One broad ethical principle for the conduct of pediatric drug studies is that
children should not be subjected to research that is not necessary to advance knowledge
that is relevant to child health. Another is that children should not participate in studies
that are designed or conducted in ways that predictably undermine the potential of the
research to generate valid and useful information.
In reviewing ethical issues in pediatric clinical trials conducted under BPCA and
PREA, the committee recognized that a number of safeguards are in place to prevent
unethical clinical studies with children. These safeguards include federal regulations and
international standards for research conduct and systems for research review and
monitoring. The safeguards also provide for the application of pediatric expertise
(including expertise in pediatric ethics) to FDA’s activities under BPCA and PREA.
Most clinical reviews that the committee examined included brief comments on
ethics, data integrity, and financial disclosures. Nonetheless, FDA clinical and other
reviews generally do not provide details sufficient for the external assessment of certain
important aspects of research conduct, for example, the adequacy of research protections
at foreign research study sites or the processes for securing parental permission for or
child assent to research participation.
One issue identifiable in the committee’s sample involves placebo-controlled
pediatric trials. Approximately half of the products were studied with a placebo control,
and some of these studies involved conditions (e.g., asthma) for which effective therapies
exist. Such trials do not necessarily present ethical problems, but the committee suggests
that FDA’s written requests and clinical reviews describe the scientific and ethical
rationales for the use of such trial designs.
Another issue is that despite substantial improvements in public access to
information, limitations continue, for example, as a result of the lack of access to reviews
of older studies and the redaction of key sections of clinical reviews. In addition, the lack
of integration of FDA reviews of pediatric (and adult) studies into resources such as
Medline means that these detailed evaluations and analyses may not be identified and
incorporated into evidence-based reviews of clinical therapeutics. Congress could further
improve access by directing FDA to make public reviews for labeling changes approved
before September 2007 and to identify all PREA-related labeling changes for biologics. It
could also request an independent evaluation of the extent and appropriateness of
redactions in FDA reviews of pediatric studies and ask FDA to explore the integration of
clinical and other reviews into databases such as PubMed and ClinicalTrials.gov. To
obtain a better understanding of the dissemination of information, FDA could seek an
analysis of third-party dissemination of labeling information from studies conducted
under BPCA and PREA, including both the speed of dissemination and the accuracy and
completeness of the information as disseminated.
The committee recognized FDA’s limited resources. At the same time, it was
concerned that rationales for ethically and scientifically sensitive decisions be clear and that the public have access to information in which sponsors, investigators, research
participants, taxpayers and health insurance premium payers, and FDA staff have already
invested—in different ways—considerable expense or effort.
The task for IOM did not include evaluation of the ethics of pediatric marketing
exclusivity itself, but the committee acknowledges that issues such as intergenerational
justice (e.g., higher costs for drugs used by older adults during the period of marketing
protection) warrant attention. Certainly, it is appropriate that written requests be
accompanied by clear expectations that the requested studies are necessary, soundly
designed and executed, and public in their results.
One broad ethical principle for the conduct of pediatric drug studies is that
children should not be subjected to research that is not necessary to advance knowledge
that is relevant to child health. Another is that children should not participate in studies
that are designed or conducted in ways that predictably undermine the potential of the
research to generate valid and useful information.
In reviewing ethical issues in pediatric clinical trials conducted under BPCA and
PREA, the committee recognized that a number of safeguards are in place to prevent
unethical clinical studies with children. These safeguards include federal regulations and
international standards for research conduct and systems for research review and
monitoring. The safeguards also provide for the application of pediatric expertise
(including expertise in pediatric ethics) to FDA’s activities under BPCA and PREA.
Most clinical reviews that the committee examined included brief comments on
ethics, data integrity, and financial disclosures. Nonetheless, FDA clinical and other
reviews generally do not provide details sufficient for the external assessment of certain
important aspects of research conduct, for example, the adequacy of research protections
at foreign research study sites or the processes for securing parental permission for or
child assent to research participation.
One issue identifiable in the committee’s sample involves placebo-controlled
pediatric trials. Approximately half of the products were studied with a placebo control,
and some of these studies involved conditions (e.g., asthma) for which effective therapies
exist. Such trials do not necessarily present ethical problems, but the committee suggests
that FDA’s written requests and clinical reviews describe the scientific and ethical
rationales for the use of such trial designs.
Another issue is that despite substantial improvements in public access to
information, limitations continue, for example, as a result of the lack of access to reviews
of older studies and the redaction of key sections of clinical reviews. In addition, the lack
of integration of FDA reviews of pediatric (and adult) studies into resources such as
Medline means that these detailed evaluations and analyses may not be identified and
incorporated into evidence-based reviews of clinical therapeutics. Congress could further
improve access by directing FDA to make public reviews for labeling changes approved
before September 2007 and to identify all PREA-related labeling changes for biologics. It
could also request an independent evaluation of the extent and appropriateness of
redactions in FDA reviews of pediatric studies and ask FDA to explore the integration of
clinical and other reviews into databases such as PubMed and ClinicalTrials.gov. To
obtain a better understanding of the dissemination of information, FDA could seek an
analysis of third-party dissemination of labeling information from studies conducted
under BPCA and PREA, including both the speed of dissemination and the accuracy and
completeness of the information as disseminated.
The committee recognized FDA’s limited resources. At the same time, it was
concerned that rationales for ethically and scientifically sensitive decisions be clear and that the public have access to information in which sponsors, investigators, research
participants, taxpayers and health insurance premium payers, and FDA staff have already
invested—in different ways—considerable expense or effort.
The task for IOM did not include evaluation of the ethics of pediatric marketing
exclusivity itself, but the committee acknowledges that issues such as intergenerational
justice (e.g., higher costs for drugs used by older adults during the period of marketing
protection) warrant attention. Certainly, it is appropriate that written requests be
accompanied by clear expectations that the requested studies are necessary, soundly
designed and executed, and public in their results.