Rational Therapeutics for Infants and Children Workshop Summary (2000) / Chapter Skim
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5 Raising Awareness of Regulatory, Legal, and Ethical Issues
5 Raising Awareness of Regulatory, Legal, and Ethical Issues
Pages 71-91
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From page 71... ...
Pediatric clinical trials involve many logistical challenges as well as legal and regulatory considerations. For instance, a special consideration is informed consent and whether parental consent, the assent of the child, or both are required.
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From page 72... ...
the 1998 Pediatric Rule which requires studies in the pediatric population unless such studies are waived or deferred. Under FDAMA, which is voluntary, the studies to be submitted by the sponsor must be responsive to a written request issued by FDA.
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From page 73... ...
Compliance with the Pediatric Rule is not voluntary. Under the Pediatric Rule, applications for new drug approvals must include results of studies with the pediatric population unless FDA has waived or deferred these studies.
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From page 74... ...
Finally, monitoring allows for the possibility of early termination of the trial when the results are either so strongly positive or negative that the likelihood is small that the conclusions would change if the trial were to continue to its planned conclusion. Typically, DMC members are physicians specializing in the disease being studied and biostatisticians with experience in the design and analysis of clinical trials.
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From page 75... ...
In principle, there are no reasons why DMCs for pediatric studies would operate any differently from DMCs for adult studies except for the types of expertise that would be needed on the committee. The fact that ethical concerns may, on average, be more intense for trials with pediatric populations because children are a "vulnerable population" who cannot provide full informed consent for their treatment suggests, however, that DMCs may be particularly valuable for many trials with pediatric populations.
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From page 76... ...
Also, the logistics of performing research with pediatric populations may be more difficult given, for example, the lower incidence of a disease in children, the complexity of the developmental changes that may be taking place in children, and the limited market for the recapture of the costs of drug development. The American Academy of Pediatrics (AAP)
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From page 77... ...
Anchoring Studies to "Minimal Risk" The dominant interpretation of the requirements of justice in research has been to protect so-called "vulnerable" populations from exposure to an inappropriate share of risk in the absence of certain benefit. One way to protect against the involuntary assumption of research risk is the requirement for obtaining voluntary and informed consent, a requirement that excludes persons who are incapable of providing informed consent (e.g., children and mentally disabled people)
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From page 78... ...
Policy for Protection of Human Research Subjects (45 CFR 46~. The issues of consent and assent for pediatric patients enrolled in clinical trials are discussed in this DHHS regulation.
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From page 79... ...
Approval under Section 405 requires the "prospect of direct benefit." If the inclusion of a placebo-controlled arm is interpreted as not offering the prospect of direct benefit, the protocol can be approved only under Section 404 (if the research involves no greater than minimal risk) or Section 406 (if the research involves only a minor increase over minimal risk)
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From page 80... ...
Subpart D, based on the National Commission's Report on Research Involving Children (National Commission, 1977) , incorporates these added protections on the basis of a risk classification anchored to the concept of minimal risk.
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From page 81... ...
With a definition of "minimal risk," the National Commission seeks to create a research environment that resembles this everyday context and thus to specify the limits of parental authority in permitting a child to participate in nonbeneficial research. "Minimal risk" is defined as "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical or psychological examination, of healthy children" (National Commission, 1979~.
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From page 82... ...
In effect, given the potential benefit to others, the National Commission thought that it was reasonable to allow a parent to permit a child to participate in nonbeneficial research that presented more than a minimal risk. Nevertheless, the National Commission was unwilling to extend this parental authority beyond what was called a "minor increase" over minimal risk.
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From page 83... ...
In addition, the stipulation that the research experience be commensurate with a child's actual or routine experience was meant not to increase the risk that the child may justifiably be exposed but to assist children who can assent to make knowledgeable decisions. This suggests that allowable risks are those that the child-subject would judge to be no more than a "minor increase over minimal risk." The federal regulations, based on the National Commission's report, require both parental permission and child assent except under some clearly defined limits.
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From page 85... ...
Nonetheless, the legal system influences research with pediatric populations in two ways: first, by establishing regulatory protections and controls and, second, by providing incentives and requirements to conduct research. The same general protections that exist for the protection of all human subjects exist for pediatric research subjects, the hallmarks of which are informed consent and IRB review.
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From page 86... ...
For the second category, greater than minimal risk but prospect of direct benefit, the child's assent (where capable) and parental consent are required, as is IRB review.
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From page 87... ...
The rule establishes a presumption that all new drugs and biologics will be studied in pediatric patients, but allows manufacturers to obtain a waiver of the requirement if the product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used by a substantial number of pediatric patients. The rule also provides that FDA will require studies of already marketed drugs under "compelling circumstances." As described in FDA's earlier 1994 rule on labeling for pediatric patient use, the gathering of adequate data to establish safety and effectiveness for pediatric populations may not require controlled clinical trials with pediatric patients.
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From page 88... ...
The incentives in FDAMA in particular provide a powerful engine to drive research initiatives for pediatric populations and place them on a par with competing research demands. INTERNATIONAL DEVELOPMENT OF DRUGS FOR PEDIATRIC PATIENTS: AN INDUSTRY PERSPECTIVE Stephen P
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From page 89... ...
The 1998 FDA Pediatric Rule contains additional provisions to ensure that medicines that are important for children and that will be used by pediatricians will have appropriate information on their safe and effective use. With the increase in investigative activity that has occurred, it is the hope that ICH E-1 1 can provide a framework for international cooperation on clinical investigations with pediatric populations for the benefit of all the world's children.
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From page 90... ...
With the new FDA rule (Pediatric Rule) , every drug coming through the pipeline will require appropriate evaluation for use by pediatric populations.
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From page 91... ...
Thus, insurers have an interest in encouraging safe and efficient clinical testing of drugs for use by the pediatric population. One way of building on the incentives already being supplied through FDAMA would be to encourage the use of pharmaceuticals that have received guidance and labeling instructions for administration to pediatric patients.
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