Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth.

Compared with drugs from the blockbuster era, recently authorized drugs and those expected in the future present a heterogenous mix of chemicals, biologicals, and cell and gene therapies, a sizable fraction being for rare diseases, and even individualized treatments or individualized combinations. The shift in the nature of products entails secular trends for the definitions of "drugs" and "target population" and for clinical use and evidence generation. We discuss that the lessons learned from evidence generation for 20th century medicines may have limited relevance for 21st century medicines. We explain why the future is not about randomized controlled trials (RCTs) vs. real-world evidence (RWE) but RCTs and RWE-not just for the assessment of safety but also of effectiveness. Finally, we highlight that, in the era of precision medicine, we may not be able to reliably describe some small treatment effects-either by way of RCTs or RWE.

Guidance on development and operation of Young Persons' Advisory Groups.

BACKGROUND: Engaging patients and the public as collaborators in research is increasingly recognised as important as such partnerships can help improve research relevance and acceptability. Young Persons' Advisory Groups (YPAGs) provide a forum for clinical researchers and triallists to engage with children and young people on issues relevant to the design, conduct and translation of paediatric clinical trials. Until fairly recently, there was very little information available to guide the successful development and operation of YPAGs. OBJECTIVE: To develop an evidence-based tool to guide clinical researchers and triallists in the establishment and operation of a YPAG. METHODS: An online needs assessment survey was conducted using SurveyMonkey with 60 known paediatric drug researchers to identify knowledge gaps around YPAG engagement, development and operation. Semistructured interviews with founders and coordinators of five well-established existing YPAGs and a review of the literature were performed to identify best-practice processes for starting up and operating YPAG. RESULTS: The majority of 12 survey respondents (20%) from 12 different centres indicated that while they felt YPAGs could benefit their research, guidance on how to develop and operate a YPAG was needed. Most preferred a web-based guidance tool. Ten core steps in starting up and operating a YPAG were identified and developed into an online YPAG guidance tool, now freely accessible for use by paediatric clinical researchers worldwide. Plans to evaluate the impact are in place. CONCLUSIONS: This novel tool, developed with an internationally based group of public involvement leads working across paediatric clinical research areas, provides harmonised guidance for researchers seeking to develop and operate YPAGs to help improve the quality and impact of paediatric clinical research studies.

The future of cystic fibrosis care: a global perspective.

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

Industry and Patient Perspectives on Child Participation in Clinical Trials: The Pediatric Assent Initiative Survey Report.

BACKGROUND: Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment-allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. METHODS: Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations' experience and policies regarding pediatric assent. RESULTS: Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. CONCLUSIONS: An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Pediatric Medicine Development: An Overview and Comparison of Regulatory Processes in the European Union and United States.

Pediatric legislation in the US and the EU is driving pediatric product development on an international scale. To facilitate harmonization and global development of pediatric medicines, it is important to understand the legislative requirements that must be met along with incentives that exist in the US and the EU to include pediatric patients in therapeutic clinical trials. Although there are many similarities, differences exist. This review is an effort to enhance understanding of the pediatric legislation in both regions. It is intended as an overview to supplement the region-specific legislation and guidance documents that are available on the websites of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite differences, the goal of the legislation in both the EU and the US is to incentivize and require timely, ethical, and sound scientific development of pharmaceutical products for the pediatric population and to provide information for their safe and effective use.

The future of the development of medicines in idiopathic pulmonary fibrosis.

The development of treatments for idiopathic pulmonary fibrosis (IPF) has been often disappointing. Building on authorized treatments that can benchmark the validity of treatment effect measures, the time has come to standardize endpoints and achieve consensus on their use for different clinical questions and specific IPF phenotypes. In order to facilitate the development of new medicines for IPF it is crucial that the knowledge of the disease and lessons learnt from past trials are taken forward to create international trial networks with involvement of patients, including biobanks and clinical data collection through a multinational registry. Interaction with regulators may be useful to align the initiatives of academia and pharmaceutical companies with the bodies ultimately responsible for licensing new products. Interaction can occur through the use of qualification programs for biomarkers and endpoints, and participation in innovative regulatory pathways and initiatives. Finally, the experience of IPF should be used to benefit even rarer interstitial lung diseases for which no treatment is available, including pediatric interstitial lung diseases. This commentary provides a perspective on the hurdles slowing the development and regulatory approval of medicines for IPF, and encourages close cooperation between investigators and drug regulators.

