PCOR is research that helps people and their caregivers communicate and make informed healthcare decisions and allows their perspective to be heard in assessing the value of healthcare options. PCOR answers questions related to healthcare decisions and options by investigating benefits and harms of treatments, making comparisons, focusing on outcomes that patients care about, incorporating diverse settings and patients, and evaluating how to optimize outcomes while addressing individual, societal, technological, and resource barriers (PCORI)

AASLD Clinical Research Workshop Breakout Session I: Funding Patient-Oriented Research Co-leaders: Drs. David Nelson & Donna Evon

Funding Opportunities for POR/PCOR: Funding opportunities have become more numerous over the last five years

since the focus on patient-centered medicine and the establishment of the Patient Centered Outcomes Research Institute

(PCORI) in 2010. Opportunities exist at: PCORI, AHRQ, VA, DOD, NIH, CTSA programs, and pharmaceutical-sponsored

studies.

Examples:

PCORI: http://www.pcori.org/funding-opportunities

AHRQ: http://www.ahrq.gov/cpi/initiatives/pcortf/pcor-home.html and http://grants.nih.gov/grants/guide/pa-files/PA-16-

283.html

NIH CTSAs: https://researchtraining.nih.gov/programs/career-development/K12

NIH K23: https://researchtraining.nih.gov/programs/career-development/K23

Industry: http://merckresearch.net/Patient_Engagement_Diversity_Health_Literacy.html

Roadmap to successful funding: Successful NIH POR applications need to address the following: 1) Is the proposal

hypothesis driven and do previously published data suggest that the hypothesis is sound?; 2) Is the hypothesis novel, and

will the findings make a contribution to patient care?; 3) Is the study design appropriate and is the methodological and

analytic plan sound?; 4) Can the project be completed in the time and resources requested? In addition to the above,

successful PCORI applications need to address the following five areas: 1) Impact of the condition on the health of

individuals and population; 2) Potential for the study to improve health care and outcome; 3) technical/methodological

merit; 4) patient-centeredness; and 5) patient and stakeholder engagement.

References:

1. Sacristán JA. Patient-centered medicine and patient-oriented research: improving health outcomes for individual patients. BMC Med Inform Decis Mak. 2013. PMID: 23294526.

2. Frank L, Basch E, Selby JV; Patient-Centered Outcomes Research Institute. The PCORI perspective on patient-centered outcomes research. JAMA. 2014 Oct. PMID: 25167382.

3. Methodology Committee of the PCORI. Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. JAMA. 2012 Apr. PMID: 22511692.

POR is research conducted with human subjects (or material of human origin such as tissue) for which the investigator directly interacts with human subjects. POR includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies (NIH)

PROs are any report of the status of a patient’s health condition that comes directly from the patient or surrogate, without interpretation of the patient’s response by a clinician or anyone else (FDA)

Stakeholder/Patient Engagement Stakeholder is an individual or group who is responsible for or affected by health- and healthcare-related decisions that can be informed by research evidence. Engagement is a bi-directional relationship between the stakeholder and researcher that results in informed decision-making about the selection, conduct, and use of research (Concannon Taxonomy, JGIM, 2012)

4. Concannon TW et al. A new taxonomy for stakeholder engagement in patient-centered outcomes research. J Gen Intern Med. 2012 Aug. PMID: 22528615

5. Fleurence RL et al. Engaging patients and stakeholders in research proposal review: the patient-centered outcomes research institute. Ann Intern Med. 2014. PMID: 25023251.

6. Fleurence RL et al. Patient-powered research networks aim to improve patient care and health research. Health Affairs (Millwood). 2014 Jul. PMID:25006148.

7. Basch E. New frontiers in patient-reported outcomes: adverse event reporting, comparative effectiveness, and quality assessment. Annu Rev Med. 2014. PMID: 24274179.

