Andrew E. Mulberg

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Cross-sector sponsorship of research in eosinophilic esophagitis: A collaborative model for rational drug development in rare diseases

Like many rare diseases, eosinophilic esophagitis (EoE) is a poorly understood disorder, and assessment tools to accurately determine disease activity, remission, and natural history have long been inadequate. Clinical outcome end points able to assess the effectiveness of candidate therapeutic agents in clinical trials have been a particular deficiency and are urgently needed. With no approved therapy available to patients and with the prevalence of EoE on the increase, collaborative approaches to drug development are becoming ever more important. We describe a collaborative effort mobilized across institutions, including both the public and private sectors, that was initiated within the past 18 months expressly to address the need for further clinical research into the cause and treatment of EoE. Collaborators include the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; the International Gastrointestinal Eosinophilic Researchers; and the US Food and Drug Administration. This effort has resulted in the elucidation of several parameters essential for effective EoE registration trials, including the need for clinically meaningful end points that measure changes in clinical symptoms in addition to the assessment of intraepithelial mucosal eosinophilia. The development and use of biomarkers, particularly in early-phase drug development, have become an important focus for investigations that might reduce clinical reliance on serial invasive monitoring. The concerted efforts described here to develop rational therapeutics and drug development paradigms in EoE also appear to provide a model for effective collaboration in the context of drug development for rare diseases and perhaps more generally for public health initiatives.

Literature Review of Gastrointestinal Physiology in the Elderly, in Pediatric Patients, and in Patients with Gastrointestinal Diseases

Oral bioavailability studies during the development of new medical entities or generic drugs are typically performed in healthy volunteers. Approved drug products are, however, used by patients with diverse disease backgrounds, and by pediatric and elderly patients. To provide the knowledge base for assessing the potential effects of age or co-morbidity on the in vivo performance of an orally absorbed, systemically active drug product, the literature regarding the gastrointestinal (GI) physiological characteristics (pH, permeability, and transit time) in children, in the elderly, and in patients with GI diseases (irritable bowel syndrome, ulcerative colitis, and Crohns disease) is reviewed herein, with the knowledge gaps highlighted.

Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure‐matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies’ trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti‐infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.

Development of Celiac Disease Therapeutics: Report of the Third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 CL IN IC AL PR AC TI CE UP DA TE Ceases. Although not as prevalent as irritable bowel syndrome, it is significantly more common than inflammatory bowel disease. Although patients are rarely hospitalized or undergo surgery due to celiac disease, attributable mortality is increased and burden of treatment, defined as the degree of difficulty in following treatment, is higher than other common luminal diseases. Despite the prevalence, morbidity, and treatment burden, there is significant unmet medical need for pharmacologic interventions beyond a gluten-free diet (GFD). At the time of the workshop, fewer than a dozen randomized controlled therapeutic trials had been published. Major historical obstacles to drug development include misperceptions that celiac disease is rare and mild, and that the GFD is a near-optimal therapy. In addition, there has been no precedent product approval for celiac disease that defines a guiding regulatory pathway for product developers. On March 31, 2015, the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3) workshop was held, which was sponsored by the Food and Drug Administration (FDA) Center for Drug Evaluation and Research, with co-sponsorship by the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. The meeting covered defining target populations for pharmacologic therapies, and defining and measuring clinical benefit in celiac disease trials to support marketing approval.

Practical Considerations for the Use of Clinical Outcome Assessments (COAs) in Pediatric Clinical Research Examples From Pediatric Gastroenterology

Clinical outcome assessments (COAs), including patient-reported outcome (PRO) measures, are routinely used in drug development and other clinical research initiatives to assess the impact of treatment on patient health and well-being. The FDA Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (2009), the European Medicines Agency’s Reflection Paper on the Regulatory Guidance for the Use of Health-Related Quality of Life Measures in the Evaluation of Medicinal Products (2005), and the International Society for Pharmacoeconomics and Outcomes Research PRO Good Research Practices for the Assessment of Children and Adolescence Task Force (2013) outline key considerations and good measurement principles that are relevant to the selection and use of COAs in a pediatric population. However, challenges remain in the appropriate selection and use of COAs to assess treatment benefit in pediatric clinical research. The purpose of this paper is to summarize proceedings from a panel presentation at the Critical Path Institute’s 2015 Annual PRO Consortium Workshop. This paper underscores the importance of considering children’s specific needs and the numerous challenges faced when developing and implementing well-defined and reliable COAs in pediatric clinical trials evaluating medical products, and describes some approaches to addressing these unique needs and challenges.

