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Developing Multimodal Therapies for Brain Disorders:

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D e v e l o p i n g M u l t i m o d a l T h e r a p i e s f o r B r a i n D i s o r d e
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
C o p y r i g h t N a t i o n a l A c a d e m y o f S c i e
D e v e l o p i n g M u l t i m o d a l T h e r a p i e s f o r B r a
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.
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Developing Multimodal Therapies for Brain Disorders: Proceedings of a Workshop
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PLANNING COMMITTEE ON MULTIMODAL THERAPIES

FOR BRAIN DISORDERS1
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
1
The National Academies of Sciences, Engineering, and Medicine’s planning committees
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.
v

D e v e l o p i n g M u l t i m o d a l T h e r a p i e s f o r B
C o p y r i g h t N a t i o n a l A c a d e m
FORUM ON NEUROSCIENCE AND NERVOUS

SYSTEM DISORDERS1
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
of Technology
DANIEL BURCH, Pharmaceutical Product Development, LLC
SARAH CADDICK, Gatsby Charitable Foundation
ROSA CANET-AVILES, Foundation for the National Institutes of
Health
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
1
The National Academies of Sciences, Engineering, and Medicine’s forums and 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.
vii

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
Research
DAVID SHURTLEFF, National Center for Complementary and
Integrative Health
PAUL SIEVING, National Eye Institute
NORA VOLKOW, National Institute on Drug Abuse
STEVIN ZORN, MindImmune Therapeutics, Inc.
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)
DANIEL FLYNN, Senior Program Assistant (from September 2016)
JIM BANIHASHEMI, Financial Officer
HILARY BRAGG, Program Coordinator
ANDREW M. POPE, Director, Board on Health Sciences Policy
viii

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 exami-
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.
ix


Contents
1 Introduction 1
Workshop Objectives, 1
Organization of the Proceedings, 3
2 Multimodal Therapy: Overview of Principles, Barriers, and

Opportunities 5
Defining Multimodal Therapy, 5
Rationale for Multimodal Therapies in Brain Disorders, 8
Challenges and Barriers, 10
Potential Opportunities to Advance Multimodal Therapy
Development, 14
3 Exploring the State of the Science 19

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
xi
xii CONTENTS
5 Trial Designs to Establish Efficacy and Safety in

Multimodal Therapies 37
Platform Trials and Adaptive Trials, 38
Quantifying Dose with Non-Pharmacologic Interventions, 42
Assessing Response to Interventions, 44
6 Developing Multimodal Therapies: Practical Considerations

Relating to Industry 47
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

Development 53
Role of Research Agencies in De-Risking Multimodal
Therapy Development, 54
Role of Disease-Specific Funding in Multimodal Therapy
Development, 57
APPENDIXES
A References 61
B Workshop Agenda 67
C Registered Participants 79

1
Introduction1
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).
1
The planning committee’s role was limited to planning the workshop, and the 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.
1

2 MULTIMODAL THERAPIES FOR BRAIN DISORDERS
BOX 1-1
Statement of Task
An ad hoc committee will plan and conduct a 1.5-day public work-

shop to explore multimodal therapeutic approaches for nervous system
disorders (i.e., combinations of interventions aimed at different aspects
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 en-
hance clinical outcomes for individuals with nervous system disorders.
Invited presentations and discussions will be designed to:
• 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 clinical 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.

INTRODUCTION 3
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 (super-additive) or super-
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.
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 ex-

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
of disorders, the chapter concentrates on a few salient examples. Regula-
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.

2
Multimodal Therapy: Overview of Principles,
Barriers, and Opportunities
Multimodal therapies are intended to optimize treatment of brain dis-

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.
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 pack-
age or as a unit and comprised of drug and device products, device
and biological products, or biological and drug products;

OVERV
VIEW OF PRINC
CIPLES, BARRIE
ERS, AND OPPO
ORTUNITIES 7
(3
3) A drug, device, or biological product paackaged separaately that ac-
cording to itts investigation
nal plan or prooposed labelingg is intended
for use only
y with an appro oved individuaally specified ddrug, device,
or biologicaal product wheere both are reequired to achhieve the in-
tended use, indication, or effect and whhere upon appproval of the
proposed pro oduct the labelling of the appproved productt would need
to be chang ged, e.g., to reeflect a changee in intended use, dosage
form, strenggth, route of administration,
a , or significannt change in
dose; or
(4)) Any investig gational drug, device, or bioological produuct packaged
separately thhat according to its proposeed labeling is ffor use only
with anotherr individually specified
s invesstigational drugg, device, or
biological prroduct where both
b are requirred to achieve the intended
use, indicatio
on, or effect.
FIGUR RE 2-1 Optim mizing treatmennt with multim modal therapiess. In multimoddal
treatmeent paradigms, one treatmentt modality, succh as pharmaccotherapy, can be
combinned with other therapeutic modes,
m includinng psychosociaal intervention or
non-invvasive neuromodulation.
SOURC CE: Presentatio
on by Lisanby,, June 14, 20166.

RATIONALE FOR MULTIMODAL THERAPIES

IN BRAIN DISORDERS
Several workshop participants noted that the lack of efficacious ther-

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.
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 dis-
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
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, in-
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
PD than motor symptoms, including the possibility of cognitive impair-
ment, autonomic dysfunction, sleep dysregulation, and pain.

OVERV
VIEW OF PRINC
CIPLES, BARRIE
ERS, AND OPPO
ORTUNITIES 9
FIGUR RE 2-2 Overllapping symptoms followingg mild traumaatic brain injuury

(TBI). Service membbers from the wars
w in Iraq annd Afghanistann who experiennce
mild TBI suffer from
m high and oveerlapping rates of persistent ppostconcussionnal
symptooms (PPCS), poosttraumatic sttress disorder (P
PTSD), and chhronic pain.
on by Hoffman n, June 15, 20116.
Multimodal ap pproaches maay enable moore individuaalized, targetted

treatm
ment. For exam mple, for a highly
h heteroogeneous conndition such as
epilepssy, pharmaco otherapy may y be combineed with continnuous monitoor-
ing off brain electrical activity and
a neurostim mulation to prrevent seizurees.
Indeedd, multimodal therapy is commonly uused in clinical practice annd
often recommendeed in professsional practicce guideliness, even though
there are
a many casees in which the combinatiions have nott been methoddi-
cally assessed.
a For example, meedication pluss cognitive beehavioral therra-
py is th
he standard of
o care for deppression.

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 dis-
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.
Stevin Zorn, president, CEO, and co-founder of MindImmune Ther-
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.
Insufficient Understanding of Disease

and Treatment Mechanisms
To effectively and efficiently develop multimodal therapies, a so-

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
by Amir Tamiz, program director of the NIH Blueprint Neurotherapeu-
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.
For complex and heterogeneous diseases with multiple mechanistic
pathways, such as PD, there is also a need to understand the interactions

OVERVIEW OF PRINCIPLES, BARRIERS, AND OPPORTUNITIES 11
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 treat-

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.
Complexity of Trial Design Needed to Assess

Multimodal Therapies
Hendrix highlighted some of the challenges faced when testing mul-

tiple therapies in combination. These include demonstrating the pharma-
codynamic and pharmacokinetic properties of multiple compounds,

determining the correct doses of the compounds in light of possible addi-

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.
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, reim-
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
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 suffi-
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
to multimodal therapy development, said Tamiz.
POTENTIAL OPPORTUNITIES TO ADVANCE MULTIMODAL

THERAPY DEVELOPMENT1
According to Strauman, the fields of cognitive psychology and cog-

nitive neuroscience are on the verge of a paradigm shift, with the increas-
ing ability to target specific dysfunctions in particular neurologic circuits.
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 num-

ber of areas where additional research on the fundamental aspects of neu-
rological diseases could advance the development of multimodal
therapies. These include
• 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).
1
These lists highlight topics discussed throughout this workshop, but should not be
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 mani-
festations of conditions that traditionally have been considered
neurological, such as mood dysregulation, sleep disturbances,
anxiety, and agitation in TBI, AD, and PD (Lisanby).
• 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 under-
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.
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 ran-
domization could enable resources to be shifted toward ap-
proaches that appear most promising (Lewis).
• 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 clini-
cally relevant response to treatment could potentially provide a
single readout for combination trials in AD (Hendrix).
• Developing tools for estimating drug exposure in the brain to en-
able interpretation and understanding of outcomes in clinical tri-
als (Potter).
Improving Data Gathering, Data Sharing, and Data Analysis
In addition to improving the design of clinical trials, innovative anal-

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:
• 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 us-
ing existing data from clinical trials and common data standards
to increase the scale of studies of multimodal therapies for cen-
tral nervous system (CNS) disorders, as is already being done in
oncology (Califf, Potter).
• Using innovative approaches to data analysis through crowd-
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).
• 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 electro-

corticographic (ECoG) monitoring (Morrell).
• 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, in-
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).
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 neu-
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).
NOTE: These points were made by the individual speakers identified

above; they are not intended to reflect a consensus among workshop
participants.
19

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 ther-
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.
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 treat-

EXPLO
ORING THE STATE OF THE SCI
CIENCE 21
ment ofo agitation inn AD. AVP92 23 combines ddextromethorrphan and quiin-
idine, and is a possiible example of super syneergy. By itsellf quinidine hhas
no effe
fect, but it chaanges the waay dextromethhorphan is meetabolized soo it
can reaach the brain,, said Hendrix x. The producct, marketed uunder the nam me
Nuedeexta, has alreaady been app proved for thee treatment oof pseudobulbbar
affect in amyotroph hic lateral scleerosis (ALS) and multiple sclerosis (MS S).
Drrugs being coonsidered for possible
p combbination theraapy in AD sppan
a widee variety of mechanisms,
m said Hendrixx, including thhose that targget
amyloid β and tau, the proteins that aggregaate as plaquess and tangles in
the AD D brain, and those that aree potentially neuroprotecttive (see Figuure
3-1). For
F each of th hese targets, there
t may be multiple inteervention possi-
bilitiess, for exampple, stopping production or improvinng clearance of
amyloid β or preventing the accumulation off tau. So a com mbination theer-
apy co ould potentiallly attack onee pathology inn two differeent ways, attaack
two diifferent pathoologies, or attaack one pathoology in com mbination withh a
neurop protective ageent.
Off course, commbining drugs introduces m many other chaallenges relatted
to pharmacokinetics, pharmacod dynamics, dosse finding, dru rug interactionns,
and otther adverse events,
e said Hendrix.
H The rroutes of admministration annd
dosing g regimens coould further co omplicate a trrial, for exam
mple, if one dru
rug
is admministered by infusion
i every y third week w while anotherr is taken orallly
FIGUR RE 3-1 Potentiial combination

n treatments foor AD. A hypothetical model of
the AD D pathophysioloogic pathway with
w points of intervention foor potential com
m-
bination therapies.
NOTE: MTL = mediaal temporal lob be.
SOURC CES: Presentaation by Hend drix, June 14, 2016. Adapteed from Sperliing
et al., 2014.
2

each day. Finally, regulatory and business issues should be considered,

Hendrix said, adding that possibly the biggest barrier is that few compa-
nies are large enough and have the capacity and breadth of experience in
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.