8. PCORI’s Patient Engagement: http://www.pcori.org/funding-opportunities/what-we-mean-engagement

9. PCORnet; Opportunities for Big Data research: http://pcornet.org/about-pcornet/

2016 AASLD Clinical Research Workshop: Comparative Effectiveness in Hepatitis C Elizabeth C. Verna, MD, MS, Center for Liver Disease and Transplantation, Columbia University Medical

Center, New York, NY

Camilla S. Graham, MD, MPH, Infectious Disease, Beth Israel Deaconess Medical Center, Boston, MA

“Efficacy” reflects the degree to which an intervention produces the expected result under carefully

controlled conditions chosen to maximize the likelihood of observing an effect if it exists.

“Effectiveness” addresses the extent to which an intervention is beneficial when deployed in medical

practice settings and broader populations. It takes into account:

Benefits and harms of an intervention.

External factors such as individual patient characteristics, health system features, and societal influences.

Addresses the gap between clinical trials and the “real world” impact of individual-level or population-

level interventions on health outcomes.

Includes (1) availability and accessibility of the intervention to patients who can obtain benefit in

appropriate health care settings, (2) identification of patients who are appropriate for the intervention, (3)

recommendation of the intervention by providers, (4) acceptance of the intervention by patients, and (5)

adherence to treatment at the recommended dosing for therapeutic coverage to fully achieve the benefits

of therapy.

“Comparative effectiveness” compares the benefits and harms of alternative methods to prevent, diagnose,

treat, and monitor a clinical condition or to improve the delivery of care.

Conducted in settings that are similar to those in which the intervention will be used in practice.

Measures outcomes, both benefits and harms, that are important to patients.

Directs a health policy decision from the population perspective.

Focuses on the individual rather than the average patient by analyzing results at the population and

subgroup levels.

Compares at least two alternative interventions, each with the potential to be “best practice.”

Adapted from El-Serag, Talwalkar, Kim; Efficacy, effectiveness, and comparative effectiveness in liver disease. Hepatology 2010; 52

(2): 403–407.

Examples of comparative effectiveness research gaps in HCV care (for discussion):

1. Diagnosis:

a. Rapid anti-HCV tests versus lab-based tests

b. Quantitative versus qualitative HCV RNA tests versus HCV core antigen assays

c. Screening targeted versus general populations

2. Linkage to care

a. Types of providers – specialists versus primary care

i. Sub-populations in whom outcomes may differ by type of provider

b. Care setting – local (prisons, primary care clinics, addiction services) versus tertiary

c. Use of care assistants (like navigators) or technology versus usual care

d. Optimizing patient readiness for treatment in specific settings

3. Selection of antiviral regimen

a. Patient preference for regimen, dosing and packaging, efficacy, adverse effects, medication

interactions, monitoring, cost and co-pay assistance between regimens

b. Payer preference for immediate budget impact and long-term cost effectiveness

Example reference: Chou et al. Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus

Infection in Adults: A Systematic Review. Annals Internal Medicine 2013; 158(2): 114-123.

Clinical Research Workshop Breakout Session:

Patient-Oriented Research in NAFLD

Kathleen Corey, MD, MPH, MMSc

Rohit Loomba, MD, MHSc

Outline

• Kathleen Corey:

• Describe the types of studies • Advantages and disadvantages of study designs

• Rohit Loomba:

• Provide examples of the various types of studies • Practical tips regarding how to initiate and execute

them

Cross Sectional and Case-Control Studies

Cross Sectional Studies

• Method: Descriptive study to asssess exposure and outcome in a population at a single point in time

• Goal: Determine associations but not causality

Case-Control Studies • Method: Retrospectively

compares characteristics of group with a given health outcome (cases) to a similar group without the outcome (controls)

• Goal: Identify and compare factors/exposures associated with a condition, compare odds of outcome based on exposure

Prospective Cohort Studies

• Method: Follow groups of individuals over time and regularly gather information on a variety of variables (IE change in weight, laboratory values). Outcomes over time are compared to test specific hypotheses.

• Goal: determine link between exposure/variables and outcome

• Retrospective Cohort: similar to prospective but utilizes information previously collected. Patients are identified for exposure or non-exposures and the data is followed forward to outcome of interest.

