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European Biopharmaceutical Review

Don’t Forget the Kids

It seems quite inconceivable that until 10-15 years ago, drugs were mostly developed, tested and authorised for adults only. Children were largely underserved by the whole drug development process, with some estimates suggesting that up to 75% of marketed drugs were unlabelled for use in children (1). Even more surprising is that the general population seemed to have very little knowledge of this public health concern, despite many agreeing that children deserve the right to effective and safe medicines with known dose levels and well-documented side-effects, especially given the vulnerability of this particular sub-group.

Legislative Changes


Despite the absence of properly evaluated medicines in the paediatric population, historically children have continued to receive medications by off-label or unlicensed prescribing, with alarming reviews indicating that 23-60% of adverse drug reactions are associated with this practice (2). Paediatric drug development was traditionally perceived as being both costly and risky, offering a poor return on investment. Often the most necessitous disease populations presented the largest and, sometimes, irresolvable challenges, such as recruitment for paediatric clinical trials of rare diseases, or age-appropriate drug formulations.

However, irrespective of the challenges ahead, the realisation that children have been neglected by drug development practices has underpinned legislative changes in both Europe and the US. This has been achieved by a ‘carrot and stick’ approach, whereby the ‘carrot’ is given as a reward and incentive for the completion of a paediatric development plan, and the ‘stick’ is provided by several new laws. These now make it mandatory to include paediatric assessments for all new drugs or line extensions for a patented product, unless they can be specifically excluded – for example, in geriatric disease indications – or deferred – since the completion of the paediatric investigations would delay drug approval for the adult population.

In Europe, this has been achieved with the introduction of the 2007 Paediatric Regulation, which replaced previous directives and calls for a paediatric investigation plan (PIP) to be submitted and agreed with the EMA’s Paediatric Committee (PDCO), ideally before the end of Phase 1 clinical trials. As a reward, a six-month extension of patent protection is provided for non-orphan drug products, two years’ extension is given for orphan drug products, and a 10-year extension is offered for offpatent medicines receiving Paediatric Use Marketing Authorisation.

In the US, two acts were passed which broadly achieve the same results as the European Paediatric Regulation. The 2003 Paediatric Research Equity Act makes it mandatory to submit a paediatric study plan (PSP), normally by the end of Phase 2 clinical trials, and the 2002 Best Pharmaceuticals for Children Act offers six months’ exclusivity for the fulfilment of the written request for paediatric development; both acts have since been permanently reauthorised in 2012 by the FDA Safety and Innovation Act.

Due to the time taken to develop new medicines, it is inevitable that there will be a lag before more thoroughly evaluated drugs are available to children. Following these aforementioned changes in legislation, however, pharma has responded and paediatrics are now beginning to be considered as an integral part of the drug development process, rather than just a rare exception or unexpected bolt-on. Indeed, a more recent EMA review has concluded that since the introduction of the Paediatric Regulation, there is now more high-quality research in this area, more medicines for children with age-appropriate, openly accessible information, and no unnecessary clinical trials in children (3).

Animal Safety Studies

Pivotal in both Europe and the US is the provision of a paediatric plan, which details the basis of the development of a new drug for paediatric use. This specifically provides information on the timing and measures to evaluate safety, quality and efficacy and, in particular, both the PIP and PSP require information from animal safety studies to support safe starting doses for paediatric clinical trials.

Although the standard segment three pre- and post-natal reproductive toxicity study in rodents does assess effects of maternal exposure in the F1 generation when reared to adulthood, these juvenile animals are not directly exposed to a test substance. Furthermore, both general and reproductive toxicity studies start dosing in adult animals, meaning the traditional battery of regulatory toxicity tests used to support clinical trials does not include any studies which evaluate age-related developmental toxicities from direct exposure to juvenile and maturing animals.

The result has been the development of a new type of study, with direct administration being given to juvenile animals through to maturity, along with various endpoints to assess developmental toxicities – encompassing elements of both general and reproductive toxicity approaches. While guidelines are available on how to conduct juvenile animal studies, and when or if they should be conducted, a fundamental principle is that each study is designed case by case; consequently, the guidelines are broad and non-specific, resulting in a whole new set of challenges (4-6).

