Understanding decision-making and barriers in the mental health R&amp;D ecosystem
Creators: name: Amato, Marisa
name: Trust, The Wellcome
Publisher: name: F1000 Research Limited
Year: 2024

description: Mental health challenges affect the daily life of millions of people worldwide. Yet current treatments may not be available for many or provide only limited effectiveness for certain mental health conditions. This reality underscores the urgency for further research and investment into understanding these conditions better and developing new and better interventions.<br>
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Wellcome has commissioned Technopolis to undertake a study to understand the decision-making processes of developers of mental health interventions and identify barriers, their root causes and possible solutions within the mental health R&amp;D ecosystem. The study explored the mental health R&amp;D landscape in four country contexts (i.e. in the US, the UK, Germany, and South Africa) and focused on three mental health conditions: anxiety, depression, and psychosis. The scope of intervention types included pharmaceuticals, medical devices, and digital therapeutics.<br>
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The study followed a mixed-method research approach, drawing on data from a variety of sources: literature review, interviews, case studies, workshops, and a compilation of quantitative data. It included a set of analytical packages:

 Development of a typology of mental health interventions
 Characterisation of the mental health R&amp;D ecosystem, including market sizes, pipelines and R&amp;D pathways of different mental health interventions along the innovation life cycle to approval/accreditation and early uptake
 Analysis of key stages in the decision-making process of developers of mental health interventions
 Identification and prioritisation of the longlist of documented barriers and potential solutions through dedicated workshops
 Development of recommendations for research funders and investors to foster and promote the development of innovative, inclusive and equitable interventions.

The stakeholder consultation covered over 100 individuals from a broad range of stakeholder groups: developers, regulators and policymakers, investors and funders, advocacy groups, people with lived experience, and healthcare providers. The study was guided by a bespoke expert advisory group,[1] with a range of expertise, including lived experience, clinical, regulatory, R&amp;D and innovation.<br>
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<b>Characterisation of the mental health R&amp;D ecosystem</b><br>
The mental health R&amp;D ecosystem is complex, with various key stakeholders, often specific to the type of intervention, and spans a series of defined stages from proof-of-concept or prototype of an intervention to regulatory approval, followed by market launch and uptake. While pharmaceutical R&amp;D follows a well-established pathway, medical devices and digital therapeutics (i.e. software as a medical device) may follow a markedly different route. These require a risk-based classification to determine whether the intervention needs further testing in clinical trials. For medical devices, self-certification or conformity assessment is needed before these can be placed on the market. Digital therapeutics pose particular challenges both for developers and regulators due to rapid technological progress, and pathways vary substantially across jurisdictions.<br>
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<b>Developer decision-making </b><br>
Seven case studies were developed that exemplify developers’ decision-making processes in identifying the unmet need, proposed solution, engaging with stakeholders and routes to market. The case studies include:

 gameChange, a digital intervention that leverages virtual reality to address agoraphobia-related avoidance and discomfort in people with psychosis.
 deprexis®, a web-based digital therapeutic platform offering self-help programmes for managing unipolar depression and depressive disorders. Evidence of effectiveness was generated through several randomised controlled trials.
 Woebot, an automated conversational agent (chatbot) on a smartphone specifically targeting adults, adolescents and mothers with stress, anxiety, and depression.
 Digital Pill by Inner Cosmos, an implantable medical device using transcranial magnetic stimulation for the treatment of depression.
 OAK by Fisher Wallace Labs, a wearable medical device for Cranial Electrotherapy Stimulation for the treatment of depression and other neuropsychiatric and cognitive disorders.
 Boehringer Ingelheim combine a ‘transdiagnostic’ approach and precision psychiatry (including pharmaceuticals and complementary digital therapeutics) for a range of mental health conditions including the treatment of symptoms relating to major depressive disorder, post-traumatic stress disorder, schizophrenia, and borderline personality disorder.
 Psychedelics-based treatment for mental health conditions, which explores the historical background and challenges in research and development of this class of pharmaceuticals with specific examples.

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<b>Involvement of People with Lived Experience</b><br>
Involvement of people with lived experience was identified as an essential element of the mental health R&amp;D process, from research and product design, through participant recruitment to accelerating translation of research results into policies and healthcare practices. This co-production between developers and people with lived experience contributes to ensuring the relevance and acceptability of mental health R&amp;D and helps the eventual adoption and uptake of the intervention. Engaging with people with mental health conditions for developers is however often challenging.<br>
Similarly, the involvement of people with lived experience was crucial in the current research study. Consulting with them ensured their perspectives were reflected in the data collection tools, engagement strategy and the drafting of the report. Lived experience advisors felt that their involvement contributed to a collaborative and respectful environment that encouraged meaningful participation and input from all stakeholders. Study researchers felt that involving lived experience expertise and perspective significantly enhanced their understanding of perspectives and shaped their research approach, reinforcing their commitment to inclusivity and relevance in mental health research.<br>
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<b>Priority barriers and current efforts to address these</b><br>
This study developed a list of 12 scientific and 10 non-scientific barriers which were organised into a hierarchical typology with three top-level areas:

