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PIP: Lab Perspectives

Katja Neuer-Etscheidt and Hermann Schulz at INTERLAB discuss the challenges of conducting paediatric clinical trials

It has been standard medical practice to treat children with drugs that have been approved for use in adults but for which specific clinical trials in children are lacking. Unfortunately, children cannot be treated simply as small adults. Their overall physiological functions are significantly different due to a number of reasons, such as incomplete organ development and different water to fat or body mass to surface area ratios. Such important differences do not allow us to simply scale down the dosing information intended for adults. For many drugs it could be dangerous to use, say a tenth of the adult dosing for a baby with a body weight of five to six kilograms. Unfortunately, however, this is the standard practice for 45 per cent of the doctors in hospital wards and 90 per cent of the physicians in the neonatal intensive care (1). Consequently, doctors are left to their own devices when having to decide which dosage to use. Fortunately, following the enforcement of appropriate laws by the US FDA in 2002 (Best Pharmaceuticals for Children Act [BPCA] and Paediatric Research Equity Act [PREA]) European regulations have been implemented in 2007 (2,3). This paper will describe the impact of these regulations on clinical trials in the paediatric population from the laboratory perspective.

WHY ARE PAEDIATRIC CLINICAL TRIALS NEEDED?

Since 25 per cent of the European population is below the age of 18 years, and as the metabolism of this population is significantly different from the metabolic patterns of adults, treatment of children cannot occur simply by extrapolating dosing information developed for adults. In addition, even if children may have the ‘same’ disease as adults, the disease patterns may be significantly different due to their physiological processes. It is without a doubt known that off-label use of medication is dangerous and must be avoided where possible. The risk to a child’s health can be caused by an inappropriate galenic formulation; underdosing with a possible lack of efficacy; or over-dosing, causing toxic effects. In recent years, regulatory authorities are in agreement that there is a need to conduct clinical trials in children to protect them.

Experience has shown that running studies involving children is a challenging, complex and difficult endeavour, and ethical aspects are of particular importance when planning paediatric clinical trials. Ethical review committees will request a sound scientific background before giving their approval and the drug company will have to describe why this specific clinical trial is necessary and why there is no therapeutic option available. Of course, the study design should take special care of the participating child’s physical and physiological health and no financial advantage should be provided to the study participant or their parents. The next hurdle involves obtaining the parental consent, and possibly, consent from the child as well. This may be required by ethical review committees if the age of inclusion in the study is over eight years.

Obtaining informed consent from a child or their parents requires trained staff with paediatric experience and a childfriendly environment. The child or their parents must be able to understand the information provided in order to avoid them withdrawing once the study has started. It is essential for the investigator’s team to ensure infant patients and their parents are highly motivated and continuously receive updated information.

Regrettably, the public acceptance of paediatric clinical trials is very low. Therefore the activities of organisations such as the Paediatric Working Group (PWG) or the European CRO Federation (EUCROF) to increase awareness are key to the future success of such clinical trials (4,5). In 2007 the EUCROF created PWG with the goal of raising the public awareness towards the need of conducting paediatric studies.

CHILDREN ARE NOT JUST SMALL ADULTS

When talking about children we should avoid giving the impression that they all have similar metabolic patterns irrespective of their ages. Actually, the young demographic is very heterogeneous, as can be seen in Table 1 (page 58). Each age group has different metabolic patterns and will react to patient therapy differently depending on the organ development of the subject. There are significant developmental, psychological, physiological and hormonal differences between children and adults, but also between the distinct age groups. The health problems themselves and the pattern of the diseases also differs between age groups.

This has a significant impact on the galenic formulation of the study drug, which in many cases is solved by using intravenous application. In addition, due to the existence of such age groups and the need to limit the number of children recruited for a specific study, the actual number of infant patients in each treatment group might be low, leading to an additional challenge for the statistician evaluating the study outcome.

Alongside the difficulties in subject enrolment and study compliance, there often is an underestimation of study costs by the drug company (sponsor). In view of the specific requirements of paediatric studies and the justification necessary for ethical review committees and other authorities, paediatric studies tend to be more cost intensive than studies with adults. In addition, when planning multinational paediatric studies, cultural, regulatory, logistical, operational and clinical differences between the various countries must also be taken into account.

REGULATORY SCENARIO

Recent regulatory changes in the US and Europe have been discussed in a previous issue of this publication (7). The objectives of these new medicines regulations are to facilitate the development and availability of medicines for children aged zero to 17 years and to ensure that medicines for use in children are of high quality, ethically researched and appropriately authorised. For most new drugs, a paediatric investigation plan (PIP) now has to be submitted by drug manufacturers to the Paediatric Committee of the EMA. Therefore, the European Paediatric Regulation has specified that PIPs must address all paediatric age groups, and marketing authorisation applications must contain data for use of products in each of these different paediatric age groups unless waived or deferred.