EXPLORING THE STATE OF THE SCIENCE 23
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 de-
vice to deliver stimulation when appropriate.
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 ap-
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

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 se-
lectively promotes neuroplasticity.
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.


4
Regulatory and Reimbursement
Considerations
Highlights
• Multimodal therapies represent an emerging area to the FDA;
sponsors are encouraged to consult with the agency at early stages
of development (Peña).
• The FDA has separate regulatory pathways and centers for drugs, bio-
logics, and devices, with different user fees, evidentiary and manufac-
turing standards, and cultures. Combination products are assigned to
one of the centers based on the primary mode of action (Califf, Love).
• With drug−drug combinations, each component must make a con-
tribution to the overall effect, and there should be a compelling
reason to use the drugs in combination (Dunn).
• If a multimodal therapy combines a drug or biologic plus an un-
regulated intervention such as a psychosocial intervention, the usu-
al standards of evidence apply to the drug or biologic component,
that is, substantial evidence of effectiveness and evidence that the
drug is safe (Bryan).
• Multimodal therapies may increase the cost of therapy, which may
force payers to make difficult decisions with regard to coverage.
Such decisions will be based on medical necessity and comparative
effectiveness (Robinson-Beale).
• The incremental value of a multimodal approach will need to be
demonstrated for acceptance by payers (Pizer).
participants.
29

Multimodal therapies raise a number of important issues for both

regulators and payers regarding combinations of regulated products, such
as a drug plus a device, as well as approaches in which only one compo-
nent is regulated, such as a drug or device in combination with psycho-
therapy.
From the perspective of the FDA, multimodal therapies represent an
emerging technology area, and developers are encouraged to consult with
the agency at early stages of development to help get products to patients
who desperately need them as quickly as possible, according to Carlos
Peña, director of the division of neurological and physical medicine de-
vices at the Center for Devices and Radiological Health (CDRH). He
said presubmissions are one of the best ways to gauge preliminary in-
formation needed from sponsors and developers for a particular product,
including a combination product.
While Peña’s colleagues from other centers agreed on the need for
early consultation, they also urged caution. Wilson Bryan at CBER
commented that there may be a tendency to think a combination is neces-
sary when, in fact, individual components may be just as effective on
their own. Billy Dunn at CDER said the agency’s guidance states that
there should be a compelling reason to codevelop two products and that
they should be developed independently if this is not the case.
The FDA has specific regulations that must be followed, said Robert
Califf, but that does not preclude the agency from thinking about broader
principles. For example, with regard to novel outcome measures, the
overarching principle is that the outcome should demonstrate a clinically
meaningful impact on the disease, said Dunn. If sponsors are able to de-
fine what that effect is and demonstrate that they are able to measure it,
the agency may accept the outcome measure, but may ask that it be in-
cluded in the trial design along with other established measures to pro-
vide some grounding with experience.
Moreover, as the field evolves, the FDA pays attention to consensus
within the scientific community, said Dunn. Patient-focused drug devel-
opment meetings and workshops are also increasingly important. These
meetings not only provide opportunities to talk about emerging technol-
ogy issues and policy, said Peña, but they also typically involve a lot of
cross-talk among staff at different centers.

REGULATORY AND REIMBURSEMENT CONSIDERATIONS 31
REGULATORY PATHWAYS FOR DRUGS, BIOLOGICS,

DEVICES, AND COMBINATION PRODUCTS
Peña, Bryan, and Dunn represent the three FDA centers that may be
involved in approval of multimodal therapies. While the centers want to
cooperate, each has different user fees, different evidentiary standards for
different components in the same product, different manufacturing
standards, and different cultures. According to Califf, the agency is mak-
ing an effort to modernize and adapt a system in order to increase effi-
ciency, consistency, and predictability in review; encourage innovation;
and support development of novel technologies through a lean manage-
ment approach, improved information technology systems, and harmoni-
zation at the leadership level.1 For example, Dunn said, there is a
workgroup across all centers involved in neurology products. The
workgroup discusses crosscutting issues and tries to develop consistency
in requirements and messaging.
Office of Combination Products
The Office of Combination Products (OCP) was established in 2002

as a specific entity within the FDA to serve as a focal point for combina-
tion products, which are defined as two or more differently regulated
types of medical products, according to OCP deputy director Patricia
Love. These different components may be a drug and device, drug and
biological, or device and biological; these components may be physically
or chemically combined in a single entity (e.g., drug-eluting stent or pre-
filled syringes), co-packaged as a kit (e.g., drug plus empty syringe), or
sold separately and labeled for use together. Multimodal therapies may
or may not be combination products, depending on whether they fit into
this definition.
Typically, one investigational application is needed for a combina-
tion product, and according to Love, combination products are assigned
to the center based on the primary mode of action by which the product
achieves its intended purpose. For example, a product consisting of a
drug and delivery device, in which the primary mode of action resides
with the drug, would be assigned to CDER as the lead center, said Love.
1
For additional information see http://blogs.fda.gov/fdavoice/index.php/2016/04/
developing-a-consensus-voice-the-combination-products-policy-council (accessed August
31, 2016); and http://blogs.fda.gov/fdavoice/index.php/2016/03/leaning-in-on-combination-
products (accessed August 31, 2016).

When the primary mode of action is not clear, the product is typically
assigned to the center with the most expertise in dealing with significant
safety and effectiveness questions. Love said her office works hard to
make sure that all the issues are addressed consistently and in a transpar-
ent manner, and that all of the relevant centers are at the table to address
issues that arise. Regardless of whether a product qualifies as a combina-
tion product, when a treatment involves two modalities that are regulated
in different ways, the scientific questions are the same, she said.
Drugs, Biologics, and Devices: CDER, CBER, and CDRH
While small molecule drugs and biological products, may, depending

on the product, be processed by two separate centers, CDER and CBER,
the different challenges are generally scientific not regulatory, said
Dunn. The regulatory pathways and standards of evidence are the same,
added Bryan. Moreover, some therapeutic biological products are regu-
lated by CDER, said Dunn.
Drug−drug combinations are not considered a combination product,
but are referred to as fixed-combination prescription drugs for humans
and have a separate regulation. Each component must make a contribu-
tion to the overall effect, and there should be a compelling reason to use
a combination approach, said Dunn. He added that if all the criteria for a
combination product are met, there remain implications for study design.
For example, it is not usually sufficient to, in isolation, study the combi-
nation versus placebo in most circumstances or the combination versus
only one of the components; a factorial design is often needed, if feasi-
ble, unless the contribution of each component is otherwise established.
Bryan went on to say that if the combination involves two approved
products, either two drugs and/or biologics, it could be exempt from In-
vestigational New Drug regulations; however, if the two products are
investigational, the development program will have to demonstrate that
each component contributes to the safety and/or effectiveness of the
combination. The amount and the types of data needed and the study de-
sign will depend on the particular nature of the disease and the particular
combination being tested, he said.
When OCP determines that the primary mode of action of a multi-
modal product derives from a device, it is assigned to CDRH, although
as Peña noted, the centers engage in substantial cross-talk when a sub-
mission contains multiple components that cross the lines of responsibil-
ity of the respective centers. For combinations that include a drug or

biologic plus an unregulated intervention, such as a psychosocial inter-

vention, the usual standards of evidence apply to the drug or biologic
component, said Bryan: substantial evidence of effectiveness as well as
evidence that the drug is safe. However, different sections of the label
may be influenced, in particular the “indications and usage” statement
and the “clinical studies section.” Whether the psychosocial intervention
is specified in the indication statement may depend on the evidence of
safety and effectiveness of the drug in the absence of the psychosocial
intervention, as well as the overall benefit–risk assessment for the drug in
the absence of the other intervention. Ultimately it will depend on the
data provided. If data are unavailable or insufficient regarding effective-
ness of the drug in the absence of psychosocial intervention, it will de-
pend on the FDA’s level of concern about having these data before
putting the drug on the market, said Bryan.
PAYER PERSPECTIVES ON MULTIMODAL THERAPIES
When a therapy is approved by the FDA, many government plans

automatically allow that drug or that device to be covered under Medi-
care as well as under individual group plans and Medicaid, said
Robinson-Beale of Blue Cross Idaho. However, the largest insurers or
payers are not these governmental programs; they are private health
plans, which do not automatically approve coverage and which scrutinize
the evidence differently. The major dilemma for payers is that health
costs are intolerably high, said Robinson-Beale, and multimodal thera-
pies may contribute to escalating costs. She added that many other fac-
tors contribute to the rising cost of health care, including practice
variation, uninformed preferences, and supply and demand of new tech-
nologies. As a result, between 2000 and 2013, overall health insurance
costs increased 66 percent, while take-home pay increased by only about
3 percent. The dramatically increased cost of care also reflects the fact
that whereas 20 percent of the population used to drive 80 percent of
costs, today about 6 percent of the population drives 80 percent of costs.
The reason is that treatments have become exceptionally complex and
costly, not only in terms of specialty drugs, but combinations of specialty
drugs and gene therapy. Another factor contributing to high costs, said
Robinson-Beale, is excessive waste. Indeed, a report from the Institute of
Medicine suggested that one-third of health care spending may be exces-
sive and unnecessary (IOM, 2013). High health care costs are also driven

