doi:10.1136/adc.2008.149898 2009;94;474-477; originally published online 10 Feb 2009; Arch. Dis. Child.

H Sammons

European perspectiveEthical issues of clinical trials in children: a

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Ethical issues of clinical trials in children: a EuropeanperspectiveH Sammons

Correspondence to:Helen Sammons, AcademicDivision of Child Health,University of Nottingham, TheMedical School, ClinicalSciences, Derbyshire ChildrensHospital, Uttoxeter Road, DerbyDE22 3DT, UK; helen.sammons@nottingham.ac.uk

Accepted 26 January 2009Published Online First10 February 2009

ABSTRACTChildren should not be harmed by their participation inclinical trials, therefore should no clinical trials beperformed? This is a view that needs to be balanced asclinical trials provide the evidence we need to allowchildren safe and effective prescribing of medicines.Therefore, is it unethical not to involve this population inresearch? This review looks at new ethical guidancereleased to support the recently introduced Europeanlegislation for the licensing of medicines.

European legislation, EU Directive 2001/20/EC,was introduced in January 2007.1 It should give riseto an increase in the number of clinical trialsperformed in children in Europe, as has been seenwith similar legislative efforts within the USA.2

The EU legislation provides both a legislativeframework, to necessitate trials of medicinesrelevant to the childhood population, and afinancial incentive for pharmaceutical companiesto perform them. This takes the form of a 6-monthmarketing authorisation extension for new drugapplications for licensing, which now have toinclude a Paediatric Investigation Plan (PIP).There is also consideration given to medicinesalready on the market. The paediatric-use marketingauthorisation (PUMA) will allow companies tobenefit from 10 years of data protection as a rewardfor the development of a new indication in childrenor formulations appropriate for children of all ages.Following the introduction of the legislation,

guidance has now been published relating toethical aspects of clinical trials from birth up toadulthood.3 This guidance was developed by the adhoc group, chaired by the European Commission,responsible for implementing guidelines relating togood clinical practice. It is intended for everyoneinvolved in any stage of a clinical trial includingresearchers, regulators, and ethics committeesthrough to clinicians and families. This reviewarticle aims to give a practical summary of thisguidance document,3 focusing on some of thethemes highlighted including consent and assent,trial design and methodology, evaluation of riskand the challenges faced in special populations.

WHY DO WE NEED CLINICAL TRIALS INCHILDREN?It is well documented that children are notsmall adults, both in their changing physiologicalmake-up4 and in their clinical needs.5 Therefore,although we have a responsibility to protectchildren we also have an obligation to ensure thatthey receive the best treatment. Currently, manymedicines administered during childhood have not

undergone formal studies during the licensingprocess. Approved drugs however are often usedin an unlicensed and off-label manner: 90% ofbabies in a neonatal unit and 36% of children in ageneral paediatric ward.6 7 In certain cases, eventhough the medicines are used in an off-labelmanner there is good scientific evidence justifyingtheir clinical use. This has been described for theuse of proton pump inhibitors for the treatment ofgastro-oesophageal reflux disease.8 Ethically, weneed to focus our research on those medicineswhere there is a lack of efficacy and toxicity data inpaediatric patients.

CONSENT AND ASSENTConsent is a dynamic and continuous processobtained prior to enrolling a child in a trial, and asan ongoing dialogue between the child, parents andinvestigators throughout their participation. Thispoint is highlighted in the EU guidance whichdiscusses the need for periodic checks during thetrial, suggesting a brief discussion during eachrepeat visit which could be documented in themedical notes or equivalent.A key message from the guidance is the