CENTRAL LABORATORY CHALLENGES

As shown in Table 1, children have to be allocated to specific age groups due to the development of their physiological functions. The most challenging aspect of running clinical trials in children below two years is their limited blood volume. Consequently, when treating children, blood cannot be drawn in the same quantities or by using the same type of tubes as used for adults. It is, therefore, critical to find and use appropriate sampling techniques.

Table 1: Definition of different age groups due to ICH Guidance E11
Paediatric age groups
  • Pre-term newborn infants (less than 37 weeks of gestation)
  • Term newborn infants (0 to 27 days)
  • Infants and toddlers (28 days to 23 months)
  • Children (2 to 11 years)
  • Adolescents (12 to 18 years)
Source: ICH Guidance E11 ‘Clinical Investigation of Medicinal
Products in the Paediatric Population’ (6)
 

Interestingly, the Code of Federal Regulations of the FDA merely states that blood withdrawal should be done with minimal risk to children (21 CFR 50.51 and 21 CFR 50.53). But what does this mean for practical purposes? How much blood can be withdrawn with minimal risk to children? How is minimal risk defined?

How Much is Too Much?
Institutional review boards or ethical review committees tend to consider a single blood draw equivalent to one to two per cent of the child’s total blood volume as minimal risk. But one blood draw is generally not sufficient when running a clinical trial. Therefore, other experts define it as safe if the cumulative blood volume collected over an eight-week period does not exceed 10 per cent of the child’s total blood volume. Unfortunately, the literature about this item is not consistent.

Most publications recommend that the blood volume drawn in a 24-hour period is below three to five per cent of the total blood volume. This would mean approximately 10ml blood for a newborn child with an average weight of 3kg and a total blood volume of 270ml, or approximately 3ml in case of a premature baby with less than 1kg body weight and a total blood volume of up to 90ml.

Back in 2005 Michael Cole et al published a retrospective review describing the impact of the blood volume withdrawn for research purposes on the health of paediatric subjects (8). They found that the frequently quoted safe limits of three to five per cent of total blood volume taken on any one study day are not based on published data and may not be tolerable for all patients. Actually, the individual medical situation should be taken into account.

Collection Techniques When Treating Children
Table 2 lists some equipment available for collecting blood in children. The low blood volumes collected via these devices actually mean an additional challenge to those laboratories involved. There might be a need to adapt established instrumentation and methods to allow determination from diluted samples. Also, existing methods might need to undergo a validation to enable them to operate with reduced sample volumes.

Table 2: Equipment for blood withdrawal in paediatric use
Micro-sampling techniques
  • Safety lancets for puncture and incision, for example QuickHeel
  • Microtainer vials for capillary blood withdrawal
  • Micro vacutainer for venous blood withdrawal
  • Safety-multiflies, for example 23G, 25G
  • Micro vials
  • Capillary eryhrocyte sedimentation rate (ESR)
  • Dried blood spot 

An alternative sampling method to the conventional blood withdrawal is the dried blood spot (DBS) (9). DBS offers significant practical advantages over traditional sampling methods, as the samples are easy to obtain from finger, ear lobe or heal prick. Suitable commercial sampling papers absorbing the blood sample and distributing evenly through the paper to leave a spot of blood which is allowed to dry in situ. Using DBS technology typical sample size is approximately 15μl. Thus, this method could help to overcome the challenge of collecting multiple samples to perform pharmacokinetic and pharmacodynamic evaluations which is also required in paediatric studies. With its wellcharacterised advantage of low sample volume and the relatively non-invasive nature, the DBS sampling method could be ideally suited for this type of clinical trials.

CHALLENGES FOR LABS IN PAEDIATRIC TRIALS

One side of the coin involves collecting as few millilitres of blood as possible, and the other side concerns finding a laboratory able to handle such minimal blood volumes. This is of interest because most automatic analysers have a so called ‘dead volume’, which means that the vial inserted into the analyser has to contain more fluid than is actually needed for the determination itself. Therefore, before planning a paediatric clinical trial, an appropriate laboratory should be found which is able to not only run the methods needed, but also to show sufficient expertise in supporting paediatric studies and in handling very small blood volumes.

High sensitivity assays such as LCMS/ MS allow analytics with very low blood volumes. Automation via micro plate techniques with extraction is also becoming common in many laboratories.

There are a number of techniques that can offer significant reductions in the volumes of biological fluids required for each analysis – for example multiplexing techniques such as Luminex. This method not only reduces the sample volume required, but also improves the efficiency when compared to single analyte methods. This technique allows analysis of a large number of analytes of extremely small volumes – approximately 50μl per sample. Another assay using nanotechnology for quantitative assays of macromolecules is Gyrolab – up to five assays can be run simultaneously using the same sample, with sample size being as little as 10μl. Table 3 shows an assortment of some low volume techniques for use in paediatric studies.