by the preponderance of off-label prescribing, particularly for behavioral

health indications, said Robinson-Beale.
These costs raise ethical issues as well, said Robinson-Beale, in that
the high cost of medical care is forcing difficult decisions to the forefront
for payers, providers, and patients. This has become particularly chal-
lenging in oncology. In neurology, the decisions differ in part because
the risk of mortality may be lower than in oncology, but the risk of life-
time disability may be very high. For example, the cost of treating de-
pression with TMS may be about $6,000 per month compared to about
$400 per month with a typical antidepressant, and combining the two
may cost even more. Payers therefore have to constantly readjust policies
to keep up with latest research and evidence available. Nonetheless,
Sarah H. Lisanby of NIMH said that in practice, many clinicians are now
delivering psychotherapy during the delivery of TMS because the patient
is there every day with the clinician. Although this may be more resource
efficient, whether payers will approve reimbursement will depend largely
on having reliable, measurable endpoints with good enough follow-up to
ensure that the investment is paying off, said Steven Pizer, associate pro-
fessor of health economics at Northeastern University and chief econo-
mist, health care financing and economics at the U.S. Department of
Veterans Affairs (VA).
Robinson-Beale said payers must make coverage determinations re-
garding what is medically necessary according to the generally accepted
standards of medical practice. The information they consider must in-
clude data from large randomized clinical trials, large observation stud-
ies, and practice guidelines from subspecialty societies, particularly those
based on formal consensus methodology. She noted that the clinical ap-
plication of a treatment should be clearly outlined in terms of identifying
the appropriate indications (e.g., illness, injury, or disease) as well as the
frequency, extent, site, and duration of treatment. In addition, for practice
guidelines, evidence should be sufficient that a clinician not familiar with
a particular treatment has a very clear outline of dosage, what to expect,
how to measure the treatment effect, and how to know when the treat-
ment is failing, said Robinson-Beale.
Also playing an increasingly important role for reimbursement deci-
sions are comparative effectiveness studies, in which a treatment is com-
pared not only to placebo, but also to what is called the standard of care.
Finally, payers want a demonstration that treatment effects are reproduc-
ible with fidelity, that they preserve life and functionality, and that they
do not cost more than an alternative intervention, Robinson-Beale added.

Robinson-Beale described the evidence that will be reviewed in

evaluating new technologies, including the number of people tested, the
outcomes observed, gradations of response, and the demographic details
of the responsive population. The transition from phenomenologically-
based diagnostic categories such as those embodied in the Diagnostic
and Statistical Manual, 5th Edition, to neurobiologically-based dimen-
sions promoted by the RDoC initiative, may further complicate these
assessments, she said, due to lack of standardization in how research
studies are conducted and reported. For multimodal therapies, she added
that clear indications for use are needed, including whether a step therapy
protocol should be used, when treatment starts with one drug before ini-
tiating treatment with the device or vice versa. If this approach is used,
evidence should also demonstrate that the combination of both is much
better than either alone.
Generating evidence of comparative effectiveness is currently part of
the European Medicines Agency (EMA), but not the FDA framework,
noted Karl Kieburtz. Dunn commented that comparative effectiveness
data can be challenging to interpret. However, Robinson-Beale said U.S.
payers will consider European data in their decision-making process. The
problem, she said, is that devices and drugs may not be comparable to
what is available in the United States. Pizer noted that another difference
between health care systems in the United States and national health sys-
tems in Europe is that rather than remaining within a single national sys-
tem, Americans typically change payers every few years as they change
jobs. Insurers in the United States thus have less incentive to invest in
something that might be costly in the short term, but will eventually re-
sult in cost savings. This is changing in the United States as federal and
state governments are paying a larger share of the total health care budg-
et, said Pizer.
Public payers manage costs differently than private payers do, said
Pizer, who is also the chief economist for PEPReC (Partnered Evidence-
Based Policy Resource Center), a new VA resource center made up pri-
marily of economists and health services researchers to forecast the de-
mand for care through timely, rigorous data analysis, and improve
connections between providers and researchers to get closer to the ideal
of a learning health care system. According to Pizer, the VA is in an unu-
sually good position to learn more about drugs and devices because it
comprises a large community of researchers as well as care providers.
Pharmacy services are centrally managed, with an evidence-based na-
tional formulary that can negotiate good prices for drugs. In comparison,

decisions about devices are made in a decentralized way, resulting in

reduced bargaining power. With regard to multimodal therapies, Pizer
said the incremental value from the combination will be of foremost im-
portance, which means that studies will have to be large enough to detect
an incremental benefit.
HARMONIZING EVIDENCE FOR PAYERS

AND REGULATORS
In both Europe and the United States, there is a push to generate an

evidence base that will serve three purposes—labeling, practice guide-
lines, and reimbursement—despite the fact that the criteria by which de-
cisions will be made in those three areas are very different, said Califf.
The label is the most fundamental source of information about a medical
product, he said, adding that the label should include evidence about the
population in which it is going to be used, including in multimodal ther-
apies. Moreover, the label and practice guidelines are complimentary
pieces of information, although the label is constrained by a high level of
evidence that is required, while the practice guidelines can reflect nu-
ance, filling in the gaps between knowledge and professional views of
how to put the information together, said Califf. Jeffrey Nye, vice presi-
dent of neuroscience innovation and scientific partnership strategy at
Janssen Research and Development, noted that a license from the FDA
does not assure widespread use in practices, and that other barriers, such
as restrictive reimbursement, may limit utilization.
According to Peña, some efforts have been made to bring the FDA
and the Centers for Medicare & Medicaid Services (CMS) together to try
to design studies that can address the needs of both agencies. Martha
Morrell noted that from the clinician’s standpoint, postmarket and open-
label data may be the most compelling and most representative of the
naturalistic environment. Other potential sources of data include elec-
tronic medical records and patient registries, noted Robinson-Beale. She
even suggested that a new governmental organization might be needed to
look at the both cost efficiency and effectiveness of treatments using
these and other sources of data.

5
Trial Designs to Establish Efficacy and Safety
in Multimodal Therapies
Highlights
• Developing and evaluating multimodal strategies to treat complex
diseases will require innovative strategies and the involvement of
multiple stakeholders (Lewis).
• Platform trials enable the evaluation of multiple treatments or
combinations of treatments (Lewis).
• Response-adaptive randomization and enrichment increases effi-
ciency by shifting trial resources to the most promising treatments
(Lewis).
• While methods for identifying dosing patterns and regimens are
well established for drugs, controlling the dose to determine what
does and does not work can be particularly challenging for
behavioral and neuromodulation interventions because of varia-
bility in how practitioners use scales and how devices are de-
ployed (Bikson, Lutz).
• For psychotherapy, measuring what is administered in the thera-
pist’s office will require novel methods such as video and/or
sensors that capture patient and therapist facial and body move-
ment and voice at a micro level or the internal state of the patient
(Kieburtz, Lisanby, Lutz).
participants.
37

Evaluating multimodal therapies for brain disorders is a complex

problem and likely to be slow, costly, and inefficient unless innovative
strategies are employed that directly address this complexity, said Roger
Lewis, senior medical scientist at Berry Consultants, LLC, and professor
and chair in the Department of Emergency Medicine at Harbor-UCLA
Medical Center. With the goal of delivering more effective treatments to
patients with complex diseases that require multimodal interventions,
challenges arise with regard to scaling research efforts to incentivize the
involvement of multiple vendors or stakeholders so that questions can be
asked about the interactions of multiple modes of interventions, such as
whether effects are additive or synergistic. As with other clinical trials,
failing early and efficiently is important so that resources are not wasted on
approaches that are unlikely to be successful, said Lewis. Therefore, he
proposed two intersecting strategies: platform trials and adaptive trials.
PLATFORM TRIALS AND ADAPTIVE TRIALS
Lewis defined a platform trial as an experimental infrastructure built

to efficiently evaluate multiple treatments or combinations of treatments,
either in a disease or group of diseases, that is intended to survive the
evaluation of any individual treatment. Efficiency derives from eliminat-
ing the need to repeatedly create and disable the clinical trial infrastruc-
ture as new treatments become available for testing (Berry et al., 2015).
It provides incentives for participation, teamwork, and the achievement
of scale, said Lewis, because costs⎯including the cost of the control
group⎯are shared across multiple stakeholders.
Fundamental to achieving efficiency in a platform trial is the concept
of adaptation as knowledge is gained, Lewis noted. Adaptive trials lever-
age the fact that partial information gained from patients enrolled early in
the trial can be used to make changes in the trial design in order to opti-
mize the search for treatments with the greatest promise for improving
outcomes. Lewis added that the technique of response-adaptive randomi-
zation enables modification of randomization proportions so that later
patients are preferentially shunted toward the arms, or combinations of
arms, that appear most effective. Randomization rules are prespecified to
minimize bias and errors, including false-positive and false-negative re-
sults.

TRIAL DESIGNS
D FOR EFFICACY
E AND
D SAFETY 39
FIGUR RE 5-1 Evolution of a platforrm trial over tiime. In the firsst stage of a pllat-
form trrial, interventio
ons are random
mized equally aamong a heteroogeneous popuula-
tion, sh
hown by the different
d coloreed figures. In tthe second stagge, shown in tthe
secondd column, unbalanced rando omization favoors the arms tthat appear moost
promising based on early
e data (BCC, AC, and C).. After assessinng these data, in
the thirrd stage arms with A are drropped and a ssubgroup (thosse in yellow) aare
also droopped becausee they do not ap ppear to benefiit from the treaatment.
SOURC CE: Presentatioon by Lewis, June
J 15, 2016.
Leewis illustrateed the evolutio on of a platfoorm trial over time, as show

wn
in Figu ure 5-1. In th
his illustration
n, three treatmments are tessted. In the first
group of patients, in a randomizeed equally to six arms: A, B,
nterventions are
C, ABB, BC, and AC C. Outcomes from the firsst cohort of paatients are ussed
to unbbalance the raandomization in the next sttage of testinng, emphasizinng
assignment to armss that appear most promisiing. In subseequent stages of
the triaal, an arm maay be droppeed if it appearrs ineffectivee (treatments A,
AC, an nd AB in the illustration). Other treatm ment arms couuld also be addd-
ed (noot shown in th he illustrationn). The modell also illustraates the conceept
of poppulation enricchment, anoth her adaptationn that enablees subgroups of
individduals to be drropped from the t study if thhey do not apppear to beneefit
from any
a of the treeatments und der investigatiion. Togetherr, adaptive raan-

domization and enrichment increase efficiency by shifting trial resources

to the most effective treatments and the populations most likely to benefit.
Adaptive randomization may also be based on intermediate end-
points, which is particularly important for neurological diseases, where
traditional endpoints such as survival or time to an event may require
long-duration trials. Lewis cited the example of the rare neuromuscular
disease GNE myopathy, which is characterized by slow, progressive
muscle weakness. Patients demonstrate a characteristic pattern of pro-
gression (Nishino et al., 2015) that, according to Lewis, could be trans-
lated into a quantitative endpoint, which might be used for adaptive
randomization.
Large factorial designs for multimodal therapies that involve differ-
ent therapeutic approaches such as behavioral therapies introduce addi-
tional complexity. For example, Figure 5-2 shows schematically the
number of arms (boxes) that could be required for a trial combining three
different drugs with three different therapies in three different population
subgroups. Spreading trial participants across so many arms could re-
quire huge sample sizes. However, Lewis described restricted factorial
designs that use external information to restrict the number of arms re-
quired. For example, if it is already known that certain drugs do not work
with certain therapies; those boxes could be eliminated. There are also
statistical approaches that incorporate clinical knowledge about the pa-
tient population and the effectiveness of therapies that can be used to
optimize the trial parameters.
Planning a complicated adaptive trial requires the use of simulations
to demonstrate the effects of adjusting trial parameters, including sample
size, effect size, dropouts, etc. These additional evaluations through sim-
ulation before a trial begins can be extensive, said Lewis, but will save
substantial time overall. More importantly, he said, these trials and the
simulations that are used in their design increase the likelihood of obtain-
ing a clear answer at the end. The worst thing that can happen in a large
clinical trial is to have made a substantial investment without learning
anything, such as whether the trial failed because the dose was wrong,
the duration too short, or the patient population inappropriate, noted
Lewis. He maintained that adaptive trials can be thought of as “right-
sized trials” that can also increase efficiency because failures from lack
of efficacy would be seen earlier, thus enabling sponsors to redirect re-
sources to other projects.

