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Pediatric Pharmacoepidemiology at ICPE 2017 Annual Meeting

For the third year, the ISPE annual meeting (ICPE 2017 Montreal) will offer the pre-conference course in Pediatric Pharmacoepidemiology.

Mark your calendars for Sunday, August 27, 2017 (register here).

Brief Overview of Course

The increasing use of medications by children and the history of excluding children from clinical trials have created the need for pediatric pharmacoepidemiology, a sub-specialty within pharmacoepidemiology. Unique challenges in studying children, accessing data, defining outcomes, and designing studies require specialized methodologic skills and operational approaches. This half-day course will introduce participants who have a good understanding of pharmacoepidemiology to the specialized methodologic and operational approaches used to study medications in children.

Pediatric Pharmacoepidemiology

Age is not a simple variable when studying children

Educational Objectives

The course will be taught in an interactive format with ample opportunities for questions and discussion. Regulatory issues around use of medications in children will be highlighted throughout the course. Participants will gain an understanding of key issues in pediatric pharmacoepidemiology including:

  • An overview of pediatric pharmacoepidemiology and how it differs from pharmacoepidemiology in older age groups
  • Study design and databases to monitor safety
  • Defining, measuring and validating outcomes in pediatric pharmacoepidemiology
  • Variables critical to pediatric pharmacoepidemiology such as month of birth, seasonality, growth and development

Target Audience

ICPE attendees interested in gaining a basic understanding of the need for and approaches to pediatric pharmacoepidemiology.

Course Faculty/Presentations

  • Tamar Lasky, PhD Owner, MIE Resources Why Pediatric Pharmacoepidemiology? Age Sub-groups in Children: Methodologic Considerations
  • Alan Kinlaw, PhD Post-doctoral Research Fellow, Sheps Center for Health Services Research, University of North Carolina at Chapel Hill Leveraging granular birthdate information for studies of young children
  • Rachel E. Sobel, DrPH Senior Director, Epidemiology, Worldwide Research and Development / Pfizer Inc. Monitoring Drug Safety: Study Design, Data Sources and Case Study
  • Timothy Beukelman, MD, MSCE Associate Professor of Pediatrics, Division of Pediatric Rheumatology, Department of Pediatrics, University of Alabama at Birmingham The Need for Validation in Pediatric Outcomes
  • Daniel B. Horton, MD, MSCE Assistant Professor of Pediatrics and Epidemiology, Rutgers University Growth and Development: Variables of Particular Importance in Pediatric Pharmacoepidemiology



The challenge of pediatric Patient Reported Outcomes (PROs)

Think about it. We want to know how the child experiences his or her illness and therapies, and we can just ask, right? Well, some children are too young to even understand or respond to questions, infants and young toddlers, others go through a “no” stage and answer “no” to every question, and others may be unable to respond to questions for a range of other reasons.

Pediatric patient reported outcomes (PROs)

The recent IOM workshop, Comprehensive Cancer Care for Children and their Families, touched on some key issues around use of PROs in children with cancer, and much of what was said is applicable to children with other diseases and conditions. I’m hoping that video of the presentations will be posted (they often are).

The research imperative to develop pediatric Patient Reported Outcomes (PROs)

Try presentation by Lillian Sung, The Hospital for Sick Children, Toronto has the bland title “Academic Perspective on Clinical Research”, but is a hard hitting overview of the issues around implementing Patient Reported Outcomes (PROs) in pediatric cancer patients, and includes a full list of action items and recommendations. She notes the FDA 2009 Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims and its statement,

We discourage proxy-reported outcome measures for this population (i.e., reports by someone who is not the patient responding as if that person were the patient). For patients who cannot respond for themselves (e.g., infant patients), we encourage observer reports that include only those events or behaviors that can be observed.

Pediatric Patient Reported Outcomes (PROs) to improve estimates of toxicity and adverse events

Bryce Reeve made a critical point in favor of use of PRO’s in pediatric cancers. He presented evidence that there is a low correlation between clinicians’ report and patient report for a range of symptoms. The consequence of relying on clinicians’ report for identifying adverse events is an underestimate of adverse events, something that can be corrected by broader use of PRO’s in cancer research. Presumably this is relevant to other diseases, as well.

Other resources

Pain meds used by children while in the hospital

Pediatric pain medications

When children are in the hospital, they often need pain relief or sedation, yet most drugs used for pain relief or sedation in children have not been studied in children. A first step in understanding the overall use of pain medications is to document the medications used and their frequency of use. Our publication, “Use of Analgesic, Anesthetic, and Sedative Medications During Pediatric Hospitalizations in the United States 2008”, published in the journal, Anesthesia and Analgesia in  2012, describes medications used in over 800,000 hospitalizations.

We describe use of analgesics, anesthetics, and sedatives in pediatric inpatients by conducting a statistical analysis of medication data from the Premier database. We identified all uses of a given medication, selected the first use for each child, and calculated the prevalence of use of specific medications among hospitalized children in 2008 as the number of hospitalizations in which the drug was used per 100 hospitalizations. Dose and number of doses were not considered in these analyses.