Randomized Trials

• Method: Planned experiment to assess impact of intervention/exposure on outcome; individuals randomly assigned to receive or not receive intervention

• Goal: Test efficacy of intervention

Advantages and Disadvantages of Study Methods

Advantages Disadvantages

Cross-sectional Simple and efficient way to study associations, estimate prevalence

Cannot assess causality Survivor and recall bias Inefficient for rare conditions

Case-control Useful for rare conditions Good for long latency Relatively quick Inexpensive

Assess association but not causality Subject to recall bias Control selection may introduce bias

Retrospective cohort Relatively quick Inexpensive

Exposed individuals may differ significantly from unexposed

Prospective cohort

Accurate measures of exposures (no recall bias)

Exposed may differ from unexposed Expensive and time consuming

Clinical Trial Minimize bias by randomization and blinding

Expensive and time consuming

Evidence pyramid

• Meta-analysis of RCT

• Randomized placebo controlled trial

• Prospective cohort studies

• Case-control studies

• Case series

• Opinion, case-reports

Clinical problem (or Aim)

Hypothesis

Is the hypothesis aligned with the aim and analysis plan?

Design or type of study

Is the design appropriate to test the hypothesis?

Case control studies

• Case-control study: study originally developed in epidemiology, in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute. • Utility: Rare disease or rare events

• Comparing NAFLD versus HIV-associated NAFLD

• Bias: Risk may get accentuated

Vodkin et al. APT 2015

Multivariable-adjusted risk of NASH in HIV-associated NAFLD

Vodkin et al. APT 2015

Risk of NASH is independent of age, sex, ethnicity and BMI

Cross-sectional study

• Cross-sectional study: involves data collection from a population, or a representative subset, at one specific point in time. • Diagnostic test studies comparing a new test with a gold

standard e.g. MRE versus histology in NAFLD

Cohort 1: UCSD NAFLD Cohort

NAFLD histology • NAFL • NASH

Stage Stage 0: No fibrosis

Stage 1a/b/c: Mild fibrosis

Stage 2: Moderate

fibrosis

Stage 3: Bridging fibrosis

Stage 4: Cirrhosis

Fatty liver on imaging

or Elevated ALT/AST

Confirm NAFLD : Quantify alcohol use

Rule out other causes of liver

disease

Quantify fat by Imaging

• MRI-PDFF/MRS

Quantify fibrosis

• MRE/ARFI/Fibroscan

Paired samples

Plasma/DNA/Stools

within

90 days of liver biopsy

and MRI

Pathology MRI

N = 300 (250 paired stool/plasma samples) NAFLD patients

available as October 2016

Cohort 2: UCSD Twin Study

1. Twin-pair Monozygotic

2. Twin-pair Dizygotic

Detailed metabolic phenotyping

Quantify alcohol use

Rule out other causes of liver

disease or fatty liver

Quantify fat by MRI

• MRI-Proton density fat fraction

validated by MRS (gold standard)

Paired samples

Plasma/Urine/Stools within

30 days of MRI

N = 210 paired samples on Twin/sib-sib/parent-offsprings pairs available as of

February 2016

Cohort 2: Unique and complimentary

ascertainment attributes

Community-dwelling

Random sample

Recruited via Newspaper

Advertisement

NAFLD:

MRI-PDFF > 5%

No NAFLD

MRI-PDFF < 5%

Cohort 2: Unique phenotyping for

normal (non-NAFLD) control

Resource for scientific community

as ALT and ultrasound/CT are

insensitive and liver biopsy is

unethical

Who should we screen for NASH and advanced

fibrosis?

