Using Patient Perspectives to Inform Better Clinical Trial Design and Conduct: Current Trends and Future Directions.

The approach to patient engagement (PE) in drug development has changed rapidly due to many factors, including the complexity of innovative drugs and the need to demonstrate outcomes of relevance to patients, the desire to show 'value add' of PE, and the pandemic-related changes to how clinical trials are run, e.g., decentralised studies. In parallel, there have been changes in technology-assisted ways of running clinical trials, capturing patient health outcomes and preferences, an increasing societal demand for diversity and inclusion, and efforts to improve clinical trial efficiency, transparency, and accountability. Organisations are beginning to monitor PE activities and outcomes more effectively to learn and inform future PE strategies. As a result, these factors are facilitating the incorporation of patients' lived experience, preferences and needs into the design and running of clinical trials more than ever before. In this paper, the authors reflect upon these last few years, the emerging trends and their drivers, and where we may expect PE in clinical research to progress in the near future.

Sustaining Meaningful Patient Engagement Across the Lifecycle of Medicines: A Roadmap for Action.

BACKGROUND: There is increased recognition that incorporating patients' perspectives and insights into the medicines development process results in better health outcomes and benefits for all involved stakeholders. Despite the increased interest and the existence of frameworks and practical recommendations, patient engagement (PE) is not yet considered standard practice. The objective of this work was to provide a roadmap to support systematic change in all stakeholder organisations involved in medicines development across Europe, patients and patient organisations, medicines developers, academia, regulatory authorities, Health Technology Assessment bodies, payers, policy-makers and public research funders, to sustain PE practices. METHODS: A mixed-methods approach was used by the EU-funded Innovative Medicines Initiative PARADIGM Consortium to co-develop the sustainability roadmap including background work to identify success factors and scenarios for sustainable PE. The roadmap development was based on the Theory of Change concept and populated with findings from (1) interviews with national/ and international institutions with the potential to increase PE uptake by other stakeholders; (2) multi-stakeholder workshops and webinars; and (3) consultations with specific stakeholder groups, Consortium members and a consultative body formed by international PE initiatives. RESULTS: This roadmap sets strategic goals for the PE community to achieve meaningful and systematic PE through changes in the culture, processes and resources of stakeholder organisations. It brings in key PARADIGM outputs to work in a coordinated fashion with existing frameworks and mechanisms to achieve system-wide sustained PE. CONCLUSIONS: The roadmap provides a framework for all stakeholders to take collective action within their organisations and across Europe to implement PE in a sustainable manner.

Evaluation of patient engagement in medicine development: A multi-stakeholder framework with metrics.

BACKGROUND: Patient engagement is becoming more customary in medicine development. However, embedding it in organizational decision-making remains challenging, partly due to lack of agreement on its value and the means to evaluate it. The objective of this project was to develop a monitoring and evaluation framework, with metrics, to demonstrate impact and enhance learning. METHODS: A consortium of five patient groups, 15 biopharmaceutical companies and two academic groups iteratively created a framework in a multi-phase participatory process, including analysis of its application in 24 cases. RESULTS: The framework includes six components, with 87 metrics and 15 context factors distributed among (sub)components: (a) Input: expectations, preparations, resources, representativeness of stakeholders; (b) Activities/process: structure, management, interactions, satisfaction; (c) Learnings and changes; (d) Impacts: research relevance, study ethics and inclusiveness, study quality and efficiency, quality of evidence and uptake of products, empowerment, reputation and trust, embedding of patient engagement; (e) Context: policy, institutional, community, decision-making contextual factors. Case study findings show a wide variation in use of metrics. There is no 'one size fits all' set of metrics appropriate for every initiative or organization. Presented sample sets of metrics can be tailored to individual situations. CONCLUSION: Introducing change into any process is best done when the value of that change is clear. This framework allows participants to select what metrics they value and assess to what extent patient engagement has contributed. PATIENT CONTRIBUTION: Five patient groups were involved in all phases of the study (design, conduct, interpretation of data) and in writing the manuscript.

Understanding multi-stakeholder needs, preferences and expectations to define effective practices and processes of patient engagement in medicine development: A mixed-methods study.

