Developing multimodal therapies for brain disorders

exami-Contents Workshop Objectives, 1 Organization of the Proceedings, 3 2 Multimodal Therapy: Overview of Principles, Barriers, and Defining Multimodal Therapy, 5 Rationale for Mul

Lisa Bain, Noam I Keren, and Clare Stroud, Rapporteurs

Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division

THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001

This project was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; Brain Canada Foundation; Cohen Veterans Bioscience; the Department of Health and Human Services’ Food and Drug Administration (5R13FD005362-02) and National Institutes of Health (NIH) (HHSN26300089 [Under Master Base # DHHS-10002880]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH Blueprint for Neuroscience Research; Department of Veterans Affairs (VA240-14-C-0057); Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Development, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (BCS-1064270); One Mind; Pfizer Inc.; Pharmaceutical Product Development, LLC; Sanofi; Society for Neuroscience; and Takeda Development Center Americas, Inc Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for this project

International Standard Book Number-13: 978-0-309-45026-3 International Standard Book Number-10: 0-309-45026-8 Digital Object Identifier: 10.17226/23657

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Suggested citation: National Academies of Sciences, Engineering, and

Medicine 2017 Developing multimodal therapies for brain disorders:

Proceedings of a workshop Washington, DC: The National Academies Press

doi: 10.17226/23657

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PLANNING COMMITTEE ON MULTIMODAL THERAPIES

FOR BRAIN DISORDERS 1

KARL KIEBURTZ (Co-Chair), University of Rochester Medical

Center

SARAH H LISANBY (Co-Chair), National Institute of Mental Health

ROBERT ALEXANDER, Pfizer Inc

TIM DENISON, Medtronic Inc

JAMES HENDRIX, Alzheimer’s Association THINH NGUYEN, Food and Drug Administration DAVID SHURTLEFF, National Center for Complementary and

Integrative Health

TIMOTHY STRAUMAN, Duke University STEVIN ZORN, MindImmune Therapeutics, Inc

Health and Medicine Division (HMD) Staff

CLARE STROUD, Forum Director SHEENA M POSEY NORRIS, Program Officer

NOAM I KEREN, Associate Program Officer (from June 2016) JOANNA ROBERTS, Senior Program Assistant (until April 2016)

ANDREW M POPE, Director, Board on Health Sciences Policy

are solely responsible for organizing the workshop, identifying topics, and choosing speakers The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution

FORUM ON NEUROSCIENCE AND NERVOUS

SYSTEM DISORDERS 1

STEVEN HYMAN (Chair), Broad Institute of Massachusetts Institute

of Technology and Harvard University

STORY LANDIS (Vice Chair), Director Emeritus, National Institute of

Neurological Disorders and Stroke

SUSAN AMARA, Society for Neuroscience RITA BALICE-GORDON, Sanofi

KATJA BROSE, Cell Press EMERY BROWN, Harvard Medical School and Massachusetts Institute

MARIA CARRILLO, Alzheimer’s Association

KAREN CHANDROSS, Sanofi (until June 2016)

E ANTONIO CHIOCCA, Harvard Medical School TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University

FAY LOMAX COOK, National Science Foundation

BRUCE CUTHBERT, National Institute of Mental Health (until

September 2016)

BILLY DUNN, Food and Drug Administration EMMELINE EDWARDS, National Center for Complementary and

Integrative Health (until September 2016)

JOSHUA GORDON, National Institute of Mental Health (from

September 2016)

HANK GREELY, Stanford University RAQUEL GUR, University of Pennsylvania MAGALI HAAS, Cohen Veterans Bioscience RAMONA HICKS, One Mind

RICHARD HODES, National Institute on Aging STUART HOFFMAN, U.S Department of Veterans Affairs MICHAEL IRIZARRY, Eli Lilly and Company

round-tables do not issue, review, or approve individual documents The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution

viii

INEZ JABALPURWALA, Brain Canada Foundation FRANCES JENSEN, University of Pennsylvania GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke

ALAN LESHNER, American Association for the Advancement of Science (Emeritus)

HUSSEINI MANJI, Janssen Research & Development, LLC DAVID MICHELSON, Merck Research Laboratories PATRICIO O’DONNELL, Pfizer Inc

JAMES OLDS, National Science Foundation ATUL PANDE, Tal Medical

STEVEN PAUL, Voyager Therapeutics, Inc

RODERIC PETTIGREW, National Institute of Biomedical Imaging

and Bioengineering (from September 2016)

EMILIANGELO RATTI, Takeda Pharmaceuticals International TODD SHERER, The Michael J Fox Foundation for Parkinson’s

JIM BANIHASHEMI, Financial Officer HILARY BRAGG, Program Coordinator ANDREW M POPE, Director, Board on Health Sciences Policy

Reviewers

This Proceedings of a Workshop has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise

The purpose of this independent review is to provide candid and critical

comments that will assist the institution in making its published

Proceedings of a Workshop as sound as possible and to ensure that the Proceedings of a Workshop meets institutional standards for objectivity, evidence, and responsiveness to the study charge The review comments and draft manuscript remain confidential to protect the integrity of the process We wish to thank the following individuals for their review of this Proceedings of a Workshop:

BRUCE BEBO, National Multiple Sclerosis Society BRIAN FISKE, The Michael J Fox Foundation for Parkinson’s

Research

KEITH HILDEBRAND, Medtronic, Inc

ROGER J LEWIS, David Geffen School of Medicine at UCLA HELEN S MAYBERG, Emory University School of Medicine

Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the Proceed-ings of a Workshop before its release The review of this Proceedings of a