17

18

Patients with Type 2 DM

Evaluate for liver disease Alcohol consumption

MRI

NAFLD No NAFLD

CAC + CAC- CAC + CAC -

Specimens 1. Serum 2. Plasma 3. Urine 4. Stool 5. DNA 6. Biopsy those with NAFLD

Cohort 3: Screening for NAFLD, advanced fibrosis in patients with type 2 diabetes

Central goal of this research project is to develop efficient screening program for advanced liver disease in patients with type 2 DM

Doycheva et al. APT 2016

Type 2 Diabetes in

Primary Care

Screen for

NAFLD MRI-

PDFF ≥ 5%

Screen for

advanced fibrosis MRE ≥ 3.6 kPa

NAFLD 65 %

Advanced fibrosis

7.4%

Prevalence of NAFLD and advanced fibrosis among patients with Type 2

diabetes in primary care

Doycheva et al. APT 2016

Spectrum of liver fat and fibrosis in diabetes

Doycheva et al. APT 2016

Screening: HCC in diabetes

Doycheva et al. APT 2016

Longitudinal or Cohort studies

• Longitudinal study: correlational research study that involves repeated observations of the same variables over long periods of time. • Changes in AFP over time and risk of HCC

• Cohort study: a particular form of longitudinal study where a group of patients is closely monitored over a span of time. • Risk of HCC in patients with cirrhosis

Kinetic biomarkers of

fibrosis Differentiate rapid

progressors Early indicator of anti-

fibrotic response

B

A

Novel assessment of kinetic biomarkers of fibrosis in NAFLD

Decaris et al. Hepatology 2016 in press

Joint effects of obesity and alcohol on HCC risk in men with

hepatitis B

Loomba et al. CGH 2010

Mortality is higher in NASH versus NAFL

Soderberg et al. Hepatology 2010

Surv

ival

Time, years

NAFL

NAFL

NASH

Familial Cirrhosis Study

27

Cohort 5: Familial Cirrhosis Study

1. Probands with NASH Cirrhosis

2. First-degree relatives

Detailed metabolic phenotyping

Quantify alcohol use

Rule out other causes of liver

disease or fatty liver

Quantify fat by MRI and fibrosis by MRE • MRI-Proton density fat fraction

validated by MRS (gold standard)

Paired samples

Plasma/Urine/Stools within

30 days of MRI

N = 25 families paired samples available as of

August, 2015

Cohort 5: Unique and complimentary

ascertainment attributes

What is the risk of NASH cirrhosis

if first degree relative has

NASH Cirrhosis?

NAFLD Cirrhosis

MRE > 3.6% No NAFLD cirrhosis

MRE < 3.6

Cohort 5: Unique phenotyping for

normal (non-NAFLD) control

Resource for scientific community

as ALT and ultrasound/CT are

insensitive and liver biopsy is

unethical

Novel MRI and MRE assessment of ezetimibe

versus placebo for the treatment of

nonalcoholic steatohepatitis: A randomized-

controlled trial MOZART Trial

An example of innovation in clinical trials

Loomba et al. Hepatology 2015

MOZART Trial Design: Ezetimibe vs Placebo

n=50

Ezetimibe 10 mg daily

Placebo

0 12 4 24

Follow-up

Study Weeks

Labs, MRS, MRI-PDFF,

liver biopsy +

2D MRE 3D MRE

Labs, MRS, MRI-PDFF, liver biopsy

+

2D MRE 3D MRE

Randomization in blocks 4 in 1:1 ratio Vitals, anthropometric, labs

Urine Stool plasma

Urine Stool plasma

Urine Stool plasma

First trial to assess 2D and 3D MRE in NASH

Design: Randomized, double-blind, allocation-concealed, placebo-controlled, clinical trial

Guidelines for conducting

observational studies

• What is STROBE? STROBE stands for an international, collaborative initiative of epidemiologists, methodologists, statisticians, researchers and journal editors involved in the conduct and dissemination of observational studies, with the common aim of STrengthening the Reporting of OBservational studies in Epidemiology.