Proceedings From FDA/A.S.P.E.N. Public Workshop Clinical Trial Design for Intravenous Fat Emulsion Products, October 29, 2013

The development of intravenous fat emulsion (IVFE) is the culmination of physiological, biochemical, nutritional, and medical scientific advancements. IVFEs have the ability to deliver critical nutritional substrates to the patient. Recent literature purports that they may also play roles in modulation of immune functionality and pulmonary physiology, but data supporting these potential benefits are limited. While soybean-based IVFEs have comprised the dominant fat in U.S. markets, a number of other novel IVFEs may prove to optimize the care of children and adults in both hospitalized and home settings. The October 2013 U.S. Food and Drug Administration (FDA)/American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Public Workshop brought together scientists, researchers, and clinical experts to present updated clinical perspectives of IVFEs, including historical development, current state of usage throughout the world, and considerations for the regulatory approval of new IVFEs in the United States.

Drug development: The use of unlicensed/off-label medicines in pediatrics.

Received August 30, 201 From the Probiotics Re School of Medicine, J Medicine, Universit zUniversity of New S of Paediatrics and C Stellenbosch Univers Centre for Child Heal ment of Pediatrics, Pe University of Rome, R and Inborn Errors Pro MD. Address correspondence PhD, Juntendo Univer (e-mail: yamasiro@ju The authors report no co Copyright # 2012 by E Hepatology, and Nut Gastroenterology, He DOI: 10.1097/MPG.0b01

Clinical Trials (Industry/Regulatory Perspective)

Pediatric drug development is a complex process which requires the cooperation of various stakeholders including researchers, pharmaceutical companies, and regulatory agencies. In the USA, oversight of all aspects of the drug development process is handled by the Food and Drug Administration (FDA). The FDA is tasked with ensuring that all drugs brought to market have demonstrated safety and efficacy, that they are manufactured under appropriate conditions, and that the promotional materials associated are true and not misleading. This chapter will review the history of federal regulations which guide US drug development, provide an overview of the clinical trial process, and discuss specific concerns relevant to drug development in the pediatric population, utilizing inflammatory bowel disease drug development programs as an example.

Pediatric Intestinal Failure–Associated Liver Disease Challenges in Identifying Clinically Relevant Biomarkers

BACKGROUND Intestinal failure-associated liver disease (IFALD) is complex and diagnosed by concurrent use of parenteral nutrition, clinical presentation, and alterations in hepatic biomarkers exclusive of other causes of liver disease. In comparison with individual measures, composite biomarkers may provide a more effective means for assessing disease progression and response to treatment than single parameters. Since IFALD is considered by some to be a type of drug-induced liver injury (DILI), those diagnostic criteria could potentially be used in this population. Using a preexisting database of children treated for IFALD, our aim was to determine if a similar composite biomarker could be applied to this population. STUDY DESIGN Adult DILI criteria were applied at baseline, when treatment for IFALD (ie, direct bilirubin ≥2.0 mg/dL) was initiated. RESULTS A total of 214 patients with IFALD treated at Boston Childrens Hospital were identified; 168 patients were eligible for analysis. Most patients analyzed were male (61%) and preterm (87%). Alkaline phosphatase (ALP) ≥2× upper limit of normal (ULN) captured the least amount of DILI (11%), while γ-glutamyltransferase (GGT) ≥1× ULN accounted for the most (62%). Using adult DILI criteria, 60 (39%) patients with IFALD were found to have DILI. Substituting GGT ≥1× ULN for ALP ≥2× ULN improved the sensitivity, with 105 (69%) of patients meeting at least 1 criterion for DILI. CONCLUSION Numerous challenges made it difficult to apply the DILI criteria to children with IFALD. Direct bilirubin, fractionated ALP, and perhaps GGT may be more suitable. Given its complex etiology and the age-based differences due to hepatic immaturity and growth, a more suitable composite marker needs to be developed to assess IFALD in this population.