Workshop was overseen by JOSEPH T COYLE, Harvard Medical

School He was responsible for making certain that an independent nation of this Proceedings of a Workshop was carried out in accordance with institutional procedures and that all review comments were carefully considered Responsibility for the final content of this Proceedings of a Workshop rests entirely with the rapporteurs and the institution

exami-Contents

Workshop Objectives, 1 Organization of the Proceedings, 3

2 Multimodal Therapy: Overview of Principles, Barriers, and

Defining Multimodal Therapy, 5

Rationale for Multimodal Therapies in Brain Disorders, 8 Challenges and Barriers, 10

Potential Opportunities to Advance Multimodal Therapy Development, 14

Co-Delivery of Pharmacological Interventions

for Alzheimer’s Disease, 20 Concomitant Delivery of Two Interventions with Different Modalities, 22

Simultaneous Use of Two Modalities in a Single Procedure, 25

4 Regulatory and Reimbursement Considerations 29 Regulatory Pathways for Drugs, Biologics, Devices, and

Combination Products, 31 Payer Perspectives on Multimodal Therapies, 33 Harmonizing Evidence for Payers and Regulators, 36

5 Trial Designs to Establish Efficacy and Safety in

Platform Trials and Adaptive Trials, 38

Quantifying Dose with Non-Pharmacologic Interventions, 42 Assessing Response to Interventions, 44

6 Developing Multimodal Therapies: Practical Considerations

Integrating Therapeutic Devices into Psychiatry, 48

Targeted Drug Delivery: Intrathecal Infusion Therapy for Chronic Pain, 49

A Multinational Collaboration to Develop

a Multimodal Therapy, 50

7 Role of Research Funders in Multimodal Therapy

Role of Research Agencies in De-Risking Multimodal

Therapy Development, 54 Role of Disease-Specific Funding in Multimodal Therapy Development, 57

APPENDIXES

1

Multimodal therapy approaches that combine interventions aimed at different aspects of disease are emerging as potential—and perhaps essential—ways to enhance clinical outcomes for patients with psychiat-ric and neurological disorders Indeed, for most chronic diseases, multi-ple pathways are involved simultaneously, making it unlikely that a single treatment will prove sufficiently effective, said Robert Califf, commissioner of Food and Drugs at the Food and Drug Administration (FDA) Califf was the keynote speaker at a workshop on multimodal therapies for brain disorders, convened by the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous Systems Disorders in Washington, DC, on June 14 and 15,

2016

WORKSHOP OBJECTIVES

The workshop brought together key stakeholders to examine the general principles underlying multimodal therapies and to explore chal-lenges, potential barriers, and opportunities for their development from multiple perspectives, including scientific, clinical, regulatory, and fi-nancial (see Box 1-1)

Pro-ceedings of a Workshop have been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop Statements, recommendations, and opinions expressed are those of individual presenters and participants, and have not been endorsed

or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus

BOX 1-1 Statement of Task

An ad hoc committee will plan and conduct a 1.5-day public shop to explore multimodal therapeutic approaches for nervous system disorders (i.e., combinations of interventions aimed at different aspects

work-of a disease) This could include, for example, a drug prescribed along with a device, psychosocial intervention, lifestyle adjustment, or dietary intervention The workshop will bring together key stakeholders to ex-amine scientific, clinical, regulatory, and reimbursement issues related

to multimodal approaches and identify potential opportunities to hance clinical outcomes for individuals with nervous system disorders Invited presentations and discussions will be designed to:

en-• Explore recent advances in the development of multimodal therapeutics for nervous system disorders and approaches to using these therapies (e.g., earlier versus later in disease pro-gression), and discuss future research needs to advance under-standing of these approaches

• Highlight disease areas in which a multimodal approach could

be particularly useful (e.g., areas in which the pathophysiology

is well understood)

• Discuss methodologies for establishing efficacy for

multimod-al therapies compared to monotherapies, including clinicmultimod-al and statistical considerations

• Consider regulatory issues for multimodal therapies, including for approaches in which only one component is regulated (e.g., drug plus psychosocial intervention), and discuss poten-tial opportunities for addressing challenges

• Consider reimbursement issues for multimodal therapies for nervous system disorders, and discuss potential opportunities for addressing challenges

• Incorporate lessons learned from other therapeutic areas in which multimodal approaches are more frequently used (e.g., diabetes, HIV, cancer)

The committee will develop the agenda for the workshop, select and invite speakers and discussants, and moderate the discussions A summary of the presentations and discussions at the workshop will be prepared by a designated rapporteur in accordance with institutional guidelines

The multiple modalities considered at the workshop include drugs, biologics, devices, and behavioral interventions, said Karl Kieburtz, director of the Clinical and Translational Science Institute at the Univer-sity of Rochester Medical Center In combination, these approaches may

in some cases have additive or even synergistic (additive) or synergistic effects For example, if two treatments that are only mildly effective when given individually have a much greater effect given to-gether, the effect might be considered synergistic or super-additive Su-per-synergistic refers to treatments where one component by itself has no effect on the disease, but in combination with another treatment that is modestly effective provides a much greater effect, such as carbidopa combined with levodopa for the treatment of Parkinson’s disease (PD) Whether additive or synergistic, the path to identifying, developing, test-ing, validating, and implementing multimodal approaches is fraught with layers of complexity, said Kieburtz

super-Sarah H Lisanby, director of the Division of Translational Research, National Institute of Mental Health (NIMH), noted that not only is mul-timodal therapy development an interdisciplinary enterprise, but that in the practice of medicine, multimodal approaches are often considered the standard of care Nonetheless, the development of therapeutics for neu-ropsychiatric disorders has focused primarily on monomodal product development, which largely aligns with industry investment The goal of the workshop, she said, was to break down barriers between different modalities Rather than thinking of them in isolation, she cited the need

to integrate and optimize approaches across boundaries Califf agreed that therapies are usually delivered in a multimodal environment, adding that it therefore makes sense to also evaluate them in such a setting He predicted an impending avalanche of effective targeted therapies, includ-ing both drugs and devices for a range of disorders However, he noted that the development of such therapies has lagged for complex, chronic diseases such as neurological and psychiatric disorders