Changeable Designs


With generic – as opposed to prescriptive – regulatory guidelines, the emphasis is on the applicant to propose a considered paediatric development approach on the basis of sound scientific judgement, rather than simple regulatory box ticking. As this is driven by the specific test substance and clinical indication, each juvenile animal study should be tailored, taking into consideration:
  • Intended paediatric clinical regimen (route, frequency and age at administration)
  • Most appropriate non-clinical juvenile testing species, taking temporal species differences into account
  • Pre-existing toxicity knowledge, mode of action or likely target organ toxicity considering the relevant contemporaneous organ development
As a consequence, with changeable study designs, both the EMA and FDA encourage early dialogue to agree the proposed paediatric development plan, including the non-clinical aspects. The aim of this is to prevent later delays in the development programme, should they feel the data are insufficient to support safe starting dose level selections for paediatric clinical trials (7). This brings new difficulties for testing laboratories that no longer have a standard study they can cost or schedule for, but one of changeable design, and of varying length and complexity, in addition to differing endpoints and a design subject to regulatory approval before any juvenile animal work begins. It also necessitates a more flexible approach that is often heavily reliant on niche expertise, with designs often being ‘negotiated’ with regulatory agencies.

Following initial review of the proposed non-clinical juvenile study design, it is not uncommon for unpredictable or impractical recommendations to be made of the testing labs. While efforts have been made by regulators to curb this – for example, through the formation of the Non-clinical Working Group (NcWG) within the EMA’s Paediatric Committee – these design modifi cations can complicate matters.

In these situations, push-back from expert scientists has sometimes proven successful, but these discussions still take valuable time and the NcWG only become involved approximately half way through the PIP approval process. As a result, labs conducting juvenile animal studies will often only agree to commence work once the PIP opinion has been agreed. This increases the lead time of these large and costly animal studies, which usually take over six months to complete the in-life phases and a further six months to finalise the study report.

This problem is further compounded by the lack of alignment in timing for PIPand PSP approval. The PIP submission typically occurs earlier on in the development process, therefore running the risk of regulatory disagreement on the design of non-clinical juvenile studies if the FDA has differing views at a later stage. For example, disagreements over the need for one or two juvenile animal species have been frequent for central nervous system active compounds. While regular telephone conferences are now held between the EMA and FDA with a view to encourage consistency, whether to go with the earlier European approved design or delay for FDA approval is still a gamble the developing company has to contemplate.

Technical Hurdles


Once a design has finally been agreed, irrespective of the specifi cs, testing in juvenile animals has some distinct differences compared to other animal studies; largely in the interpretation of data and study practicalities. One of the biggest challenges concerns the practical skills needed to perform this type of work. Juvenile animals are typically more vulnerable to the procedures required, such as dosing and blood sampling. Consequently, highly skilled and experienced technicians are critical to distinguish between the usual developmental differences, as opposed to test substance-related changes – for instance, how to differentiate between a well-nested and sleeping litter and a well-nested but lethargic litter?

Juvenile animals are also much smaller than their adult counterparts and so administration of the test substance can be difficult or, in some cases, impossible. Even taking blood samples for evaluation of clinical pathology data or systemic exposure can be challenging, particularly since most of these studies are conducted in rodents. Furthermore, sampling routes requiring anaesthesia are exceptionally difficult in juvenile animals, or simply infeasible at some ages, due to the inability to maintain a sufficient plane of anaesthesia. Even when a suitable blood sampling route is available, the circulating blood volume is often so small that increased numbers of animals are needed to provide adequate samples.

Recent developments in micro-sampling techniques are likely to have huge benefits in these types of studies, but this is not yet commonplace. Just having sufficient animals born on the correct days to allow selection to the study is a hurdle in itself, as it is crucial that animals are dosed uniformly from the same age to ensure appropriate exposure through the relevant developmental phases. With juvenile rodent studies often employing more animals than a carcinogenicity study, this is not to be underestimated, and often means that labs have to run juvenile animal studies in batches, further complicating an already tricky study design.

Pathology Examinations


It is not just the offspring but also the mother that increases the numbers of animals required. Although some labs still rely on in-house littered animals – and use only a few animals born per litter to ensure genetic variability – more recent collaborations with UK animal suppliers have enabled the employment of cross-fostering techniques at the breeding establishment to reduce the numbers of animals needed and increase genetic variability.