TRIAL DESIGNS
D FOR EFFICACY
E AND
D SAFETY 41
FIGUR RE 5-2 Buildin ng a platform trial for multiimodal therapyy. In a trial comm-
bining three drugs an
nd three differeent therapeuticc interventions in three popuula-
tion su
ubgroups, trial participants would
w have too spread over an unwieldy 48
arms, unless
u some waay of restrictingg the number oof arms was ideentified.
on by Lewis, June
J 15, 2016.
Addaptive trials are particulaarly valuable iin disease areeas where theere
w regard too defining thee parameters of
is a larrge degree off uncertainty with
the triaal, Lewis said
d. The adaptiv ve approach sspecifically adddresses unceer-
tainty by utilizing simulations overo the full range of unccertainty to dde-
terminne how well the trial willl perform unnder certain cconditions, annd
under which condittions the trial is less likely to perform w well.
Allthough adapttive randomizzation1 has bbeen endorsedd by regulators,
becausse of the noveelty of these approaches
a thhe analysis annd interpretation
of data emerging from f these sttudies will bee considered carefully onn a
case-by-case basis, according to o Dunn. The high-level isssue, he said, is
whetheer the submittter has tested d its hypothessis in a rigoroous manner thhat
resultss in interpretable data.
1
For additional
a inform
mation and exam
mples of adaptivee randomizationn see Kuehn (20006)
and Meuurer et al. (2012).

QUANTIFYING DOSE WITH NON-PHARMACOLOGIC

INTERVENTIONS
With any intervention, controlling the dose is essential to determin-

ing what does and does not work; however, this can be particularly chal-
lenging for behavioral and neuromodulation interventions because of
variability in how practitioners use scales and how devices are deployed,
according to Marom Bikson of the City University of New York.
Quantifying dose and determining the correct dose are two different
things, added Bikson. For both pharmaceuticals and neurostimulation,
the body transforms the dose into some level of activity. The response to
the dose can thus be used to adjust the dose to the appropriate level. Dos-
ing is further complicated by the fact that for some diseases, such as epi-
lepsy, doses are not generalizable, but must be individualized, said
Martha Morrell. Moreover, there is not a dose for everybody, and the
appropriate dose for a single individual changes depending on environ-
mental conditions, time of day, stress, stage of disease, etc. What is
needed, said Morrell, are dynamic markers that can be quantitated in real
time.
Quantifying Dose with Devices
With neuromodulation, the dose is defined by all parameters of the

stimulation device that affect the electric and current density fields gen-
erated in the body (Peterchev et al., 2012), that is, the position and elec-
trical properties of the electrode/coil (waveform), repetition frequency,
train duration, interval, and number of sessions, said Bikson. The result
is current flow in the body, which produces physiologic changes that can
be measured as clinical outcomes; however, the response itself is not the
dose, but can be used to adjust the dose, for example, by moving
the placement of the coil or dialing back on the intensity. Thus, because
placement of the coil or electrode is one of the parameters that deter-
mines dose, two people getting DBS with the same delivery platform, for
example, may be getting very different doses. Bikson compared this to
changing the chemical composition of a drug, such that two tablets can
provide very different doses and have different effects. Moreover, be-
cause of individual variations in the body, as with pharmaceuticals, what
shows up at the target tissue may be very different despite delivery of the
same dose, said Bikson. The dose is defined by parameters that can be

TRIAL DESIGNS FOR EFFICACY AND SAFETY 43
controlled by the operator, but outcomes relate to what actually shows up

at the target.
Quantifying Dose with Psychosocial Interventions
Standardizing and quantifying how psychosocial interventions are

delivered and measured is particularly challenging, said Karl Kieburtz. In
psychotherapy, for example, dose is usually defined by the number of
sessions and the duration of treatment, said Wolfgang Lutz from the
University of Trier in Germany. Based on a meta-analysis of 15 studies
comprising more than 2,400 patients, Howard and colleagues (1986)
proposed a dose−response model in 1986 that linked the number of ses-
sions to improvement in symptoms. This and subsequent studies have
indicated a log-linear dose−response relationship over the course of
treatment; that is, a dose−response curve that shows diminishing effec-
tiveness of treatment over time (Stulz et al., 2013). Another model,
called the “good enough model,” proposes that clients stay in treatment
until they believe they have a good enough level of improvement (Bark-
ham et al., 2006). All of these studies define dose as number of sessions,
said Lutz.
Lutz added that within the field, there is debate about whether psy-
chometric feedback over the course of treatment might provide addition-
al information about treatment response that could lead to more
optimized and personalized dosing strategies. This has led to the devel-
opment of treatment prediction, selection, and adaptation tools
(DeRubeis et al., 2014; Lutz et al., 2014; Rubel et al., 2015). However,
he has also shown that the receptiveness of the therapist to feedback de-
termines, in part, the likelihood of a positive response to the therapy
(Lutz et al., 2015). Furthermore, Lutz said most treatment decisions are
determined by how many sessions an insurer will cover rather than by
empirical methods, and he suggested that dose is a neglected area of re-
search in psychosocial interventions.
Payers are especially interested in determining the number of ses-
sions needed for psychotherapy. However, according to Rhonda
Robinson-Beale, studies are typically based on a protocol rather than on
the natural trajectory of the illness. Another problem related to dose in
psychotherapy, said Robinson-Beale, is that training varies from disci-
pline to discipline and from one therapist to the next, and rarely involves
the use of feedback and validated tools. Providing feedback to the practi-
tioner and patient, such as by assessing and reporting global distress,

may provide a feedback loop to better identify the appropriate number of

sessions, she said.
ASSESSING RESPONSE TO INTERVENTIONS
Regardless of how the dose of neuromodulation is measured, the ef-

fect of the intervention is determined not just by what is administered,
but by the brain’s response to it, and this requires measurement of both
the neurophysiological effects of the intervention (e.g., through EEG or
functional magnetic resonance imaging), the effects on the function of
the neural circuit that was targeted (e.g., working memory performance),
and the patient’s subjectively reported symptoms (e.g., depression rating
scales), said Lisanby. She added that while there are limitations to self-
report scales, subjective assessments of symptoms are also used to make
a diagnosis. For neurostimulation, the most valuable markers, particular-
ly for interventions that are delivered over a long period of time, are
those that precede a clinical signal, said Bikson, such as intracranial epi-
leptiform activity in epilepsy. Lisanby cited the need to identify short-
term markers that are objective and quantifiable, and that could predict
long-term change in a complex behavioral disorder such as depression or
pain. Bikson concurred, noting that there is a strong precedent in the neu-
romodulation field for using adaptation and monitoring. For example, a
single-session measure that indicates how responsive a patient might be
to TMS could dramatically increase the ability to adjust dose.
In the psychotherapy area, what is actually administered in the thera-
pist’s office is not typically measured, said Lisanby. There is potential to
rectify this by using sensors that assess social, auditory, and nonverbal
interactions between therapist and patient, she said. Lutz’s group is in-
vestigating using video recording to capture movements and interactions
between therapist and patient at a micro level. Kieburtz added that it
might also be helpful to measure objectively the subject’s internal state at
the time a therapy is administered by measuring galvanic skin response
or EEG, for example. Although these measures might interfere with psy-
chosocial interventions, Lisanby noted that sensors are available to
measure facial expression, facial intonation, the verbal content of speech,
and other responses that reflect the social context and psychological state
might be measured less intrusively. This is analogous, she said, to the
measures used during multimodal therapy involving cognitive training in
combination with brain stimulation, described earlier in the workshop by

TRIAL DESIGNS FOR EFFICACY AND SAFETY 45
Luber, where reaction time, accuracy, and other variables are quantified
and these data are used in an iterative feedback fashion to adjust the
training. These measures represent a behavioral readout of neural cir-
cuits, and may also provide some information about the biological ori-
gins of the psychological state, said Lisanby. The complexities associated
with obtaining reliable and objective measures of treatment response fur-
ther highlight the challenge in studying and assessing the efficacy of mul-
timodal therapies that include a psychosocial intervention component.