importance that consent is given free from coer-cion. Article 4(d) of the EU directive states thatthere must be no financial inducement to enrol achild in a trial, either for the parents or the child.The exception to this is the offer of compensationfor the familys time and expenses. In countrieswhere inducements can be offered it has beenshown this may have some influence on parentalreasons for consent,9 with a correlation betweenthe importance of free medication as a reason forconsent and lower family income being shown.The complex relationship between a parent andtheir physician also needs to be considered,especially in patients with chronic disease, acuteserious illnesses and in the situation of lesseducated parents. A parents wish to please theirdoctor may influence their reasons to consent.10 Itis good practice for consent to be taken by theinvestigative team and wherever possible not thetreating physician. This however may not bepractically possible, especially in the emergencysituation. The investigator must however nevertake part in the decision-making, only ensuring theinformation has been understood and sufficienttime has been allowed to come to a decision.The directive requires a minors assent is

considered, but it is not a legal requirement.The guidance recommends whenever appropriatethat the child should participate in the informedconsent process, and if a childs assent is notsought, documentation of a justification of this

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takes place. Separate information sheets for adults and children,and separate consent and assent forms need to be provided, asunderstanding and language will change with age. It has beenshown that children from 9 years old may be able to understandthe benefits and risks of research.11 A recent study of healthychildren aged 68 years taking part in a follow-up study for avaccine12 showed that two-thirds understood that they were tohave a blood test but two-thirds did not know why. Three-quarters of parents in this study felt that they alone shouldmake the decision and only half of children felt they were oldenough. Consent like assent needs to be a continuing processand a childs objections need to be considered. We need torespect a childs will, in conjunction with their parents whoknow them best, and respect a childs right to freely withdrawfrom a trial at any time.

TRIAL DESIGN AND METHODOLOGYA typical pharmacokinetic (PK) study in adults will involvearound 15 blood samples taken following the administration ofthe drug of interest. It is important that adult protocols are notused for children. Paediatric trials need to be designed by thosewith experience both in clinical trials and childrens medicines.There needs to be consultation from parents, and patients fromthe age groups to be included in the trial, where appropriate. Atrial that involved a large number of samples examining thepharmacokinetics and efficacy of cyclosporine A in paediatricrenal transplant13 was criticised, by an editorial in the samejournal,14 as being unethical. It involved 13 blood samples of5 ml during one dose interval in 18 patients. The invasiveness ofthis protocol was felt to be unnecessary and it was felt that thetrial could have achieved its objectives with fewer samples.Design methods can be optimised to allow for the smallest

number of patients to be recruited to give a statistically andclinically significant result. The technique of populationpharmacokinetics15 allows for fewer blood samples to be takenfrom a larger number of patients and Bayesian sequentialdesign16 allows for the sample size to be recalculated after eachobservation. This potentially decreases the number of patientsthat need to be recruited. These methods are the same as thoseemployed in adults. Interestingly, one of the authors from thecyclosporine paper mentioned above has published a morerecent study examining a similar question using populationpharmacokinetics and Bayesian modelling.17 The use of equiva-lence trials and non-inferiority trials is considered in theguidance. They usually involve recruiting a higher number ofparticipants and their use should be limited to where superioritytrials are not scientifically justified. Off-label treatments shouldbe considered for use as a comparator drug in a trial if they areconsidered to be standard of care.Study design needs to try to limit the invasiveness of the

methods used. Alternative sampling methods such as urine18 orbreath testing19 should be considered, although it has beendifficult to find reproducible non-invasive methods to thestandards that clinical trials require. When blood is needed foranalysis, the timing of samples should coordinate as far aspossible with therapeutic sampling. Micro-volumes and micro-assays20 should be used when available. Local anaesthetics needto be used for blood taking and indwelling catheters utilisedwhenever possible. If appropriate, sedation should be used forprocedures and pain should be monitored by age-appropriatescales21 with prompt treatment. Pain, distress and fear should beminimised by using facilities appropriate to the childs age, withpersonnel trained to look after children.

