Informed consent for paediatric clinical trials in Europe

In o med consen o paedia ic clinical ials in Eu ope Pi kko Lepola, 1,2 Allison Needham, 3 Jo Mendum, 4 Pe e Sallabank, 5 Da id Neubaue , 6 Saskia de Wild 7 1 Finnish In es iga o s Ne wo k o Pedia ic Medicines, Clinical Resea ch Ins i u e Helsinki Uni e si y Cen al Hospi al L d, Helsinki, Finland 2 Tampe e Cen e o Child Heal h Resea ch, 33014 Uni e si y o Tampe e, Tampe e, Finland 3 The Hospi al o Sick Child en Resea ch Ins i u e, To on o, Canada 4 PRA Heal h Sciences, Reading, UK 5 RegulinX, Su bi on, UK 6 Depa men o Child, Adolescen and De elopmen al Neu ology, Uni e si y Child en’s Hospi al/Uni e si y Medical Cen e Ljubljana, Ljubljana, Slo enia 7 Depa men o Pha macology and Toxicology, Radboud Uni e si y, Nijmegen, The Ne he lands Co espondence o M s Pi kko Lepola, Finnish In es iga o s Ne wo k o Pedia ic Medicines, Clinical Resea ch Ins i u e Helsinki Uni e si y Cen al Hospi al, 00290, Helsinki, Finland; pi kko.lepola@u a.fi Recei ed 23 Decembe 2015 Re ised 4 May 2016 Accep ed 9 May 2016 Published Online Fi s 25 May 2016 To ci e: Lepola P, Needham A, Mendum J, e al.A ch Dis Child 2016;101:1017–1025. ABSTRACT Objec i e Paedia ic clinical ials a e o en conduc ed as mul ina ional ials. In o med consen o assen is pa o he e hics commi ee app o al o clinical ials. The consen equi emen s a y be ween coun ies due o na ional laws and egula ions, which a e no ha monised in Eu ope. These disc epancies can p esen challenges o paedia ic clinical ials. The aim o his s udy was o assemble hese consen and assen equi emen s ac oss he Eu opean Economic A ea. The colla ed na ional equi emen s ha e no been publicly a ailable be o e, despi e a eal need o his da a. Me hods Na ional consen and assen equi emen s o paedia ic clinical ials we e analysed and colla ed o 25 Eu opean Union Membe S a es and 2 Eu opean F ee T ade Associa ion coun ies un il he end o 2014. The da a we e e ie ed om exis ing da abases and h ough communica ion wi h he compe en au ho i ies and selec ed e hics commi ees. Resul s om a li e a u e sea ch o in e na ional o na ional guidelines, decla a ions and con en ions and academic socie ies’ publica ions se ed as compa ison ma e ial. Resul s Consen and assen equi emen s a e he e ogeneous ac oss hese coun ies. We compiled ou findings in ‘The In o med Consen and Assen Tool Ki ’, a able including 27 na ional consen and assen equi emen s lis ed by indi idual coun y. Conclusions Wide a ia ion in paedia ic consen s and assen s p esen s challenges o mul ina ional paedia ic ials in Eu ope. The oolki is a ailable o all hose in ol ed in paedia ic clinical ials and e hics commi ees, p o iding a new pla o m o p oac i e eedback on in o med consen equi emen s, and may finally lead o a needed ha monisa ion p ocess, including uni o m s anda ds accep ed ac oss Eu ope. INTRODUCTION Clinical ials (CTs) in child en a e o en conduc ed as mul ina ional, mul icen e ials, necessi a ed by small pa ien popula ions, a i y o disease and limi ed specialis acili ies. As CTs need a sepa a e compe en au ho i y (CA) and e hics commi ee (EC) app o al in each pa icipa ing coun y, he pha maceu ical indus y and in es iga o s spend much ime and esou ces p epa ing documen a ion and co espondence o hese submissions. In Janua y 2007, he Eu opean Union (EU) Paedia ic Regula ion ((Eu opean Commission) No 1901/2006) 1 came in o o ce equi ing he conduc o mo e paedia ic CTs o acili a e he de elop- men and accessibili y o medicinal p oduc s o child en. A u he EU CT Regula ion will come in o o ce a e 28 May 2016, 2 bu while his ha monises he clinical ial applica ion (CTA) p ocess, i does no add ess he di e si y in e iew and conduc o EC app o als a each si e. The p ocess o ob aining EC app o al (wi h consen o assen equi emen s o child en) is no ha monised in he EU. Despi e in e na ionally accep ed e hical p inciples 3–11 and se e al EU-le el guidelines, 12–16 his a ea p esen s a majo challenge o paedia ic CTs ac oss he EU. Al hough he doc- ine o consen is an e hical co ne s one o medical esea ch conduc ed in