Medical Research Charities and Biopharmaceutical Companies as Partners in Patient-Centred R&D.

Life science research and development (R&D) companies are all too aware of the importance of patient perspectives but also of the barriers to engaging directly with patients, not least compliance, complex technical and regulatory issues, and the need to meet multifaceted expectations. Medical research charities (MRCs), highly technical and professional organisations, work directly with patients; they represent an expert resource for the science of their field, for disease-related patient advocacy issues and to advise and assist R&D companies in devising meaningful trials. The Pistoia Alliance, a non-profit organisation facilitating life sciences R&D, gathered a number of UK MRCs focused on complex lifelong conditions. The group used workshops and an opinion questionnaire for a snapshot of how the charities believe their knowledge and patient experiences could contribute insights and efficiencies to commercial R&D. MRCs argued that for chronic conditions, the patient perspective is vital in facilitating and de-risking trials, promoting patient motivation, compliance and study viability. MRCs and the patients they represent want to see successful trials, and it is in everyone's interest that well considered studies can proceed. Today, with remote assessments, consumer wearables and digital health technologies, MRCs and patients are already collating substantial data sets that are relevant to quality-of-life benefits, regulatory and value assessments, all of great interest to biopharmaceutical companies. In turn, MRCs would benefit from the experience of biopharma in generating clinical data and implementing novel technologies.

Prophylactic anti-staphylococcal antibiotics for cystic fibrosis.

BACKGROUND: Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review. OBJECTIVES: To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested the following hypotheses to investigate whether prophylaxis: 1. improves clinical status, lung function and survival; 2. leads to fewer isolates of Staphylococcus aureus; 3. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis); 4. leads to fewer isolates of other common pathogens from respiratory secretions; 5. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted. Most recent search of the Group's Register: 27 February 2020. Online trials registries were also searched. Most recent search of online trials registries: 15 September 2020. SELECTION CRITERIA: Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and methodological quality and extracted data. The quality of the evidence was assessed using the GRADE criteria. The review's primary outcomes of interest were lung function by spirometry (forced expiratory volume in one second (FEV1)) and the number of people with one or more isolates of Staphylococcus aureus (sensitive strains). MAIN RESULTS: We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence quality was judged to be low for all outcomes assessed after being downgraded based on GRADE assessments. Downgrading decisions were due to limitations in study design (all outcomes), for imprecision and for inconsistency . Prophylactic anti-staphylococcal antibiotics probably make little or no difference to lung function measured as FEV1 % predicted after six years (mean difference (MD) -2.30, 95% confidence interval (CI) -13.59 to 8.99, one study, n = 119, low-quality evidence); but may reduce the number of children having one or more isolates of Staphylococcus aureus at two years (odds ratio (OR) 0.21, 95% CI 0.13 to 0.35, three studies, n = 315, low-quality evidence). At the same time point, there may be little or no effect on nutrition as reported using weight z score (MD 0.06, 95% CI -0.33 to 0.45, two studies, n = 140, low-quality evidence), additional courses of antibiotics (OR 0.18, 95% CI 0.01 to 3.60, one study, n = 119, low-quality evidence) or adverse effects (low-quality evidence). There was no difference in the number of isolates of Pseudomonas aeruginosa between groups at two years (OR 0.74, 95% CI 0.45 to 1.23, three studies, n = 312, low-quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis. AUTHORS' CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.

Characterising burden of treatment in cystic fibrosis to identify priority areas for clinical trials.

In a recent James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF) the top priority clinical research question was: "What are effective ways of simplifying the treatment burden of people with CF?" We aimed to summarise the lived experience of treatment burden and suggest research themes aimed at reducing it. An online questionnaire was co-produced and responses subjected to quantitative and thematic analysis. 941 survey responses were received (641 from lay community). People with CF reported a median of 10 (interquartile range: 6-15) current treatments. Seven main themes relating to simplifying treatment burden were identified. Treatment burden is high, extending beyond time taken to perform routine daily treatments, with impact varying according to person-specific factors. Approaches to communication, support, evaluation of current treatments, service set-up, and treatment logistics (obtaining/administration) contribute to burden, offering scope for evaluation in clinical trials or service improvement.

The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders.

Oral calorie supplements for cystic fibrosis.