Placebo-controlled trials were regarded as the gold standard.This thinking has changed over the last few years and this ishighlighted in the EU guidance. It states that placebo should notbe used when this means that an effective treatment will bewithheld. This has been the case in some asthma trials,22 forexample, a study examining the efficacy and safety of nebulisedbudesonide which compared three different doses to placebo inchildren aged 48 years.23 Just under two-thirds of theirrecruited population were already being treated with a regularinhaled steroid, so children in their placebo group had a goodchance of having a proven treatment stopped. The resultsshowed a larger proportion in the placebo group dropped outdue to asthma exacerbations and a higher number of courses oforal/parental steroids were prescribed. A comparator group ofcurrent treatment for these children would have been moreclinically relevant and ethically acceptable. Placebos can beconsidered, for example, when there is no commonly acceptedtherapy for the condition or when the commonly used therapyis of questionable efficacy or has a high frequency of adversedrug reactions. Their use now needs careful consideration andgood scientific justification.

RISK/BENEFIT ASSESSMENTRisks and benefits need to be viewed in balance and a childsinterests should always prevail over society and science. Therisks should be considered in conjunction with the severity ofthe condition or diseases to be studied, the age of the child andthe risks and benefits of alternative treatments. For example, inoncology trials, the adverse drug reactions tolerated for a newtreatment in a relapsing cancer would be higher than those foran antibiotic to treat otitis media. Potential harms can bephysical, psychological or social, and they may be immediate ordelayed. They can takemany forms, from the risk of themedicinalproduct tested, or the control, through to the invasiveness andintrusiveness of the research. The guidance also discouragesenrolment in multiple clinical trials which can take place when acondition is rare in childhood, such as hypertension.Risk is summarised into three categories. These are shown in

table 1, with examples of procedures that fall into eachcategory. Minimal risk is defined as a probability of harm ordiscomfort not greater than that ordinarily encountered in dailylife or during the performance of routine physical or psycholo-gical examination of tests. This definition can be debated: asingle car trip across town during a rush hour posesapproximately a 1 in 100 000 chance of death in a child.Therefore, if a PK research study poses a risk of death of 1 in100 000, is it no more dangerous than an ordinary activity ofnormal life? In a telephone interview study around two-thirdsof institutional review board chairs in the USA24 categorised this

Table 1 Examples of risk categories. Adapted from Annex 44

Risk category Procedures

Minimal risk History and examination; blood pressure

Ultrasound

Single venepuncture

Minor risk over minimal risk Multiple venepuncture; nasogastric tube

CT scan

Lumbar puncture; peripheral venous line

Greater than minor increase over Endoscopy

minimal risk Sedation

Anaesthesia

Surgery

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proposed PK study as posing a risk of greater than minorincrease over minimal risk.Parents and children were asked their views on facing research

risks for others in an interview study.25 Children were aged714 years with 81 childparent pairs interviewed. Overall, thechildren and parents were equally willing to enrol in non-beneficial research as charitable activities that posed the samerisk. For a study that posed a one in a million chance of death,40% of children and 19% of parents were willing to participate.Interestingly when the risk was described as the same risks asriding in a car, 89% of children and 93% of parents agreed. Asthe risk of riding in a car is higher, we can see the way that risksare described have an impact on their assessment. More researchis needed on evaluating descriptions to enable children andparents to understand the true risks of clinical research.Benefit can be defined as a progress in treatment, diagnosis or

prevention for the child or the group of children affected. Thiscould be seen as an increase in efficacy, a better safety profile or analternative to an existing treatment. This alternative treatmentmay offer a better route of administration, decreased frequency ofdosing, reduced treatment duration, a more relevant age-appro-priate formulation or an improvement in relation to potentialmedication errors. The guidance gives the following levels of riskas being considered to be in balance with the benefit:c Minimal risk with benefit for an individual or group.

c Minor increase over minimal risk, with benefit to theindividual or group, and with the benefit to risk balance asbeing at least as favourable as that of the available alternatives.

c Greater than minor over increased risk with benefit for theindividual that is especially favourable in relation to thealternative available approaches for the individuals condition.

