Safe and Effective Medicines for Children Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (2012) / Chapter Skim
Currently Skimming:
4 Ethical Issues in Pediatric Drug Studies
4 Ethical Issues in Pediatric Drug Studies
Pages 89-110
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 89... ...
to provide guidance on ethical questions related to pediatric studies. It then considers several specific ethical issues, including the public availability of information from clinical trials, the enrollment of healthy children in pharmacokinetic studies, and the use of placebo controls in pediatric trials.
|
From page 90... ...
General Protections The special protections for children in research function in the context of broader protections for all human research participants. Today, all clinical research regulated by FDA, regardless of source of funding and auspices, must meet certain ethical standards (21 CFR 50 and 56)
|
From page 91... ...
FDA reviews any disclosures to assess whether the interests had the potential to bias the findings of the research. A thorough discussion of conflict of interest in pediatric drug studies is beyond the scope of this report, but the financial significance of such studies not only to sponsors but also to many academic programs and investigators and to some community-based physicians does raise concerns about the potential for bias in the design, evaluation, and reporting of research.
|
From page 92... ...
. An analysis of published reports of studies conducted for pediatric exclusivity from 1998 to 2007 found that 65 percent of the studies that reported study locations had at least one site outside the United States, 38 percent had at least one site in a developing/transition country, and 11 percent had no U.S.
|
From page 93... ...
regulations define four categories of research involving children that IRBs can approve. As an example of how the regulations may limit studies that are permitted for adults, these definitions would preclude the participation of healthy children in pharmacokinetic studies that involve more than minimal risk.
|
From page 94... ...
• linical investigations involving greater than minimal risk and no prospect of C direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects' disorder or condition and (a) the risk represents a minor increase over minimal risk; (b)
|
From page 95... ...
The 2004 IOM report cited above made several recommendations about the interpretation of key concepts in the HHS and FDA regulations. In brief, it recommended that investigators and reviewers of research protocols should • interpret minimal risk in relation to the normal experiences of average, " healthy, normal children" and "focus on the equivalence of potential harms or discomfort anticipated in research with the harms or discom fort that average, healthy, normal children may encounter in their daily lives or experience in routine physical or psychological examinations or tests; • interpret minor increase over minimal risk to mean a slight increase in " the potential for harms or discomfort beyond minimal risk" and "assess whether the research procedures or interventions present experiences that are commensurate with, that is, reasonably comparable to, experi ences already familiar to the children being studied"; • consider the risk of harms or discomfort in relation to the ages of the " children to be studied and assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk"; and • nterpret condition to mean "a specific (or a set of specific)
|
From page 96... ...
Expertise in Pediatrics, Pediatric Research, and Research Ethics In 1999, FDA created a pediatric advisory subcommittee to its AntiInfectives Advisory Committee. Among other issues, the subcommittee advised on ethical questions in pediatric studies.
|
From page 97... ...
In addition to topics considered during committee or subcommittee meetings, issues may be brought to the FDA pediatric ethics staff for consultation. Such consultations have covered the ethical implications of many elements of pediatric drug studies, including the definition of the pediatric population to be studied, the choice of control group, the use of invasive placebos, the requirements for parental permission and child assent, the assessment of risk and benefit, the appropriate standard of care in international studies, and the planning of first-in-children studies (i.e., when a drug or an indication has not been previously studied in adults)
|
From page 98... ...
Although the committee could not reasonably assess the sufficiency of past or current pediatric expertise across CDER and CBER review divisions and in the Office of the Commissioner, this report emphasizes that such expertise is critical to the design, conduct, and evaluation of scientifically and ethically sound pediatric drug studies. Other Resources Relevant to Research Integrity Among other resources, FDA has developed a number of guidance or draft guidance documents on ethics and integrity in FDA-regulated trials, including guidance for IRBs and investigators about FDA policies and expectations (FDA, 2010b)
|
From page 99... ...
. ETHICAL ISSUES IN STUDIES CONDUCTED UNDER BPCA AND PREA An overarching ethical question for pediatric studies is whether the expected benefit of the knowledge to be gained from the research is reasonable in relation to the potential risk to child participants.
|
From page 100... ...
It also required FDA to make public the staff clinical, clinical pharmacology, and statistical reviews associated with requested or required studies in a timely way and to make written requests public following exclusivity determinations. Before these changes, BPCA of 2002 required posting of brief summaries of product reviews for studies requested under BPCA, but the requirement did not apply to studies required under PREA.
|
From page 101... ...
At the time that the drug was withdrawn, a spokesman for a children's hospital at which a child had died during a clinical trial of the drug said the drug "has been widely prescribed by pediatricians and pediatric specialists for the treatment of gastroesophageal reflux in children and infants due to its efficacy and presumed safety based on the adult data" (Neergaard, 2000)
|
From page 102... ...
FDA Reviewer Comments on Study Integrity and Ethics Particularly in recent years, FDA clinical reviews of sponsor applications have included sections that variously comment on study integrity, ethics and good clinical practices, and financial disclosures or conflicts of interest. In these sections, reviewers may discuss protocol violations, sponsor affirmations about compliance with ethical principles or good clinical practices (which should subsume compliance with regulatory protections for children)
|
From page 103... ...
, or both, are deemed to involve more than minimal risk without the prospect of direct benefit to the child, then the regulatory framework outlined earlier precludes the enrollment of healthy children in such studies. Alternatives to such studies might involve pharmacokinetic studies of children with the condition under investigation or pharmacokinetic studies undertaken as part of an efficacy and safety trial.
|
From page 104... ...
Because children are a vulnerable population and because many challenges surround parental permission and child assent for a child's participation in research, particular caution is needed when placebos are employed in pediatric trials. When the use of a placebo control in a pediatric clinical trial is proposed or contemplated, several questions warrant consideration.
|
From page 105... ...
The conditions studied in placebo-controlled pediatric trials included asthma, anxiety, hypertension, schizophrenia, mania associated with bipolar disorder, migraine, osteogenesis imperfecta, attention deficit hyperactivity disorder, and juvenile rheumatoid arthritis. At the time of some of the placebo-controlled trials, no treatments had been approved by FDA (for the pediatric age group studied)
|
From page 106... ...
were available at the time of placebo-controlled pediatric studies, investigators examined adverse events and serious adverse events in 10 placebo-controlled efficacy trials of drugs for hypertension (Benjamin et al., 2008)
|
From page 107... ...
Although generally favorable about the benefits of BPCA, the authors concluded that the pediatric exclusivity incentive of BPCA "overcompensates blockbuster products for performing clinical trials in children while other products have more modest returns on investment under this program" (p.
|
From page 108... ...
Still, an ethical tension may exist in pediatric drug studies and, indeed, 7 As of February 1, 2012, and as required by FDAAA, FDA had posted 47 written requests (with amendments) at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Development Resources/ucm049997.htm.
|
From page 109... ...
Justification should also be considered in some other situations, for example, when FDA accepts the use of an unapproved drug as the active comparator in a controlled trial or to the inclusion of healthy children in pharmacokinetic studies. Another concern that the committee identified is some continuing limitations on public access to information from studies conducted under BPCA and PREA.
|
From page 110... ...
The committee recognizes FDA's limited resources. At the same time, it is concerned that rationales for ethically sensitive decisions be clear and also that the public have access to information in which sponsors, investigators, research participants, taxpayers and premium payers, and FDA staff have already invested -- in different ways -- considerable expense or effort.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.