The dataset contained records for 877,201 hospitalizations of children younger than 18 years of age at the time of admission. Thirty-three medications and an additional 11 combinations were administered in this population, including nonsteroidal antiinflammatory drugs, local and regional anesthetics, opioids, benzodiazepines, sedative-hypnotics, barbiturates, and others. The 10 most frequently administered analgesic, anesthetic, or sedative medications used in this population were acetaminophen (14.7%), lidocaine (11.0%), fentanyl (6.6%), ibuprofen (6.3%), morphine (6.2%), midazolam (4.5%), propofol (4.1%), lidocaine/ prilocaine (2.5%), hydrocodone/acetaminophen (2.1%), and acetaminophen/codeine (2.0%).

Use changed with age, and the direction of change (increases and decreases) and the type of change (linear, u-shaped, or other) appeared to be specific to each drug.

Figure 1 shows the number and percentage of pediatric hospitalizations with nonsteroidal antiinflammatory drug (NSAID) use, by age group. Bars indicate number of hospitalizations. Lines indicate percentage of hospitalizations. Acetaminophen was considered in these analyses as an NSAID for the sake of categorical simplicity; however, pharmacologically, the antiinflammatory activity of acetaminophen is minimal, such that some do not consider it a true NSAID.

Pediatric pain medications by age group.

Figure 1. Number and percentage of pediatric hospitalizations with non steroidal anti-inflammatory drug (NSAID) use, by age group.

Figure 2 shows the number and percentage of pediatric hospitalizations with opioid use, by age group. Bars indicate number of hospitalizations. Lines indicate percentage of hospitalizations.

hospitalizations with use of pediatric pain medications (opioids), by age group.

Figure 2. Number and percentage of pediatric hospitalizations with opioid use, by age group.

See the accompanying editorial by Joseph Tobin, MD, “Pediatric Drug Labeling: Still an Unfinished Need”. As he says,

Chronic pain in children is seriously underrecognized in comparison with the prevalence of chronic pain in adults. This is one more circumstance in which labeling in children would be very beneficial to anesthesiologists and their patients.

Pediatric hospitalizations for mood disorders

Children get hospitalized for depression and bipolar disorders.

I wasn’t aware of how frequently this happens until I got my hands on some BIG DATA – the HCUP KID database of children’s hospitalizations. My colleagues and I analyzed hospitalizations in 2000, 2003 and 2006 and published our results in the journal, Child and Adolescent Psychiatry and Mental Health in 2011. For each of these years, we were able to look at records for over 2 million hospitalizations, and able to project these to the entire number of pediatric hospitalizations in the US in those years.

Some take home points

Percentages of hospitalizations where the principal diagnosis was a mental health diagnosis

  • In children age 15-17, 13.7 to 15.2% of hospitalizations had a mental health principal diagnosis
  • In children age 10-14, 15.0 to 15.6% of hospitalizations had a mental health principal diagnosis
  • In children age 5-9, 4.4 to 4.8% of hospitalizations had a mental health principal diagnosis accounted

The incidence of hospitalizations with mood disorders as the principal diagnosis compared to the entire population of children

12.1-13.0 out of every 10,000 children were hospitalized with mood disorders as the principal diagnosis in 2000-2006.


The incidence of hospitalizations for children with mood disorders increased with age – this figure uses data from 2006 to show the trend.

Children mood disorders by age

Region of the country

A surprising finding was the big differences between regions of the country. As an example, in 2006, the Western region experienced the lowest rates (10.2/10,000) while the Midwest had the highest rates (25.4/10,000). This figure shows the rates for 2000, 2003 and 2006.

children mood disorders by region of the US

Did you know?

Mood disorders including depression and bipolar disorders are a major cause of morbidity in childhood and adolescence, and hospitalizations for mood disorders are the leading diagnosis for all hospitalizations in general hospitals for children age 13 to 17.

Between 2000 and 2006, inflation-adjusted hospital charges increased from $10,600 to $16,300.

Morphine Use in Pediatric Inpatients

Pediatric morphine use in the hospital

As with so many medications used widely to treat children, morphine is not labeled for pediatric use. Describing patterns of use helps us understand how many children are receiving a drug that is not approved for pediatric use by the FDA.

A statistical analysis of 877,201 pediatric hospitalizations in the United States in 2008 estimated that morphine was used in 54,613 (6.2%) hospitalizations in the database. If this percentage is applied to the total number of children’s hospitalizations in the US in 2008, as many as 476,205 children will have received morphine during their hospital stay that year. Fractures and appendicitis were two of the diagnoses most frequently listed for children receiving morphine.

While morphine can be used safely for pain management during hospital procedures, and has been used for this purpose for several decades, the lack of pediatric labeling is undesirable. In a discussion about whether the off-label use of a drug constitutes experimentation and research, the American Academy of Pediatrics Committee on Drugs noted that “discussion about the off-label status of a drug may, as a matter of professional judgment, be part of the information provided to the patient or parents.”

The article reporting statistical analysis on morphine use in pediatric inpatients can be found here:”Morphine Use in Hospitalized Children in the United States: A Descriptive Analysis of Data From Pediatric Hospitalizations in 2008″Lasky T, Greenspan J, Ernst FR, and Gonzalez L Clinical Therapeutics 2012, 34(3): pp.720-727.

The American Academy of Pediatrics discussion on “Uses of drugs not described in the package insert (off-label uses)” can be found here. Pediatrics. 2002;110: 181–183.

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