humans, special p o- isions o child en a y be ween and, in some cases, wi hin coun ies due o di e ences in na ional laws and p ac ices. Wi hin he Eu opean Economic A ea (EEA), h ee egula o y amewo ks go e n he conduc o paedia ic esea ch: he Con en ion on Human Righ s and Biomedicine ( he O iedo Con en ion); 12 Di ec i e 2001/20/EC (Eu opean Wha is al eady known on his opic? ▸The e a e no iceable di e ences be ween na ional consen and assen equi emen s o paedia ic clinical ials in Eu ope due o na ional laws and egula ions. ▸The in e na ional and he e hics socie ies’ guidelines a e no based on uni o m s anda ds and a ely p o ide de ailed consen o assen ecommenda ions o child en. ▸A single sou ce o comp ehensi e mul ina ional da a on in o med consen and assen equi emen s o paedia ic clinical ials ac oss Eu ope is no publicly a ailable. Wha his s udy adds? ▸The ‘In o med Consen and Assen Tool Ki ’is a publicly a ailable esou ce o s akeholde s in ol ed in he unning o paedia ic clinical ials in Eu ope. ▸These da a p o ide a new pla o m o p oac i e eedback om s akeholde s o main ain a common esou ce and app oach o consen and assen equi emen s in Eu ope. ▸These da a hope o p omo e discussion o long- e m decisions and p ac ical changes leading o uni o m e hics commi ee p ocedu es ac oss he Eu opean Economic A ea. Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 1017 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Commission Di ec i e) 14 and he Paedia ic Regula ion ((Eu opean Commission) No 1901/2006). 1 Disc epancies exis be ween hese h ee amewo ks. Fo example, he e o powe o a child o pa icipa e in esea ch is no co e ed in he Paedia ic Regula ion, while he O iedo Con en ion allows a mo e ex ensi e decision-making capaci y by he child han he Eu opean Commission Di ec i e, which elies on in es iga o ’s conside a ion o he explici wish o a child. The aim o his wo k is o desc ibe he he e ogenei y in consen and assen equi emen s o paedia ic CTs and o p o ide a abula ed summa y o hese equi emen s by coun y as a ool o s ake- holde s p epa ing paedia ic CT submissions in he EEA. METHODS The wo king g oup (WG) o he Eu opean Ne wo k o Paedia ic Resea ch a he Eu opean Medicines Agency (Enp -EMA) collec ed specific legal equi emen s o consen and assen o child en and adolescen s om he na ional legisla ions o 25 EU membe s a es and 2 Eu opean F ee T ade Associa ion (EFTA) coun ies (No way and Iceland) du ing 2014. The p ima y da a sou ce was a eposi o y o EC submissions om na ional au ho i ies p o ided by he Con ac Resea ch O ganiza ion (CRO), PRA Heal h Sciences (PRAHS). 17 Seconda y sou ces we e publicly a ailable da a ound on na ional websi es o egula o y au ho i ies, such as Medicines Agencies and Na ional E hics Commi ees. Addi ional da a came h ough Regulinx, 18 a UK-based company specialised in consul - ing on egula o y a ai s, and om he Finnish In es iga o s Ne wo k o Pedia ic Medicines (FinPedMed). 19 Table 1 p o ides a snapsho o he in o ma ion colla ed in 2014. The da a a e a anged by coun y unde h ee main head- ings. The fi s heading, ‘Consen /Assen om child’, includes da a on he legal age o consen and manda o y o sugges ed age anges defined o assen (o consen i assen is no used). The second heading, ‘Consen om pa en (s)/gua dian(s)’, includes legal equi emen s o he numbe o equi ed signa o - ies. The hi d heading, ‘Gene al in o med consen in o ma ion’ includes o ficial language equi emen s and consen empla e(s), guidelines o addi ional na ional in o ma ion wi h exis ing web links. In addi ion, he WG sys ema ically sea ched online sou ces o iden i y subjec - ela ed a icles, lea ned socie ies’ ecommenda- ions and e hical guidelines, con en ions and ecommenda ions. The sea ch was conduc ed in he PubMed (US Na ional Lib a y o Medicine, Na ional Ins i u es o Heal h) da abase, EU Commission websi e, na ional compe en au ho i ies’websi es and Google sou ces using he keywo ds: e hics, guideline, egu- la ions, paedia ic, mino s, child en, biomedical esea ch, clin- ical ials, human igh s and child en’s igh s. The sea ch esul ed in 28 ele