Developing Multimodal Therapies for Brain Disorders Proceedings of a Workshop (2017) / Chapter Skim
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2 Multimodal Therapy: Overview of Principles, Barriers, and Opportunities
2 Multimodal Therapy: Overview of Principles, Barriers, and Opportunities
Pages 5-18
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From page 5... ...
, or one modality may be used to activate 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.
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From page 6... ...
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 developed 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)
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From page 7... ...
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.
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From page 8... ...
Multimodal approaches may combine therapies that alone have only modest effects, but have dramatic effects when put together. For example, 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 interventions, such as diet and exercise.
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From page 9... ...
For exam mple, for a highly h heteroogeneous conndition such as epilepssy, pharmaco otherapy may y be combineed with continnuous monitooring 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 methoddically assessed.
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From page 10... ...
Insufficient Understanding of Disease and Treatment Mechanisms To effectively and efficiently develop multimodal therapies, a sophisticated 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 phenotypes, 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 Neurotherapeutics Network, limited preclinical models for central nervous system diseases make it difficult to develop a specific monotherapy, let alone combine therapies and understand whether there is an additive or synergistic effect.
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From page 11... ...
Lisanby added that neuroscience trials frequently have a small sample size and are statistically 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.
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From page 12... ...
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 exacerbated by separate regulatory pathways and different evidentiary standards for drugs, biologics, and devices.
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From page 13... ...
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.
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From page 14... ...
POTENTIAL OPPORTUNITIES TO ADVANCE MULTIMODAL THERAPY DEVELOPMENT1 According to Strauman, the fields of cognitive psychology and cognitive neuroscience are on the verge of a paradigm shift, with the increasing 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.
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From page 15... ...
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)
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From page 16... ...
. Improving Data Gathering, Data Sharing, and Data Analysis In addition to improving the design of clinical trials, innovative analyses 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.
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From page 17... ...
. 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)
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