BACKGROUND: The holistic evolution of patient engagement in medicines development requires a more detailed understanding of the needs of all involved stakeholders, and one that better accounts for the specific needs of some potentially vulnerable patient populations and key stages in medicines development. OBJECTIVE: The purpose of this convergent mixed-methods study was to better understand the needs of different stakeholders concerning patient engagement at three key stages in medicines development: research priority setting, clinical trial design and early dialogues with Health Technology Assessment bodies and regulators. DESIGN: This study brought together findings from three sources: i) an online questionnaire, ii) face-to-face consultations with two potentially vulnerable patient populations, a workshop with Health Technology Assessment bodies, and iii) three-step modified Delphi methodology. RESULTS: Overall stakeholders still need additional varied support mechanisms to undertake, sustain or measure value of patient engagement. Health Technology Assessment bodies need better rationale for patient engagement in early dialogue and tools to support its implementation. Improved awareness and understanding of the need and value that involving patients, who are often considered as potentially vulnerable, can bring is needed, as is better accommodation of their specific needs. Similarly, weighted Delphi categories were as follows: aims and objectives, and sustainability. Several additional themes were common across the three key stages in medicines development. CONCLUSION: This broad-reaching study provides the blocks needed to build a framework for patient engagement in medicines development. PATIENT OR PUBLIC CONTRIBUTION: Patients were involved in review and interpretation of data.

Evaluating the "return on patient engagement initiatives" in medicines research and development: A literature review.

BACKGROUND: Showing how engagement adds value for all stakeholders can be an effective motivator for broader implementation of patient engagement. However, it is unclear what methods can best be used to evaluate patient engagement. This paper is focused on ways to evaluate patient engagement at three decision-making points in the medicines research and development process: research priority setting, clinical trial design and early dialogues with regulators and health technology assessment bodies. OBJECTIVE: Our aim was to review the literature on monitoring and evaluation of patient engagement, with a focus on indicators and methods. SEARCH STRATEGY AND INCLUSION CRITERIA: We undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut-off of publications after July 2018. DATA EXTRACTION AND SYNTHESIS: Data were extracted from 91 publications, coded and thematically analysed. MAIN RESULTS: A total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for the evaluation of benefits and costs of patient engagement. DISCUSSION AND CONCLUSIONS: Currently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures.

Medicines Adaptive Pathways to Patients: Why, When, and How to Engage?

Medicines Adaptive Pathways to Patients (MAPPs) seeks to foster access to novel beneficial treatments for the right patient groups at the earliest appropriate time in the product life-span, in a sustainable fashion. We summarize the MAPPs engagement process and critical questions to be asked at each milestone of the product life-span. These considerations are of relevance for regulatory and access pathways that strive to address the "evidence vs. access" conundrum.

What do stakeholders expect from patient engagement: Are these expectations being met?

BACKGROUND: Meaningful patient engagement (PE) in medicines development and during the life cycle of a product requires all stakeholders have a clear understanding of respective expectations. OBJECTIVE: A qualitative survey was undertaken to understand stakeholder expectations. DESIGN: The survey explored 4 themes from the perspective of each stakeholder group: meaning, views, expectations and priorities for PE. Participants were grouped into 7 categories: policymakers/regulators; health-care professionals (HCPs); research funders; payers/purchasers/HTA; patients/patient representatives; pharmaceutical/life sciences industry; and academic researchers. RESULTS: Fifty-nine interviews were conducted across a range of geographies, PE experience and job seniority/role. There was consensus across stakeholders on meaning of PE; importance of promoting PE to a higher level than currently; need for a more structured process and guidance. There was little consensus on stakeholder expectations and roles. Policymakers/regulators were expected by others to drive PE, create a framework and facilitate PE, provide guidelines of good practice and connect stakeholders, but this expectation was not shared by the policymakers/regulators group. HCPs were seen as the link between patients and other stakeholders, but HCPs did not necessarily share this view. DISCUSSION AND CONCLUSIONS: Despite broad stakeholder categories, clear themes emerged: there is no "leader"; no stakeholder has a clear view on how to meaningfully engage with patients; there are educational gaps; and a structure and guidance for PE is urgently required. Given the diversity of stakeholders, there needs to be multistakeholder collaborative leadership. Effective collaboration requires consensus on roles, responsibilities and expectations to synergize efforts to deliver meaningful PE in medicines life cycle.

Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol.

