An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. ...Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The World Health Organization's (WHO) policy for control centres on three groups, preschool aged children (pre-SAC), school-aged children (SAC), and women of child bearing age, on the basis that ...heavy infection in these groups will have a detrimental impact on anaemia, child growth, and development. In many areas of infectious disease epidemiology and the design of interventions, the impact of control is today assessed by simulations based on mathematical models using parameter estimates from epidemiological studies (e.g., HIV and Plasmodium falciparum 7,8).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Amongst the world’s poorest populations, availability of anthelmintic treatments for the control of soil transmitted helminths (STH) by mass or targeted chemotherapy has increased ...dramatically in recent years. However, the design of community based treatment programmes to achieve the greatest impact on transmission is still open to debate. Questions include: who should be treated, how often should they be treated, how long should treatment be continued for? METHODS: Simulation and analysis of a dynamic transmission model and novel data analyses suggest refinements of the World Health Organization guidelines for the community based treatment of STH. RESULTS: This analysis shows that treatment levels and frequency must be much higher, and the breadth of coverage across age classes broader than is typically the current practice, if transmission is to be interrupted by mass chemotherapy alone. CONCLUSIONS: When planning interventions to reduce transmission, rather than purely to reduce morbidity, current school-based interventions are unlikely to be enough to achieve the desired results.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Select the trial for the patient, not the patient for the trial.•A new paradigm of patient-centric drug development, as precision medicine continues to shape the oncology drug development ...landscape.•Success will require continued innovation, and collaboration and co-operation between and across all parties and sectors involved in development and delivery of cancer therapeutics and care.
A rapid expansion in precision medicine founded on the potential for durable clinical benefit through matching a drug to a predictive marker used to select patients has driven the development of targeted drugs with accompanied companion diagnostics for patient selection. Oncology has been at the forefront, with the improvements in patient survival notable. Increasing numbers of molecular subgroups require an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments, posing significant challenges for drug development. Innovative trial designs (umbrella or basket studies) are emerging as patient-centric approaches and public–private partnerships, cross-industry, government and non-profit sector collaborations are enabling implementation. Success will require continued innovation, new paradigms in oncology drug development and market approval and continued collaboration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background The coverage of mass drug administration (MDA) for neglected tropical diseases, such as the soil-transmitted helminths (STHs), needs to rapidly expand to meet WHO's 2020 targets. ...We aimed to compare use of a cost function to take into account economies of scale to the standard method of assuming a constant cost per treatment when investigating the cost and cost-effectiveness of scaling up a STH MDA programme targeting Ascaris lumbricoides. Methods We fitted a cost function describing how the costs of MDA change with scale to empirical cost data and incorporated it into a STH transmission model. Using this cost function, we investigated the consequences of taking into account economies of scale on the projected cost-effectiveness of STH control, by comparison with the standard method of assuming a constant cost per treatment. The cost function was fitted to economic cost data collected as part of a school-based deworming programme in Uganda using maximum likelihood methods. We used the model to investigate the total reduction in the overall worm burden, the total number of prevalent infection case-years averted, and the total number of heavy infection case-years averted. For each year, we calculated the effectiveness as the difference between the worm burden or number of cases and the number in absence of treatment. Findings When using the cost function, the cost-effectiveness of STH control markedly increased as the programme was scaled up. By contrast, the standard method (constant cost per treatment) undervalued this and generated misleading conclusions. For example, when scaling up control in the projected district from 10% to 75% coverage of at-risk school-age children, the cost-effectiveness in terms of prevention of heavy burden infections was projected to increase by over 70% when using the cost function, but decrease by 18% when assuming a constant cost per treatment. Interpretation The current exclusion of economies of scale in most economic analyses must be addressed if the most cost-effective policies for the control of neglected tropical diseases are to be formulated. These findings are also relevant to other large-scale disease interventions. Funding GlaxoSmithKline, Bill & Melinda Gates Foundation, Partnership for Child Development, and Wellcome Trust.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The London Declaration on neglected tropical diseases was based in part on a new World Health Organization roadmap to "sustain, expand and extend drug access programmes to ensure the necessary supply ...of drugs and other interventions to help control by 2020". Large drug donations from the pharmaceutical industry form the backbone to this aim, especially for soil-transmitted helminths (STHs) raising the question of how best to use these resources. Deworming for STHs is often targeted at school children because they are at greatest risk of morbidity and because it is remarkably cost-effective. However, the impact of school-based deworming on transmission in the wider community remains unclear.
We first estimate the proportion of parasites targeted by school-based deworming using demography, school enrolment, and data from a small number of example settings where age-specific intensity of infection (either worms or eggs) has been measured for all ages. We also use transmission models to investigate the potential impact of this coverage on transmission for different mixing scenarios.
In the example settings <30% of the population are 5 to <15 years old. Combining this demography with the infection age-intensity profile we estimate that in one setting school children output as little as 15% of hookworm eggs, whereas in another setting they harbour up to 50% of Ascaris lumbricoides worms (the highest proportion of parasites for our examples). In addition, it is estimated that from 40-70% of these children are enrolled at school.
These estimates suggest that, whilst school-based programmes have many important benefits, the proportion of infective stages targeted by school-based deworming may be limited, particularly where hookworm predominates. We discuss the consequences for transmission for a range of scenarios, including when infective stages deposited by children are more likely to contribute to transmission than those from adults.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key ...challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.
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This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with ...carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers.
Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed.
Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4-13 and 40 mg once daily on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n = 2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in 3 patients. Ceralasertib was quickly absorbed (tmax ∼1 hour), with a terminal plasma half-life of 8-11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (ATM) activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease.
The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg once daily on days 1-2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed.
In this time of rapidly expanding mass drug administration (MDA) coverage and the new commitments for soil-transmitted helminth (STH) control, it is essential that resources are allocated in an ...efficient manner to have the greatest impact. However, many questions remain regarding how best to deliver STH treatment programmes; these include which age-groups should be targeted and how often. To perform further analyses to investigate what the most cost-effective control strategies are in different settings, accurate cost data for targeting different age groups at different treatment frequencies (in a range of settings) are essential.
Using the electronic databases PubMed, MEDLINE, and ISI Web of Knowledge, we perform a systematic review of costing studies and cost-effectiveness evaluations for potential STH treatment strategies. We use this review to highlight research gaps and outline the key future research needs.
We identified 29 studies reporting costs of STH treatment and 17 studies that investigated its cost-effectiveness. The majority of these pertained to programmes only targeting school-aged children (SAC), with relatively few studies investigating alternative preventive chemotherapy (PCT) treatment strategies. The methods of cost data collection, analysis and reporting were highly variable among the different studies. Only four of the costing studies were found to have high applicability for use in forthcoming economic evaluations. There are also very few studies quantifying the costs of increasing the treatment frequency.
The absence of cost data and inconsistencies in the collection and analysis methods constitutes a major research gap for STH control. Detailed and accurate costs of targeting different age groups or increasing treatment frequency will be essential to formulate cost-effective public health policy. Defining the most cost-effective control strategies in different settings is of high significance during this period of expanding MDA coverage and new resource commitments for STH control.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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