BACKGROUND: Poor nutrition occurs frequently in people with cystic fibrosis and is associated with other adverse outcomes. Oral calorie supplements are used to increase total daily calorie intake and improve weight gain. However, they are expensive and there are concerns they may reduce the amount of food eaten and not improve overall energy intake. This is an update of a previously published review. OBJECTIVES: To establish whether in people with cystic fibrosis, oral calorie supplements: increase daily calorie intake; and improve overall nutritional intake, nutritional indices, lung function, survival and quality of life. To assess adverse effects associated with using these supplements. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register comprising references from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We contacted companies marketing oral calorie supplements.Last search: 18 October 2016. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing use of oral calorie supplements for at least one month to increase calorie intake with no specific intervention or additional nutritional advice in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: We independently selected the included trials, assessed risk of bias and extracted data. We contacted the authors of included trials and obtained additional information for two trials. MAIN RESULTS: We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were concerns surrounding allocation concealment. There were no significant differences between people receiving supplements or dietary advice alone for change in weight, height, body mass index, z score or other indices of nutrition or growth. Changes in weight (kg) at three, six and 12 months respectively were: mean difference (MD) 0.32 (95% confidence interval (CI) -0.09 to 0.72); MD 0.47 (95% CI -0.07 to 1.02 ); and MD 0.16 (-0.68 to 1.00). Total calorie intake was greater in people taking supplements at 12 months, MD 265.70 (95% CI 42.94 to 488.46). There were no significant differences between the groups for anthropometric measures of body composition, lung function, gastro-intestinal adverse effects or activity levels. Moderate quality evidence exists for the outcomes of changes in weight and height and low quality evidence exists for the outcomes of change in total calories, total fat and total protein intake as results are applicable only to children between the ages of 2 and 15 years and many post-treatment diet diaries were not returned. Evidence for the rate of adverse events in the treatment groups was extremely limited and judged to be of very low quality AUTHORS' CONCLUSIONS: Oral calorie supplements do not confer any additional benefit in the nutritional management of moderately malnourished children with cystic fibrosis over and above the use of dietary advice and monitoring alone. While nutritional supplements may be used, they should not be regarded as essential. Further randomised controlled trials are needed to establish the role of short-term oral protein energy supplements in people with cystic fibrosis and acute weight loss and also for the long-term nutritional management of adults with cystic fibrosis or advanced lung disease, or both.

A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability.

BACKGROUND: The palatability of flucloxacillin oral liquid is poor. Parents/carers use strategies to aid the administration of poorly palatable medicines. AIM: To assess views on the palatability of flucloxacillin oral liquid and identify factors associated with successful administration. METHODS: A mixed methods study which included a structured review of online forums and a survey of parent/carers of children with cystic fibrosis (CF) to obtain parent/carer views on the administration of flucloxacillin oral liquid. RESULTS: A total of 18 strategies to aid the administration of flucloxacillin suspension to children were identified on 10 different public online forums. A total of 255 responses to the open online survey were received with 47% of respondents reporting that administration of flucloxacillin was more problematic compared to other medicines and 38% reporting the need to improve the palatability. The brand of flucloxacillin oral liquid significantly influenced the degree of difficulty associated with administration to children. A significant relationship was found between the concentration of flucloxacillin and the reported number of doses successfully administered. The use of food and drink to aid administration was more commonly stated in online forums (44%) compared to the survey data of parents/carers of children with CF (15.9%). CONCLUSION: The administration of flucloxacillin oral liquid is perceived as a challenge by parent/carers because of palatability. For chronic use, a more concentrated oral liquid and certain brands are likely to improve acceptability.

CHILDREN WITH CYSTIC FIBROSIS: UNDERSTANDING ISSUES RELATED TO ORAL ADMINISTRATION OF LIQUID FLUCLOXACILLIN.

