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.

For complex and heterogeneous diseases with multiple mechanistic pathways, such as PD, there is also a need to understand the interactions of these multiple pathways, said Kieburtz and Brian Fiske, senior vice president for research programs at The Michael J. Fox Foundation for Parkinson's Research (MJFF). An incomplete knowledge of mechanisms also translates into lack of knowledge about what markers could and should be measured, including early biomarkers that predict a later response 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, insufficient 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 concomitant cognitive-behavioral interventions and pharmacotherapy) interact 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 treatments 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 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.

Complexity of Trial Design Needed to Assess Multimodal Therapies

Hendrix highlighted some of the challenges faced when testing multiple therapies in combination. These include demonstrating the pharmacodynamic and pharmacokinetic properties of multiple compounds, determining the correct doses of the compounds in light of possible additive or synergistic effects, and assessing potential drug−drug interactions. The route of administration (e.g., oral versus infusion therapy) adds further 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 professor 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 restructuring, and emotion regulation) or the therapeutic alliance, interpersonal 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 biomedical 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 exacerbated by separate regulatory pathways and different evidentiary standards for drugs, biologics, and devices. Moreover, no regulatory framework exists for behavioral interventions or other psychosocial therapies, said Kieburtz and Strauman, including components such as neurocognitive 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, reimbursement 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 different 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 sufficient 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.

Advancing Understanding of Disease Mechanisms and Treatments

Throughout the workshop, individual participants identified a number of areas where additional research on the fundamental aspects of neurological 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).
• 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 manifestations 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 dynamics 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 understanding of whether symptoms share a common underlying biologic 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 randomization could enable resources to be shifted toward approaches 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 transdiagnostic approach for drug discovery could exploit the overlap between all neurodegenerative diseases (Hendrix), or neuropsychiatric 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 biologically rational mechanisms before initiating large, expensive Phase III trials (Koroshetz).
• Identifying and validating biomarkers that demonstrate a clinically 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 enable interpretation and understanding of outcomes in clinical trials (Potter).

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. 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 using existing data from clinical trials and common data standards to increase the scale of studies of multimodal therapies for central 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 electrocorticographic (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, including 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 organizations and patients (Califf, Lisanby).