SAFETY MONITORINGThe level of risk can evolve over time, during recruitment into atrial and with evolving knowledge. It is essential thatmonitoring takes place. A review of paediatric randomisedcontrolled trials26 from 1996 to 2002 has shown that very few(13%) paediatric trials had a data and safety monitoring board(DSMB). It is recommended in the guidance that an indepen-dent DSMB with appropriate expertise of conduct of clinicaltrials in children is used. When not appropriate, for example, incertain small PK studies, this should be justified. Age-appropriate formulations are recommended to reduce the riskof adverse reactions (eg, younger children choking on tablets)and the risk of dosing errors due to inaccuracy.

INTERNATIONAL DIFFERENCESIt is very important in a multinational study that researchethical review is carried out in each of the participatingcountries. Different international jurisdictions will have differ-ent regulations which will need to be considered and patientinformation needs to be presented in a culturally appropriatemanner. For example, in the USA and Canada, studies can beapproved that do not offer a prospect of direct benefit tohealthy children when they pose either only minimal risk orminor increase over minimal risk.27 28

SPECIAL POPULATIONSHealthy child researchIn principle, children should not be enrolled as healthyvolunteers within the EU. The exceptions in the EU that arehighlighted in the recommendations are palatability testingsuch as swill and spit taste testing of a new medicine. Studies

have shown that childrens tastes are different from adults29 andare very difficult to reproduce in an artificial environment. Incertain situations, studies will need to take place in childrenwho are healthy at the time of the trial. Prevention or vaccinetrials contain healthy children but target a population likely tobenefit from the result of those trials overall. Research hasshown that within the UK and Canada views were very similarin health professionals when asked about research in healthychildren. Over half felt that healthy children should not takepart in research for general paediatric conditions even if thismay be relevant to them in the future.30 The role of the healthychild in research still remains to be clearly defined.

NeonatesNeonates, be they preterm or term, represent the most vulnerableof our paediatric populations. Informed consent can be challen-ging especially in the emergency situation.31 They have limitedblood volumes and are often anaemic due to frequent samplingrelated to pathological conditions.32 Limits for trial-related bloodloss are recommended in the guidance. This equates to 2.4 mlblood per kg body weight for the 3% limit over a 4-week period,that is, ,2 ml in an 800 g preterm neonate.

AdolescentsResearch in this group can be challenging, as adolescents belongto the paediatric age group but may have the capacity to makeadult decisions in many other areas of their lives. The need forassent, as already discussed, is paramount. There needs to beprotection of confidentiality, and the disclosure of informationto parents and other health professionals, needs to betransparent to the adolescent concerned at the start of anytrial they assent to. An adolescent may cease to be a minor andbecome legally competent during a prolonged trial. This must berecognised and informed consent must be sought as soon aspossible when this occurs.

CONCLUSIONThe EU directive means that more clinical trials will be takingplace within the paediatric population. The legislation repre-sents a huge step forward for childrens medicines, in the testingof both new and established drugs. Research needs to focus onthose drugs and conditions for which information is mostlacking. We need to make sure that the conduct of these trials isboth safe and ethical. This involves including those withknowledge of medicines, trial methodology and childrenthemselves at the onset of a trials design. There are manyethical issues unique to children, as highlighted in this review.The EU guidance gives a good overview of these issues and is agood reference for anyone involved in drug research.

Competing interests: None.

REFERENCES1. Choonara I. Unlicensed and off-label drug use in children: implications for safety.

Expert Opin Drug Saf 2004;3:813.2. European Parliament and the Council of the European Union. Regulation (EC) No

1902/2006 of the European Parliament and the Council onmedicinal products for paediatricuse. Published in the Official Journal of the European Union on 27/12/2006 (L 378/20).

3. Benjamin DKJ, Smith PB, Murphy D, et al. Peer-reviewed publication of clinical trialscompleted for pediatric exclusivity. JAMA 2006;296:126673.

4. Sammons HM. Ethical considerations for clinical trials on medicinal productsconducted in the paediatric population. Recommendations of the ad hoc group for thedevelopment of implementing guidelines for Directive 2001/20/EC relating to goodclinical practice in the conduct of clinical trials on medicinal products for human use.http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/ethical_considerations.pdf (accessed 27 Aug 2008).

