Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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2 The Necessity and Challenges of Clinical Research Involving Children
2 The Necessity and Challenges of Clinical Research Involving Children
Pages 58-92
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From page 58... ...
For medical problems for which these advances have not resulted in prevention, cure, or improved health, the promise of future progress still gives many children and families hope in dark times. This chapter discusses why research with adults cannot simply be generalized or extrapolated to infants, children, and adolescents and, thus, why research involving children is essential if children are to share fully in the benefits derived from advances in medical science.
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From page 59... ...
The next sections of this chapter provide additional historical context; discuss definitions used for the periods of infancy, childhood, and adolescence in different research arenas; and expand on the rationale and complex challenges of pediatric research. The last sections describe government policies adopted in recent years to encourage research involving children while protecting them from research risks.
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From page 60... ...
. The American Academy of Pediatrics has argued that the shortage of pediatric research creates an ethical dilemma for physicians, who "must frequently either not treat children with potentially beneficial medications or treat them with medications based on adult studies or anecdotal empirical experience in children" (AAP, 1995, p.
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From page 61... ...
For research sponsors and investigators, the challenges of research involving children are compounded by normal developmental variability. For many conditions and interventions, separate studies are required for infants, young children, and adolescents.
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From page 62... ...
The adoption of special protections for child research participants and the growing awareness of researchers' ethical obligations have curbed what are now regarded as unethical and harmful research practices. Notwithstanding these benefits, some of these protections have also made some research involving children more administratively burdensome in certain respects than research involving adults.
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From page 63... ...
The discussion later in this chapter on pediatric pharmacokinetics underscores the significance for drug studies of developmental differences and changes during the earliest period of life. The importance of these differences and changes is reflected in FDA's guidance on pediatric drug testing, which categorizes those under age 2 years as infants (FDA, 1994a; 21 CFR 201.57(f)
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From page 64... ...
. The definitions of child in federal regulations on human research protections are cast in legal terms and do not cite an age or age range.3 In guidance encouraging testing of drugs in studies involving children for the purpose of establishing safe dosing levels, the FDA categorizes those ages 2 to 11 years ("up to 12 years")
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From page 65... ...
. The spectrum of pediatric or adolescent care may also be stretched to cover the situation of children with conditions such as congenital heart disease or cystic fibrosis who survive into adulthood but who continue to benefit from care and support provided by their pediatric care team.
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From page 66... ...
627-628 Much of the progress in pediatric oncology that Simone's statement acknowledges stems from a concerted effort to identify promising chemotherapeutic agents for childhood cancers, set priorities for the testing of these agents, and then design and conduct clinical trials through a national cooperative network of investigators and research institutions. This effort has been necessary because childhood cancers sometimes differ biologically from adult cancers and because other physiologic differences between children and adults may affect the ways in which chemotherapeutic agents work in the body.
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From page 67... ...
. In developing countries, pediatric deaths have been associated with local formulations of acetaminophen containing diethylene glycol (Hanif et al., 1995; O'Brien et al., 1998)
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From page 68... ...
As discussed later in this chapter, one goal of the Best Pharmaceuticals for Children Act of 2002 is to encourage pharmaceutical companies to develop safe, effective formulations of drugs for children. Development Affects Drug Distribution in and Excretion from the Body: Pharmacokinetics Pharmacokinetic studies investigate the way in which medicines are absorbed (including when they are given orally, topically on the skin, or rectally)
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From page 69... ...
and brain damage. The objective of pharmacokinetic studies with infants, children, and adolescents is to identify such toxic effects before rather than after a drug is used in pediatric clinical care.
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From page 70... ...
. These changes emphasize the importance of pharmacokinetic studies of drugs that are expected to be beneficial for children of various ages.
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From page 71... ...
determine whether the same relationship holds for children of various ages. FDA and ICH guidelines provide for minimizing the burden of full clinical trials with children if a combination of clinical information about the similarity of the disease in children and adults, pharmacokinetic and pharmacodynamic measurements, and safety and other studies provide sufficient confidence that efficacy can be extrapolated from adults or older children and that an appropriate dose can be defined (FDA, 2000b)
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From page 72... ...
Before drug studies are initiated with children, several steps should be completed to minimize the number of children required for research protocols and to maximize the quality of the data collected. Whenever possible, the first step should be the completion and evaluation of phase 1 studies with adults to investigate the tolerability, bioavailability and pharmacokinetics of the drug of interest and provide the basis for designing phase 1 and phase 2 pharmacokinetic studies involving children.
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From page 73... ...
