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Pediatric Drug Development—An Introduction to the 2006 Annual General Meeting of the British Society of Toxicological Pathologists

Amgen Inc., Thousand Oaks, California, 91320, USA

Recent and ongoing regulatory agency activities have required the understanding of the safety and efficacy of novel medicines specifically in the pediatric population. Developing drugs for pediatric indications present many scientific challenges, particularly in the preclinical stage where there are very few publications describing a successful preclinical development package and/or interpretation of data from preclinical studies. It is imperative that those involved in preclinical evaluation of drugs design and interpret studies using the best scientific approach to ensure that those children dosed with the drugs are treated safely, but also that the pediatric population is not denied access to effective treatment due to an inappropriately negative interpretation of data. This Annual General Meeting brings together leading experts in academia, industry, politics, and regulatory authorities to discuss the scientific and political issues associated with the need to provide preclinical understanding of the safety of drugs that will be administered to children. In particular, previous experience of juvenile toxicology studies that have supported dosing of drugs to children will be discussed in detail.

The Current Availability of Drugs for Use in Children—Issues and Solutions

Clinical Director of Pharmacy, Royal Liverpool Children’s NHS Trust and Associate Director, Medicines for Children Research Network, University of Liverpool, Eaton Road, Liverpool L12 2AP, United Kingdom

The "gold standard" for demonstrating quality, safety, and efficacy of a medicine in Europe is to obtain a Marketing Authorization (MA) following presentation of data obtained from experimentation and clinical trials. Most medicines for adults have a MA, but up to 70% of medicines prescribed for babies and children have no authorization or are used in circumstances not covered by the MA. Only 30% of recently marketed medicines have a MA for children and 25% of these do not have an age-appropriate formulation. Children have been described as "therapeutic orphans." Pharmacists frequently have to adapt "adult" formulations by producing liquids or powders derived from the adult dosage form or from chemicals. Quality of these formulations is not established and bioavailability studies are rarely undertaken. Adult dosage forms may have to be adapted by carers before administration, for example by splitting or crushing tablets and mixing with food or liquid, by cutting transdermal patches to reduce dose absorbed, or by using injection solutions orally. The evidence base for these manipulations is weak and some research suggests inaccuracy in dose delivery. Recent U.K. Department of Health (DH) strategy has seen production of the British National Formulary for Children, setting up of the Medicines for Children Research Network (MCRN), and initiatives to improve quality of pediatric formulations. A new European regulation on medicines for children will see incentives and requirements linked to obtaining a MA for "adult" medicines. At the end of phase I studies a Pediatric Investigation Plan must be agreed with the European Agency for the Evaluation of Medicinal Products (EMEA), and successful completion of agreed studies will bring 6 months’ patent extension. An increased number of clinical trials should result and MCRN should be in a good position to provide a competitive research environment to encourage the pharmaceutical industry to undertake trials in the United Kingdom. Children deserve access to appropriate, authorized medicines with age-adapted formulations. New initiatives and legislation should provide better drug information, more research, and more authorized medicines in the next few years.

Medicines for Children—What Do We Expect from the Pharmaceutical Industry?

Shadow Secretary of State for Health in the United Kingdom

This is a time of substantial change in the legislative and regulatory environment in developing medicines for children. Industry and government have a responsibility to ensure that children have access to the best quality prescribing. A decade ago, the House of Commons Health Select Committee expressed its concern that children were being treated as small adults, with drug dosages far too often simply scaled down for children from adult doses, for which there was no clinical trial data. Similar concerns were appreciated in the United States, where legislation was enacted to increase pediatric studies. The problem is especially prevalent in home-based maintenance therapy, with 1 in 3 caregivers reporting problems of obtaining medicines. Overcoming these problems has proven difficult, in particular addressing the ethical requirements for enrolling children in trials, especially concerning any degree of discomfort or risk that may be entailed. However, the balance of the argument has clearly shifted. The benefits of acquiring evidence about the efficacy of medicines in children clearly require us to organize for this. In 2000, the European Union’s Council of Health Ministers resolved to address this issue. The result is the newly enacted EU Regulation on Medical Products for Pediatric Use. This legislation imposes new requirements, but also offers incentives in the form of extension of patent protection. The Regulation also provides for regulatory support to stimulate the effectiveness of clinical studies and research. In return, society expects drug companies to act with integrity and vigor in the search for new medicines. This includes being open with data, even if this may be detrimental to the immediate needs of the company. Society understands the financial risks, and the need for substantial reward for success, but requires that companies are to have a corporate social responsibility. That may take many forms—support for patients, investment in bringing therapeutic benefits through to patients, investment in orphan diseases that may not necessarily be viable, and the provision of drug therapies in developing countries who, even with aid support, could never hope to pay a commercial price for drugs. Improving the health of our populations is a corporate responsibility, as well as a social responsibility, and certainly not just a state responsibility.