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5. De Wildt SA, Johnson TN, Choonara I. The effect of age on drug metabolism.Paediatr Perinat Drug Ther 2003;5:1016.

6. Turner SA, Longworth A, Nunn AJ, et al. Unlicensed and off label drug use inpaediatric wards: prospective study. BMJ 1998;316:3435.

7. Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates [seecomment]. Arch Dis Child Fetal Neonatal Ed 1999;80:F1424.

8. Tafuri G, Trotta F, Leufkens HGM, et al. Off-label use of medicines in children: canavailable evidence avoid useless paediatric trials? Eur J Clin Pharmacol. http://dx.doi.org/10.1007/s00228-008-0560-0 (accessed 25 Feb 2009).

9. Rothmier JD, Lasley MV. Factors influencing parental consent in pediatric clinicalresearch. Pediatrics 2003;111:103741.

10. Sammons HM, Atkinson M, Choonara I, et al. What motivates British parents toconsent for research? A Questionnaire Study. BMC Pediatr 2007;7:12.

11. Ondrusek N, Aramovitch R, Pencharz P, et al. Empirical examination of the ability ofchildren to consent to clinical research. J Med Ethics 1998;24:15865.

12. John T, Hope T, Savulescu J, et al. Childrens consent and paediatric research: is itappropriate for healthy children to be the decision makers in clinical research? ArchDis Child 2008;93:37983.

13. Charlebois JE, Lum BL, Cooney GF, et al. Comparison and validation of limitedsampling equations for cyclosporine area-under-the-curve monitoring calculations inpediatric renal transplant recipients. Ther Drug Monit 1997;19:27780.

14. Loebstein RMD, Koren GMD. The Ethics of multiple blood sampling in children forresearch. Ther Drug Monit 1997;19:251.

15. Flynn JT, Nahata MC, Mahan JD Jnr, et al. Population pharmacokinetics of amlodipinein hypertensive children and adolescents. J Clin Pharmacol 2006;46:90516.

16. Desfrere L, Zohar S, Morville P, et al. Dose-finding study of ibuprofen in patentductus arteriosus using the continual reassessment method. J Clin Pharm Ther2005;20:12132.

17. Bourgoin H, Paintaud G, Buchler M, et al. Bayesian estimation of cyclosporineexposure for routine therapeutic drug monitoring in kidney transplant patients. Br J ClinPharmacol 2005;59:1827.

18. Krumbiegel P, Herbarth O, Kiess W, et al. Diagnosis of Helicobacter pylori infectionin children: is the 15N urine test more reliable than the 13C breath test?Scand J Gastroenterol 2000;35:3538.

19. Parker A, Pritchard CP, Preston T, et al. Induction of CYP1A2 activity bycarbamazepine in children using the caffeine breath test. Br J Clin Pharmacol1998;45:1768.

20. Naserke HE, Dozio N, Ziegler AG, et al. Comparison of a novel micro-assay for insulinautoantibodies with the conventional radiobinding assay. Diabetologia 1998;41:6813.

21. Franck LS, Greenburg CS, Stevens B, et al. Pain assessment in infants and children.Pediatr Clin North Am 2000;47:487512.

22. Miller FG, Shorr AF. Unnecessary use of placebo controls. Arch Intern Med2008;162:67377.

23. Shapiro G, Mendelson L, Kraemer MJ, et al. Efficacy and safety of Budesonideinhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998;102:78996.

24. Shah S, Whittle A, Wilfond B, et al. How do institutional review boards apply thefederal risk and benefit standards for pediatric research? JAMA 2004;291:47682.

25. Wendler D, Jenkins T. Childrens and their parents views on facing research risksfor the benefit of others. Arch Pediatr Adolesc Med 2008;162:914.

26. Sammons HM, Gray C, Hudson H, et al. Safety in paediatric clinical trials a 7 yearreview. Acta Paediatr 2008;97:4747.