To exert its analgesic action, paracetamol requires complex metabolism to produce a brain-specific lipoamino acid compound, AM404, which targets central transient receptor potential vanilloid receptors (TRPV1). Lipoamino acids are also known to induce analgesia through T-type calcium-channel inhibition (Ca(v)3.2). In this study we show that the antinociceptive effect of paracetamol in mice is lost when supraspinal Ca(v)3.2 channels are inhibited. Therefore, we hypothesized a relationship between supraspinal Ca(v)3.2 and TRPV1, via AM404, which mediates the analgesic effect of paracetamol. AM404 is able to activate TRPV1 and weakly inhibits Ca(v)3.2. Interestingly, activation of TRPV1 induces a strong inhibition of Ca(v)3.2 current. Supporting this, intracerebroventricular administration of AM404 or capsaicin produces antinociception that is lost in Ca(v)3.2(-/-) mice. Our study, for the first time, (1) provides a molecular mechanism for the supraspinal antinociceptive effect of paracetamol; (2) identifies the relationship between TRPV1 and the Ca(v)3.2 channel; and (3) suggests supraspinal Ca(v)3.2 inhibition as a potential pharmacological strategy to alleviate pain.

Crucial role of TRPC1 and TRPC4 in cystitis-induced neuronal sprouting and bladder overactivity.

PURPOSE: During cystitis, increased innervation of the bladder by sensory nerves may contribute to bladder overactivity and pain. The mechanisms whereby cystitis leads to hyperinnervation of the bladder are, however, poorly understood. Since TRP channels have been implicated in the guidance of growth cones and survival of neurons, we investigated their involvement in the increases in bladder innervation and bladder activity in rodent models of cystitis. MATERIALS AND METHODS: To induce bladder hyperactivity, we chronically injected cyclophosphamide in rats and mice. All experiments were performed a week later. We used quantitative transcriptional analysis and immunohistochemistry to determine TRP channel expression on retrolabelled bladder sensory neurons. To assess bladder function and referred hyperalgesia, urodynamic analysis, detrusor strip contractility and Von Frey filament experiments were done in wild type and knock-out mice. RESULTS: Repeated cyclophosphamide injections induce a specific increase in the expression of TRPC1 and TRPC4 in bladder-innervating sensory neurons and the sprouting of sensory fibers in the bladder mucosa. Interestingly, cyclophosphamide-treated Trpc1/c4(-/-) mice no longer exhibited increased bladder innervations, and, concomitantly, the development of bladder overactivity was diminished in these mice. We did not observe a difference neither in bladder contraction features of double knock-out animals nor in cyclophosphamide-induced referred pain behavior. CONCLUSIONS: Collectively, our data suggest that TRPC1 and TRPC4 are involved in the sprouting of sensory neurons following bladder cystitis, which leads to overactive bladder disease.

Chronic administration of anticholinergics in rats induces a shift from muscarinic to purinergic transmission in the bladder wall.

BACKGROUND: First-line pharmacotherapy for overactive bladder consists of anticholinergics. However, patient compliance is exceptionally low, which may be due to progressive loss of effectiveness. OBJECTIVE: To decipher the involved molecular mechanisms and to evaluate the effects of chronic systemic administration of anticholinergics on bladder function and on muscarinic and purinergic receptors expression in rats. DESIGN, SETTING, AND PARTICIPANTS: Female Wistar rats were implanted with an osmotic pump that chronically administered vehicle (Vehc), 0.36 mg/kg per day oxybutynin (Oxyc), or 0.19 mg/kg per day fesoterodine (Fesoc) for 28 d. INTERVENTIONS: For cystometry experiments, a small catheter was implanted in the bladder. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urologic phenotype was evaluated by the analysis of the micturition pattern and urodynamics. Expression of muscarinic and purinergic receptors was assessed by Western blot analysis of detrusor membrane protein. Functional responses to carbachol and adenosine triphosphate (ATP) were evaluated using muscle-strip contractility experiments. RESULTS AND LIMITATIONS: The number of voided spots was transiently decreased in Oxyc rats. In Oxyc rats, the effect of an acute high dose of oxybutynin (1mg/kg intraperitoneally [IP]) on the intermicturition interval was abolished. Expression experiments revealed a decrease of muscarinic acetylcholine receptors M2 (mAChR2) and M3 (mAChR3), whereas the purinergic receptor P2X, ligand-gated ion channel, 1 (P2X1) was enhanced in Oxyc and Fesoc rats compared to Vehc rats. In concordance with the modification of the expression pattern in Oxyc rats, the force generated by carbachol and ATP in muscle-strip contractility experiments was, respectively, lower and higher. Urodynamics revealed that the effects of systemic administration of the purinergic blocker pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (50mg/kg IP) were enhanced in Oxyc rats. As rat bladder physiology is different from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS: Chronic administration of anticholinergics in rats induces receptor loss of efficiency and a shift from muscarinic to purinergic transmission.

Bladder dysfunction in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α-synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)-human α-synuclein (hαSyn) transgenic and control wild-type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age-related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP-hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn-related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA.