ORGANIZATION OF THE PROCEEDINGS

The following proceedings summarizes the workshop presentations and discussions Chapter 2 sets the stage by reviewing the definition of multimodal therapies and discussing the rationale for their use, then ex-ploring the challenges, opportunities, and research gaps identified by in-dividual participants as needing to be addressed for the field to move

forward In Chapter 3, the state of the art is explored by discussing amples of different approaches: co-delivery of two pharmacological agents; concomitant use of two interventions with different modalities, such as a drug and device; and simultaneous use of two modalities in a single procedure, for example, combining devices with either cognitive enhancement or psychosocial intervention While combination and mul-timodal treatments exist and are being developed for a very wide range

ex-of disorders, the chapter concentrates on a few salient examples tory and reimbursement challenges are explored in Chapter 4, and issues related to trial design and establishing efficacy and safety of multimodal therapies are discussed in Chapter 5 In Chapter 6, the industry perspec-tive is presented through several examples of existing products as well as novel approaches in development Finally, Chapter 7 addresses the roles that governmental agencies and nonprofit foundations can play in ad-vancing multimodal therapy development through funding as well as by promoting collaborations across stakeholder groups

Regula-2 Multimodal Therapy: Overview of Principles,

Barriers, and Opportunities

Multimodal therapies are intended to optimize treatment of brain orders by delivering different types of therapy together The multiple modes used may include pharmacotherapy (small molecule drugs and bio-logics), devices, and behavioral/psychosocial interventions (see Figure 2-1) These different modalities may target a particular neural system (e.g., a drug plus neurostimulation), or one modality may be used to acti-vate or potentiate a neurological circuit so that the other modality can have a therapeutic effect

dis-An overarching theme that emerged from the workshop was that to effectively develop multimodal therapies, a sophisticated understanding

of disease processes and disease phenomena is needed, said Karl Kieburtz A second major theme, raised by FDA commissioner Califf, relates to the challenge of achieving the scale needed for trials in the neu-rosciences by reducing costs and improving efficiency Multimodal ther-apies increase the complexity of this challenge because evidence is required about both the independent and combined contributions of con-stituent modes across practice, regulatory, and reimbursement decision-making contexts, said Kieburtz

DEFINING MULTIMODAL THERAPY

This workshop generally considered “multimodal therapy” as a broad category that involves combining two or more modalities that tar-get different aspects of a disease During workshop discussions, howev-

er, it was clear that there is no single set of terminology used across the

field and that there is partial overlap among various commonly used terms

“Combination therapy” is frequently used to refer to two or more drugs or biologics used in combination—either to enhance delivery of a drug or target different aspects of a disease, or to improve outcomes to-ward the same aspect of a disease—and also sometimes used to refer to approaches involving multiple modalities

A “combination product,” according to the FDA definition, is one that combines two or more types of medical products that may be differ-ently regulated These may be two different components combined into a single entity, such as a drug-eluting stent, co-packaged as a kit or sold separately and labeled for use together (see Box 2-1) Some—but not all—combination products involve combining modalities to target differ-ent aspects of a disease Conversely, some multimodal therapies do not meet the formal definition of a combination product, for example, be-cause one component is not a regulated product, such as psychotherapy For clarity in this document, “multimodal therapy” is used except when discussing drug−drug combinations or when specifically referenc-ing a product that meets the FDA’s formal definition of a combination product Importantly, although they did not meet the working definition

of a multimodal therapy, the workshop included discussion of drug−drug combinations and FDA-defined combination products that do not address different aspects of a disease, because such approaches have been devel-oped further and involve similar challenges; therefore, lessons learned may be applied to multimodal therapy development

BOX 2-1 Combination Product Definition

The Food and Drug Administration’s Definition of a Combination Product is provided in 21 CFR Part 3.2 (Government Publishing Office, 2016):

(e) Combination product includes:

(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

(2) Two or more separate products packaged together in a single age or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

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RATIONALE FOR MULTIMODAL THERAPIES

IN BRAIN DISORDERS

Several workshop participants noted that the lack of efficacious apies for numerous neurological and psychiatric disorders, as well as di-minishing returns from the addition of new monotherapies, have fueled the pursuit of multimodal therapies Moreover, in other disease areas, such as cancer or HIV/AIDS, the use of combination therapies has dra-matically improved the treatment of disease

ther-Multimodal approaches may combine therapies that alone have only modest effects, but have dramatic effects when put together For exam-ple, in coronary artery disease, the multiple modes used may include a drug-eluting stent; multiple pharmacologic therapies, including blood thinners, statins, antihypertensives, and biologics; and behavioral inter-ventions, such as diet and exercise Multimodal approaches (as well as some combinations of multiple drugs) also offer the potential to target different pathological mechanisms simultaneously according to a number

of presenters at the workshop For example, in PD and Alzheimer’s ease (AD), protein misfolding and dysfunction in how proteins are traf-ficked and cleared, neuroinflammation, mitochondrial dysfunction, oxidative stress, and other aging pathways have all been implicated and may need to be targeted in combination Some workshop participants pointed out that there may be additive or synergistic effects of combined therapies Even a drug that has an insignificant effect when used as mon-otherapy may be effective when combined with another agent For ex-ample, carbidopa by itself has no impact on PD symptoms, but is used in combination with levodopa to prevent peripheral metabolism of levodopa

dis-so more of it can reach the brain Multimodal approaches are also often necessary for conditions such

as traumatic brain injury (TBI), which has multiple consequences, cluding cognitive disability, psychological injury, behavioral disorders, sensory disturbances, and pain; it is also accompanied by other visceral and orthopedic injuries (see Figure 2-2) Similarly, there is much more to