Regulatory Perspective—Current and Upcoming Guidelines on Juvenile Toxicology in the United States

FDA/CDER Division of Metabolism and Endocrinology Products, Silver Spring, Maryland 20993-0002, USA

Many therapeutics marketed in the United States and used in pediatrics lack adequate information in the product label for use in children. Recent legislation has focused attention on current practices for evaluation of drug safety in this population. Data from pediatric studies submitted under the Pediatric Rule/BPCA/PREA have identified significant changes for dosing, risk, or have extended the age and safety profile, resulting in improved product labeling. Pediatric patients are individuals at various stages of development, rather than simply small adults. Their susceptibility to the intended and unintended effects of therapeutics may differ from adults. In addition, and perhaps more importantly, therapeutic agents may alter development in children. Historically, animal data has been used to support safety for clinical trial in adults and pediatrics. These traditional study designs are not designed to assess drug effects on postnatal developing processes specific to pediatrics. Some effects may be difficult to detect in a clinical trial or during postmarketing surveillance (e.g., long-term effects, nonmonitorable toxicity). Pharmacokinetic studies can provide useful data for adjusting therapy in children. PK differences in children are often associated with physical differences from adults such as: smaller body size, differences in body composition, higher metabolic/respiratory rates, differences in metabolic enzyme maturity, and clearance. Likewise, pharmacodynamic differences may account for altered functional responses in children compared to adults. The complexity of development in children often delays the predictive capability of PD model systems. Drug effects specific to pediatric populations may not always be reasonable, ethical, or safely assessed in pediatric clinical trials. Juvenile animal models can be useful in providing a safety assessment when conducted during an analogous developmental period to the intended pediatric population. Juvenile animal models may be useful in designing appropriate monitoring, timing, and phasing of trials for initial enrollment. The importance and need for PK/PD assessment in pediatrics will likely continue to increase as the mechanisms of toxicity and associated ontological processes are better understood. Compliance with the current USFDA regulations has led to an increasing need for juvenile animal studies particularly to address safety concerns. There are challenges involved in the application of juvenile animal studies to assess safety. An overview of the USFDA/CDER experience with juvenile animal study design and interpretation in safety assessment following the recently published FDA/CDER Guidance to Industry: Nonclinical Safety Assessment of Pediatric Drugs (February 2006) will be provided by illustrative example.

Note: The author is Chair of the PTCC Pediatric Working Group.

