Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles. METHODS: In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions. FINDINGS: Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug. INTERPRETATION: Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. FUNDING: Bill & Melinda Gates Foundation and the Swiss National Science Foundation.

Modelling to inform next-generation medical interventions for malaria prevention and treatment.

Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention.

The Patient Experience: Symptoms and Impact of Dry Age-Related Macular Degeneration.

INTRODUCTION: No published literature systematically explores the dry age-related macular degeneration (AMD) patient experience. To inform the development of patient-reported outcome measures (PROMs), the important and relevant signs, symptoms, and impacts for patients with dry AMD were identified. METHODS: A holistic approach was used to capture, define, and organize the signs, symptoms, and impacts that are important to patients with dry AMD. Qualitative evidence was identified through a targeted literature review and clinician (N = 5) and patient (N = 20) interviews. The targeted review was expanded to include patients with AMD, as few studies specific to dry AMD were identified. The qualitative evidence was incorporated into a conceptual model that included the signs, symptoms, and impacts of dry AMD affecting the patient experience. RESULTS: Twenty-nine articles (dry AMD, N = 5; general AMD, N = 24) exploring health-related quality-of-life evidence in patients with AMD were identified. Concepts identified and included in the preliminary, literature-based model included signs and symptoms related to general vision loss and general impacts (e.g., dependency on others, poor spatial perception/mobility, difficulty reading, emotional affects). No concepts unique to dry AMD were identified. Interviewed clinicians refined the literature-based model. Across all visual acuity severities, ≥ 80% of patients reported difficulty driving, reading, and completing activities of daily living, along with frustration and dependency on others; all patients reported blurred vision. The final model included 35 signs, symptoms, and impacts, with 19 considered salient. CONCLUSIONS: To better understand the patient experience, we captured, defined, and organized signs, symptoms, and impacts into a dry AMD conceptual model. This model can aid in the development of PROMs reflecting the experience of patients with dry AMD.