6
Developing Multimodal Therapies: Practical
Considerations Relating to Industry
Highlights
• Even when a multimodal or other innovative therapy provides
increased value, barriers exist with regard to adoption, use, and
reimbursement (Nye).
• Altering practice patterns among physicians will require increased
data regarding comparative benefits to existing treatments,
education, and new business models (Lisanby, Nye).
• An implanted device for intrathecal infusion of pain medication
has been used to treat chronic pain for more than 20 years, and this
device may also be useful for other indications. Lessons learned
during this period may inform future multimodal therapy
development and include careful consideration of drug and device
compatibility and implementing dosing schedules that increase
efficacy while reducing risk (Hildebrand).
• The development of novel multimodal treatments for diseases,
such as PD, may require complex partnerships involving multiple
companies, countries, and therapeutic modes (Mohr, Shaffer).
participants.
While bringing multimodal therapies forward to the market presents

substantial challenges for industry, some companies have already success-
fully taken on this challenge, and others are creating new models for
bringing partners together into symbiotic relationships, said Christopher
47

Shaffer, associate research fellow at Pfizer Inc. Shaffer participated in a

panel of industry representatives that discussed the challenges related to
developing multimodal therapies and provided examples of how
corporate partners are working together to advance such therapies to the
marketplace.
INTEGRATING THERAPEUTIC DEVICES

INTO PSYCHIATRY
According to Jeffrey Nye, barriers exist with regard to adoption, use,

and reimbursement of innovative therapies, even when they provide
increased therapeutic value. For example, an estimated 35 percent of
patients with depression are resistant to treatment, many of them
refractory to two or more medicines. TMS has thus been proposed as an
alternative. This was discussed at great length at another Forum on
Neuroscience and Nervous Systems Disorders workshop in March 2015
(NASEM, 2015). In a recent meta-analysis of 32 trials evaluating the
efficacy of selective serotonin reuptake inhibitors (SSRIs), the effect size
for all SSRIs ranged from 0.02 to 0.53, with a median of 0.24
(Hieronymus et al., 2016). In contrast, said Nye, in studies of patients
with depression who have failed at least one and up to four
antidepressants, the effect size of TMS ranged from 0.29 to 0.76, with a
mean of 0.53. Despite the superiority of TMS in treating depression, the
market uptake has been much slower than for antidepressants.
The reasons for limited market uptake include psychiatric practice
patterns, patient burden, high cost and low levels of reimbursement by
payers, and limited evidence of the comparative effectiveness of TMS to
pharmacotherapy, said Nye. Psychiatrists resist the implementation of
TMS in their practices in part because to do so would require additional
expensive equipment, space, and personnel. Moreover, they are not
convinced of its benefits and have concerns about potential risks. For
patients, the fact that a full course of TMS therapy requires more than 20
sessions of treatment imposes substantial time constraints, and the
slowness of response to therapy sometimes leads to discontinuation.
Although insurance coverage has improved in recent years, co-pays can
make TMS unaffordable for many patients. As noted by Rhonda
Robinson-Beale in Chapter 4, payers may favor pharmacotherapy
because the cost is much lower than TMS. Furthermore, Nye explained
that despite the seeming superiority of TMS over pharmacotherapy in

PRACTICAL CONSIDERATIONS RELATING TO INDUSTRY 49
terms of effect size, as noted above, there have been few or no head-to-
head studies comparing the different devices available; TMS versus
adjunctive pharmacotherapy; or multimodality therapies combining TMS
with pharmacotherapy or psychotherapy versus standard of care. Studies
about the durability of such treatments are also limited. Such evidence is
needed, said Nye, not only for the FDA, but also for payers, professional
societies, physicians, and patients.
Education of physicians—not just psychiatrists but neurologists and
pain specialists as well—will also be needed to alter practice patterns,
said Nye. Alternative providers such as TMS treatment centers, as well
as less expensive, mobile devices that require less medical supervision,
could also dramatically influence usage and uptake. Sarah Lisanby added
that another factor affecting uptake of TMS is increased competition
from device manufacturers, and she cited the need for new business
models that make financial sense for clinical programs.
TARGETED DRUG DELIVERY: INTRATHECAL INFUSION

THERAPY FOR CHRONIC PAIN
Medtronic introduced a combination product to treat chronic pain

more than 20 years ago, according to Keith Hildebrand. The approach
fits into the category of cross-labeled products, as discussed by Patricia
Love earlier. Medtronic sells the drug-delivery device, and two FDA-
approved monotherapies have been cross-labeled to be used with the
pump: Infumorph, a branded form of morphine, and Prialt, a branded
form of ziconotide. The device allows high concentrations of drugs to be
delivered directly to the CNS, and a physician can regulate delivery of
drugs according to flexible dosing patterns as needed by the patient. The
pump is refillable via a syringe and hypodermic needle, and can remain
implanted for up to 7 years.
Hildebrand said that since the device was introduced, the company
has made design changes to address cost and several complications,
including unpredictable episodes of pain, local toxicity at the catheter tip,
drug interactions when multiple drugs are delivered by the pump, drug
incompatibility with the pump components, tolerance to the drugs, and
invasiveness. Modification of this therapy to patient needs included
development of a patient-controlled device that allows patients to deliver
an extra bolus of morphine when experiencing breakthrough pain. This
feature gives patients control and increases their engagement in their

care, both of which can benefit patients, said Hildebrand. He noted that
both physician education and understanding the mechanisms underlying
complications such as catheter-tip granulomas are needed to ensure the
devices are used properly (Yaksh et al., 2002). For example, rather
than increasing the morphine dose in response to increased pain
and neurologic symptoms, using the minimum dose at the lowest
concentration possible may mitigate this problem.
Hildebrand said the key to expanding the use of such a delivery
system is to understand the underlying drug mechanisms. For example,
Medtronic investigated the potential for using a combination of clonidine
and morphine for the treatment of intractable pain (Hildebrand et al.,
2003), and stumbled on a side effect with potential therapeutic benefit:
lower blood pressure due to activation of alpha2 adrenoceptors on
presynaptic sympathetic fibers in the lateral horn of the spinal cord. They
are now investigating whether this side effect could be turned into a
therapeutic effect for hypertensive patients (Komanski et al., 2015).
A MULTINATIONAL COLLABORATION TO DEVELOP A

MULTIMODAL THERAPY
A different model of collaboration among industry partners—one

that brought together a big pharmaceutical company and a small
company developing a novel protein-device combination therapy—was
presented by Erich Mohr, chairman and chief executive officer of
MedGenesis Therapeutix, Inc., and Christopher Shaffer from Pfizer Inc.
The complex story started in 1994, Mohr said, when Amgen acquired the
patent for glial cell line–derived neurotrophic factor (GDNF) as part of
its purchase of the biotechnology company Synergen. GDNF is a
naturally occurring protein found in the brain that enhances the survival
of mid-brain dopaminergic neurons, and thus was hypothesized to be
effective for the treatment of PD (Lin et al., 1993). Furthermore, the
dorsal putamen is the brain region with the greatest dopamine depletion
in PD. Following promising preclinical studies (Gash et al., 1998), a
Phase I study in 2005 showed marked improvement in five patients who
received continual GDNF intraputamenal infusion for 2 years (Patel et
al., 2005). However, Phase II double-blind, placebo-controlled studies by
Amgen failed to show efficacy and demonstrated adverse events.
Mohr’s team at MedGenesis, along with partners at the University of
California, San Francisco, and the University of Bristol, hypothesized

PRACTICAL CONSIDERATIONS RELATING TO INDUSTRY 51
that the failure to optimally deliver adequate GDNF quantities to the

intended target resulted in the negative Phase II trial. They proposed
using a technique called intermittent convection-enhanced delivery
(CED) to bypass the blood−brain barrier and deliver GDNF directly to
the putamen (Gimenez et al., 2011). In December 2009, MedGenesis
licensed GDNF from Amgen, and subsequently launched two Phase II
studies of the treatment in 2012 and entered into an agreement with
Pfizer Inc. granting it an exclusive option to license GDNF in 2014. Both
the necessary preclinical and clinical efforts were variously supported by
MJFF, Parkinson’s UK, The Cure Parkinson’s Trust, as well as the
Deutsche Parkinson Vereinigung in Germany. The trials were conducted
at the North Bristol National Health Service (NHS) Trust, which also
functioned as the sponsor of this investigator-initiated program. For
patients enrolled in the trials, the CED device was stereotactically
implanted using robot-assisted surgery, with a skull-mounted multiaccess
port hidden behind the ear. Once per month, patients undergo an infusion
lasting approximately 90 minutes administered via a programmable
pump.
Shaffer said these trials represent multinational partnerships. Four
players from three countries are involved: MedGenesis (Victoria, British
Columbia, Canada), the drug manufacturer and the commercial owner of
the clinical data North Bristol NHS Trust (Bristol, United Kingdom), the
regulatory sponsor and academic owner of the clinical data; Renishaw
plc (Bristol, United Kingdom), manufacturer of the device on behalf of
the North Bristol Trust; and Pfizer Inc., which has collaborative research
agreements with both MedGenesis and Renishaw. The program is
overseen by a joint steering committee, equally weighted with
MedGenesis and Pfizer colleagues. Pfizer’s global infrastructure enabled
the group to establish advisory boards in Europe, Japan, and North
America. Although this is indeed a complex partnership, additional
complexity might be introduced if partners end up being competitors,
suggested Karl Kieburtz.
The results from the double-blind, placebo-controlled study,
announced just 3 weeks after the workshop, showed no statistically
significant effect on the primary outcome measure.1 Mohr said that
additional analyses are ongoing and may yet lead to more promising
conclusions. Even before the outcome of the trial was known, he added,
the study had demonstrated success in delivering a compound to where it
1
For additional information see news announcement from July 7, 2016, at http://
www.medgenesis.com/news.htm (accessed August 30, 2016).

belongs, and may open the door to other compounds and trials for other
illnesses for which localized delivery is essential, such as glioblastoma
and Huntington’s disease. Walter Koroshetz, director of the National
Institute of Neurological Disorders and Stroke (NINDS), added another
twist to the potential for CED: viral delivery of compounds or biologics,
including gene therapy.
Several workshop participants note that the GDNF−CED example
demonstrates a number of common issues related to the development of
multimodal therapies that present challenges to companies working in
isolation, or even to small companies with limited resources. In
particular, understanding the underlying biology of the combination and
effective collaborations between device and drug companies and
clinicians are integral to successful development and implementation of
multimodal therapies. In addition, Stevin Zorn noted that compounds
such as GDNF could have remained buried had it not been for the
determination of individuals who believed in the product.
Brian Fiske suggested that, with respect to GDNF and possibly other
treatments, there may also be a need for combinations of drugs to be
given together, for example, to make growth factor uptake more robust.
Hendrix suggested that one path forward for a company with an asset
that might be useful in combination with something else could be to find
a biotech company or other partner to bring the combination forward.