General Considerations for Study Design in Juvenile Toxicology Studies

GlaxoSmithKline, General Toxicology, Ware, Herts, SG12 ODP, United Kingdom

Juvenile toxicity studies are sometimes required to support pediatric use of pharmaceuticals/biological products. Juvenile studies require study designs that mesh both developmental and adult toxicity studies to address potential safety concerns. Juvenile animal studies are designed to determine if there are toxicities that might be unique to immature animals, and what stage of development might be more sensitive. Postnatal development continues as a complex "moving target," not only for assessing target organ sensitivity, but also within other systems that affect exposure. The design of these studies can impact the ability to identify treatment-related delayed, accelerated, or altered development as well as specific toxicity. Regulatory guidance suggests a flexible case-by-case approach to study design. A variety of study types appropriate to assess the potential hazards or concerns of the test article can be used. The selection of the appropriate study design depends on many factors. Prior to starting a juvenile animal study, one should consider: (i) the intended or likely use of the test article in pediatric populations, (ii) the timing and duration in relation to growth and development in juvenile animals and pediatric populations, (iii) the potential differences in pharmacological and toxicological profiles between mature and immature systems, (iv) the existing data from nonclinical safety studies and adult clinical trials where available, and (v) any particular concerns regarding the test article/pharmacological class. Treatment routes, including oral, dermal, inhalation, and subcutaneous may be used; however, there are practical constraints for some procedures at early ages. Standard toxicological assessments including clinical pathology, electrocardiography, and histopathology can be applied to these studies, but again practical constraints may affect the earliest assessment occasions. Juvenile studies should be targeted studies in terms of both the endpoints and developmental periods assessed. The development of several organ systems, including nervous, pulmonary, renal, immune, skeletal (growth), and reproductive have been identified by regulators as key systems/endpoints that should be considered. Screens to assess these systems can be added to rodent or nonrodent studies. A tiered approach is often used where more complex investigations can be employed to investigate findings noted during the studies, or they may be incorporated into initial studies where there are specific concerns. Toxicokinetic assessments are frequently of help in interpretation of findings and are often incorporated into study designs. Using these strategies and designs, potential safety issues for infants and children in clinical trails or in marketing of drugs for use in pediatric patients can be identified.

Histology of the Developing Rat—Normal Variations in Juvenile Toxicity Studies

Sequani Ltd., Ledbury, HR8 1LH, United Kingdom

As part of the evaluation of current juvenile studies, it is important to be able to differentiate between treatment-related changes and variations in appearance that are related to the different stages of juvenile development. Physiological changes such as changes to p450 activity and glomerular filtration rate may impact on the exposure of targets to both target and metabolites. The role of the thyroid hormones is also considered.

Experience of Juvenile Toxicity Studies from a Pathologist’s Perspective—Developing Drugs for Children

Discovery and Regulatory Pathology, Glaxo Smith-Kline, Ware, Hertfordshire, United Kingdom

This presentation will focus on the development of an inhaled combination of a corticosteroid and a β-agonist for use in children with asthma, a therapeutic indication of which GSK has many years of experience. Descriptions of asthma (derived from the Greek word for "panting") go back over 3,000 years, but it is only in the last 30 years that effective pharmacological therapies have become available that are delivered directly into the airways, thus reducing unwanted systemic effects. At the same time there seems to have been a marked increase of the number young children diagnosed with this condition. Until relatively recently no specific preclinical or clinical testing was performed in young animals or children for new chemical entities intended for this age group.

The development in our laboratory of a fixed-dose combination of a corticosteroid and β-agonist for the treatment of asthma utilized individual components that had already been successfully marketed for adults. Combination doses of the corticosteroid and β-agonist had been subjected to extensive preclinical evaluation in young adult rats and dogs. In order to support the dosing of young children, preclinical evaluation in juvenile animals was performed, in which the two components were tested independently. Rats were exposed to the test compound in a number of studies by the subcutaneous route (owing to their small size) from Day 3 postpartum up to Day 45. Dogs were exposed by the inhalation route from 2 weeks of age. Since a major concern of treatment of still-growing animals is the potential for effects on tissue development, this was extensively evaluated. A number of nonconventional endpoints were selected for evaluation, including testes descent, vaginal opening, bone length and, since the respiratory tract is the main site of delivery of the test compounds, tracheal measurements and dry lung weight. Adrenal function tests were also performed. Findings observed in the juvenile toxicity studies revealed no additional toxicities. Expected effects of corticosteroids on hematological parameters and adrenal function were seen. However, there were no indications of an increased sensitivity of juvenile animals to the pharmacological and toxic effects of the two test compounds. No major issues were encountered in the execution of these studies. In one study, in young dogs, a number of infections were observed (including animals receiving vehicle), which may have been related to the waning of passive immunity. An understanding of the normal development and histology of young growing animals is essential in the pathological evaluation of this age group. To this end we are building up a library of tissues from animals of different ages.

