Archive | Pediatric Medication Use

Making Real-World Evidence (RWE) Work for Kids

The increased attention given to Real-World Evidence is a welcome development

The National Academies of Science held a workshop last October, “Real-World Evidence Generation and Evaluation of Therapeutics—A Workshop”, bringing together key thinkers to examine opportunities and challenges for incorporating real-world evidence into evaluation of medical products. Regulatory experts and FDA scientists followed-up with a cogent discussion of RWE and its use in the regulatory setting published in the New England Journal of Medicine, “Real-World Evidence — What Is It and What Can It Tell Us?” They reported that “the FDA is developing guidance on the use of ‘real-world evidence’ — health care information from atypical sources, including electronic health records, billing databases, and product and disease registries — to assess the safety and effectiveness of drugs and devices.”

Real-world evidence and the regulatory process

NAS workshop reviews RWE

Kids stand to benefit

Real-world evidence is of special importance to children because we can’t always conduct randomized clinical trials in pediatric populations. Real-world evidence, from large databases, electronic health records, and similar sources, may be the only evidence we have about medications or devices used by children. All the more reason to make sure that real-world evidence meets the unique needs we have when studying children: adequate sample sizes for all age sub-groups, critical data such as birth date, birth weight, and gestational age, ability to link to parental (and even sibling) data, and linkage with school performance metrics.

As efforts increase to address the challenge of developing high-quality RWE, we must consider and address the special considerations and challenges in using RWE to answer questions about the effects of medications in children. Asking these questions now will ensure that advances in the use of RWE will benefit children as well as other sectors of the population.

See Tamar Lasky’s editorial in the journal Drugs – Real World Outcomes, “In the Real-World, Kids Use Medications and Devices”.

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

Deciding which meds are best for each child

“One Drug or 2? Parents See Risk but Also Hope”, a recent article in the NYTimes, caught my attention because of its focus on pediatric medication use.

The article portrays the issues around the decision to add an antipsychotic medication, Risperdal, to a daily regime of Adderall for attention deficit hyperactivity disorder, and begins with a story about Matthias, 6 years old.

The article describes the mother’s dilemma,

Her dilemma is shared by a steadily rising number of American families who are using multiple psychotropic drugs — stimulants, antipsychotics, antidepressants and others — to temper their children’s troublesome behavior, even though many doctors who mix such medications acknowledge that little is known about the overall benefits and risks for children.

It describes a family with a child who has not responded to the guideline recommended treatment of methylphenidate combined with behavioral therapy, and interviews physicians to find out their opinions about the treatment options. One psychiatrist interviewed, underscored the lack of evidence and and anecdotal nature of decision making when there is no evidence, saying, “When I prescribe multiple psychotropics, there’s a good reason — even if I don’t know the exact interactions or efficacy, there’s a clinical reason to give it a shot,” said Dr. J. Wesley Boyd, a psychiatrist at the Cambridge Health Alliance in Massachusetts. “But saying, ‘The last time I gave x, y and z to someone they did fine,’ that’s not science.” Another physician is quoted as cautioning the mother, “We’re really feeling around in the dark with this stuff.” He followed up by saying that he had never prescribed both medications to a child so young.

Questions are raised by this story

First of all, the glaring lack of evidence to inform clinical decisions and support evidence-based medicine.

Evidence based medicine means just that – a treatment or other medical procedure is studied, the evidence is weighed, and guidelines are developed to help providers decide on the best course for each patient. Unfortunately, we are without an evidence base for many medications used in children. Children have historically been excluded from clinical trials to protect them from research risks. This policy has been reversed in the past 10 or 20 years after realizing that children have not been served by this policy and that children are being treated with medications without an evidence base or guidelines to inform practice.

To clarify what this means, the pediatric labeling for Adderall (the first drug used to treat Matthias) is based on one study of 584 children with ADHD (age 6-12) for three weeks and on a second study of 51 patients (age and duration of the study not specified). Risperidone (the second drug being considered to treat Matthias) has been study in children age 13-17 with schizophrenia, age 10-17 with bipolar disorder, in combination with lithium or valproate for acute manic or mixed episodes associated with bipolar disorder, and in children age 5-17 with autistic disorder.

Second, the wide-spread off-label use of medications

One clinician quoted in the article says, “You cannot tell the family, ‘Come back in five years and we’ll treat you with this medication’ until the F.D.A.’s going to approve it.” The physician is referring to the lack of FDA labeling or approval to use the medication in children. When there is a lack of evidence for an indication or specific age group, FDA cannot approve the medication for that use. When clinicians believe that the drug should be used, despite the lack of evidence, this is termed “off-label” use. As the AAP notes in their press release along with the release of their policy statement, “Off-Label Use of Drugs in Children”,

“Pediatricians must prescribe drugs off-label, simply because an overwhelming number of critical drugs still have no information on the label for use in children”

AAP statement on off-label prescribing

The AAP policy statement proceeds to address ethical and legal concerns practitioners may have about off-label use of medications. The policy statement begins by saying, “The use of a drug, whether off or on label, should be based on sound scientific evidence, expert medical judgment, or published literature whenever possible.” For the reader, lack of evidence and lack of FDA approval are not identical, although evidence should lead to labeling, and lack of labeling suggests a lack of evidence. It is not clear what types of off-label use might meet the AAP criteria of sound scientific evidence, expert medical judgment and published literature in the absence of enough evidence to support practice.

If there is no evidence, is off-label use research? AAP policy states,

In most situations, off-label use of medications is neither experimentation nor research. The administration of an approved drug for a use that is not approved by the FDA is not considered research and does not warrant special consent or review if it is deemed to be in the individual patient’s best interest. In general, if existing evidence supports the use of a drug for a specific indication in a particular patient, the usual informed-consent conversations should be conducted, including anticipated risks, benefits, and alternatives. If the off-label use is based on sound medical evidence, no additional informed consent beyond that routinely used in therapeutic decision-making is needed. However, if the off-label use is experimental, then the patient (or parent) should be informed of its experimental status.