Check-list

Check-list

http://www.strobe-statement.org/index.php?id=available-checklists

Check-list

http://www.strobe-statement.org/index.php?id=available-checklists

UCSD Twin Study

1. Twin-pair Monozygotic

2. Twin-pair Dizygotic

Detailed metabolic phenotyping

Quantify alcohol use

Rule out other causes of liver

disease or fatty liver

Quantify fat by MRI • MRI-Proton density fat fraction

validated by MRS (gold standard)

Paired samples

Plasma/Urine/Stools within

30 days of MRI and MRE

Unique ascertainment attributes

Community-dwelling

Random sample

Recruited via Newspaper

Advertisement

NAFLD:

MRI-PDFF > 5%

MRE

No NAFLD

MRI-PDFF < 5%

MRE

Unique phenotyping for normal

(non-NAFLD) control

Resource for scientific community

as ALT and ultrasound/CT are

insensitive and liver biopsy is

unethical

MRI-PDFF is the most accurate non-invasive method to quantify liver fat MRE is the most accurate non-invasive method of quantify liver fibrosis

Aims

• Specific aim 1: To determine the heritability of hepatic steatosis

• Specific aim 2: To determine the heritability of hepatic fibrosis

37

Loomba et al. Gastroenterology 2015

Baseline characteristics of the twin-cohort stratified by NAFLD status

Variable Overall NAFLD MRI-PDFF ≥

5%

Non-NAFLD MRI-PDFF

<5%

P-value

N 96 20 76

Demographics • Age • Sex (%men) • Race

(white)

48.6 (20.6) 24 (25%) 72 (75%)

57.1 (16.1)

8 (40%) 13 (65%)

46.3 (21.2) 16 (21.2%) 59 (77.6%)

<0.05 0.08 0.09

BMI (kg/m2) 24.9 (5.8) 30 (5.7) 23.6 (5.0) <0.0001

Glucose (mg/dl)

92.5 (19) 108.7 (33.9) 88.2 (8.9) <0.02

Insulin (U/l) 8.0 (4.8) 12.7 (5.2) 6.8 (3.9) <0.0001

HbA1c (%) 5.8 (0.5) 6.2 (0.7) 5.7 (0.3) <0.002

HOMA-IR 1.9 (1.5) 3.5 (1.8) 1.5 (1.0) <0.0001

TG (mg/dl) 90 (55) 142 (76) 76 (38) <0.0001

ALT (U/l) 21 (12) 27 (14) 20 (11) <0.01

MRI-PDFF (%) 3.9 (3.8) 10.4 (3.9) 2.3 (0.4) <0.0001

MRE (Kpa) 2.3 (0.73) 2.9 (1.2) 2.1 (0.4) <0.005

Heritability of hepatic steatosis content

Heritability estimate of liver fat = 0.5, p-value < 1.1 x 10-15

Loomba et al. Gastroenterology 2015

Heritability of hepatic fibrosis content

Heritability estimate of hepatic fibrosis = 0.5, p-value < 9.7 x 10-14

Loomba et al. Gastroenterology 2015

Integrated OMIC + phenotype data access

16S rRNA

UCSD Computational

Proteomics Unit

OMICS core

Translated Gene Sequences

Metagenomics

Metatranscriptome

Metaproteomics

Lipidomics/ metabolomics

Mass Spectrometry

Bio

info

rmatics co

re

Phenotype data Clinical Biopsy

Imaging

NO

MIC

PO

RTA

L

Quantitative Lipid/metabolomic

Profiles

Integrated OMICs in personalizing disease progression and treatment response in NAFLD and NASH

Whole genome sequencing

Microbiome

Metabolome

miRome

Phenotype Work-in-progress

Summary

• Well-designed observational studies can have a major impact on clinical practice

• Alignment of study aims, hypothesis, design and population is key before initiation of an observational study

• We discussed various examples of observational studies with each designed to answer a specific set of questions