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CHALLENGES AND BARRIERS

The challenges of getting a single drug approved are magnified in the development of multimodal therapies, said James Hendrix, director of global science initiatives at the Alzheimer’s Association These include

an insufficient understanding of the underlying neurobiology of the eases, inefficient trial designs, and unclear regulatory and marketing pathways While non-pharmacologic therapies may be important compo-nents of multimodal therapies, these are in some cases even less well un-derstood than are the pharmacologic components

dis-Stevin Zorn, president, CEO, and co-founder of MindImmune apeutics, Inc., noted that current cost constraints demand the develop-ment of more efficient drug development pathways Timothy Strauman, professor of psychology and neuroscience at Duke University, added that novel and complex research designs, treatment protocols, and statistical algorithms are required to translate insights from neuroscience and cog-nitive science about the pathophysiology of complex disorders and po-tential treatment mechanisms of action into improved treatments, including multimodal and personalized medicine approaches This chap-ter provides an overview of barriers and opportunities identified by indi-vidual participants; these topics are discussed in greater detail in later chapters

Ther-Insufficient Understanding of Disease and Treatment Mechanisms

To effectively and efficiently develop multimodal therapies, a phisticated understanding of disease process and disease phenomena is needed, including linking target engagement to a biological response, tracking the trajectory of a disease over time, understanding risk pheno-types, and understanding the mechanism of action of the intervention, noted Kieburtz, Zorn, and Keith Hildebrand, senior principal scientist and technical fellow for neuromodulation at Medtronic, Inc Yet as noted

so-by Amir Tamiz, program director of the NIH Blueprint tics Network, limited preclinical models for central nervous system dis-eases make it difficult to develop a specific monotherapy, let alone combine therapies and understand whether there is an additive or syner-gistic effect

Neurotherapeu-For complex and heterogeneous diseases with multiple mechanistic pathways, such as PD, there is also a need to understand the interactions

of these multiple pathways, said Kieburtz and Brian Fiske, senior vice president for research programs at The Michael J Fox Foundation for Parkinson’s Research (MJFF) An incomplete knowledge of mechanisms also translates into lack of knowledge about what markers could and should be measured, including early biomarkers that predict a later re-sponse to treatment, noted Lisanby and Hildebrand

Non-pharmacologic therapies are an important component of many multimodal approaches, yet the details of how such therapies work are poorly understood, said Lisanby For example, for neuromodulation, in-sufficient knowledge about how the delivered dosage (composed of the spatial distribution of the induced field and the temporal dynamics of the field) and the context in which the field is administered (composed of brain state at time of stimulation, phase of neural oscillations, and con-comitant cognitive-behavioral interventions and pharmacotherapy) inter-act at a mechanistic level represents a research gap that impairs the ability to optimize the efficacy of multimodal therapies, she said

Translating Acquired Knowledge to Scale for Effective

Multimodal Therapies

The challenge of translating new discoveries into effective ments useful in real-world settings is also exacerbated for multimodal therapies due to insufficient scale, according to Califf He added that stakeholders have not identified mechanisms to create the scale needed to bring down costs and truly understand how various treatments interact or could cumulatively interact for more effective treatments Lisanby added that neuroscience trials frequently have a small sample size and are sta-tistically underpowered to detect a signal for each component part, which impedes scale-up and examination of the components combined Kieburtz added that for chronic diseases, a lack of proximate measures to what are often long-term outcomes result in lengthy trials and limit the use of adaptive designs and other trial design innovations that may be needed for multimodal therapies

treat-Complexity of Trial Design Needed to Assess

Multimodal Therapies

Hendrix highlighted some of the challenges faced when testing tiple therapies in combination These include demonstrating the pharma-codynamic and pharmacokinetic properties of multiple compounds,

mul-determining the correct doses of the compounds in light of possible tive or synergistic effects, and assessing potential drug−drug interactions The route of administration (e.g., oral versus infusion therapy) adds fur-ther complexity to dosing strategies and regimens, he said

addi-Dose is particularly challenging in trials of non-drug approaches For neuromodulatory therapies, quantifying dose requires consideration of parameters across three dimensions: spatial distribution of the induced field, temporal dynamics of the field, and the context in which the field is administered, which is affected by what the person is thinking or doing, who is in the room, environmental conditions, stress, etc., said Lisanby and Martha Morrell, chief medical officer at NeuroPace and clinical pro-fessor of neurology and neurosurgery at Stanford University Morrell added that the effects of neurostimulation may require months or even years to fully manifest, making it difficult to design a trial of reasonable duration that will truly represent treatment efficacy

For psychosocial interventions, quantifying dose has typically relied

on measures such as number of contacts with a therapist and duration of treatment; however, other factors that are less easy to quantify also affect dose, such as applied treatment techniques (e.g., exposure, cognitive re-structuring, and emotion regulation) or the therapeutic alliance, interper-sonal functioning, and variability among practitioners, said Wolfgang Lutz, professor and head of clinical psychology and psychotherapy at the University of Trier, Germany, and Marom Bikson, professor of biomedi-cal engineering at The City College of the City University of New York