7
Role of Research Funders in Multimodal
Therapy Development
Highlights
• Government and charitable funding agencies can play an im-
portant role in filling the gaps that may exist in the development of
multimodal therapies (Califf).
• NIH has numerous translational funding opportunities to fill the
gaps at different stages of therapy development (Tamiz).
• The VA is particularly interested in funding multimodal therapy
research for traumatic brain injury, a complex injury with comor-
bidities that result in a range of symptoms requiring different types
of treatment (Hoffman).
• Foundations, including ones that focus on complex diseases such
as Alzheimer’s and Parkinson’s, can advance the development of
multimodal therapies through targeted research funding, conven-
ing experts across stakeholder groups, providing funds for clinical
trial infrastructure, and promoting data sharing (Fiske, Hendrix).
participants.
As demonstrated in the previous chapter and mentioned by FDA

commissioner Robert Califf and others, governmental and charitable
funding agencies play an important role in filling the gaps that may exist
with respect to industry investment in developing novel multimodal in-
terventions. For example, Karl Kieburtz suggested that third party invest-
ments might help mitigate the risk of partnerships among competitors, and
Erich Mohr commented that peer-reviewed funding adds essential credibil-
53

ity to risky projects, such as the GDNF−CED project discussed in the previ-
ous chapter.
Califf suggested another example of how a neutral third party can
help facilitate progress: by providing funding for a study that industry
partners have no commercial incentive to pursue. Califf described a
head-to-head trial of two interventions—one a drug and the other a
device—for congestive heart failure (Bardy et al., 2005). Neither of the
manufacturers was motivated to do the trial, but the field was driven to
make it happen, so NIH put up foundational money to help the industry
participate. The answer was clear when the trial was completed: The de-
vice was superior. This led not only to an update of the label by the FDA,
but also the reimbursement policy of CMS, said Califf.
Partnerships among potential competitors may be easier to achieve
when the partners have overlapping goals or synergistic components to
offer, noted Christopher Shaffer. Brian Fiske agreed, noting that MJFF
routinely brings competitors together in precompetitive space for a varie-
ty of purposes related to PD therapy development, including fundamental
research to understand the biology of a target, and building infrastruc-
ture, including patient registries, to increase the efficiency of clinical tri-
als. Another area where funding agencies—both public and private—
may facilitate progress is by bringing industry partners together to con-
tribute compounds for repurposing, which have passed through safety end-
points in Phase II, but failed for the intended indication, said Stevin Zorn.
ROLE OF RESEARCH AGENCIES IN DE-RISKING

MULTIMODAL THERAPY DEVELOPMENT
The NIH Blueprint for Neuroscience Research is a cooperative effort

across 15 NIH centers and institutes to support discovery and develop-
ment of therapeutics to combat nervous system disorders and conditions
through grants, contract resources, and expert consultants. The Blueprint
Neurotherapeutics Network is specifically designed to help investigators
translate knowledge into products that could benefit patients, according
to Amir Tamiz. For example, the Blueprint network is among several
funding streams that enable NINDS to focus funding at the early stages
of drug discovery and development with strong scientific rational, rigor-
ously designed studies, and transparent reporting in order to move pro-
jects to a stage where they can be handed off to industry and nonprofits,

RESEARCH FUNDERS IN MULTIMODAL THERAPY DEVELOPMENT 55
who may have the resources to conduct clinical trials and bring products
to commercialization.
Tamiz provided two examples of projects that NINDS is funding that
combine therapies as a way of achieving greater effects. In the first,
Karen Aboody, professor of developmental and stem cell biology at the
City of Hope, is using neural stem cells (NSCs) as a delivery vehicle to
target tumor cells in the brain with anticancer agents. She has engineered
the NSCs to express an enzyme that converts the nontoxic prodrug 5-
fluorocytosine to the active chemotherapeutic 5-fluorouracil (Aboody et
al., 2013). Her preclinical work has led to approval of a first-in-human
study of NSC-mediated enzyme/prodrug targeted cancer therapy in pa-
tients with recurrent glioblastoma.
The second example combines a catheter-based intervention for
brain aneurysm—one of two currently approved treatment options for
aneurysms—with a bioactive compound that will stabilize the clot to re-
duce the rate of recurrence. Tamiz said this project benefitted from a
Small Business Innovation Research grant. This is just one of several
translational funding mechanisms available through NIH (see Figure 7-1).
Of particular interest for early discovery efforts are the IGNITE (Innova-
tion Grants to Nurture Initial Translational Efforts), CREATE (Coopera-
tive Research to Enable and Advance Translational Enterprises), and
Blueprint Neurotherapeutics (BPN) programs. CREATE is further split
into two programs, one for therapeutic devices (CREATE Device) and
the other for biotechnology products and biologics (CREATE Bio). Un-
der the auspices of BPN, NIH has also established robust contracts with-
in the United States to provide investigators with medicinal chemistry,
pharmacokinetic and toxicology, data management, manufacturing and
formulation, and clinical trials resources, added Tamiz.
Multimodal treatment research is also funded and conducted by other
government agencies, such as the Department of Defense (DoD) and the
Veterans Health Administration (VHA). Indeed, said Stuart Hoffman,
senior scientific advisor for brain injury in the VHA Office of Research
and Development, multimodal approaches are often necessary because a
condition such as TBI has multiple consequences, including cognitive
disability, psychological and behavioral disorders, sensory dysfunction,
and pain; such a condition is typically accompanied by other visceral and
orthopedic injuries. Since 2000, nearly 350,000 service members from
the recent wars in Iraq and Afghanistan have been diagnosed with TBI
(DVBIC, 2016). Most of these cases are mild, but in some people may
result in persistent postconcussional symptoms often accompanied by

56 MULT
TIMODAL THER
RAPIES FOR BR
RAIN DISORDE
ERS
FIGUR RE 7-1 Transllation funding opportunities at NIH. The agency offerss a

numberr of translation pportunities at different stagees of therapy dde-
nal funding op
ment, ranging frrom discovery to small cliniccal trials.
velopm
NOTE: SBIR = smaall business in nnovation reseearch; STTR = small busineess
technollogy transfer.
SOURC CE: Presentatio on by Tamiz, June
J 15, 2016.
comorrbidities, such h as posttraumatic stress disorder, andd chronic paiin,

said Hoffman
H (see Figure 2-2). In addition, he noted thatt recent studiies
have identified
i lon
ng-term chro onic degeneraation and infflammatory rre-
sponsees in the brain ns of service members annd veterans exxposed to blaast.
Sarah Lisanby com mmented that collaborationn across discciplines, incluud-
ing neeuropsychiatry y, will be neeeded to studyy the full spectrum of manni-
festatio
ons of brain injury. Reco ognizing this,, in 2012 Prresident Obam ma
issued an Executive Order callin ng for impro ved access too mental heallth
servicees for veteranns, service meembers, and m military famiilies and the ees-
tablish
hment of a National
N Reseearch Action Plan coordinnated by DoD,
VA, an nd Departmen nts of Health and Human S Services and E Education.
Stuuart Hoffman n, senior scien
ntific advisorr for brain injjury at the V
VA,
co-chaairs the steering committeee for a large VA and DoD D clinical study
on the chronic effeccts of TBI. The
T study is m made possiblee because of tthe
integraation of reseaarch and care within the VVA health systtem, and acceess

to data housed in the Federal Interagency TBI Research informatics sys-

tem (FITBIR). The VA also created the Million Veteran Program (MVP)
in 2012 to advance genomic research and bring precision medicine to
veterans. Now partnered with the federal government’s Precision Medi-
cine Initiative, MVP already has nearly 500,000 veterans. Other partner-
ships, including with industry, are also planned through the VA Center
for Innovation, said Hoffman.
ROLE OF DISEASE-SPECIFIC FUNDING IN MULTIMODAL

THERAPY DEVELOPMENT
The Alzheimer’s Association and MJFF exemplify how disease-

specific organizations can advance the development of multimodal ther-
apies through targeted research funding. According to James Hendrix,
the Alzheimer’s Association currently funds more than $80 million for
300 active projects in 20 countries worldwide. MJFF is the largest non-
profit funder of Parkinson’s research, last year providing more than $87
million globally to research programs, said Brian Fiske.
One of the multimodal intervention programs funded by the Alz-
heimer’s Association—the Finnish Geriatric Intervention Study to Pre-
vent Cognitive Impairment and Disability (FINGER)—investigated
whether a combination of lifestyle interventions, including exercise, diet,
social engagement, and cognitive training, could slow cognitive decline
among non-demented older individuals. Results from this 2-year ran-
domized controlled trial study published in 2015 suggested that the mul-
tidomain intervention improved or maintained cognitive functioning in
at-risk elderly (Ngandu et al., 2015). The Alzheimer’s Association fol-
lowed this by publishing a summary of evidence collected in many pre-
vention studies, concluding that strong evidence indicates that physical
exercise and management of cardiovascular risk factors reduce the risk of
cognitive decline and may reduce the risk of dementia, and that healthy
diet and lifelong learning or cognitive training may also reduce the risk
of cognitive decline. However, the study also noted many unanswered
questions and called for more research in the area of prevention (Baumgart
et al., 2015).
Other combinatorial approaches that target multiple symptoms are
being investigated for the treatment of PD, said Fiske. This is essential,
he said, because there is much more to PD than motor symptoms, includ-
ing the possibility of cognitive impairment, autonomic dysfunction, sleep

dysregulation, and pain. Indeed, sleep disturbances are common to many

neurological and psychiatric diseases, such as depression and TBI, said
Lisanby and Hoffman.
Potentially more promising for both AD and PD would be combina-
tions that target multiple disease mechanisms. For example, protein mis-
folding and dysfunction in how proteins are trafficked and cleared,
neuroinflammation, mitochondrial dysfunction, oxidative stress, and oth-
er aging pathways have all been implicated in both diseases and may
need to be targeted in combination. Fiske noted, however, that many
questions remain about the role of these pathways in PD; for example, do
they represent distinct forms of the disease with a similar clinical pheno-
type or are all these pathways converging on the same process? Should
combinations target multiple mechanisms or multiple points along one
mechanistic pathway? Kieburtz asked another question: Do these phe-
nomena coexist with the disease or are they core features? Answers to
these questions will be needed to build a rationale or argument for any
type of combination therapy, said Fiske.
In addition to funding studies, another way disease-focused organiza-
tions can help advance the development of multimodal therapies is by
convening experts to push things forward. For example, as described in
Chapter 3, in 2015 the Alzheimer’s Association convened a workshop
with experts from academia and industry to recommend a path forward
for drug−drug combination therapies to treat AD (Hendrix et al., 2016).
They followed this with a new grant mechanism, Alzheimer’s Combina-
tion Therapy Opportunities (ACTO), which will provide up to $2 million
for a clinical trial testing repurposed drug combinations that target multi-
ple biological mechanisms through Phase II proof of concept. Hendrix
said another recent meeting of the Alzheimer’s Association’s Research
Roundtable focused on neuropsychiatric symptoms associated with AD,
in recognition that AD is more than a disease of cognition and that treat-
ments are needed for these other disabling symptoms. Hendrix noted that
one of the strengths of the Research Roundtable is that it brings companies
together in precompetitive space to advance drug development.
Disease-focused foundations can also expedite drug development by
building trial infrastructure such as platform and adaptive trials and reg-
istries that provide access to patients, said Fiske. He said MJFF supports
cohort development that enables the collection of clinical and biological

data from large numbers of patients with PD and that can also be used to
validate biomarkers1 and other outcome measures.
The Alzheimer’s Association and MJFF have also led the field in
promoting data sharing among academic and industry researchers. For
example, Hendrix said that a workgroup convened after a Research
Roundtable on Amyloid-Related Imaging Abnormalities (ARIA)—a rare
side effect of treatment with antiamyloid antibodies—convinced five or
six companies to share their data. The workgroup subsequently issued
recommendations for monitoring ARIA in clinical trials (Sperling et al.,
2011). Meanwhile, MJFF has brought a number of companies together to
address potential safety issues associated with inhibitors of the LRRK2
gene. They have been remarkably willing to contribute information and
data, said Fiske. The key is to find the right common ground.
1
Additional information on biomarkers and their importance for therapeutic develop-
ment for specific disorders can be found at: https://www.michaeljfox.org/research/
priority-area-detail.php?biomarkers (accessed October 24, 2016); and http://www.
alz.org/research/funding/global_biomarker_consortium.asp (accessed October 24, 2016).


