Abstract
Pediatric research is ethically challenging, requiring protection of children from potentially harmful exposure while encouraging drug development and pediatric labeling. Over time, numerous adult medications have been approved without corresponding labeling in children, leading to off-label pediatric use, often with little data to support appropriate dosing. This paper discusses US and EU legislation regarding pediatric research, and the challenges associated with conducting safe, efficient and ethical clinical trials in this population.
Introduction
Drug development in children presents a number of practical and ethical dilemmas. While insufficient research can lead to potential harm from inappropriate dosing or exposure, the public prefers to spare children from the potential risks involved with the research itself. In an effort to mitigate these concerns and increase pediatric information contained in labeling, regulations have been created in the United States and European Union to encourage pediatric drug development. These regulations allow that when the disease states and drug effect are similar in adults and children, it may be appropriate to extrapolate information derived from adult studies to children, thereby limiting studies in the pediatric population to supportive safety, efficacy and pharmacologic studies. Despite increased pediatric research resulting from regulatory promotion of pediatric drug development, conducting clinical trials in this population presents extreme clinical, ethical, and operational challenges.
Regulatory Landscape
The Pediatric Rule
The Pediatric Rule (Table 1) was finalized on December 2, 1998 by the United States (US) Food and Drug Administration (FDA) [1]. In 2003, Congress passed the Pediatric Research Equity Act (PREA), reestablishing the mandate of the Pediatric Rule [2].
Table 1. US and EU Legislation Aff ecting Pediatric Research
| Regulatory Body |
Regulation |
Year Finalized |
Objective |
Incentive |
| FDA |
The Pediatric Rule |
1998 |
Mandates the conduct of studies assessing the safety and efficacy of new drugs and biologic products in order to provide adequate labeling for the use in pediatric patients |
The “stick”. No additional patent protection given upon completion
The FDA cannot require conduct of a pediatric study for an indication not approved in adults |
| FDA |
Food and Drug Modernization Act (FDAMA) of 1997 |
1997 |
Focused legislation containing an economic incentive to encourage pediatric drug development |
The “carrot”. Provides 6 months of market exclusivity extending the existing patent-life for a drug whose manufacturer conducts and submits pediatric studies in compliance with FDA requirements.
FDA is permitted to request studies in conditions for which an indication does not exist in the adult population, if it is determined that the product could have meaningful health benefi ts in this indication in pediatric patients. |
| EMA |
EU Pediatric Regulation |
2006 |
Regulation requiring inclusion of information relating to potential pediatric use of a product when fi ling a marketing authorization application, in the form of a pediatric investigational plan (PIP) |
Once the PIP is agreed to and is fully executed in compliance with the agreement, the sponsor is granted an additional 6 months of marketing exclusivity
The PIP requires studies in children similar to those completed in adults and frequently also requires studies of specifi c medical importance in pediatrics |
This regulation requires pediatric studies for a product that is likely to be used in a substantial number of pediatric patients, if it would provide a meaningful therapeutic benefit, or if the absence of relevant labeling could pose a substantial risk to children. This rule is designed to ensure adequate pediatric labeling of new products at the time of (or soon after) approval, and has also been applied to marketed products submitting applications for changes in active ingredient, indication, dosage form, dosing regimen, or route of administration. This regulation allows the FDA to require a new formulation, if it is needed, for a pediatric age group in which the drug will be used. In general, studies are only required in cases where the information is not obtained through pediatric exclusivity or other elective measures.
Pediatric Exclusivity Provision
Before the Pediatric Rule was finalized, US Congress passed the Food and Drug Modernization Act (FDAMA) in 1997 [3]. This regulation was reauthorized in January 2002 under the Best Pharmaceuticals for Children Act (BPCA) [4]. The success of the pediatric incentive (FDAMA/BCPA) and PREA were contributory to Congress passing the Food and Drug Administration Amendment (FDAAA) in 2007 [5], which reauthorized both BCPA and PREA, leading to completion of more than 300 pediatric studies through the end of 2010 [6].
