Of Trials In Children With Cancer

Children and adolescents constitute a special vulnerable population of research subjects, often grouped with other special classes, like the mentally retarded, mentally ill and prisoners. There are special federal protections which apply to all research involving children as subjects which are covered by Subpart D of Part 46 of Title 45 of the Code of Federal Regulations (45 CFR 46), requiring that institutional review boards (IRBS) give consideration to the degree of risk, the benefit to child subjects, the nature of the knowledge to be gained, permission of the parent or guardian, and the concurrence of the child subjects, known as assent. A child's capacity to give assent is conditioned by his or her developmental level.44'45

Subsequent to the promulgation of the original rules, adopted in 1983 and modified in 1991, there has been nearly continuous debate and controversy surrounding safeguards for all human subjects of research and for children especially.

The tragic death of an 18-year-old research subject in 1999 in a gene-transfer trial at a major research university in which human subjects were not protected, adverse events had not been reported and financial conflicts of interest were involved, served to trigger several new federal initiatives to further strengthen protections of human research subjects in clinical trials,46 including the imposition of sanctions on investigators who fail to adhere to regulations. As this chapter goes to press, the federal Office for Protection from Research Risks (OPRR) has been reorganised, expanded and renamed the Office for Human Research Protections (OHRP) and transferred to the Office of the Secretary, Health and Human Services (HHS) and the National Biothetics Advisory Commission, at the request of the President, has undertaken a sweeping examination of the ethical and policy issues in the oversight of human research in the United States (see www.bioethics.gov). As a result, the ethical and regulatory framework within which paediatric cancer clinical trials are conducted, now and in the future, will continue to evolve, and investigators must remain abreast.

Specific ethical issues impacting statisticians involved in collaborative research include ensuring confidentiality, data and safety monitoring, and problems and pitfalls in interpretation of interim analyses and planning studies to answer negative questions.47 A negative question, e.g., what is the minimum therapy needed to produce cure?, has particular relevance for paediatric cancer trials which are (often) aimed at reduction of the acute or delayed effects of cancer treatment on the growing child.

Notwithstanding the strict ethical guidelines and regulations surrounding research in children, there is substantial and even increasing pressure to enroll children in clinical trials as a result of other federal policies and recent legislation, including the Food and Drug Administration's (FDA's) 1998 paediatric rule, the paediatric provisions of the FDA Modernization Act (FDAMA) of 1997, and the sweeping Children's Health Act of 2000 (PL 106-310), the sum of which is certain to increase paediatric clinical trials, particularly drug trials. Federal NIH policies promulgated in 1998 were aimed at increasing the participation of children in research so that adequate data would be developed to support the treatment for disorders affecting adults which also affect children, and rules mandated that children (i.e., individuals under age 21) must be included in all human subjects research unless there are scientific and ethical reasons not to include them. The FDA rules and regulations48 require pharmaceutical manufacturers to assess the safety and effectiveness of new drugs and biologics in paediatric patients and established powerful economic incentives for manufacturers (six-months' extension of market exclusivity) on any drug for which FDA requested paediatric studies (see www.fda.gov/cder/cancer for further information on regulatory aspects of paediatric oncology drug development).

In addition to ethical and regulatory issues which impact the conduct of paediatric trials, there are also practical problems associated with clinical cancer research in children. Due to an understandably greater concern for long-term adverse consequences of treatment in a population of patients, the majority of whom are likely to be cured and alive for decades at risk for late effects, it is absolutely essential that long-term follow-up and serial surveillance of survivors is built into the studies. While follow-up is essential, it is also exceedingly difficult and expensive to maintain, as children and adolescents grow up, go away to school, leave home, marry, change name, etc. The frequency and severity of late effects also tend to progress with time off treatment, making follow-up beyond 15 or 20 or 30 years critical and identification of risk factors for the development of these late consequences of treatment essential. For example, Lipshultz et at.49 studied 120 survivors of childhood ALL or osteogenic sarcoma who had been treated with doxorubicin a mean of 8.1 years earlier (range 2-14 years) and compared their cardiac function to a control population, and evaluated the impact of gender, age at diagnosis, length of time since completion of therapy, and dosage and cumulative dose of doxorubicin on cardiac status. Calculating sex-specific standardised scores or z scores (expressed as the number of standard deviations above or below the value for the normal controls) for cardiac contractility, wall thickness and afterload, the results of univariate and multivariate analysis showed that female sex and higher cumulative dose of doxorubicin were associated with depressed contractility, that there was an association between younger age at diagnosis and reduced left ventricular wall thickness and increased afterload, and that the prevalence and severity of abnormalities increased with longer follow-up.49 Such studies typify the challenge of methodologic and statistical issues in the study of late effects of childhood cancer, the greatest challenge being data collection.

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