• STROBE Guidelines should be utilized for observational studies

http://www.strobe-statement.org/index.php?id=available-checklists

Thank you Email: roloomba@ucsd.edu

Web: http://fattyliver.ucsd.edu Research supported by 1. R01, NIDDK, NIH 2. U01, NASH-CRN, NIDDK, NIH 3. K23, Genetic epidemiology of NAFLD, NIDDK, NIH 4. Investigator Initiated Research Grant Gilead Sciences Inc 5. Investigator Initiated Research Grant Daiichi Sankyo Inc 6. Investigator Initiated Research Grant-1 Merck Inc 7. C-Treat, Digestive Disease Center, UCSD, NIDDK, NIH 8. Investigator Initiated Research Grant- 2 Merck Inc 9. Kinemed Inc 10. American Gastroenterology Association-Research Scholar

Award 11. The T Franklin Williams Scholars Program 12. National Science Foundation

43

AASLD Clinical Research Workshop Breakout Session IV: Quality Measures in Liver Disease Mario Strazzabosco, MD, PhD and Ziad Gellad, MD Learning Objectives (for breakout): Upon completion of this activity, participants will be able to:

Recognize how quality measures are being developed and implemented in liver disease. In the current environment of value-based healthcare delivery, quality measures serve a number of key purposes: First and foremost, quality measures are vital tools in continuous quality improvement efforts among healthcare providers; Second, they serve as consensus-based benchmarks for documenting high quality care to patients, peers, payers and regulators; Finally, quality measures are also used in various payer programs to incentivize “high value” care. Because of these varying roles, development and implementation of quality measures can be a complex tug-of-war between validity and feasibility. This challenge is clearly evident in liver disease, and this session will review the process by which liver disease quality measures are developed and implemented. Potential questions we will address include:

1) Outcomes vs Process Measurements 2) What is the role of Clinical Outcome Indicators 3) What is the role of patient-reported outcomes in quality measurement? 4) What are the existing quality measures for public reporting of liver disease quality? 5) What is the process for developing a new quality measure? 6) What is the difference between measure “concepts” and measure “specifications?” 7) How can quality measures be used to drive performance improvement?

References: Kanwal F et al. An explicit Quality Indicator Set for Measurement of Quality of Care in Patients with Cirrhosis. Clin Gastroenterol Hepatology. 2010; 8: 709-717. Kanwal, F. Quality of Care Assessment in Chronic Liver Disease. Clin Liver Disease 2014; 4(6): 149-152. Tapper et al. A Quality Improvement Initiative Reduces 30-Day Rate of Readmissions for Patients with Cirrhosis. Clin Gastroenterol Hepatology. 2016; 14:753-759. Volk ML, Kanwal F. Quality of Care in the Cirrhotic Patient. Clinical & Translational Gastroenterology (2016). 7, e166. Porter M and Teisberg OM. How Physician Can Change the Future of Healthcare? JAMA 207; 397:1103-1111 Porter M What is Value in Healthcare? NEJM 2010; 363:2477-2481

Clinical Research Workshop: Breakout Session V

Ray Kim and Sammy Saab

There are a number of definitions of what constitutes patient-oriented research. What is common in

most of the definitions is the inclusion of the issues and themes directly important to the patient; in

other words, a greater participation of patients. For instance, the Canadian Institutes of Health

Research defines patient-oriented research as “a continuum of research that engages patients as

partners, focusses on patient-identified priorities and improves patient outcomes”.

Inclusion of patient-related outcomes has become an important goal of clinical research. Examples of

tools used to measure patient-related outcomes depend on the proposed question and include surveys,

clinical trials, cost-effectiveness analysis, and systematic reviews/meta-analyses. For instance, an

objective of many hepatitis C antiviral therapies was to assess the impact of achieving a sustained viral

response on work productivity.

We will discuss the following topics in an interactive fashion:

- How PRO is different from traditional biomedical measurements

- What are the steps involved in the development of PRO instruments

- What are measurement properties for PRO instruments?

o Reliability

o Validity

o Responsiveness

- What PRO instruments have been used in Hepatology?

- What are some of special considerations in studies assessing PRO?

The following papers are recommended as a pre-read:

1. Younossi Z, Henry L. Systematic review: patient-reported outcomes in chronic hepatitis C – the

impact of liver disease and new treatment regimens. Aliment Pharmacol Ther 2015;41:497-520.