Obtaining Regulatory Approval for a Multimodal Therapy

Establishing the safety and effectiveness of a single therapy in order

to gain regulatory approval is challenging, and adding other components

to a trial increases the complexity and difficulty of achieving approval, said Hendrix Kieburtz and Lisanby added that the challenge is exacer-bated by separate regulatory pathways and different evidentiary stand-ards for drugs, biologics, and devices Moreover, no regulatory framework exists for behavioral interventions or other psychosocial ther-apies, said Kieburtz and Strauman, including components such as neu-rocognitive tasks, brain-training games, and cognitive-behavioral therapy, added Lisanby

Billy Dunn, director of the FDA’s Division of Neurology Products at the Center for Drug Evaluation and Research (CDER), said that with drug−drug combinations, each component must make a contribution to

the overall effect, and there should be a compelling reason to use the drugs in combination Wilson Bryan, director of the division of clinical evaluation and pharmacology/toxicology at the Center for Biologics Evaluation and Research (CBER), added that if multimodal therapy combines a drug or biologic plus an unregulated intervention, such as a psychosocial intervention, the same standards of evidence apply as would apply to the drug alone

Payers’ and Regulators’ Perspectives

on Multimodal Therapies

The high cost of medical care is forcing difficult decisions to the forefront for payers, providers, and patients, and multimodal therapies may be escalating those costs, said Rhonda Robinson-Beale, senior vice president and chief medical officer of Blue Cross Idaho She said that payers often require comparative effectiveness studies, which Kieburtz noted are not part of the FDA framework for approval Moreover, said Lisanby, regulators and payers often have different evidentiary standards for efficacy and safety across modalities

As the scientific understanding of multimodal therapy evolves, bursement issues need to be addressed in early stages of development, said Lisanby A particular challenge for developers, noted Califf, is that conducting one set of studies for regulatory approval and a whole differ-ent set of studies for payers is an inefficient use of resources Another concern for developers is that if a multimodal therapy is shown to be more effective than monotherapy, this could lead to payers incentivizing

reim-or requiring the use of the intervention in the multimodal rather than monomodal context, noted Lisanby

Complexities and Challenges in Bringing Multimodal

Therapies to Market

In addition to the technical and scientific challenges of developing multimodal therapies, companies face commercial challenges in bringing those therapies to market, particularly because multimodal approaches often involve multiple companies as well as multiple modalities, said Califf For example, companies or investors may be reluctant to pursue development of multimodal therapies because of concern about treatment interactions If multiple treatments are to be evaluated in a single trial, a company may refrain because they fear their treatment will lose out to an

alternative There is also little commercial incentive for companies to participate in head-to-head trials

Hendrix added that few companies are large enough or have cient resources to conduct combination or multimodal trials in-house and thus must rely on collaborations with other companies, which present further complications Intellectual property concerns represent a barrier

suffi-to multimodal therapy development, said Tamiz

POTENTIAL OPPORTUNITIES TO ADVANCE MULTIMODAL

According to Strauman, the fields of cognitive psychology and nitive neuroscience are on the verge of a paradigm shift, with the increas-ing ability to target specific dysfunctions in particular neurologic circuits

cog-To effectively tackle the many complexities and realize this potential, said Lisanby, innovation is needed at all levels: in trial design, analytic approaches, and partnerships across stakeholder groups Following is an overview of the opportunities raised by individual workshop participants These opportunities are explored further in later chapters

Advancing Understanding of Disease Mechanisms and Treatments

Throughout the workshop, individual participants identified a ber of areas where additional research on the fundamental aspects of neu-rological diseases could advance the development of multimodal therapies These include

num-• Research that envisions and generates multimodal therapies that hit different targets, similar to the way heart disease is currently treated (Koroshetz)

• Clinical research aimed at promoting multimodal therapy that targets at-risk populations for early intervention and prevention (Edwards)

construed as reflecting a consensus of workshop participants or any endorsement by the National Academies of Sciences, Engineering, and Medicine or the Forum on Neurosci- ence and Nervous System Disorders

• Research to develop short-term markers that are objective and quantifiable and that could predict long-term change in a variety

of conditions, including pain and complex behavioral disorders such as depression (Lisanby)

• Research to develop targeted interventions for behavioral festations of conditions that traditionally have been considered neurological, such as mood dysregulation, sleep disturbances, anxiety, and agitation in TBI, AD, and PD (Lisanby)

mani-• Research to optimize parameters for neuromodulatory devices across three dimensions: spatial distribution and temporal dy-namics of the induced field and the context in which the field is administered (Lisanby)

• Research targeting behavioral manifestations such as agitation in the context of AD, and nonmotor symptoms such as cognition in

PD (Fiske, Hendrix) This includes developing a better standing of whether symptoms share a common underlying bio-logic substrate or if there are multiple mechanisms, and whether these symptoms are epiphenomena or core features of the disease

under-Improving Efficiency Through Trial Design Innovations

• For co-development of pharmaceutical agents, using innovative trial designs—including adaptive trials, 2 × 2 factorial designs, and fractional factorial designs—could offer efficient ways to accurately detect and quantify the synergistic or additive effects

of treatments (Kieburtz, Lewis)