AIM: Palatability of flucloxacillin is poor, yet is used long-term in the management of children with cystic fibrosis (CF). Strategies to aid administration of unpalatable medicines have been reported, however there has never been a systematic approach to gathering views of many parents/carers all administering the same medication to the same population of children. This study aimed to quantify the extent of flucloxacillin palatability issues for parents/cares of children with CF and identify parent/carer and healthcare professional (HCP) reported age-specific strategies to aid administration of flucloxacillin to children with CF. METHOD: Passive analysis reviews of public online forums were conducted using search terms including, 'flucloxacillin' and 'taste' or 'palatability' or 'child' to identify evidence of tactics used by parents to aid administration of flucloxacillin to children, not only those with CF (strategies were only included if the age of the child was disclosed). A bespoke online questionnaire was developed and partially validated for parents/carers of children with CF to identify age-specific strategies to aid administration of flucloxacillin. Healthcare professionals (HCPs) were purposively selected for semi-structured interviews to further explore age-specific strategies to aid administration of flucloxacillin. RESULTS: 18 individual strategies were identified on 10 different public online forums to aid the administration of flucloxacillin to children. These included mixing with food/drink: milk was commonly used for children aged 6-20 months; honey, Nutella, jam, ice cream and squash for those aged 21-36 months. The use of an oral syringe to direct the medicine slowly into the back/side of the mouth, and pinching a child's nose was reported.253 parents/carers of children with CF completed the online survey and 11 HCPs were involved in the semi-structured interviews. 50.2% of parents/carers reported that administration of flucloxacillin was problematic, yet 89.3% reported that they administered 'most' or 'all doses' of flucloxacillin. 90.5% of parents/carers found administration of flucloxacillin more problematic than other medicines in pre-weaned babies. 162 of 253 parents/carers chose to comment on ways that administration of flucloxacillin could be improved/eased, with 38.3% of these respondents suggesting improved palatability was necessary. Mixing with food/drink was rarely reported by parents/carers of children with CF (15.9%) or HCPs (27.3%), contrary to data identified within online forums. This difference highlights that parents of children with CF are less likely to use food to aid administration compared to those using flucloxacillin for acute infections. A multi-methods approach to obtain information on manipulation of medicines by parents/carers would provide greater insights into explaining this finding. CONCLUSION: The results from this study showed that flucloxacillin is unpalatable and that parents/carers use a range of strategies to improve acceptability of this product. Although food is an obvious strategy for making flucloxacillin more palatable when treating an acute infection; it may be that this doesn't work in longer term therapy (eg CF) and the wider population can learn from parents/carers with more experience with this medicine. Parents of children with CF and HCPs have provided useful age-specific strategies to ease administration of the known poorly tolerated medicine, liquid flucloxacillin.

Oral calorie supplements for cystic fibrosis.

BACKGROUND: Poor nutrition occurs frequently in people with cystic fibrosis (CF) and is associated with other adverse outcomes. Oral calorie supplements are used to increase total daily calorie intake and improve weight gain. However, they are expensive and there are concerns they may reduce the amount of food eaten and not improve overall energy intake. OBJECTIVES: To establish whether in people with CF, oral calorie supplements: increase daily calorie intake; and improve overall nutritional intake, nutritional indices, lung function, survival and quality of life. To assess adverse effects associated with using these supplements. SEARCH METHODS: We searched the Cochrane CF Trials Register comprising references from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We contacted companies marketing oral calorie supplements.Last search: 03 July 2014. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing use of oral calorie supplements for at least one month to increase calorie intake with no specific intervention or additional nutritional advice in people with CF. DATA COLLECTION AND ANALYSIS: We independently selected the included trials, assessed risk of bias and extracted data. We contacted the authors of included trials and obtained additional information for two trials. MAIN RESULTS: We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were concerns surrounding allocation concealment. There were no significant differences between people receiving supplements or dietary advice alone for change in weight, height, body mass index, z score or other indices of nutrition or growth. Changes in weight (kg) at three, six and twelve months respectively were: MD 0.32 (95% CI -0.09 to 0.72); MD 0.47 (95% CI -0.07 to 1.02 ); and MD 0.16 (-0.68 to 1.00). Total calorie intake was greater in people taking supplements at 12 months, MD 265.70 (95% CI 42.94 to 488.46). There were no significant differences between the groups for anthropometric measures of body composition, lung function, gastrointestinal adverse effects or activity levels. AUTHORS' CONCLUSIONS: Oral calorie supplements do not confer any additional benefit in the nutritional management of moderately malnourished children with CF over and above the use of dietary advice and monitoring alone. While nutritional supplements may be used, they should not be regarded as essential. Further randomised controlled trials are needed to establish the role of short-term oral protein energy supplements in people with CF and acute weight loss and also for the long-term nutritional management of adults with CF or advanced lung disease, or both.