27. Health Canada Therapeutic products Directorate. Adoption of ICH Guidance:Clinical Investigation of Medicinal Products in the Pediatric Population E11. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e11-eng.php (accessed 27 Aug 2008).

28. American Academy of Pediatrics. Committee on Drugs. Guidelines for the ethicalconduct of studies to evaluate drugs in pediatric populations. Pediatrics1995;95:28694.

29. Matsui D, Lim R, Tschen T, et al. Assessment of the palatability of beta-lactamase-resistant antibiotics in children. Arch Pediatr Adolesc Med 1997;151:599602.

30. Sammons HM, Malhotra J, Choonara I, et al. British and Canadian views on theethics of paediatric clinical trials. Eur J Clin 2007;63:4316.

31. Stenson BJ, Becher C, McIntosh N, et al. Neonatal research: the parentalperspective. Arch Dis Child Fetal Neonatal Ed 2004;89:F321.

32. Madsen LP. Impact of blood sampling in very preterm infants. Scand J Clin LabInvest 2000;60:125.

Acanthosis nigricansA 9-year-old Malay girl was referred for simple obesity. She wasdevelopmentally normal and academically average in school.Her mother had type 2 diabetes mellitus. Examination revealeda pre-pubertal child with a weight of 77.1 kg (.97th centile),height 149 cm (9097th centile) and a body mass index of 35.There was acanthosis nigricans of the neck (fig 1), axillae andcubital fossae. Her blood pressure was 128/70 mmHg. Thefasting blood sugar was normal as was a random insulin level.She had an elevated total cholesterol level of 7.7 mmol/l (95thcentile: 5.4 mmol/l) with an elevated low-density lipoprotein(LDL) of 5.7 mmol/l (95th centile: 3.6 mmol/l).Acanthosis nigricans in children is usually associated with

obesity.1 This association has been described in many differentethnic groups.2 The skin lesions are a manifestation of insulinresistance which activates epidermal growth. These childrenhave an increased risk of developing type 2 diabetes mellitus.3

Management of this child involves lifestyle modification as wellas dietary advice. Statins are contraindicated at present as thechild is still pre-pubertal.4 Drug treatment is recommended forchildren 10 years of age or older, whose LDL levels persist at.4.1 mmol/l despite dietary restriction.5

S Marimuthu,1 B S Menon2

1 Paediatric Institute, General Hospital Kuala Lumpur, Kuala Lumpur, Malasia;2 Department of Paediatrics, Universiti Putra Malaysia, Kuala Lumpur, Malaysia

Correspondence to: Bina Sharine Menon, Department of Paediatrics, Faculty ofMedicine & Health Sciences, Universiti Putra Malaysia, Level 10B, Grand SeasonsAvenue, 72, Jalan Pahang, 53000 Kuala Lumpur; drmenon2003@hotmail.com

Competing interests: None.

Patient consent: Parental/guardian consent obtained.

Arch Dis Child 2009;94:477. doi:10.1136/adc.2008.155713

REFERENCES1. Brickman WJ, Binns HJ, Jovanovic BD, et al. Acanthosis nigricans: a common finding

in overweight youth. Pediatr Dermatol 2007;24:6016.2. Caceres M, Teran CG, Rodriguez S, et al. Prevalence of insulin resistance and its

association with metabolic syndrome criteria among Bolivian children and adolescentswith obesity. BMC Pediatr 2008;8:31.

3. Guran T, Turan S, Akcay T, et al. Significance of acanthosis nigricans in childhoodobesity. J Paediatr Child Health 2008;44:33841.

4. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipidabnormalities in children and adolescents: a scientific statement from the AmericanHeart Association Atherosclerosis, Hypertension and Obesity in Youth Committee,Council of Cardiovascular Disease in the Young, with the Council on CardiovascularNursing. Circulation 2007;115:194867.

5. Daniels SR, Greer FR, Committee on Nutrition. Lipid screening and cardiovascularhealth in childhood. Pediatrics 2008;122:198208.

Figure 1 Hyperpigmented, hyperkeratotic plagues on the neck.

Images in paediatrics

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