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Editorial |
Chief, Pharmacology & Experimental Therapeutics Section, Pediatric Oncology Branch, NCI
For most FDA approved drugs, pediatric labeling consists of the statement "safety and effectiveness in pediatric patients have not been established." This lack of clinical data in children for most marketed and new drugs can result in an increased risk of toxicity or reduced efficacy if children are dosed based only on clinical data extrapolated from adults. In addition, many clinicians may be unwilling to prescribe newer, better drugs for children before FDA-approved pediatric dosing recommendations become available.
Dosing children by scaling adult doses based on body weight or surface area does not account for developmental changes that affect drug disposition (pharmacokinetics) or tissue/organ sensitivity to a drug (pharmacodynamics). Unfortunately, the pharmacological impact of these developmental changes is often discovered only when unexpected or severe toxicity in infants and children leads to detailed pharmacological studies, as was the case with chloramphenicol use for infections in the newborn nursery [1]. Therapeutic tragedies such as this could be avoided by performing pediatric pharmacological studies during the drug development process and before widespread off-label use of agents in infants and children becomes common practice.
Ethical, economic, regulatory, and technical issues have contributed to the deficiency of pediatric data for new and marketed drugs. Children are afforded special protection under current Federal regulations (45 CRF Part 46) that govern biomedical research. These regulations require that research studies provide the potential for direct benefit to the pediatric subjects who participate in the trial. This limits the population of subjects that is potentially eligible for clinical trials of new drugs, because it is difficult to justify performing the initial pharmacokinetic and safety testing in normal pediatric volunteers as is frequently done in adults. Pediatric anticancer drug trials can only be performed in children who have the type of cancer that the drug is intended to treat. Many childhood diseases, including childhood cancers, are rare, and as a result there is not a financial incentive to develop new drugs that are specific for childhood diseases or to study pediatric indications for drugs that are being developed for more common adults diseases. Since 1962, FDA regulations have required that the safety and effectiveness of a new drug be demonstrated under the conditions of its intended use, but the FDA did not require clinical data in the pediatric population before approving new drugs. Until recently, the FDA relied only on voluntary compliance measures, which were ineffective at stimulating systematic studies of new and marketed drugs in children. Therefore, in 1999 new regulations that require safety and efficacy studies in pediatric patients for new and marketed drugs that are likely to be used to treat children were implemented. These new regulations rely on positive and negative incentives to encourage pediatric studies. It is obviously too early to judge the impact of these new regulations on pediatric drug development. Finally, performing clinical trials in children, especially young children, is technically difficult, because frequent blood testing, which is required for pharmacokinetic studies and for toxicity monitoring, is challenging to the clinician and traumatic to the patient.
For diseases that are similar in children and adults, such as infections, pediatric clinical trials during the drug development process only focus on evaluating the safety and pharmacokinetics of new drugs. The efficacy of the agent need not be demonstrated separately in children, if the drug is efficacious in adults with the same disease. This approach does not apply to the development of new drugs for childhood cancers, because these tumors have different tissues of origin, pathogenesis, disease manifestations and drug sensitivity profiles than cancers that occur in adults. Therefore, even though pediatric oncology has been on the forefront of studying new drugs in the pediatric population, demonstrating the safety, pharmacokinetics, and efficacy of new anticancer drugs for childhood cancers remains an arduous and demanding task. Phase I trials of anti-cancer drugs in children are not initiated until after completion of adult phase I trials and can take up to two years to complete. Broad phase II trials, which accrue patients with each of the common childhood cancers to separate disease strata, are then conducted, and may also take several years to complete. For active drugs, incorporation into already effective frontline regimens and demonstration of efficacy usually requires a nationwide multi-institutional randomized phase III trial, which may take three to five years to complete accrual and another three to five years to mature to the point that survival differences can be assessed. For many pediatric solid tumors, there are too few patients to conduct more than one phase III trial nationwide every five years. This creates a significant bottleneck for developing new agents and obtaining the clinical data required for FDA approval of a pediatric indication.
The actions taken by the FDA to increase awareness of and compliance with testing new drugs in children are important steps to develop specific pediatric dosing recommendations at an earlier stage in the development process and to improve the safety of new agents in children. Pediatric oncologists must now devise more rational methods of selecting which new anticancer drugs to develop for childhood cancers and develop new and more efficient trial designs to evaluate the safety, pharmacokinetics, and efficacy of new anti-cancer drugs in children with cancer, as more new anti-cancer drugs become available for testing in children at an earlier stage in the drug development process.
References
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