Examining the Developing Nervous System of the Rat; Study Design, Normal Histology and Examples of Pathology

AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, United Kingdom

Specific regulatory guidelines for developmental or juvenile neurotoxicity testing of pharmaceuticals do not exist, and bespoke studies need to be designed based around the established adult and developmental neurotoxicity (DNT) guidelines required by the U.S. Environmental Protection Agency (EPA). The current EPA DNT guideline calls for gestational and postnatal exposure of out bred rats, with neuropathological examination of the brain at a single postnatal time point, while the brain and peripheral nervous system are examined at the young adult stage. A thorough understanding of the comparative timelines for neural development in rat and man are thus required to ensure that dosing schedules adequately model the age of humans at risk. The problem of working with the smaller size of the postnatal rat brain has given rise to considerable debate as to the optimal postnatal time point for neuropathological examination. Early postnatal times (Day 11) are difficult to perfuse-fix, and the friable nature of the brain requires delicate handling to avoid damage. Later postnatal times (Day 22) allow for perfusion fixation, but the histological appearance of the brain is more similar to the adult. The fundamental difference between adult neurotoxicity and DNT studies is the requirement to undertake brain morphometry. Most sponsors to date have undertaken simple linear measurements of selected brain regions from coronal sections. Since the dimensions of many brain structures vary considerably over microscopic distances in a rostro-caudal plane, the generation of homologous brain sections is imperative to avoid large variations in the data generated. Artefactual shrinkage arising from fixation or processing are further potential confounders in the interpretation of morphometry data, and study protocols must ensure standardization across the groups. Debate continues as to whether peripheral nerves should be paraffin- or resin-embedded, but the latter allows for analysis of fiber size, should a subtle peripheral neuropathy become evident. The use of additional stains beyond hematoxylin and eosin should be employed at the discretion of the study pathologist, but immunohistochemistry and other specialized techniques must be validated and reproducible in order to avoid the generation of uninterpretable data. The manifestation of DNT in humans ranges from frank malformation to microscopic neural disruption. Data from rodent DNT studies submitted to the EPA, to date, suggest that for the chemicals assessed, overt morphological changes in the brain are a rare event.

Issues in Juvenile Toxicity: The Challenge of Developmental Drug Biotrans-formation

Section of Developmental Pharmacology and Experimental Therapeutics, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri 64108, USA

Consideration of issues related to the pathogenesis of adverse drug reactions (ADRs) in children raises the possibility that there may be periods of increased vulnerability to both concentration-dependent and idiosyncratic toxicities. For example, cardiovascular collapse in newborns treated with chloramphenicol (also known as "gray baby syndrome") has been attributed to delayed maturation of chloramphenicol glucuronidation in this age group. Similarly, the risk of fatal hepatotoxicity associated with valproate treatment is highest in children less than 2 years of age receiving concomitant enzyme-inducing anti-epileptic drugs. Events such as these, as well as other concentration-dependent and idiosyncratic reactions, are not readily predicted from animal studies for several reasons. These include a compressed developmental schedule in animals (especially in rodents) compared to humans, prenatal vs. postnatal developmental events (e.g., CNS development), physical scaling, and factors related to drug disposition and response. The drug-metabolizing enzymes of the cytochrome P450 2D (CYP2D) subfamily represent just one example of the difficulties that may be encountered in extrapolating drug biotransformation data from animals to humans for assessment of drug exposure. Humans have only a single functional CYP2D gene, CYP2D6, and the gene product is considered to be involved in the biotransformation of approximately 25% of drugs used clinically, including medications, such as opiate analgesics, serotonin reuptake inhibitors and anti-emetics, prescribed to children. In contrast, rats have at least 5 functional CYP2D genes and mice have 9. Beyond the impossibility of translating substrate specificity and preferences from 9 mouse and 5 rat CYP2D enzymes to 1 human protein, ontogeny and pharmacogenetic variability of CYP2D6 activity in humans adds further complexity. Strategies involving longitudinal phenotyping studies with relatively safe probes (e.g., dextromethorphan) have been applied to better understand the extent of variability of CYP2D6 activity in children, and have revealed important new insights into other pathways as well. Examples of the application of CYP2D6 phenotyping and genotyping approaches to ADRs involving CYP2D6 substrates in newborns to adolescents will be presented.

Toxicologic Pathology, Vol. 35, No. 3, 444-446 (2007)
DOI: 10.1080/01926230701267454


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This Article Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Pyrah, I. T. G. Articles by Leeder, J. S. Search for Related Content PubMed Articles by Pyrah, I. T. G. Articles by Leeder, J. S. Social Bookmarking                         What's this?