 High development costs
 Complex regulatory and policy environment
 Lack of attractiveness of the mental health market to developers, investors, and funders

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High development costs were largely rooted in gaps in scientific knowledge and failure rates of mental health clinical trials, linked to the lack of biomarkers and animal models to robustly measure the effects of mental health interventions, clinical heterogeneity of mental health conditions, challenges in clinical trial recruitment and retention, and challenges in designing appropriate placebo for clinical trials. These ultimately lead to results that do not translate to real-world scenarios.<br>
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Developers, funders, and investors face significant challenges navigating the complex regulatory and policy environment for market access, which hinders product development and adoption. This is especially true for small companies developing innovative and digital therapeutics, who find the authorisation, pricing, and reimbursement models particularly difficult. Consequently, they often seek direct access to alternative well-being markets, frequently without sufficient evidence of effectiveness.<br>
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Developers and investors do not perceive the regulated mental health treatment market as attractive with sufficient return on investment for mental health interventions. This is due to demand-side challenges linked to low treatment-seeking and/or low adherence to treatment by patients, and health professionals not prescribing adapted treatments for patients (further widening treatment gaps).<br>
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There are several current initiatives to help address some of the barriers identified in the mental health R&amp;D ecosystem. We collected these initiatives and expanded further the list of potential solutions by exploring adjacent areas with relevance to specific barriers in mental health, for example:

 Pain where biomarkers are not available to support R&amp;D
 HIV where stigma is stifling treatment-seeking behaviour
 Developing antimicrobial drugs where market failure/no return on investment is a significant challenge
 Rare diseases where low numbers of patients and the need for real-world evidence present bespoke challenges.

The specific initiatives are listed in the report and the accompanying appendices.<br>
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<b>Recommendations for future actions</b><br>
The R&amp;D pathway that developers of mental health interventions need to navigate represents a ‘leaky research pipeline’, suffering from attrition at various stages. Research funders and investors with an interest in mental health therapeutics could focus on three main types of actions to leverage their influence:

 <b>Funding</b> to encourage and enable innovation through financial support for educational activities, research programmes, and infrastructure development to drive innovation and accessibility in mental health research.
 <b>Convening </b>to catalyse collaborations by bringing stakeholders together to launch campaigns, workshops, and regulatory discussions, fostering collaboration and best practice sharing.
 <b>Advocating </b>and influencing to drive change in the research funding landscape, policy and regulatory context of mental health interventions, and for the meaningful involvement of individuals with lived experience.

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The mental health R&amp;D pathway, from research to early adoption of solutions, has several key challenges identified and described in the study. We provide specific recommendations for future actions to address the challenges which the community identified as being the largest blockers to progress:<br>
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<b>1. Gaps in basic scientific knowledge</b> about the biological mechanisms of mental health conditions and the lack of suitable animal models make hypothesis-driven traditional experimentation challenging, especially for pharmaceuticals and medical devices. As a result, researchers and developers may therefore decide not to enter the technology development pathway to target mental health conditions. The following actions (in synergy) could unblock this barrier in the longer term:


 Fund large-scale interdisciplinary research programmes to attract talent to the field
 Convene global multi-stakeholder meetings to develop a strategic research agenda
 Advocate an increase in global research funding into mental health research to match the share of its disease burden
 Fund a mental health R&amp;D funds tracking portal and monitor investment trends and priorities.

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<b>2. Challenging participant recruitment and retention in clinical studies</b> further exacerbates clinical research in mental health. The root causes are stigma, fear and negative perceptions in a vulnerable participant cohort, among others, contributing to developers’ perception of high risk of obtaining the required sample sizes. Research funders, investors and other stakeholders could consider the following actions:


 Fund research initiatives that develop linked datasets, tools and methods for better identification of subtypes of mental health conditions
 Fund the expansion of a global Lived Experience Network to create local champions that developers can engage with and who can support participant recruitment to trials
 Advocate the importance of mental health research in the broader population through engagement with mental health charities and networks of PWLE
 Advocate the use of enhanced informed consent forms in mental health trials that are clear, comprehensive, and culturally sensitive.