• Incorporating statistical modeling and response adaptive domization could enable resources to be shifted toward ap-proaches that appear most promising (Lewis)

ran-• Building platform trials could enable the efficient exploration of the effects of multiple treatments in heterogeneous populations over extended periods of time (Lewis) For example, a transdi-agnostic approach for drug discovery could exploit the overlap between all neurodegenerative diseases (Hendrix), or neuropsy-chiatric diseases through the Research Domain Criteria (RDoC) initiative of NIMH (Lisanby)

Identifying Measures and Biomarkers for Improving

Clinical Trials

• Identifying and validating measures of target engagement in precompetitive space could enable drugs to be tested against bio-logically rational mechanisms before initiating large, expensive Phase III trials (Koroshetz)

• Identifying and validating biomarkers that demonstrate a cally relevant response to treatment could potentially provide a single readout for combination trials in AD (Hendrix)

clini-• Developing tools for estimating drug exposure in the brain to able interpretation and understanding of outcomes in clinical tri-als (Potter)

en-Improving Data Gathering, Data Sharing, and Data Analysis

In addition to improving the design of clinical trials, innovative yses and methods for obtaining and disseminating relevant high-quality data are particularly important for multimodal therapy because of the increased complexity of these approaches, according to some workshop participants Ideas discussed at the workshop include the following:

anal-• Capturing data from electronic health records and integrated health systems could provide opportunities to achieve the scale and real-world data needed for successful clinical trials (Califf, Edwards, Pizer)

• The FDA, with the cooperation of industry, is moving toward ing existing data from clinical trials and common data standards

us-to increase the scale of studies of multimodal therapies for tral nervous system (CNS) disorders, as is already being done in oncology (Califf, Potter)

cen-• Using innovative approaches to data analysis through sourcing and contests could expedite development and expand the community of researchers exploring multimodal therapy (Hicks) Prize models may also encourage the participation of investigators from diverse disciplines, including quantitative analysts from the financial world (Kieburtz)

crowd-• Incorporating big-data methods and large-scale analytics could allow investigators to capture and learn from devices already

used in clinical practice, such as long-term ambulatory corticographic (ECoG) monitoring (Morrell)

electro-• Calling for people to enable their data to be used by researchers

to answer questions and volunteer for trials, a major focus of the Precision Medicine Initiative, offers the potential for gathering large quantities of data from heterogeneous populations (Califf)

• Improving training of the next generation of neuroscientists, cluding data scientists, and reeducating students and scientists about the range of options for study design and data analysis are essential for continued progress in the field (Strauman)

in-De-Risking Multimodal Therapy Development

Through Collaborations

• Building a collaborative consortium of competing companies to tackle preclinical and infrastructure issues in precompetitive space could help move multimodal drug development forward (Hendrix)

• Addressing intellectual property issues by ensuring that each partner receives benefits from innovative partnerships could help mitigate the risk of such partnerships (Zorn)

• Providing research funding at the federal level and from private funders focused on particular diseases can play an important role

in de-risking drug development, for example, by investing in head-to-head trials for which there is no commercial incentive for companies (Lisanby), or promoting the repurposing of drugs for combination therapy (Hendrix)

• Developing programs for head-to-head trials to develop evidence across modalities, which incorporate provider/professional or-ganizations and patients (Califf, Lisanby)

3 Exploring the State of the Science

Highlights

• Multimodal therapies are already being used to treat a variety of neurodegenerative and neuropsychiatric diseases, including

PD, epilepsy, and depression (Fiske, Morrell, Strauman)

• Co-delivery of multiple pharmacologic interventions that target different pathological mechanisms has proved effective for the treatment of many diseases, such as cancer, but is still in the exper-imental stage for AD (Hendrix)

• Pharmacotherapy combined with continuous monitoring of brain electrical activity and neurostimulation offers a means for targeted and individualized treatment to prevent seizures (Morrell)

• Pharmacotherapy and psychotherapy can both be used to activate certain brain circuits, and it may be possible to use them in combi-nation to prevent progression of bipolar disorder in at-risk children (Chang)

• Transcranial magnetic stimulation (TMS), a noninvasive rostimulation procedure, can have acute and long-lasting effects on the brain, alleviating depression and enhancing cognitive perfor-mance; TMS may provide additional benefits when combined with cognitive stimulation and psychosocial intervention (Luber, Strauman)

neu-NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants

Multimodal therapeutic approaches have been used successfully to treat some complex neurological diseases such as pain and epilepsy for many years Indeed, combination therapy is the standard of care for the treatment of PD, said Fiske For example, levodopa, which is converted

to dopamine in the brain and is the first-line treatment for PD, is nearly always given in combination with carbidopa, a levodopa enhancer that enables the use of a lower dose of levodopa and thus reduces the side effects of nausea and vomiting

These examples not only provide lessons for future multimodal apy development, but also illuminate the research gaps that need to be addressed in order to move ahead into new disease areas as efficiently and synergistically as possible, said Timothy Strauman The theoretical considerations of seemingly simple approaches—using two drugs at the same time—are useful and apply to more complicated multimodal thera-pies, such as those that coadminister drugs with psychosocial interven-tion or neurostimulation, added Hildebrand

ther-CO-DELIVERY OF PHARMACOLOGICAL INTERVENTIONS

FOR ALZHEIMER’S DISEASE

Currently, more than 35 million people worldwide are estimated to have AD, with these numbers expected to triple by 2050 unless an effec-tive treatment is found to slow or prevent the disease (Alzheimer’s Asso-ciation, 2014; Prince et al., 2013) Pharmaceutical drug development across all disease areas is risky, but drug development for AD has been particularly disappointing with only about 0.5 percent of compounds successfully proceeding from the preclinical phase to an approved drug (Calcoen et al., 2015), said Hendrix

