Pediatric Drug Safety Studies

Acknowledgement

The opinions offered in this article are those of the authors, and do not represent the official position of the U.S. Food and Drug Administration.

Introduction

Safety studies are required for all drugs undergoing testing in pediatric patients. While efficacy can be extrapolated in some cases on the basis of adult studies, safety studies must be separately conducted in pediatric patients. The FDA Amendment Act of 2007 is very specific about the inclusion of pediatric safety information in drug labels. Comparisons between adult and pediatric safety studies provide some valuable insight into study design issues that impact on the value of the information obtained in a pediatric safety study. New means of collecting pediatric safety data are becoming available as consortia are forming that have electronic medical records for pediatric patients available. Pediatric safety studies are improving, and a better understanding of these studies will drive pediatric drug development.

The objectives of this discussion are to review previous pediatric drug safety studies and regulations, to make note of new systems for pediatric safety that are developing in the United States and Canada, and to predict how these changes may affect pediatric safety studies in the future.

Pediatric Regulations and Policy

The record of pediatric legislation and regulations has a long history[1-3] which includes the Section on Pediatric Exclusivity in the FDA Modernization Act (FDAMA) in 1997 that provided incentives for sponsors to submit pediatric information to the FDA. This was followed in 1998 by the Pediatric Rule Regulation which required that pediatric information be provided to the Agency. In 2002, however, the Federal courts ruled that FDA did not have authority to issue such requirements. In 2002, the Best Pharmaceuticals for Children Act (BPCA) was introduced that provided six-month exclusivity for voluntary studies of drug moieties in children. This was followed in 2003 by the Pediatric Research Equity Act which required pediatric studies in children for certain types of applications. In 2007, the FDA Amendments Act was passed which updated the BPCA and PREA legislation [4].

In 2007, Congress enacted the FDA Amendments Act (FDAAA) that included two major sections covering the use of drugs and biologics in pediatric patients. These sections included Title IV, the Pediatric Research Equity Act and Title V, the Best Practices for Children Act. As part of the law a pediatric assessment and plan are required outlining the pediatric studies (e.g., pharmacokinetics/pharmacodynamics, safety, efficacy) that the sponsor plans to conduct. This plan should address the development of an age-appropriate formulation and, under PREA 2007, must contain a timeline for the completion of studies. FDA recommended that the timeline should include the dates the applicant will: (1) submit the protocol; (2) complete the studies; and (3) submit the study reports.

Section IV. C of FDAAA covering PREA states that the data submitted under PREA will depend on the nature of the application, what is known about the product in pediatric populations, and the underlying disease or condition being treated. PREA does not require applicants to conduct separate effectiveness studies in pediatric patients in every case. PREA states that if the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in Section V.D. Safety is not mentioned in relation to extrapolation. The Agency recognizes that in certain cases scientific and ethical considerations will dictate that pediatric studies should not begin until after approval of the drug or biological product for use by adults. For example, when a product has not shown any benefit over other adequately labeled products in the class, when the therapeutic benefit is likely to be low, or when the risks of exposing pediatric patients to the new product may not be justified until after the product’s safety profile is well established in adults, then pediatric studies should be deferred until after the approval of the drug in adult patients.

A Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act explains the term "pediatric assessment" and describes the information needed in PREA submissions. This includes data that are adequate to assess safety and effectiveness and support dosing and administration for claimed indications in all relevant pediatric populations (section 505B(a)(1) and (2) of the Act). The pediatric assessment contains data gathered from pediatric studies using appropriate formulations for each age group for which the assessment is required, and other data that are adequate to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric sub-populations and support dosing and administration for each pediatric sub-population for which the drug or the biological product has been assessed to be safe and effective. If the effectiveness of a pharmaceutical can be extrapolated from adults to pediatric patients, approval in pediatric patients is then based upon pharmacokinetic and pharmacodynamic studies and a pediatric safety trial.