Again, it would be very helpful to have clarification on when the off-label use is considered to be experimental, and perhaps some examples or guidelines.

 What about the legal issues? AAP policy recommends,

… because the use of drugs in an off-label capacity can increase the liability risk for a practitioner should an adverse event or poor outcome ensue, it is essential that practitioners document the decision-making process to use a drug off label in the patient’s medical record.

The level of detail and type of documentation is not specified.

 So, what about the evidence?

Anti-psychotic medication children

FDA approvals for anti-psychotics in children

Neither the journalist nor the physicians interviewed mentioned any of evidence regarding the treatment decision, and while the evidence base is inadequate some evidence exists. Several reports have emerged in the literature describing the use of respiridone in addition to stimulants (methylphenidate) to manage ADHD, and the Agency for Healthcare Research and Quality published an extensive review, “First- and Second-Generation Antipsychotics for Children and Young Adults” summarizing the evidence around pediatric use of anti-psychotics. With over 156 pages plus appendices and state-of-the art systematic review methodology, the authors’ search strategy identified 10,745 citations, of which, 140 articles met the inclusion criteria, and 81 were unique studies. They reported low to moderate evidence that second generation anti-psychotics had beneficial effect on ADHD and disruptive behavior disorder (Table B). They also reported information about adverse events showing low to moderate quality evidence that placebo and anti-psychotic produce no differences for some adverse events, and favor placebo for others. The review excluded studies of combination treatments and does not directly inform the decision whether to add an anti-psychotic to the adderal regimen.


ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, Ganiats TG, Kaplanek B, Meyer B, Perrin J, Pierce K, Reiff M, Stein MT, Visser S. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011 Nov;128(5):1007-22.

Aman et al, Journal of the American Academy of Child and Adolescent Psychiatry, January 2014 “What Does Risperidone Add to Parent Training and Stimulant for Severe Aggression in Child Attention-Deficit/Hyperactivity Disorder?”

Atypical Antipsychotic Medications: Use in Pediatric Patients CMS Fact Sheet 2013

Gadow et al, Journal of the American Academy of Child and Adolescent Psychiatry, September 2014 “Risperidone Added to Parent Training and Stimulant Medication: Effects on Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Peer Aggression”


Seida JC, Schouten JR, Mousavi SS, Hamm M, Beaith A, Vandermeer B, Dryden DM, Boylan K, Newton AS, Carrey N. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021.) AHRQ Publication No. 11(12)-EHC077-EF. Rockville, MD. Agency for Healthcare Research and Quality. February 2012.

Improving Medicines for Children in Canada

“Studying medicines in children is always possible and is in their best interests”

A sentiment that can’t be repeated often enough.

The Council of Canadian Academies just released their report, Improving Medicines for Children in Canada, and while the title indicates a focus on Canada, much of the report is relevant to goal of improving medicines for children everywhere.

Children have historically been excluded from clinical trials and drug research to protect them from the risks of research.

As a result, there is a lack of information about medicines and how they affect children at different ages and stages of development. Throughout, the panel stresses the importance of including children in research,

The assumption that children must be protected from research is misguided. Children should be protected through research. Despite the many challenges to research with children, a range of methods and designs are increasingly accepted as ethically and scientifically sound. Demonstrating safety and efficacy of a medicine in studies with children is always feasible and desirable. It is now globally recognized that the medical community, the pharmaceutical industry, and regulatory agencies have an ethical responsibility to design, conduct, and report on high-quality studies of medicines in children.

Key findings

As with so much of the report, the key findings are applicable in the US, Europe and elsewhere. As they note,

  • Children take medications, many of which have not been proven safe and effective for their use.
  • Children respond to medications differently from adults; thus, medicines must be studied in children and formulated for children.
  • Studying medicines in children is always possible and is in their best interests.

The panel reviewed a comprehensive body of information and brings together relevant science from several disciplines. As such, it provides a cogent synthesis of the many issues around pediatric medication use. It begins with a description of the current environment and regulations, variation in children’s response to medications, issues around formulation, and covers current approaches to studying efficacy in children, monitoring and studying the safety of drugs used by children, and a thoughtful discussion around practices to support safe and effective products for children.

Off-label use

The overview of the current environment provides this useful chart summarizing different types of off-label practices, with examples of both the authorized (on-label) and off-label use.

Medicines for children

Off-label practices

Variability in response to medications

Chapter 3 includes this schematic of the factors affecting variability in children’s responses to medications.


Medicines for children

CCA schematic – drug response in children

They return to this issue in their conclusions, as they underscore the affect of human development from infancy to youth, and its affect on clinical pharmacology,

As children progress from infancy through to adolescence, a number of significant developmental changes occur. These changes impact how their bodies deal with medications (pharmacokinetics) and how medications, in turn, affect their bodies (pharmacodynamics). These factors cannot be accommodated by simply adjusting an adult dose. The physiological systems that process drugs change over time, with the most dramatic age-related physiological changes taking place during the first year of life. A newborn will respond to a drug differently than an adolescent will, and this variability in response is not a linear progression but rather a dynamic process dependent on age, weight, the drugs and conditions involved, and individual and environmental factors.

The report concludes with a fervent call to action,

Children’s right to health includes a right to medicines that are well-studied and approved for use in their age group. Children deserve timely and equitable access to safe and effective treatments and care, including participation in research.

The Expert Panel on the State of Therapeutic Products for Infants, Children, and Youth was chaired by Dr. Stuart MacLeod, Professor of pediatrics at the University of British Columbia in Vancouver.