A
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B
Workshop Agenda
Multimodal Therapies for Brain Disorders: A Workshop
June 14-15, 2016
Keck Center
500 Fifth Street, NW | Room 100
Washington, DC 20001
Background: Multimodal therapy approaches (i.e., combinations of in-

terventions aimed at different aspects of a disease) are emerging
as potential ways to enhance clinical outcomes for patients with
psychiatric and neurological disorders. This could include, for example,
concomitant prescription of a drug along with a device, biologic, or
behavioral/psychosocial intervention (including, e.g., cognitive remedia-
tion, lifestyle adjustment, dietary intervention, or animate therapy). An-
other example would be the simultaneous use of a neuromodulation
device during performance of a specific neurocognitive task. While such
a multimodal approach is consistent with the common clinical practice of
combining interventions, there are important questions regarding how
these interventions interact (in terms of additive, subtractive, or synergis-
tic therapeutic as well as adverse effects), how they should be used, in
what subsets of patients, and in what amounts or for what period of time.
Further discussion is needed about methodologies for determining effica-
cy and safety in multimodal therapies compared with monotherapies and
for comparing across multiple types of multimodal therapy. Multimodal
therapy approaches also raise a number of important regulatory issues,
both regarding combinations of regulated products (e.g., drug plus de-
67

vice) and approaches in which only one product is regulated (e.g.,

drug/device plus psychosocial intervention). Related questions arise for
reimbursement, for example, would payers only pay for care if it includes
both drugs and psychotherapy if that is what the data show is effective?
This workshop, hosted by the Forum on Neuroscience and Nervous
System Disorders, will bring together key stakeholders to examine scien-
tific, clinical, regulatory, and reimbursement issues related to multimodal
approaches and identify potential opportunities to enhance clinical out-
comes for individuals with psychiatric and neurological disorders. Rather
than delving deeply into specific interventions, the workshop will aim to
examine general principles, barriers, and potential solutions and opportu-
nities that may apply across multimodal therapy development for brain
disorders.
Meeting Objectives:
• Explore recent advances in the development of multimodal ther-

apeutic approaches for psychiatric and neurological disorders
and approaches to using these therapies (e.g., earlier versus later
in disease progression), and discuss future research needs to fur-
ther advance understanding 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, or areas in which mono-modal approaches have
been insufficiently effective).
• Discuss methodologies for establishing efficacy and safety for
multimodal therapies compared to monotherapies, including
clinical trials 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 potential op-
portunities 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., cardiolo-
gy, diabetes, cancer).

APPENDIX B 69
DAY ONE: June 14, 2016
1:30 p.m. Opening Remarks and Discussion of Definitions

KARL KIEBURTZ, Workshop Co-Chair
Robert J. Joynt Professor in Neurology
Senior Associate Dean for Clinical Research
Director of the Clinical & Translational Science Institute
University of Rochester Medical Center
SARAH H. LISANBY, Workshop Co-Chair

Director, Division of Translational Research
National Institute of Mental Health
National Institutes of Health
SESSION I: STATE-OF-THE-SCIENCE IN MULTIMODAL

THERAPIES FOR BRAIN DISORDERS
Session Objectives:
• Explore examples of recent advances in the development of
multimodal therapeutic approaches for brain disorders and
approaches to using these therapies.
• Discuss future research needs to further advance understanding
of these approaches.
• Highlight disease areas in which a multimodal approach could be
particularly useful.
1:50 p.m. Overview and Session Objectives

TIMOTHY STRAUMAN, Session Co-Moderator
Professor of Psychology and Neuroscience
Duke University
KEITH HILDEBRAND, Session Co-Moderator

Senior Principal Scientist, Technical Fellow
Neuromodulation
Medtronic, Inc.
2:00 p.m. Part A: Two Pharmacological Interventions Approved as

a Co-Delivery
Drug/Drug and Drug/Biologic Combinations for
Alzheimer’s Disease
JAMES HENDRIX
Director, Global Science Initiatives, Medical and
Scientific Relations
Alzheimer’s Association
2:10 p.m. Part B: Concomitant Prescription of Two Interventions

with Different Modalities
Drug−Device Combinations for Epilepsy
MARTHA MORRELL
Chief Medical Officer, NeuroPace
Clinical Professor of Neurology and, by courtesy,
Neurosurgery
Stanford University
Combining Drugs and Psychosocial Interventions in
Adolescents with Bipolar Disorder
KIKI CHANG (via WebEx)
Professor of Psychiatry and Behavioral Sciences
Stanford University Medical Center
2:30 p.m. Part C: Simultaneous Use of Two Modalities in a Single

Procedure
Combining Devices with Cognitive Enhancement
BRUCE LUBER
Staff Scientist
Experimental Therapeutics & Pathophysiology Branch
Individually Targeted Combination of Transcranial
Magnetic Stimulation and a Psychosocial Intervention
TIMOTHY STRAUMAN
Professor of Psychology and Neuroscience
Duke University
2:50 p.m. Discussion Among Speakers and Workshop Participants
3:30 p.m. BREAK

APPENDIX B 71
SESSION II: REGULATORY AND REIMBURSEMENT

CONSIDERATIONS
Session Objectives:
• Consider regulatory and reimbursement issues for multimodal
therapies, including for approaches in which two components are
regulated (e.g., drug plus device) and approaches in which only one
component is regulated (e.g., drug plus psychosocial intervention).
• Explore evidentiary standards needed for regulation and
reimbursement, and consider how different approval pathways and
evidentiary standards across FDA centers impact multimodal
approaches.
• Discuss potential opportunities for addressing challenges.
3:45 p.m. Session Overview and Objectives

SARAH H. LISANBY, Session Moderator
Director, Division of Translational Research
3:55 p.m. Part A: Regulatory Considerations

Combination Products at the Food and Drug Administration
PATRICIA LOVE
Deputy Director, Office of Combination Products
Food and Drug Administration
Evaluating Multimodal Products at the Center for Drug
Evaluation and Research
BILLY DUNN
Director, Division of Neurology Products
Office of Drug Evaluation I
Center for Drug Evaluation and Research
Evaluating Multimodal Products at the Center for Devices
and Radiological Health
CARLOS PEÑA
Director, Division of Neurological and Physical
Medicine Devices
Office of Device Evaluation
Center for Devices and Radiological Health

Evaluating Multimodal Products at the Center for Biologics

Evaluation and Research
WILSON BRYAN
Director, Division of Clinical Evaluation &
Pharmacology/Toxicology
Office of Cellular, Tissue, and Gene Therapies
Center for Biologics Evaluation and Research
4:35 p.m. Part B: Payer Considerations

Private Payer Considerations
RHONDA ROBINSON-BEALE
Senior Vice President and Chief Medical Officer
Blue Cross of Idaho
Perspectives from a Government Payer
STEVEN PIZER
Associate Professor of Health Economics
Department of Pharmacy and Health Systems Sciences
Northeastern University
and Chief Economist, Health Care Financing &
Economics
U.S. Department of Veterans Affairs
5:30 p.m. Adjourn Day One
APPENDIX B 73
DAY TWO: June 15, 2016
8:30 a.m. Day Two Opening Remarks

KEYNOTE TALK: FUTURE DIRECTIONS IN CLINICAL

TRIALS AND REGULATORY APPROACHES FOR
MULTIMODAL THERAPIES
8:40 a.m. ROBERT CALIFF

Commissioner of Food and Drugs
9:00 a.m. Questions and Answers with Workshop Participants
9:30 a.m. BREAK
SESSION III: ESTABLISHING EFFICACY AND SAFETY IN

MULTIMODAL THERAPIES FOR BRAIN DISORDERS
Session Objectives: Discuss methodologies for establishing efficacy and

safety for multimodal therapies compared to monotherapies, including
clinical and statistical considerations. Potential topics may include
• Addressing challenges of intervention fidelity (e.g., site-to-

site and time-to-time consistency) with behavioral interven-
tions (psychotherapy, exercise);
• Interpretation when the two modalities have different time
courses (e.g., drug goes for longer than behavioral
intervention);
• Interpretation when one modality encounters more
intolerability;
• Different approaches to assessing dose, especially in psycho-
social interventions; or

• Innovative approaches to trial design that are specifically rele-

vant to multimodal approaches and may help address the lev-
els of evidence required for regulation and reimbursement.
9:45 a.m. Session Overview and Objectives

KARL KIEBURTZ, Session Moderator
Robert J. Joynt Professor in Neurology
Senior Associate Dean for Clinical Research
Director of the Clinical & Translational Science Institute
University of Rochester Medical Center
9:55 a.m. Platform Trials for Multimodal Therapies

ROGER LEWIS
Senior Medical Scientist, Berry Consultants
Professor and Chair, Department of Emergency
Medicine, Harbor-UCLA Medical Center
Quantification of Dose with Devices
MAROM BIKSON
Professor of Biomedical Engineering
The City College of the City University of New York
Quantification of Dose in Psychosocial Interventions
WOLFGANG LUTZ (via WebEx)
Professor and Head of Clinical Psychology and
Psychotherapy
University of Trier, Germany
10:45 a.m. Discussants:

BILLY DUNN
Director, Division of Neurology Products
Office of Drug Evaluation I
Center for Drug Evaluation and Research
RHONDA ROBINSON-BEALE
Senior Vice President and Chief Medical Officer
Blue Cross of Idaho
APPENDIX B 75
STEVEN PIZER
Associate Professor of Health Economics
Department of Pharmacy and Health Systems Sciences
Northeastern University
and Chief Economist, Health Care Financing &
Economics
U.S. Department of Veterans Affairs
11:15 a.m. Discussion Among Speakers, Discussants, and

Workshop Participants
11:45 a.m. LUNCH
SESSION IV: INDUSTRY PERSPECTIVES
Session Objectives:
• Discuss industry perspectives on particular technical, scientific, and
commercial challenges to bringing these systems to market, and
examine lessons learned from successful examples of
collaborations on multimodal approaches.
• Explore potential mechanisms for addressing challenges and
enabling multimodal therapy development programs.