Pediatric Drug Safety Studies

The result of these legislative and regulatory policies has been a significant increase in pediatric studies and labeling changes and the quality of the information submitted. From June 1998 through September 2009, there were 372 FDA Requests for pediatric studies made that resulted in 355 products with new labeling. An examination of those 355 labeling changes showed that 258 had expanded the age range, 57 labels indicated that safety and efficacy had not been established, 64 had new or enhanced safety information, 31 had specific dosing changes or adjustments, 23 had new pediatric formulation and 7 showed pharmacokinetic differences between children and adults [3,5].

The safety studies conducted for pediatric patients are generally much smaller than those conducted for adult patients. Antiviral and antipsychotic agent labels were recently evaluated for safety information in pediatric and adult patients. Eleven of 17 antiviral drugs had both pediatric and adult safety information available. For the 11 antiviral agents, 1534 pediatric patients were included in the safety studies versus 4188 adult patients. Only 3 of the 11 antipsychotic agents had both pediatric and adult safety information. Those three safety studies were conducted in 1045 pediatric patients and 2831 adult patients. No agreement was found for the adverse effect profile between the pediatric and adult patients. This limited evaluation demonstrates that pediatric safety information cannot be predicted from adult safety information, and supports including larger numbers of pediatric patients in safety trials. Smaller numbers of pediatric patients in drug safety trials compromises signal detection and the certainty that can be attached to any particular signal.

No one would question that certain adverse drug effects are different in children than in adults. This is the case for any drug that may have an effect on growth and development, such as a corticosteroid or steroid derivative. However, increasing evidence demonstrates that even minor adverse effects which occur frequently in adults do not have the same incidence in pediatric patients. In the case of cough after angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), the frequency of cough is much less in pediatric patients [6]. The frequency of cough in children after ACEi’s was 3.2% and after ARB’s was 1.8%, but cough in adults after ACEi’s and ARB’s is reported to be 7.2%. Therefore the type of adverse effect, the frequency, and the severity of an adverse effect cannot be predicted in children from the adult experience.

Much of the pediatric safety information that has been added to labels has come about as a result of BPCA. One recently published study examined the studies that were conducted for pediatric exclusivity from 1997 to 2007 [4]. Out of 137 labeling changes, 33 (26%) had pediatric safety information added to the labeling. Of those 33 trials, only 16 (48%) were fully presented in the peer-reviewed literature. Nine of the 16 studies presented information that was consistent with the FDA reviews and safety labeling changes. However, seven published studies focused on aspects of the study that were substantially different from that of the FDA reviews. Consequently, only 9 out of the 33 pediatric studies resulting in labeling changes related to safety information were correctly reported in the published literature.

An important part of the analysis of safety information for pediatric patients is the cost associated with performing these studies. Two studies of the benefit-to-cost ratio have been published for the drugs studied under BPCA. One study evaluated 24 trials in 2,506 pediatric patients for nine oral antihypertensive agents [7]. The median cost of performing safety and efficacy trials for these agents was $4.3 million, but the ratio of economic return to cost was 17. The authors concluded that the 6 months exclusivity awarded for pediatric studies conducted under BPCA was economically beneficial to sponsors. A broader analysis of a wider group of drug products studied under BPCA demonstrated a more variable economic return [8]. In this analysis, the benefit to cost ratio varied from -0.7 to 73. This underscores the need for sponsors to start early in planning pediatric studies to take advantage of the full period of exclusivity.

Another area of continued research is the comparisons between adult and pediatric safety studies which can provide valuable insight into study design issues that impact on the value of the information obtained in a pediatric safety study. These comparisons also have the advantage of demonstrating differences in how ontogeny impacts on safety signals. Another advantage of these studies is the potential to show unexpected changes in blood or plasma levels of drugs. These studies assist in demonstrating the existence of changes in disease or drug pathways related to maturation and genomics, and in avoiding adverse events due to incorrect dosing [9].