Emerging interest in using combination therapy to treat AD derives not only from the urgency to find new treatments, but also from experi-ence in other disease areas such as cancer and HIV/AIDS, where cock-tails of drugs have proven to be required for successful treatment (Hendrix et al., 2016) Moreover, the complex neuropathology of AD (Holtzman et al., 2011) suggests that it may be necessary to attack multi-ple pathways in order to slow the disease, said Hendrix Indeed, treat-ments currently in the pipeline are being tested in combination with cholinesterase inhibitors, which are one of only two classes of drugs cur-rently approved for the symptomatic treatment of AD For example, one

of these drugs, AVP923, is being tested in a Phase III trial for the

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AD to take on a combination trial This is where an organization such as the Alzheimer’s Association comes in, building collaborative partner-ships with multiple stakeholders It was with this in mind that they con-vened a workgroup of regulators, academicians, and industry representatives to map out a path forward for AD combination therapy (Hendrix et al., 2016) The workgroup recommended proceeding with a

2 × 2 factorial four-arm design combining an anti-amyloid and anti-tau drug, where one arm would test the anti-amyloid drug alone, one arm would test the anti-tau drug alone, one arm would combine the two drugs, and one arm would be the placebo

To advance combination therapy more generally, the workgroup also recommended using transgenic animal models and human neuronal cell culture models to test combinations and using adaptive trials Ideally, a biomarker that provides a single readout of treatment effect would enable these studies to move forward efficiently, said Hendrix

CONCOMITANT DELIVERY OF TWO INTERVENTIONS

WITH DIFFERENT MODALITIES

In addition to co-delivery of pharmaceuticals, multimodal therapies using two different modalities, such as administration of a drug and neurostimulation from a device or psychosocial therapy, can be effective treatment approaches for neurological and psychiatric conditions such

as epilepsy and bipolar disorder in adolescents, said several workshop participants

Drug −Device Combinations for Epilepsy

Epilepsy is a common but diverse group of neurologic conditions characterized by recurrent seizures and many comorbidities, including depression and anxiety, said Martha Morrell Many effective anti-epileptic medications are available, each with different features and dif-ferent mechanisms of action, yet still about 30 percent of patients with partial onset seizures continue to have seizures, and only about 15 per-cent are candidates for a surgical procedure where a portion of the brain

is removed or destroyed to control the seizures

Neurostimulation is a safe and effective alternative for some of these patients, despite the fact that the mechanism of action is not well under-stood, said Morrell The first neuromodulation device to be used in the treatment of epilepsy was the vagus nerve stimulator (VNS), which pro-vides scheduled stimulation to the vagus nerve and has been used to treat partial seizures since 1997 Another approach is deep-brain stimulation (DBS), in which an electrode implanted in the area of brain from which the seizure emanates delivers electrical impulses that stop or shorten the seizure activity (Morrell and Halpern, 2016) While not approved for the treatment of epilepsy in the United States, DBS is available in more than

30 countries worldwide, said Morrell Brian Fiske commented that DBS is also commonly used in combination with pharmacotherapy to treat PD Other neuromodulation devices are used not for treatment per se, but for sensing when a patient is going to have, or has had, a seizure Some

of these devices are widely available from retail outlets, including those that measure galvanic skin response or sense bed shaking and other atyp-ical movements Morrell described a device she has been working with that combines sensing with responsive neurostimulation, which was ap-proved by the FDA for treatment of uncontrolled partial-onset seizures after 12 years of clinical trials Such devices offer the potential to move from waiting for an event such as a seizure to occur and having a patient suffer the consequences, to intervening before the event occurs, said Morrell The Responsive Neurostimulator System (RNS) combines a neurostimulator attached to the skull with electrodes placed according to the patient’s seizure focus, and continuously monitors electrical activity

in the brain A programming device enables the physician to set the vice to deliver stimulation when appropriate

de-The data captured by the system has proved to be “unexpectedly powerful,” said Morrell Each patient has a signature that is the same seizure after seizure The temporal patterns detected by the device are biomarkers that allow physicians to individualize treatment and develop multimodal treatment synergies For example, if a patient has problems

in the morning, the physician can increase medication at that time; or if a female patient has problems associated with the menstrual cycle—what are called catamenial seizures—the physician may choose to prescribe continuous birth control

Morrell cited a number of potential opportunities for multimodal proaches that combine both multiple therapies (drugs and neurostimula-tion) as well as stimulation that is combined with a device for sensing brain activity For example, targeted spatial delivery of a drug with an

ap-implanted device could allow delivery of a pharmacologic agent to the seizure focus when seizure activity is detected It may also be possible to select drugs that facilitate other drug effects Finally, she said, these de-tection and treatment methods can be used in combination with other types of multidisciplinary care, for example, psychotherapy or cognitive-behavioral therapy to deal with suicidal thoughts

Combining Drugs with Psychosocial Interventions in Adolescents

with Bipolar Disorder

Bipolar disorder (BD) is another common and disabling brain dis-ease According to Kiki Chang, professor of psychiatry and behavioral sciences at Stanford University Medical Center, as much as 2 to 4 per-cent of the population experiences BD, with onset typically in childhood (Perlis et al., 2004) He plans to use two modalities—pharmacotherapy plus psychotherapy—to treat children with a type of subthreshold BD called “not otherwise specified” or BD-NOS that does not meet the full criteria for mania or BD, as well as children with depression or a family history of BD All of these children are thought to be at higher risk for later meeting the clinical criteria for BD Treating them early may pre-vent progression, said Chang