FDAMA recognized the importance of pediatric studies by providing an economic incentive, extending the existing patent-life by 6 months for a drug whose manufacturer conducts and submits pediatric studies in compliance with FDA requirements. Pediatric exclusivity applies to all formulations, dosage forms, and indications for products with existing marketing exclusivity or patent life containing the same active marketed moiety.
To obtain this additional patent protection, a manufacturer must submit studies that meet the conditions detailed in a written request from the FDA. The written request is a document issued by the FDA, defining the size and design of pediatric clinical studies in the population for which a medical need exists. The written request can originate directly from the FDA, or more commonly, is initiated via a Proposed Pediatric Study Request (PPSR) by interested manufacturers. The PPSR may be negotiated between the FDA and manufacturer before a written request is issued, a process which can take up to several years for an agreement to be reached.
Granting exclusivity is based on compliance with the written request, not on the approval of the medication for pediatric use. Because the process is voluntary, the sponsor can elect to conduct the studies and possibly gain pediatric exclusivity, or decline the written request.
European Union (EU) Pediatric Regulation
As early as 1997, the European Commission organized a panel of experts at the European Medicines Agency (EMA) to discuss the use of pediatric medications, and the need for supportive legislation to encourage pediatric development. The European guideline, ‘Note for guidance on clinical investigation of medicinal products in the pediatric population,' was subsequently released and has been in effect since July 2002 [7]. These efforts ultimately led to the publication of the EU Pediatric Regulation, adopted on December 12, 2006, introducing the requirement
for including information relating to potential pediatric use of a product [8]. This information is based on studies described in a pediatric investigational plan (PIP), submitted to the Pediatric Committee (PDCO) responsible for the scientific assessment of the content of the pediatric components of the development plan. Submission of the PIP is required, but is also rewarded once completed by granting the sponsor an additional 6 months of marketing exclusivity. As with the PREA and the FDA Pediatric Rule, the PIP requires studies in children similar to those completed in adults and frequently also requires studies of specific medical importance in pediatrics.
Challenges with Pediatric Development
Pediatric research presents various clinical, ethical, and operational challenges. Key issues to be considered include the physiological and disease state changes that occur with age that necessitate age stratification (possibly including neonatal, gestational and postnatal age grouping), small blood volumes of the subjects, the small numbers of patients at a given center, differences in care among centers, and the difficulties involved with diagnosis and assessing outcomes in this population, particularly, the very young.
Clinical Challenges
The definition of a child varies according to the governing body, as well as the applicable law of jurisdiction in which the research will be conducted. The National Institute of Health (NIH) classifies a child as any individual under 21 years of age [9]. In contrast, the Code of Federal Regulations (CFR) for the protection of human subjects ambiguously states that children are persons who have not attained the legal age for consent to treatments or procedures involved in the research [10]. The FDA most clearly classifies pediatrics as patients 0 to 16 years of age, divided into the following subgroups: newborns (0 to 27 days of age), infants and toddlers (28 days to 23 months of age), children (2 to 11 years of age), or adolescents (12 to 16 years of age) [11].
As children grow, their physiology, composition, and cognitive and motor function change, causing substantial variation in the metabolism and toxicity of medications across the pediatric age range. Each age group, from preterm neonates through adolescents, has intricate considerations for research. These concerns span from high body surface-area-to-weight ratio and immature blood-brain barrier maturation in newborn infants, to heightened hepatic and renal clearance pathways in toddlers, and potential interference with sexual maturation and hormone development in adolescents. In addition, most disease states present and progress differently at different ages, often necessitating age-related refinements in study entry criteria and endpoints. This consideration and the inconsistent maturation and variability of drug clearance mechanisms, can translate into several different dosing regimens over the pediatric age spectrum. In addition, extrapolation of efficacy and safety from studies in adults or older pediatric patients down to the youngest age groups is not always possible.