New Approaches to Electronically Collecting Drug Safety Information

The use of computers in identifying signals for safety surveillance has been reported for some time now [10]. In hospitals, voluntary incident reports detect only about 6% of adverse drug effects. As more and more data become available electronically, computerized systems have been developed that automatically detect a signal which may indicate that an adverse event has occurred. The signals can then be researched by a trained health care practitioner (physician, pharmacist, nurse), and a decision can be made as to whether a true adverse event occurred. These systems can be used to provide better surveillance for known adverse drug effects, or can be used to detect and amplify safety signals related to previously undetected adverse events. Not all adverse event consortia rely solely on computers, and some involve a scientific goal of identifying the causes of adverse events.

The extrapolation of efficacy is based on the core assumptions that the mechanistic pathways of the disease being treated and the mechanism of action of the drug used to treat the disease are similar in both pediatric and adult patients. Safety, however, is typically not extrapolated as there is significantly less information available to support those assumptions and as adverse events can be idiosyncratic. Moreover, pediatric clinical studies rarely have sufficient numbers of patients enrolled in clinical studies to be statistically powered to fully assess pediatric safety and adverse events. As a consequence, other means of collecting pediatric safety data are becoming available such as post-marketing commitments, and postmarketing requirements consortia that have electronic medical records for pediatric patients available. Examples of these include: Pediatric Pharmacology and Therapeutics Research Consortium (PPTRC) at the National Institutes of Health, the Pediatric Sedation Research Consortium [11] and the study on Improving Pediatric Safety and Quality With Health Care Information Technology sponsored by Massachusetts General Hospital and AHQC [12].

One of the better examples of how this type of system works in pediatrics is the Genotypic Approaches to Therapy in Children (GATC) network in Canada. The GATC is a network of eight major children’s hospitals in Canada, and involves the collection of DNA for genotyping as part of identification of genetic markers of adverse drug effects [13]. In November of 2009, the GATC published their study of cisplatin ototoxicity in children, and two genetic variants which were associated with this adverse effect [14]. Although cisplatin-induced hearing loss occurs in all age groups, 40-60% of all children receiving cisplatin are affected and the impact is greatest in children. With the availability of the GATC network, the group was able to identify variants of thiopurine methyltransferase (TPMT) and catechol O-methyltransferase (COMT) which were associated with cisplatin-induced ototoxicity in both a discovery group and a confirmatory group of children. The odds ratio for the TPMT genetic variants was 17.0. Therefore, the children that are going to be affected by cisplatin can more readily be identified, which will allow for earlier intervention with either supportive treatment or, eventually, alternative therapy. The GATC group is also working on codeine-induced infant mortality and anthracycline-induced cardiotoxicity [15].

An example of a network in the United States is the Automated Adverse Event Detection Consortium (AAEDC) based in Children’s National Medical Center in Washington DC [16]. This consortium ties together multiple children’s hospitals based on an identical vendor for an electronic medical records system. Therefore, the possibility exists that such a system has access to thousands of pediatric patients in the inpatient and outpatient systems of major children’s hospitals. Such a system would then make conducting a large safety study in a pediatric population feasible to the same extent that these studies are presently conducted in adults.

Table 1- Examples of adverse event detection and reporting systems in the United States and Canada for pediatric patients

Other pediatric-oriented electronic systems for adverse event detection and reporting have now grown and matured [17-24]. The Table is a partial listing of some of the systems that are available in the U.S. for adverse event detection and reporting for pediatric patients.

Conclusions

Significant improvements in pediatric and drug legislation have improved drug labeling for both efficacy and safety in the last decade. These improvements have resulted in 355 labeling changes for pediatric use, and have resulted in 64 labeling changes for pediatric safety. As new pediatric studies continue to be approved under PREA and BPCA, this trend will no doubt accelerate in the future. Even so, current pediatric safety studies still fall far short of matching patient numbers in relation to adult studies, and therefore lack the power to adequately characterize the pediatric safety profile. Given our understanding of the differences in adverse drug effects between pediatric patients and adults, patient safety trials should be improved in the future. Continued progress in developing new pediatric clinical safety consortia based on electronic data collection will soon provide access to larger numbers of pediatric patients for pre- and post-approval pediatric drug safety trials.

References

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