Table 3: Low volume techniques
  • Special devices with possibilities for small volumes for applications such as ferritin,
    TSH and clinical chemistry (Roche Modular/Integra)
  • Semiautomatic devices for substances such as TPA, 12-Hydroxy Vit D3, bone marker,
    renin and thymidinkinase (Liaison/Diasorin)
  • ELISA devices for diptheria, tetanus, EBV and CMV (runs with several pre-dilutions, manually)
  • Method adaption for diluted samples
  • Method validation for small volumes, for example HPLC-MS/MS
  • Capillary blood from newborns for homocystein for example
  • Dried blood spots sampling for amino acids and acylcarnitin
  • Gyrolab for quantitative assays of macromolecules
  • Luminex for multiplexing techniques 

HOW CAN A CENTRAL LAB ASSIST?

In view of the specific requirements when running paediatric studies, and due to the fact that each blood sample collected is very valuable as it cannot simply be reproduced, the involvement of a centralised laboratory over local laboratories should be evaluated. A central laboratory experienced in supporting paediatric clinical trials will smooth the initiation process, for example by: providing study specific instructions; producing visit-specific kits with the appropriate micro-sampling materials; using low-volume analysers; or offering the logistical support to ensure a fast and reliable sample transportation and storage.

In addition to such operational advantages, a central laboratory will avoid investigators having to transfer lab results into their case record forms as they will receive standardised lab reports from the central laboratory. The sponsor will have access to a single, consistent and clean database with all lab data for all sites involved. All processes at a central laboratory should follow GCP standards, which generally is not the case in local laboratories. Table 4 shows some advantages when using a centralised laboratory dedicated to supporting paediatric trials (10).

Table 4: Advantages of a central laboratory in paediatric trials 
  • Assistance while compiling the PIP
  • Provision of micro sampling techniques
  • Visit specific kits and study specific manuals
  • Specific analysers for low-volume testing
  • Shipping logistics, extended frozen storage
  • Project support
  • One single, consistent and clean database

CONCLUSION

Regulatory authorities and pharmaceutical manufacturers agree on the need for running paediatric studies to reduce the ‘off-label use’ of drugs in children. Paediatric clinical trials are demanding as they represent a significant challenge for authorities, ethical review committees, sponsors, laboratories and, last but not least, the children involved and their parents. Children are not simply small adults and their blood volume is very scarce, and hence highly valuable. Involving experienced professionals in the investigational sites and in the laboratory sector, for example by selecting a central laboratory, may contribute to a successful completion of each paediatric study.

References

  1. Conroy S, Choonara I, Impicciatore P et al, Survey of Unlicensed and Off- Label Drug Use in Wards in European Countries, British Medical Journal 320: pp79-82, 2000
  2. Regulation EC No 1901/2006 on Medicinal Products for Paediatric Use, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:378:0001:0019:EN:PDF
  3. Amending Regulation EC No 1902/2006 on Medicinal Products for Paediatric Use,http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol- 1/reg_2006_1902_en.pdf
  4. Dehlinger-Kremer M, Kreutz C, Cournot A, Alemany A, Saalbach KP, Schaefer J and Smit-Marshall P, Testing medicines for children in Europe, Good Clinical Practice Journal pp10-15, July 2009
  5. Svobodnik A, Alemany A, Cournot A, Schaefer J, Dehlinger-Kremer M, Mas M, Levy M and Smit-Marshall P, How to improve Children’s Research, Applied Clinical Trials pp46-53, February 2010
  6. ICH Guidance E11: Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population (CPMP/ICH/2711/99),http://www.ema.europa.eu/pdfs/human/ich/271199en.pdf
  7. Nayak N, Doing it for the Kids, European Pharmaceutical Contractor pp64-65, September 2010
  8. Cole M, Boddy AV, Kearns P, The KH, Price L, Parry A, Pearson ADJ and Veal GJ, Potential impact of taking multiple samples for research studies in oncology: How much do we really know?, Paediatric Blood & Cancer 46(7): pp723-727, 2005
  9. Hannam S, Allinson J and Briggs R, Minimising Volume, Maximising Returns, European Biopharmaceutical Review, pp46-48, April 2010
  10. Schulz H, Successfully involving central laboratories: How to avoid fundamental errors, International Pharmaceutical Industry pp74-77, Autumn 2009

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Prior to joining INTERLAB as Business Development Manager in 2008, Katja Neuer-Etscheidt worked as a research associate for Analytical Organic Chemistry at the Institute for Physics, University of Augsburg. She was a postdoctoral research fellow at the Institute of Ecological Chemistry at the Helmholtz Institute (formerly GSF), Neuherberg. In the past Katja has been invited to talk about paediatric studies at scientific conferences.

Before founding INTERLAB in Munich in 1994, Hermann Schulz held senior R&D positions in pharmaceutical industry (Merck & Co, AstraZeneca/ICI and UCB/Schwarz) for 12 years. As a visiting professor, Hermann is head lecturer for applied clinical pharmacology for the Pharmaceutical Medicine postgraduate course at the University Duisburg-Essen (formerly Witten-Herdecke). He has written more than 35 scientific publications and is invited regularly to speak at international conferences.

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