Pathology examinations have their own unique set of challenges, with full tissue lists usually retained for microscopic examination. While animals are usually in adulthood by the end of the study, any early decedent can be as young as one day old, and so identifying smaller tissues – like thyroid glands – can be extremely hard. Even once processed to slide, the pathologist must have suitable experience to determine between normal variations in development or test substance-related delays in development, let alone frank toxicity – for example, treatment-induced apoptosis in the brain, as opposed to the usual process of neuronal apoptosis, which occurs as part of normal brain maturation (8).

Age-Appropriate Considerations


It is largely these inter-animal variations in development that compound interpretation and highlight the importance of ageappropriate study designs. It is not as simple as dosing the youngest animals possible, for as long as possible, as this runs the risk of eliciting irrelevant toxicities in developing organs.

One of the major differences compared with toxicity testing in adult animals is the potential for change in exposure. Drug handling properties in juvenile animals are notably different to adults due to immaturity in the organ systems typically involved, such as the hepatic and renal systems; this is further complicated by an immature bloodbrain barrier and gastrointestinal tract, affecting absorption. Consequently, peak and total systemic exposure in the early dosing period can be much greater and longer lasting, thereby increasing the likelihood for toxicity. Furthermore, previously uncharacterised toxicities may be identified because equivalent exposures in adult animals have never before been achieved.

To counter this, dose range finding studies in juvenile animals are essential, particularly considering the vulnerability to initial toxic insults, with changes in body weight being less welltolerated and the propensity for juvenile animals to succumb much sooner to effects of dehydration through lack of milk intake.

Another factor to be considered is the effects mediated by the mother: although genetic maternal bias can be negated by the use of cross-fostered litters, it is a natural characteristic of many animals to abandon young which are not thriving, and focus their attention on the strongest in a litter. For these reasons, careful and specific dose level selection is essential in juvenile animal studies, requiring substantial expertise.

Young Minds

Juvenile animal studies were traditionally considered to be an offshoot from the field of reproduction toxicology; however, there are as many, if not more, general toxicity endpoints in these studies and it could be argued that a whole new field of regulatory toxicology is emerging in its own right. As the regulatory requests for juvenile animal studies become more commonplace, the experience required for their successful design, completion and interpretation should not be underestimated and has led to labs specialising in this niche field.

With juvenile toxicology being one of the few areas of regulatory toxicology where nothing is fixed – except the legislative need to conduct the work – it is an exciting new field, ultimately leading to better researched and intelligently developed medicines for children. After all, who could argue against this, with some of the smallest customers of drug developers having the biggest unmet needs.

References

1. Roberts R, Rodriguez W, Murphy D and Crescenzi T, Pediatric drug labeling: Improving the safety and efficacy of pediatric therapies, JAMA 290(7): pp905-911, 2003
2. Cuzzolin L, Atzei A and Fanos V, Off-label and unlicensed prescribing for newborns and children in different settings: A review of the literature and a consideration about drug safety, Expert Opin Drug Saf 5(5): pp703-718, 2006
3. Human medicines development and evaluation EMA/250577/2013: Successes of the paediatric regulation after 5 years
4. EMA Committee for Human Medicinal Products: Guideline on the Need for Non-Clinical Testing in Juvenile Animals of Pharmaceuticals for Paediatric Indications, adopted January 2008
5. Guidance for Industry. Nonclinical Safety Evaluation of Paediatric Drug Products. US Department of Health and Human Services, FDA Center for Drug Evaluation and Research, February 2006
6. ICH Harmonised Tripartite Guideline: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals M3 (R2), finalised June 2009
7. Carleer J and Karres J, Juvenile animal studies and pediatric drug development: A European regulatory perspective, Birth Defects Res B Dev Reprod Toxicol 92(4): pp254-260, 2011
8. Bittigau P et al, Antiepiletic drugs and apoptopic neurodegeneration in the developing brain, Proc Natl Acad Sci USA 99(23): pp15,089-15,094, 2002


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Emily Richmond is a Senior Reproduction and Juvenile Toxicologist at Sequani Ltd. She joined the company in 2005 having completed her MSc in Toxicology at the University of Birmingham. Although initially a reproduction toxicology Study Director, and after a period of running general toxicology studies, Emily began specialising in juvenile toxicology and has since designed and study-directed over 25 juvenile rat studies. With several publications in the field, she is now one of the key scientists involved in the validation, study design and regulatory liaison for juvenile studies at Sequani.
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