The use of cystometry in small rodents: a study of bladder chemosensation.

The lower urinary tract (LUT) functions as a dynamic reservoir that is able to store urine and to efficiently expel it at a convenient time. While storing urine, however, the bladder is exposed for prolonged periods to waste products. By acting as a tight barrier, the epithelial lining of the LUT, the urothelium, avoids re-absorption of harmful substances. Moreover, noxious chemicals stimulate the bladder's nociceptive innervation and initiate voiding contractions that expel the bladder's contents. Interestingly, the bladder's sensitivity to noxious chemicals has been used successfully in clinical practice, by intravesically infusing the TRPV1 agonist capsaicin to treat neurogenic bladder overactivity. This underscores the advantage of viewing the bladder as a chemosensory organ and prompts for further clinical research. However, ethical issues severely limit the possibilities to perform, in human subjects, the invasive measurements that are necessary to unravel the molecular bases of LUT clinical pharmacology. A way to overcome this limitation is the use of several animal models. Here we describe the implementation of cystometry in mice and rats, a technique that allows measuring the intravesical pressure in conditions of controlled bladder perfusion. After laparotomy, a catheter is implanted in the bladder dome and tunneled subcutaneously to the interscapular region. Then the bladder can be filled at a controlled rate, while the urethra is left free for micturition. During the repetitive cycles of filling and voiding, intravesical pressure can be measured via the implanted catheter. As such, the pressure changes can be quantified and analyzed. Moreover, simultaneous measurement of the voided volume allows distinguishing voiding contractions from non-voiding contractions. Importantly, due to the differences in micturition control between rodents and humans, cystometric measurements in these animals have only limited translational value. Nevertheless, they are quite instrumental in the study of bladder pathophysiology and pharmacology in experimental pre-clinical settings. Recent research using this technique has revealed the key role of novel molecular players in the mechano- and chemo-sensory properties of the bladder.

Calcium-activated chloride current expression in axotomized sensory neurons: what for?

Calcium-activated chloride currents (CaCCs) are activated by an increase in intracellular calcium concentration. Peripheral nerve injury induces the expression of CaCCs in a subset of adult sensory neurons in primary culture including mechano- and proprioceptors, though not nociceptors. Functional screenings of potential candidate genes established that Best1 is a molecular determinant for CaCC expression among axotomized sensory neurons, while Tmem16a is acutely activated by inflammatory mediators in nociceptors. In nociceptors, such CaCCs are preferentially activated under receptor-induced calcium mobilization contributing to cell excitability and pain. In axotomized mechano- and proprioceptors, CaCC activation does not promote electrical activity and prevents firing, a finding consistent with electrical silencing for growth competence of adult sensory neurons. In favor of a role in the process of neurite growth, CaCC expression is temporally correlated to neurons displaying a regenerative mode of growth. This perspective focuses on the molecular identity and role of CaCC in axotomized sensory neurons and the future directions to decipher the cellular mechanisms regulating CaCC during neurite (re)growth.

An autocrine neuronal interleukin-6 loop mediates chloride accumulation and NKCC1 phosphorylation in axotomized sensory neurons.

The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6⁻/⁻ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6⁻/⁻ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice.

AIMS: To describe a new mouse model of overactive bladder (OAB) at the histological level, pain, voiding behavior, and urodynamics, while assessing the physiological state of mice. METHODS: This paper compares the pathophysiological features of mice that received intraperitoneal injections of cyclophosphamide (CYP) (40 and 80 mg/kg - body weight) every 2 days for 7 days. Specifically, the heart rate, the body temperature, and the general activity were assessed by telemetry. The abdominal sensitivity was determined with Von Frey filaments. Voiding behavior and detrusor activity were respectively quantified by urine spotting experiments and cystometry. Hematoxylin & Eosin staining was performed to detect inflammation in tissue and NGF concentration in urine was quantified. RESULTS: Affected mice exhibit clearly an OAB characterized by an increase in the number of voiding events and an urodynamically-demonstrated detrusor overactivity associated with referred hyperalgesia. The injected mice displayed inflamed bladder, urothelial hyperplasia, and increased NGF concentration in urine in dose dependant manner. However, the physiological features of mice with CYP-induced cystitis are not changed. CONCLUSIONS: We can show that this model of chronic OAB with pain in mice fits more closely to the clinical signs of patients with OAB than the available animal models (acute and chronic) and will therefore be useful to highlight potential drug targets in genetically modified mice in the future.