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<b>3. Trials results do not translate to real-world scenarios</b> for various reasons, e.g. the efficacy of interventions under trial conditions not matching that of the home environment, the clinical heterogeneity of mental health conditions, and marginalised groups not being involved in clinical trials. Consequently, there can be multiple lines of action to ensure that future mental health interventions produce positive outcomes:


 Fund the development and use of innovative trial methodologies, including adaptive, pragmatic, and decentralised trials that collect real-world (digital) data as evidence for regulators
 Fund large-scale demonstrators to provide a platform for digital therapeutics developers to test, validate, and optimise emerging technologies and systems at scale
 Fund trials that ensure the inclusion of people historically underrepresented in mental health research to ensure equity of health outcomes of the interventions developed, e.g. through diversity-enhancement strategies in clinical trials
 Advocate research led by people with lived experience to empower them, foster trust with developers, and ensure relevance of research
 Advocate the involvement of people with lived experience in the selection of outcome measures, ensuring they align with the experiences, priorities and perspectives of the target population.

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<b>4. Regulatory uncertainty related to obtaining marketing authorisation </b>poses a significant challenge, especially for innovative approaches and digital therapeutics. The study has shown that regulatory science and practice are not always able to accept novel data and evidence generated by developers, and in some drug types, such as psychedelics, there are legal and regulatory hurdles to obtaining marketing authorisation.  The following actions may be taken by research funders to help to address the issue:


 Convene international forums to foster collaboration and knowledge-sharing among regulators, aiming for more efficient and globally aligned regulatory frameworks on areas of relevance for mental health interventions
 Convene meetings focused on controversial interventions, such as psychedelics, and facilitate discussions to address regulatory obstacles effectively
 Advocate the recognition of mental health as a global unmet medical need and unblock regulatory incentives to accelerate marketing authorisation for mental health technologies.

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<b>5. The variability and complexity of pricing and reimbursement models</b> across global markets pose significant challenges. Fragmented national rules around cost-effectiveness assessment and health system recommendations vary greatly, adversely affecting developers’ decisions about the attractiveness of regulated markets. This makes scaling up products regionally a costly endeavour, especially for smaller developers of digital therapeutics. Research funders and investors may consider the following actions:


 Convene international forums to foster collaboration and knowledge-sharing among health technology assessment (HTA) bodies, aiming for more efficient and globally aligned scientific frameworks on areas of relevance for mental health interventions and specifically for digital therapeutics
 Advocate the involvement of people with lived experience in decision-making on the most effective mental health products to ensure their perspectives are considered in assessments
 Fund clinical comparative effectiveness studies, specifically for small to medium-sized enterprises (SMEs), to develop evidence for submission to HTA and P&amp;R bodies to facilitate entry of digital therapeutics to the regulated health market.

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<b>6. The alternative direct market access route</b> for digital well-being products opens a new, faster and less costly route for developers of mental health products (often without sufficient evidence of effectiveness). The lack of evidence can create confusion for patients to choose the right product, the associated (out of pocket) cost may become a barrier to access for marginalised groups, and health professionals are unable to prescribe these well-being products. Research funders may use their power and influence to help tackle this problem by considering the following actions:


 Convene focus group discussions with industry on quality control measures and rigorous standards for mental health intervention development
 Fund a bespoke prize for developers of popular digital apps on the well-being market to demonstrate the effectiveness of their solutions and, on positive outcome, facilitate deployment and uptake of their product in the national health system
 Advocate easier deployment and uptake of mental health interventions in the health systems.

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<b>7.</b> <b>Low treatment-seeking by patients </b>driven by stigma, fear, or perception of not needing treatment, creates a significant ‘treatment gap’. This gap represents demand-side challenges for developers, as the estimated large market size does not translate into real demand. This issue is particularly acute for marginalised groups and populations in LMICs. Moreover, this barrier is closely linked to the challenges of participant recruitment and retention in clinical studies, suggesting that similar actions may be considered to address both issues:


 Advocate awareness programmes and information campaigns in target populations through engagement with mental health charities and networks of people with lived experience about the importance of recognising and seeking treatment for mental health conditions.

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<b>8. Access to patients is limited due to shortage of prescribing health professionals.</b> The challenge of patients not presenting may be further exacerbated by health professionals not prescribing available treatments for patients. This leads to a lower apparent demand for new therapies by patients. Research funders may have limited options to unblock this barrier but could consider the following:


 Advocate more education programmes for primary care providers about mental health and available treatment options
 Advocate the integration of evidence-based digital interventions into healthcare delivery systems, highlighting their potential benefits in improving mental health outcomes.

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Authors: Marisa Amato, Rebecca Babb, Ruth Dixon, Guillermo Larbalestier, Rima Martin, Nadya Mihaylova, Maike Rentel, Laura Sutinen, Peter Varnai<br>
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[1] Membership of the Expert Advisory Group: Steve Appleton, Professor James Barlow, Professor Hugo Critchley, Hayden Holmes, Dr Thomas Kabir, Dr Nicholas Prior, Claudia Sartor, Dr Farhad Shokraneh, Dr Divya Srivastava, and Professor Karin Waldherr.