Ethical Challenges
Participation in clinical research first begins with educating the participant on the benefits and risks involved with the clinical trial, which allows for the subject to choose whether or not to participate. The informed consent process is built on this progression from investigator disclosure to the participant’s decision, and relies on the intellectual capability of the participant. This process is skewed in pediatric research as consent is provided by the parent or legal guardian, acting as an advocate on behalf of the child. In most cases of children of appropriate age, assent is required as an accompaniment to parental consent, which is the minor’s willingness to participate in research following an age-appropriate disclosure of the risks and benefits involved.
Federal regulations consider children a vulnerable group requiring additional protection as research subjects, beyond that of parental consent [10]. These additional requirements include careful analysis of the trial by the site institutional review boards to carefully assess the potential risks and benefits of all research involving children.
Operational Challenges
From a practical standpoint, studying medications in children can be remarkably challenging. Obstacles to pediatric research include small numbers of pediatric patients with a given condition, the inability to translate findings in one age group to another age group, and difficulty recruiting patients.
In addition, study design challenges arise when taking into consideration the differing needs of pediatric patients versus adults. One challenge is that the volume of blood draws should be minimized in pediatric patients, which can be achieved with sparse sampling approaches or population pharmacokinetic analyses. Sparse sampling leads to less complete data to analyze, but minimizes the risk to children. An additional consideration is the necessity of varying formulations of study medications to balance ease of use for the child, while maintaining efficacious and safe concentrations of the medication.
Conclusions
The off-label use of medicines in children is widespread, and has become of increasing concern over time. General lack of information and appropriate dosing information may expose children to overdosing with unwanted side effects, or underdosing with lack of efficacy. The need for pediatric research is encouraged internationally, with the objective to provide safe, efficient and ethical study of medicinal products in pediatric patients.
References
- Food and Drug Administration. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients: final rule. Federal register 1998;63:66632-66672.
- Pediatric Research Equity Act (PREA) of 2003. Public Law 108-155, 108th Congress.
- Food and Drug Modernization Act (FDAMA) of 1997. Public Law 105-115. 105th Congress: November 21, 1997.
- Best Pharmaceuticals for Children Act (BPCA). Public Law 107-109, 107th Congress: January 4, 2002.
- Food and Drug Administration Amendments Act (FDAAA) of 2007. Public Law 110-85, 110th Congress: September 27, 2007.
- Breakdown of FDAAA Completed Pediatric Studies (2011). US Food and Drug Administration [Online]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm190622.htm [Date accessed 3 June 2011].
- European Medicines Agency. ICH Topic E11: Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population. January 2001.
- Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on Medicinal Products for Paediatric Use.
- National Institutes of Health. NIH policy and guidelines on the inclusion of children as participants in research involving human subjects. March 6, 1998.
- Protection of Human Subjects, subpart D – additional protections for children involved in research, 24 C.F.R. § 46.401-09.
- Guidance for Industry. E11 Clinical Investigation of Medicinal Products in the Pediatric Population. December 2000.
Ian Friedland, MD, is the VP of Clinical Research at Cubist Pharmaceuticals, Inc., responsible for clinical development of the anti-infective franchise. Prior to joining Cubist in 2009, he became a compound development team leader at Johnson and Johnson Pharmaceuticals and a senior director at Peninsula Pharmaceuticals, Inc after joining the pharmaceutical industry with Merck. Dr. Friedland earned his MD at the University of the Witwatersrand in Johannesburg, South Africa, and completed his pediatric residency at the Montefiore Medical Center in New York and his infectious disease fellowship at the University of Texas Southwestern Medical Center in Dallas. Dr. Friedland is a pediatric infectious disease specialist with more than 12 years’ industry experience.
Jennifer Huntington, PharmD, is a Clinical Research Scientist at Cubist Pharmaceuticals, Inc. She received her PharmD degree from the University of Connecticut in Storrs, CT, and completed a post-doctoral fellowship at the Massachusetts College of Pharmacy in conjunction with Cubist. She joined Cubist in 2009.