In the United States, the majority of single-dose pediatric pharmacokinetic studies involve children with an illness likely to be treated by the drug under study. Depending on what is known in advance based on trials with adults, preclinical studies, and other information, some of these early-phase trials -- unlike typical phase 1 trials involving adults -- may arguably be viewed as having the prospect of providing a direct benefit to the child participants.
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From page 74... ...
CHALLENGES OF DESIGNING AND CONDUCTING PEDIATRIC STUDIES Clearly, determining how children's development affects drugs in the body is both a major rationale and a significant challenge for pediatric research. In addition, researchers committed to clinical research involving infants, children, and adolescents face a number of other challenges beyond those typically encountered in research involving adults.
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From page 75... ...
, death has become -- as hoped -- an uncommon or long-delayed outcome of these illnesses. As a result, other outcome measures become more significant in further clinical studies.
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From page 76... ...
. As a result, FEV1 was a key factor in FDA approval of these therapies and has become the primary outcome measure for most subsequent clinical trials (Fuchs et al., 1994; Ramsey and Boat, 1994; Ramsey et al., 1999)
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From page 77... ...
In evaluating protocols, institutional review boards (IRBs) will need to consider whether the proposed outcome measures are developmentally appropriate.
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From page 78... ...
An advantage of disease-specific clinical trials cooperatives or networks is their greater ability to collect age- and disease-specific normative data across multiple trials. Baseline data collected before administration of a study drug(s)
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From page 79... ...
The involvement of child-life specialists and child psychologists may reduce the stress on children and families during clinical studies as well as during usual clinical care.
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From page 80... ...
Although the numbers of children affected by some of these illnesses are greater than the numbers affected by rare genetic disorders, not all children with a disorder or condition will be eligible or able to participate in clinical trials. For any one research location, the numbers available for a study are usually quite low.
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From page 81... ...
Large, multisite trials have become increasingly important for studies with adults as researchers seek to understand differences in medical conditions and treatment effects among population subgroups and to demonstrate reliably treatment effects that are modest but still important. Even more often than with adults, research involving children requires multisite trials and fairly long periods of participant enrollment to generate the minimum required numbers of study participants.
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From page 82... ...
Designing Long-Term Studies Importance of Long-Term Studies in Pediatric Populations As mentioned earlier in this chapter, long-term studies are a particular challenge and a particular need for many serious pediatric medical conditions. Assessing the possible developmental effects of medical treatments or interventions may require extremely lengthy follow-up, well beyond what the immediate study outcomes appear to mandate.
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From page 83... ...
It is obvious that families may move, but so may researchers. Within research institutions, where both physicians and other study staff tend to change positions over time, the study infrastructure must have an "institutional memory" to manage ongoing data collection and interaction with research participants despite staff turnover.
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From page 84... ...
Some research involving children raises highly sensitive issues for their families and, perhaps, their communities. Studies of such important issues as suicide, drug use, sexual behavior, family dysfunction, and other topics are sensitive enough when they involve adults.
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From page 85... ...
The regulations restrict the range of research that can be undertaken with children, particularly studies that involve more than minimal risks for healthy children or children who have no prospect of directly benefiting from participation in the research. For example, traditional phase 1 clinical trials that use healthy volunteers to test the safety of a new medication face higher hurdles to approval if investigators propose to include children.
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From page 86... ...
To ensure that new and established investigators alike are sufficiently knowledgeable about the protection of human research participants, NIH requires education on this topic for all investigators submitting new NIH grant or contract applications or receiving non-competing awards for research involving human participants (NIH, 2001)
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From page 87... ...
A simple search of the NIH clinical trials website (http://www.clinicaltrials.gov/) generated a list of 163 leukemia studies for children from birth to age 17 years, 14 studies for cystic fibrosis, 12 studies for prematurity, and 29 studies for diabetes (all types)
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From page 88... ...
. The high referral and enrollment rates for child cancer patients in clinical trials likely reflects a number of factors, including the imminent threat posed by many types of cancer and the success of researchers in increasing survival rates for important childhood cancers, such as leukemia.
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From page 89... ...
Legislation Congress has long provided funding and directives to NIH and other agencies to support research on a variety of child health problems. In 1963, it established NICHD as part of NIH.
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From page 90... ...
The secretary of DHHS announced that $25 million in federal funds would be allocated to support research on these drugs in 2003. Recently, Congress passed the Pediatric Research Equity Act of 2003, (P.L.
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From page 91... ...
. The rules also provided that clinical trials with children might not be required to support labeling if sufficient evidence existed that the disease and the drug's effects allowed extrapolation from the results of trials with adults.
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From page 92... ...
. CONCLUSION Recent years have seen a number of actions to encourage research involving children and help investigators cope with the many methodological, practical, and ethical challenges of pediatric studies.
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