Assessing the relative efficacy of new drugs: an emerging opportunity.

The increasing availability of individual-level data from clinical trials could allow the relative efficacy of new drugs to be assessed in a robust, cost-effective and timely way.

Lung transplantation in children and young adults: a 20-year single-centre experience.

Lung transplantation in adults is an accepted therapeutic option, whereas there is ongoing debate on its positive impact on survival in children. We report our experience of the first 20 yrs of paediatric lung transplantation at a single centre in Austria. Patient survival, organ survival and freedom from bronchiolitis obliterans were estimated by Kaplan-Meier curves. Pre- and post-transplant parameters were assessed and their influence on patient and organ survival evaluated by univariate tests and stepwise multivariate analyses. A total of 55 transplantations were performed in 43 patients. 1- and 5-yr patient survival rates were 72.1% and 60.6%, respectively, and 52.6% of patients were found to be free from bronchiolitis obliterans syndrome at 5 yrs post-transplant. Analysing different eras of transplantation suggests an improvement over the years with a 5-yr survival rate of 70.6% in the second decade. A positive effect of pre-transplant diabetes mellitus and immunosuppression was found with the newer drug tacrolimus, and a negative effect of pre-transplant in-hospital admission was reported. A high rate of successful re-transplantation prolonged total patient survival.

The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients.

BACKGROUND: The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. METHODS: We studied the effects of 1-EBIO on CFTR-mediated Cl⁻ secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl⁻ secretion. RESULTS: Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²âº-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance. CONCLUSIONS: We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF.

Minimal acute rejection in pediatric lung transplantation--does it matter?

In adult lung transplantation, a single minimal AR episode is a significant predictor of BOS independent of other factors. However, the significance of single minimal AR episodes in children is unknown. A retrospective, multi-center analysis was performed to determine whether isolated single AR episodes are associated with an increased BOS risk in children. Risk factors for BOS, death, or re-transplantation, and a combined outcome of BOS, death, or re-transplantation were assessed. Original data included 577 patients (<21 yr of age). A total of 383 subjects were eligible for the study. Fifteen percent of patients developed BOS, and 13% of patients either died or underwent re-transplant within one-yr post-transplant. In the multivariable survival model for time to BOS, there was no significant risk to developing BOS after a single minimal AR (A1) episode (HR 1.7, 95% CI 0.64-4.8; p=0.28). Even after a second minimal AR episode, no significant risk for BOS was appreciated. However, a single episode of mild AR (A2) was associated with twice the risk of BOS within one-yr post-transplant. In this select cohort, a single minimal AR episode was not associated with an increased risk for BOS within one yr following lung transplantation, in contrast to previous reports in adults.

Cytomegalovirus immunoglobulin decreases the risk of cytomegalovirus infection but not disease after pediatric lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. METHODS: A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. RESULTS: Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2-9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation. CONCLUSION: The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation.

The risk, prevention, and outcome of cytomegalovirus after pediatric lung transplantation.

BACKGROUND: A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy. METHODS: Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models. RESULTS: Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D-/R- subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4-8.4; D+/R- 1.9, 1.02-3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1-3.6; P=0.024). CONCLUSIONS: CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Increased mortality after pulmonary fungal infection within the first year after pediatric lung transplantation.

BACKGROUND: Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized. METHODS: A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models. RESULTS: Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8). CONCLUSIONS: Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.

Variability in immunization guidelines in children before and after lung transplantation.

Lung transplant candidates and recipients are at high risk of infections from vaccine-preventable diseases. However, well-established guidelines neither exist for pre- and post-transplant vaccination nor do monitoring guidelines for pediatric lung transplant recipients. To ascertain the current vaccination and monitoring practices of pediatric lung transplant centers, a self-administered questionnaire was distributed to the 18 pediatric lung transplant centers within the International Pediatric Lung Transplant Collaborative in April 2006. Sixteen of 18 centers (89%) surveyed responded. Pretransplant, national vaccination guidelines are followed. Eleven centers reported following standardized vaccination guidelines post-transplant. Vaccines were more commonly provided by the primary-care physician pretransplant (69%) rather than post-transplant (38%). Post-transplant, 50% of the centers recommend live vaccines for household contacts but not for the transplant recipient. Pretransplant monitoring of response to prior vaccination was performed inconsistently except for varicella (88%). Only 44% of the transplant centers measure for response to vaccination post-transplant, mostly hepatitis B. Current vaccination practices of pediatric lung transplant centers are heterogeneous. The lung transplant community would be well served by studies designed to evaluate the efficacy of vaccinations in this population.

