EMA is using IMI projects to expand and inform its future-facing strategies to regulation of these new treatment modalities (see also Section A on qualification of novel methodologies). The IMI projects where PM approaches for CNS disorders are in development include the following: • EBiSC: European Bank for induced pluripotent stem cells including AD (Innovative Medicines Initiative, 2018a) • EPAD: European prevention of Alzheimer’s dementia consortium (Innovative Medicines Initiative, 2018b) • EU-AIMS: European Autism Interventions—a multicenter study for developing new medications (Innovative Medicines Initiative, 2018c) • NEWMEDS: Novel methods leading to new medications in depression and schizophrenia (Innovative Medicines Initiative, 2018d) • PRISM: Psychiatric Ratings using Intermediate Stratified Markers: providing quantitative biological measures to facilitate the discovery and development of new treatments for social and cognitive deficits in AD, schizophrenia, and major depression (Innovative Medicines Initiative, 2018e) The IMI projects also include the adaptive pathway program from the EMA that utilizes a life cycle approach of acquiring and assessing evidence through the product life cycle, namely, development, licensing, reimbursement, monitoring/postlicense evidence, and utilization (Eichler et al., 2015). The collaborative project Accelerated

Development of Appropriate Patients Therapies led by the EMA (ADAPT SMART, n.d.) was set up to formulate collaborative solutions to foster the development of Medicines Adaptive Pathways to Patients (MAPPs) in Europe. This is a platform to accelerate the availability of MAPPs to all health-care stakeholders and foster access to beneficial treatments to the patients in the product life span in a sustainable manner and could hold promise for development of new PMs and label expansion for new patient groups. Another relevant IMI project is the GetReal initiative, which aims to show how new methods of real-world evidence collection and synthesis could be adopted earlier in pharmaceutical research and development and the health-care decision-making process (GetReal Initiative, 2018). A new initiative from the EMA is the Priority Medicines (PRIME) scheme (similar to the FDA Breakthrough Therapy designation process) (EMA, 2018l), which provides proactive regulatory support for accelerated assessment in disease areas with high unmet need. The key benefits of this approach include appointment of a rapporteur from the CHMP during the development phase, meetings with the CHMP/CAT rapporteur and group of experts, scientific advice at key development milestones, and a dedicated EMA contact point. As of January 2018, two products each in neurology and psychiatry have been accepted into the PRIME program. These are (i) adeno-associated viral vector serotype 9 containing the human SMN gene (AVXS-101) for treatment of pediatric patients diagnosed with SMA type 1, (ii) aducanumab for treatment of AD, (iii) allopregnanolone for treatment of postpartum depression, and (iv) rapastinel for adjunctive treatment of major depressive disorder. Products with PRIME designation can expect to be eligible for accelerated assessment at time of MAA (i.e., reduced review time by EMA, similar to FDA priority review) to further expedite approval and patient access to such innovative treatments. Products accepted into facilitated regulatory development schemes such as PRIME may also be eligible for conditional (i.e., early) marketing authorization on the basis of compelling preliminary clinical data, which could provide early access to innovative therapies for unmet clinical needs but may require more intensive risk minimization strategies due to limited clinical trial knowledge of a drug’s safety profile at time of approval, in addition to conduct of postauthorization confirmatory efficacy studies (EMA, 2018e).

VIII CONCLUSIONS As described earlier, there are multiple mechanisms through which the European regulatory network is encouraging and facilitating the development of PM approaches including those for CNS disorders. A greater

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focus on patient centricity and involvement of patient groups has led to increasing support from regulatory agencies in the form of new guidance documents, scientific standards, encouraging use of surrogate endpoints, and use of small nonrandomized trials. In addition to provision of enhanced regulatory support such as dedicated scientific advice resources, the EMA has also established platforms such as multistakeholder meetings to address challenges within this important emerging area of pharmaceutical medicine development. These initiatives have resulted in some early successes in the development of PM approaches for CNS disorders such as BM qualification, and it is hoped that these initiatives and the commitment of the EMA and other regulatory agencies will aid future approval of personalized CNS medicines to address this area of high unmet clinical need.

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