2. Anderson RT, et al. Psychometric evaluation of the hepatitis C virus patient-reported outcomes

(HCV-PRO) instrument: validity, responsiveness, and identification of the minimally important

difference in a phase 2 clinical trial. Qual Life Res 2014;23:877-886.

3. Spiegel BM, et al. Development and Validation of a Diseases-Targeted Quality of Life Instrument

in Chronic Hepatitis B: The Hepatitis B Quality of Life Instrument, Version 1.0. Hepatology

2007;46:113-121.

4. Saab S, et al. Development of a diseases-specific questionnaire to measure health-related quality of

life in liver transplant recipients. Liver Transpl 2011;17:567-579

Further reading:

FDA Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product

Development to Support Labeling Claims December 2009.

Canadian Institutes of Health Research. Canada’s Strategy for Patient-Oriented Research. Improving

health outcomes through evidence-informed care. August 2011.

Breakout Session VI: Designing and Implementing Clinical Trials in Children

Time: November 11th, 11:00 AM – 12:00 PM

Speakers: Stavra Xanthakos, MD, MS and Joel Lavine, MD, Ph.D

Abstract: Randomized controlled trials are the basis of the highest level of evidence supporting clinical

practice and depend on the voluntary participation of human subjects, even when no direct benefit may

result from participation. Clinical trials in children present additional challenges and are less widely

performed. Previously, the lack of pediatric trial-based data often resulted in extrapolation of

treatments studied only in adults to children. However, developmental differences in drug metabolism,

varying weights and age-specific variations in disease severity or mechanisms can result in unforeseen

risks and consequences. Pediatric clinical trials provide critical data on efficacy and safety of untested or

novel treatments in children and have been recognized as a priority by the National Institutes of Health

and Food and Drug Administration, and Congressional legislation now mandates testing of new

treatments in children. Nonetheless, successful initiation and completion of pediatric trials still face

significant barriers. These include difficulty securing funding from both industry and government

sources due in part to concerns about safety and liability, understandable hesitation from parents to

involve children in research (particularly those studies involving more than minimal risk), and the ethical

and practical challenge of recruiting and retaining patients who may not understand or assent to the

implications of participation. Further, there is often lack of multicenter network infrastructure and

center-specific infrastructure to facilitate pediatric trial conduct, insufficient supply of trained pediatric

researchers, uncertainty surrounding appropriate endpoints, and lack of pediatric formulations. For

liver and gastrointestinal disease, many of the endpoints require invasive technology. To foster clinical

trials and expand data about the effectiveness and safety of interventions in children, it is critical to

further develop multicenter pediatric networks, involve and adequately support pediatric clinicians and

well-trained pediatric clinical researchers in the design and conduct of pediatric trials, and to have

access to pediatric-focused regulatory and ethical oversight to ensure minimal risk and maximal benefit

to participating children.

References:

Pica N and Bourgeois F. Discontinuation and Nonpublication of Randomized Clinical Trials Conducted

in Children. Pediatrics 2016 Sept;138(3). PMID 27492817. DOI: 10.1542/peds.2016-0223

Bavdekar S. Pediatric Clinical Trials. Perspect Clin Res 2013;4(1):88-89. PMCID: PMC3601714

DOI: 10.4103/2229-3485.106403

Tishler CL and Reiss Staats N. Pediatric Drug-Trial Recruitment: Enticement without Coercion.

Pediatrics 2011;127(5). PMID 2146419. DOI: 10.1542/peds.2010-2585

Sanyal AJ et al. Challenges and Opportunities in Drug and Biomarker Development for Nonalcoholic

Steatohepatitis: Findings and Recommendations from an American Association for the Study of Liver

Diseases (AASLD)- Food and Drug Administration (FDA) Joint Workshop. Hepatology 2015;61(4):1392-

1405. PMCID: PMC4900161. DOI: 10.1002/hep.27678