Clinical pharmacology study of Bramitob, a tobramycin solution for nebulization, in comparison with Tobi.

BACKGROUND AND OBJECTIVES: To compare in vitro characteristics and pharmacokinetics of Bramitob, a preservative-free tobramycin solution for nebulization, and Tobi in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa infection. METHODS: In vitro characteristics of Bramitob and Tobi were evaluated using Pari TurboBoy/LC Plus and the Systam 290 LS nebulizers. In the randomized, double-blind, two-way crossover pharmacokinetic study, 11 patients with CF received a single nebulized dose (300mg) of Bramitob or Tobi, separated by a 7-day washout period. Plasma and sputum tobramycin concentrations were measured immediately before and over 24 hours after administration. RESULTS: Bramitob and Tobi performed alike during nebulization. The fine particle fraction was 33-37% and the mass median aerodynamic diameter was <5microm. Nine patients completed the pharmacokinetic study. Tobramycin plasma profiles after administration of Bramitob or Tobi were similar, with a peak at 90 and 72 minutes after inhalation of Bramitob and Tobi, respectively. The elimination half-life was ~5 hours for both products. The relative bioavailability of Bramitob to Tobi was 1.01, indicating comparable systemic exposure. Peak sputum concentration of tobramycin was 816 +/- 681 microg/g for Tobi and 1289 +/- 851 microg/g for Bramitob and was >400 microg/g (threshold sufficient for an antibacterial effect against P. aeruginosa) in 5 out of 9 patients receiving Tobi and 8 out of 9 patients receiving Bramitob. All adverse events were considered mild and judged not related to the study drugs. CONCLUSIONS: In vitro performance of Bramitob((R)) was similar when nebulized with Pari TurboBoy k/LC Plus and Systam 290 LS nebulizers and comparable to that of TobiThe systemic bioavailability of tobramycin was similar after administration of either Bramitob or Tobi; however, in sputum samples the tobramycin peak concentration was slightly greater after administration of Bramitob than after Tobi.

Laser acupuncture and probiotics in school age children with asthma: a randomized, placebo-controlled pilot study of therapy guided by principles of Traditional Chinese Medicine.

Traditional Chinese Medicine (TCM) postulates an interaction between the lung as a Yin-organ and the large intestine as a Yang-organ. The aim of this pilot study was to investigate in asthmatic school age children whether treatment with laser acupuncture and probiotics according to TCM portends a clinical benefit to standard medical treatment performed according to pediatric guidelines. Seventeen children aged 6-12 yr with intermittent or mild persistent asthma were enrolled in this randomized, placebo-controlled, double-blind pilot study. Eight patients received laser acupuncture for 10 wk and probiotic treatment in the form of oral drops (living non-pathogenic Enterococcus faecalis) for 7 wk. Nine patients in the control group were treated with a laser pen which did not emit laser light and were given placebo drops. Peak flow variability (PFV) and forced expiratory volume in 1 s (FEV(1)) were measured and Quality of Life was assessed by a standardized questionnaire. Laser acupuncture and probiotics significantly decreased mean (standard deviation) weekly PFV as a measurement of bronchial hyperreactivity by -17.4% (14.2) in the TCM group vs. 2.2% (22.5) in the control group (p = 0.034). No significant effect was detected for FEV(1), Quality of Life criteria and additional medication. As an exploratory result, patients in the TCM group had fewer days of acute febrile infections when compared with the control group [1.14 (1.4) vs. 2.66 (2.5), p = 0.18]. In conclusion, this pilot study generates the hypothesis that the interactive treatment of lung and large intestine according to TCM by laser acupuncture and probiotics has a beneficial clinical effect on bronchial hyperreactivity in school age children with intermittent or mild persistent asthma and might be helpful in the prevention of acute respiratory exacerbations. These results should be confirmed by further studies.