Chang’s approach targets circuitry in the brain that is implicated in mood dysregulation, specifically prefrontal-subcortical circuits (Chang et al., 2004) The pharmacotherapy component of his study used the seizure medication divalproex, which has been shown to produce symptomatic improvement as well as a change in brain structure in individuals with

BD in an open-label study (Chang et al., 2003), but not in placebo study (Findling et al., 2007), except in those who had a family history of BD The psychotherapy component of the multimodal therapy used a tech-nique called family-focused therapy, which has been shown to activate dorsal and prefrontal circuits and is accompanied by improvement in symptoms (Garrett et al., 2015) Chang said he hopes the combination of targeted pharmacologic plus psychotherapy at a critical time in brain de-velopment will restore healthy neuronal connectivity and function in these at-risk children Long-term follow-up will be needed to determine

if this approach actually prevents the development of BD

Lisanby suggested an alternative approach: combining two modalities selected because of previous knowledge regarding the mechanism of ac-tion of the device, such as inducing plasticity in focal regions of the brain, coupled with a medication that enhances that mechanism For example,

one approach might combine TMS with a pharmacological agent that lectively promotes neuroplasticity

se-SIMULTANEOUS USE OF TWO MODALITIES

IN A SINGLE PROCEDURE

The use of different treatment modalities administered at the same time allows researchers and clinicians to leverage the action of one ther-apy to enhance the effects of the second Examples of these emerging approaches include the use of noninvasive stimulation with concurrent behavioral training to improve cognitive performance, or combined with psychotherapy to increase mood regulation in depression The use of feedback derived from electroencephalogram (EEG) recordings to en-hance meditation effects in real-time is another example of concurrent use of two different modalities

Combining Devices with Cognitive Enhancement

TMS is a noninvasive neurostimulation approach to the study of brain function that has both acute and long-lasting effects on the brain, including modulating network activity and neuroplasticity, according to Bruce Luber, staff scientist in the Experimental Therapeutics and Patho-physiology Branch of NIMH It is approved by the FDA for treatment-resistant depression and has also been shown to enhance cognitive per-formance (Luber and Lisanby, 2014)

Luber discussed a more active approach for cognitive enhancement,

in which direct modulation with TMS is paired with another form of stimulation such as cognitive activity This approach, called Cognitive Paired Associate Stimulation (C-PAS), is based on the original PAS technique, which combined peripheral stimulation of the median nerve in the hand with TMS to increase excitability changes in the motor cortex and thus potentially increase the therapeutic potential (Ridding and Taylor, 2001) But in C-PAS, instead of stimulating the median nerve peripherally, neural circuits are activated by giving people a visual memory task to do According to Luber, stimulating a given network with TMS at the same time the network is activated by the cognitive task strengthens the connectivity within the circuit For example, he has shown that the technique is able to improve cognitive performance (Luber et al., 2007) and eliminate the effects of sleep deprivation on a

targeted cognitive task (Luber et al., 2008) Subsequent studies also showed that the combination of TMS with working memory training may prevent cognitive deficits in people who are sleep deprived (Luber et al., 2013), suggesting that the technique may be able to help people with cognitive deficits or even alleviate memory problems associated with normal aging, which is presently being tested with NIH funding

Luber acknowledged that there are many challenges to address in further developing the approach First, the mechanisms underlying TMS-induced cognitive enhancement are unknown, and there is also much to learn about timing, spacing, and intensity parameters involved in TMS dosing Finally, state dependence, that is, the baseline level of activity in the circuit, is probably the biggest source of variability, he said

Combining Devices with Psychosocial Intervention

Another application of the concept of tuning different modalities to target the same dysfunctional neurocircuitry was described by Strauman, who combines TMS with a form of psychotherapy called self-system therapy (SST) to treat depression The rationale, he said, is that TMS will increase plasticity in a network, which should have a synergistic effect

on learning behaviors and skills for regulating mood that engage the same network The approach involves, first, an individualized assessment

to identify regions in the left prefrontal cortex that are most responsive to whatever the person finds most rewarding, then targeting that predeter-mined region/circuit with TMS while engaging the person in SST Strauman described preliminary clinical data obtained from five people during early trials, using both clinician report and patient self-report These early results, which require further validation, suggest that patients who receive the combination treatment showed improvements in depressive symptoms in a shorter period of time than would be seen in response to typical monotherapy approaches, said Strauman Using pre-treatment and posttreatment neuroimaging data, preliminary results also indicate that in response to motivational cues, patients show significantly increased activity in areas of the brain that are relevant for approach and avoidance cues

Strauman emphasized that confirmation of the mechanism of action and validation of the targeting strategy will be needed before taking this approach to a larger scale clinical trial In addition, he cited regulatory challenges given that most psychosocial therapies have no regulatory framework to follow

Integrating Complementary Approaches

with Conventional Care

Emmeline Edwards, director of the division of extramural research at the National Center for Complementary and Integrative Health (NCCIH), described another approach that incorporates mindfulness meditation with real-time feedback EEG Meditation has been shown to increase activity in the posterior cingulate cortex (PCC) Using the EEG feedback, patients can learn to both increase their PCC activity and enhance the effect of meditation, said Edwards (van Lutterveld and Brewer, 2015) She said they are applying this technique to reduce craving for individu-als trying to stop smoking Another study supported by NCCIH incorpo-rates mindfulness meditation for the treatment of pain and demonstrates that mindfulness meditation does not rely on the endogenous opioid ac-tivity to reduce pain, since naloxone administration did not block medita-tion’s pain-relieving effects—an important consideration for using meditation to treat chronic pain and reduce opioid use, said Edwards