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.
BACKGROUND AND INTRODUCTION TO
PEDIATRIC ISSUES
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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