Highlights from the Joint Meeting of the FDA Advisory Committee on Anesthetics and Analgesics, Drug Safety and Risk Management Advisory Committee and the Pediatric Advisory Committee

September 15 and 16, 2016, Silver Spring, Maryland

By Rae Brown, MD, FAAP
Chair, FDA Advisory Committee on Anesthetics and Analgesics
Constance Houck, MD, FAAP
Committee on Drugs AAP
Rita Agarwal, MD, FAAP
Chair, Section on Anesthesiology and Pain Medicine
American Academy of Pediatrics

The Food and Drug Administration is charged by the Congress with protecting the public health by insuring the safety and efficacy of drugs marketed within the United States. The regulatory capacity of the FDA is closely monitored and is dictated by federal law. Although the Agency can interpret the law in the best interest of the public, it is the congress that legislates and provides the legal basis for this agency. The FDA is large, (10,000) and includes scientists, statisticians, administrators, medical practitioners, veterinarians and pharmacologists. It is a complex organization and my observation is that, to a person, they are dedicated to maintaining the health and safety of each and every American.

The issue of what to do about the public health crisis that is prescription opioid abuse has touched many federal agencies; FDA among them. Congressional pressure to stem the dramatic rise of death and disability in the U.S., as well as recognition that few drugs are rigorously tested in pediatric population prior to marketing, led the agency to call together three advisory bodies to discuss the current method of evaluating opioids that are to be labeled for use in children, and to help strike a balance between providing adequate and safe pain control in pediatric patients while mitigating the risk of this special class of drugs in developing humans.

Over the course of an intense two-day meeting pediatric pain experts, ethicists, biostatisticians, pharmacologists, and epidemiologist from the Agency and academic programs around the country reviewed the current knowledge concerning acute and chronic pain control in children, the risks of using opioids in children and adolescents, and models for studying the efficacy and safety of opioids in the pediatric age groups.

After a day of intense review and an open public forum, the advisory committees deliberated for four hours and provided the FDA with answers to many of the questions that had been asked. Some of the highlights of the deliberations and recommendations are listed below:

1. Children suffer acute and chronic pain. This pain, if untreated, can and will produce long term and deleterious effects in the developing brain. The safety of providing analgesia with opioids notwithstanding, no child should be allowed to suffer for lack of thoughtful management of that pain by practitioners familiar with the risks and benefits.
   
2. Ethical considerations about involving children in clinical trials have evolved from protecting them from research to recognition that it is in their best interest to be a focus of research. It is understood that this involvement will be difficult and that the costs may be substantial. In order to defray the financial costs for trials as well as defend the reasoning, the involvement of the National Institutes of Health and the American Academy of Pediatrics will be essential. Models for opioid trials can be found in the study of the treatment of cancer in children. There is no organization that is better positioned than the AAP to market this initiative to the congress, the FDA, the NIH, and the public.
   
3. Premature infants and adolescents are two groups where the lack of studies of safety and efficacy for opioids are substantial. But all groups within the pediatric age range must be considered. This includes gathering data from the most premature to the young adult. Our knowledge of the effects of opioids on the developing brain up to age twenty-five, including toxicological studies, is minimal and must be substantially supplemented.
   
4. The design of trials for the use of opioids in children below the age of consent is complicated by parental fears of addiction and abuse. Pediatric research relating to opioids should reflect ethical principles that include only gathering data that is essential and cannot be defined without trials. The concept of the safety of the child as well as reducing the inconvenience, fear, and number of diagnostic procedures to a minimum will require investigators to define unique methods for trial design, unlike those currently used in adults.
   
5. Extrapolation of adult data derived from trials sponsored by industry has been used for some time by the FDA to establish important concepts like initial starting dose in children. There is now discussion about the lack of validity of this method in some pediatric age groups and for some specific drugs. Historical data concerning many of the older opioid compounds provide a reasonable safety backstop in many cases but the observation of unexplained outliers that do not follow expected statistical and pharmacologic patterns, give us pause and provides an increased need to understand how, despite the difficulties involved, safety and efficacy trial for all children can be done.

This conversation will continue over the next years as we work to provide the same protections for children that are available for adults. The Society for Pediatric Pain Medicine, working with the Section on Anesthesiology and Pain Medicine of the American Academy of Pediatrics can and should focus on this initiative for the development of the Society, but most importantly, for the patients that we care for daily.