Background and Introduction to Pediatric Issues

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Chapter: Pharmacovigilance: Pharmacovigilance in Pediatrics

The views expressed are those of the authors. No official support or endorsements by the US Food and Drug Administration is provided or should be inferred. No commercial interest or other conflict of interest exists between the authors and the pharmaceutical companies.

Pharmacovigilance in Pediatrics

The views expressed are those of the authors. No official support or endorsements by the US Food and Drug Administration is provided or should be inferred. No commercial interest or other conflict of interest exists between the authors and the pharmaceutical companies.


There are two very humane behaviours adults have, which can or have resulted in poor outcomes for children. The first behaviour is to give children medicines that have been developed for adults. Denying children a therapy, because it has not been studied in children or has not been produced or marketed in a form which children can or will ingest, is not reasonable. Therefore, any therapy that becomes available for adults is likely to be used for the same or similar conditions in children, even when we have not studied the product in children, may not have a sound scientific basis for establishing a dose (besides scaling down the dose on a weight basis), and have no understanding of how children may react differently than adults to the therapy

The second humane behaviour is to protect our chil-dren from unknown and uncertain situations. This has also included ‘protecting’ them from research even when the research may provide a potentially better therapy or access to a therapy not otherwise available. As a result, the 20th century is replete with tragic stories of therapeutic misadventures involving chil-dren. By the end of the 20th century, children had essentially been left behind in the amazing pharma-cologic advances of that era.1 2 In addition, if chil-dren are not studied in clinical trials, the adverse events defined during the trial are limited to adults. Therefore, most products do not have information on specific pediatric adverse events noted even though the product may be used extensively in the pediatric population.

The impetus for the formation of the United States’ Food and Drug Administration (FDA) has much to do with pediatric therapeutic disasters. The 1938 Federal Food, drug and cosmetic (FD&C) Act was passed after ethylene glycol, a solvent, and raspberry syrup, a sweet-tasting flavouring, were used by the manu-facturer’s chemist in an effort to market an elixir of sulfanilamide.3 The solvent caused renal failure, and many children died because of the chemist’s efforts to provide a needed antibiotic to children in a formulation they would take. This Act required demonstration of the safe use of a new drug product before marketing. The 1962 Kefauver amendments to the FD&C Act required that a product be proven not only safe but effective for the labelled indica-tion.4 The amendment was partially a response to the thalidomide disaster. Although thalidomide was safe for the mother who took the product, it caused severe limb abnormalities (phocomelia) in the fetus. Another pediatric therapeutic disaster occurred when chloramphenicol therapy caused toxicity and deaths in infants (i.e., grey baby syndrome). This occurred because physicians were not aware that neonates and infants were unable to metabolize chlorampheni-col adequately. These examples, which demonstrate the lack of pediatric-appropriate preparations, knowl-edge regarding teratogenicity, or the understanding of the need for appropriate dosing modifications in certain pediatric subpopulations, highlight the prob-lems which still exist today.

Despite urging, in 1977 and 1995 from the American Academy of Pediatrics, that the continued use of untested therapies in the pediatric population was essentially unethical, as it subjected children to a never-ending experiment where little was learned, most products continued to be developed and studied only in adults. Few studies were being performed to answer the dosing and safety issues associated with pediatric use of a product.

At the very end of the 20th century, the US Congress passed legislation which changed the world of pediatric drug development. In addition, the FDA had put into place a series of efforts to encourage pedi-atric drug development and assessments. A number of FDA’s regulatory efforts were also incorporated into legislation. The main components of these changes were as follows:

·   An incentive of 6 additional months of market-ing exclusivity for products studied in response to the FDA issuance of a document called a Writ-ten Request for pediatric studies. This incentive element was first enacted in the Food and Drug Administration Modernization Act (FDAMA) of 19977 and renewed in 2002 in the Best Pharma-ceuticals for Children Act (BPCA).

·   The requirement that the sponsor of a product to be studied in adults, and would have the same use in children, also conduct and submit pediatric studies or a plan and timeline for pediatric studies. This final regulation was published by FDA in 19989 and enacted into law by Congress in the Pediatric Research Equity Act (PREA) of 2003.

·   The concept of extrapolation of pediatric efficacy data from adult efficacy data, provided the disease and the response to therapy in children and adults are sufficiently similar to permit this approach was introduced into regulation. If this approach is utilized to establish efficacy, other studies to define dosing and safety in the pediatric populations are mandated. The FDA first proposed this approach in 199211 and finalized this regulation in 1994.12 Congress then incorporated the concept into its 2002 BPCA.

It has been recognized that most pediatric stud-ies performed for the intent of satisfying require-ments for any of the above-mentioned legislative initiatives are not likely to be replicated nor other indications be sought. Therefore, this information should be publicly available. Since the implemen-tation of BPCA, study results from trials conducted in response to FDA’s Written Request are posted in summary form on FDA’s website.13 This summary is made public irrespective of the approval status of the application. This does not occur for pediatric studies conducted in response to PREA.

·   A specific focus on monitoring pediatric adverse events was put in place. Many new products have been and will be studied in pediatrics. The BPCA required a special safety review for adverse events for the year after a product received its extra 6 months of pediatric exclusivity. The adverse events are to be provided to the newly mandated Office of Pediatric Therapeutics, then a review is to be presented to the Pediatrics Advisory Committee and their recommendations obtained on any neces-sary actions. The review of products assessed under this program, the presentations to the pediatric advisory committee and the transcripts of the meet-ing can be accessed via FDA’s website.

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