Introduction

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 psychiatric and neurological disorders. Indeed, for most chronic diseases, multiple 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 challenges, potential barriers, and opportunities for their development from multiple perspectives, including scientific, clinical, regulatory, and financial (see Box 1-1).

BOX 1-1
Statement of Task

An ad hoc committee will plan and conduct a 1.5-day public workshop 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 examine scientific, clinical, regulatory, and reimbursement issues related to multimodal approaches and identify potential opportunities to enhance 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 progression), and discuss future research needs to 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).
Discuss methodologies for establishing efficacy for multimodal 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 potential opportunities for addressing challenges.
Consider reimbursement issues for multimodal therapies for nervous system disorders, and discuss potential opportunities for addressing challenges.
Incorporate lessons learned from other therapeutic areas in which multimodal approaches are more frequently used (e.g., diabetes, HIV, cancer).

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

The multiple modalities considered at the workshop include drugs, biologics, devices, and behavioral interventions, said Karl Kieburtz, director of the Clinical and Translational Science Institute at the University 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 together, the effect might be considered synergistic or super-additive. Super-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, testing, 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 multimodal 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 neuropsychiatric 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, including 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 exploring the challenges, opportunities, and research gaps identified by individual participants as needing to be addressed for the field to move forward. In Chapter 3, the state of the art is explored by discussing examples 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 multimodal treatments exist and are being developed for a very wide range of disorders, the chapter concentrates on a few salient examples. Regulatory 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 perspective 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 advancing multimodal therapy development through funding as well as by promoting collaborations across stakeholder groups.

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

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