STEVIN ZORN, Session Moderator
Executive Scientist in Residence
Lundbeck
12:40 p.m. Challenges and Opportunities for Integration of

Therapeutic Devices into Psychiatry
JEFFREY NYE
Vice President, Neuroscience Innovation and
Scientific Partnership Strategy
Janssen Research and Development, LLC
Johnson & Johnson Innovation
Intrathecal Infusion Therapy for Chronic Pain: Challenges,

Lessons, and Opportunities
KEITH HILDEBRAND
Senior Principal Scientist, Technical Fellow
Neuromodulation
Medtronic, Inc.
Pfizer–MedGenesis Therapeutix Collaboration on Glial Cell
Line-Derived Neurotrophic Factor (GDNF) Protein and
Convection Enhanced Delivery (CED) Technology for
Parkinson’s Disease
ERICH MOHR
Chair & Chief Executive Officer
MedGenesis Therapeutix Inc.
CHRISTOPHER SHAFFER
Associate Research Fellow
Pfizer Inc.
2:00 p.m. BREAK
SESSION V: MOVING FORWARD
Session Objectives:
• Discuss the roles of NIH, other research agencies, and disease-
specific organizations in supporting the development of
multimodal therapies.
• Synthesize and discuss key highlights from the workshop
presentations and discussions and, most importantly, identify
next steps and promising areas for future action and research.

KARL KIEBURTZ, Workshop Co-Chair and Session
Moderator
SARAH H. LISANBY, Workshop Co-Chair and Session
Moderator

APPENDIX B 77
2:20 p.m. Role of Research Agencies in De-Risking Multimodal

Therapy Development
AMIR TAMIZ
Program Director, NIH Blueprint NeuroTherapeutics
Network
National Institutes of Health
STUART HOFFMAN
Senior Scientific Advisor for Brain Injury
Office of Research and Development
Department of Veterans Affairs
2:40 p.m. Role of Disease-Specific Research Funding in Multimodal

Therapy Development
JAMES HENDRIX
Director, Global Science Initiatives, Medical and
Scientific Relations
Alzheimer’s Association
BRIAN FISKE
Senior Vice President, Research Programs
The Michael J. Fox Foundation for Parkinson’s Research
3:00 p.m. Discussion with Workshop Participants
3:15 p.m. Panel Discussion: Identifying Gaps, Opportunities, and Next

Steps Highlighted in Workshop Presentations and
Discussions
KARL KIEBURTZ, Workshop Co-Chair and Session III
Moderator
SARAH H. LISANBY, Workshop Co-Chair and Session II
Moderator
KEITH HILDEBRAND, Session I Co-Moderator
TIMOTHY STRAUMAN, Session I Co-Moderator
STEVIN ZORN, Session IV Moderator
EMMELINE EDWARDS
Director, Division of Extramural Research
National Center for Complementary and Integrative
Health

4:00 p.m. Discussion with Workshop Participants
4:20 p.m. Closing Remarks

4:30 p.m. Adjourn Workshop

C
Registered Participants
Neeraj Agarwal Kristopher Bough

National Eye Institute National Institute on Drug
Abuse
Seun Ajiboye
Johns Hopkins Medical Linda Brady
Institution National Institute of Mental
Health
Irina Antonijevic
Sanofi Jeremy Brown
National Institute of General
Shelli Avenevoli Medical Sciences
National Institute of Mental
Health Wilson Bryan
Rita Balice-Gordon
Sanofi Ethan Buch
National Institute of
Sonia Bansal Neurological Disorders and
George Mason University Stroke
Marom Bikson Sarah Caddick

The City College of the City The Gatsby Charitable
University of New York Foundation
Chris Boshoff Robert Califf
National Institute of Food and Drug Administration
Neurological Disorders and
Stroke
79

Maria Carrillo Emmeline Edwards

Alzheimer’s Association National Center for
Complementary and
Karen Chandross Integrative Health
Sanofi
Rebecca English
Kiki Chang National Academies of
Stanford University Medical Sciences, Engineering, and
Center Medicine
Timothy Coetzee Jennifer Evans

National Multiple Sclerosis National Institute of Mental
Society Health
Richard Conroy Jovier Evans

National Institute of Biomedical National Institute of Mental
Imaging and Bioengineering Health
Nathaniel Counts Brian Fiske

Mental Health America The Michael J. Fox Foundation
for Parkinson’s Research
Bruce Cuthbert
National Institute of Mental Naz Ghassemian
Health Food and Drug Administration
Mads Dalsgaard Theresa Gleason

Lundbeck U.S. Department of Veterans
Affairs
Ann Marie D’Angelo
Family Care Connections, LLC Alex Goddard
Tal Medical
James Deshler
National Science Foundation Anupama Govindarajan
Sonya Dumanis
Milken Institute Hank Greely
Stanford University
Billy Dunn
Food and Drug Administration Laura Helbling
The RPM Report

APPENDIX C 81
James Hendrix Claire Kaplan

Alzheimer’s Association University of Maryland, College
Park
Ramona Hicks
One Mind Morris Kaplan
Keith Hildebrand
Medtronic, Inc. John Kehne
J. Terrell Hoffeld Neurological Disorders and
U.S. Public Health Service Stroke
(Retired)
Karl Kieburtz
Stuart Hoffman University of Rochester Medical
U.S. Department of Veterans Center
Affairs
Walter Koroshetz
Euchay Horsman National Institute of
University of Arkansas at Little Neurological Disorders and
Rock Stroke
Steven Hyman Judith Lelchook

Broad Institute of Massachusetts Solace Center
Institute of Technology and
Harvard University Alan Leshner
American Association for the
Debbie Indyk Advancement of Science
Icahn School of Medicine at
Mount Sinai Laura Levit
American Society of Clinical
Michael Irizarry Oncology
Eli Lilly and Company
Roger Lewis
Inez Jabalpurwala Harbor-UCLA Medical Center
Brain Canada Foundation
Sarah H. Lisanby
John Johnson National Institute of Mental
Physical Rehabilitation Inc. Health
Leonid Livshitz Lawrence Park

Food and Drug Administration National Institute of Mental
Health
Patricia Love
Food and Drug Administration Mary Pelleymounter
Ying Lu Neurological Disorders and
U.S. Department of Veterans Stroke
Affairs
Carlos Peña
Bruce Luber Food and Drug Administration
Health Linda M. Picon
U.S. Department of Veterans
Wolfgang Lutz Affairs
University of Trier
Steven Pizer
Erich Mohr Northeastern University/Veteran
MedGenesis Affairs Boston Health Care
System
Martha J. Morrell
NeuroPace William Potter
Joan Murray Health
Murray Enterprises
Thomas Radman
Venkatesha Murthy National Institute on Drug
Takeda Abuse
Jeffrey Nye Vesper Ramos

Johnson & Johnson Innovation Food and Drug Administration
Robert O’Brien John Reppas

U.S. Department of Veterans Neurotechnology Industry
Affairs Organization
Gerald Overman Rhonda Robinson-Beale

National Institute of Mental Blue Cross of Idaho
Health
APPENDIX C 83
Judith Rumsey Paul Wilburn

National Institute of Mental U.S. Department of Justice
Health (Retired)
Alexander Runko Alex Wong

U.S. Department of Health and Washington University School
Human Services of Medicine
Aminata Sallah Ling Wong

Consultant National Institute of
Betty Jo Salmeron Stroke
National Institute on Drug
Abuse Winifred Wu
Strategic Regulatory Partners,
Joel Scholten LLC
U.S. Department of Veterans
Affairs Farid Yaghouby
Christopher Shaffer
Pfizer Inc. Danna Zimmer
University of Maryland School
Daniel Stevenson of Medicine
Walter Reed Army Institute of
Research Stevin Zorn
MindImmune Therapeutics, Inc.
Timothy Strauman
Duke University
Domenica Tambasco
University of Toronto
Amir Tamiz
Stroke


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Reporrts documen nt the evidence-based cconsensus off an authorin

Proceeedings chroonicle the prresentationss and discusssions at a

For information about

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PLANNING COMMITTEE ON MULTIMODAL THERAPIES

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

Health and Medicine Division (HMD) Staff

CLARE STROUD, Forum Director

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FORUM ON NEUROSCIENCE AND NERVOUS

STEVEN HYMAN (Chair), Broad Institute of Massachusetts Institute

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INEZ JABALPURWALA, Brain Canada Foundation

CLARE STROUD, Forum Director

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This Proceedings of a Workshop has been reviewed in draft form by

BRUCE BEBO, National Multiple Sclerosis Society

Although the reviewers listed above have provided many constructive

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2 Multimodal Therapy: Overview of Principles, Barriers, and

3 Exploring the State of the Science 19

4 Regulatory and Reimbursement Considerations 29

5 Trial Designs to Establish Efficacy and Safety in

6 Developing Multimodal Therapies: Practical Considerations

7 Role of Research Funders in Multimodal Therapy

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Multimodal therapy approaches that combine interventions aimed at

The workshop brought together key stakeholders to examine the

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2 MULTIMODAL THERAPIES FOR BRAIN DISORDERS

An ad hoc committee will plan and conduct a 1.5-day public work-

• Explore recent advances in the development of multimodal

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The multiple modalities considered at the workshop include drugs,

ORGANIZATION OF THE PROCEEDINGS

The following proceedings summarizes the workshop presentations

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4 MULTIMODAL THERAPIES FOR BRAIN DISORDERS

forward. In Chapter 3, the state of the art is explored by discussing ex-

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Multimodal therapies are intended to optimize treatment of brain dis-

DEFINING MULTIMODAL THERAPY

This workshop generally considered “multimodal therapy” as a

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6 MULTIMODAL THERAPIES FOR BRAIN DISORDERS