an documen s ela ed o medical esea ch e hics on humans and, mo e specifically, on child en. Ten had a wo ldwide scope, nine a con inen al o na ional scope, and nine we e publica ions om academic socie ies. 2–14 20–34 These docu- men s we e compa ed wi h he cu en o ficial and legal ecom- menda ions by e i ying he consen - ela ed and assen - ela ed ex s o hese documen s. Finally, pe sonal expe iences o he WG membe s (ie, in he conduc ed mul icen e ials and communica ion wi h ECs) we e used o supplemen a y compa ison. Once all he da a sou ces o consen and assen equi emen s in he EEA had been colla ed, he WG compa ed and analysed he sou ces o disc epancy in p ac ice ac oss he ju isdic ions. This e ealed se e al disc epancies, which a e add essed in he discussion sec ion. RESULTS Assen and consen : di e ences in use and defini ions Bo h he e m ‘consen ’and ‘assen ’a e in e p e ed di e en ly in legal ex s be ween EEA coun ies. Gene ally, each coun y’s na ional legisla ion includes legal age anges and equi emen s o ei he consen o assen om a child, in addi ion o any legal (pa en al o gua dian) signa u es. The defini ion o hese wo e ms es s on he need o hese signa u es: ei he gi en by he ial subjec alone, o in conjunc ion wi h he pa en s/gua - dians. Usually, consen is defined acco ding o he legal age limi o majo i y, which di e s be ween coun ies. This is no he case in all coun ies, like he Ne he lands whe e in an in o med consen is needed, in addi ion o pa en al consen in child en be ween 12 and 17 yea s o age. Assen is a non-legal ag ee- men , and an addi ional pa en al/gua dian signa u e (consen ) is always equi ed be o e he pa icipa ion o he child in a ial is legally accep ed. Di e ences in consen and assen age limi s and legal signa u es In mos o he EEA coun ies, 18 yea s is he legal age o inde- penden consen , bu he ollowing excep ions should be no ed: 14 yea s in Aus ia, 15 yea s in Finland and Denma k and 16 yea s in he UK. These excep ions come wi h ce ain limi a- ions and wi h he obliga ion o no i y pa en s/legal gua dians. Howe e , ac oss all he EEA coun ies, 32 di e en age g oup- ings o he legal age exis o ecommended addi ional assen o consen needed om he child pa icipa ing in he CT. These g oupings include, o example, 4–11 yea s, 12–14 yea s and 14–17 yea s. Only h ee coun ies (C oa ia, Li huania and Slo akia) ha e no specified age g oups o assen o consen . Di e ences a e also seen in he equi emen o signa u es om pa en s o legal gua dians. Se en een coun ies (63%) equi e signa u es o bo h pa en s in addi ion o he child’sown assen o consen . Specific guidelines wi h consen o m em- pla es and addi ional aid ma e ial (eg, pic u es) o child en in paedia ic CTs ha e been gene ally accep ed by some EU membe s a es (eg, Finland and UK). DISCUSSION The Uni ed Na ions Con en ion on he Righ s o he Child defines a child as e e yone unde 18, unless, ‘unde he law applicable o he child, majo i y is a ained ea lie ’. 3 Fo chil- d en below ha age, he e a e no iceable di e ences be ween na ional and o ganisa ional egula ions on e hical consen in paedia ic CTs. These conce n specifically non-uni o m age limi s and age anges, di e en defini ions o legal consen and he equi emen o pa en al o legal gua dian signa u es. I appea s ha hese c i e ia, o unknown easons, a e no uni o mly defined in Eu opean guidelines o ecommenda ions. We also ound ha he in e na ional and he e hics socie ies’ guidelines and ecommenda ions a ely de ail consen o assen p ocedu es o child en, 71327–31 bu o en e y gene ic ins uc- ions wi hou specificdefini ions. 2–68–12 20–26 32–34 Fo he g ea e pa , hese c i e ia do no seem o be based on he de el- opmen al s age o he child and his/he compe ency le el o in o med consen o assen . Compe ency, in addi ion o heal h condi ion, is impo an o de e mining u he ac ions i ial subjec s each he age o majo i y du ing he s udy and need o gi e hei own (legal) consen o con inue. 2 The e ms ‘consen ’and ‘assen ’a e also no defined in gene al guidelines and a e no ha monised ac oss he EEA. Some Eu opean coun ies use he e m consen o bo h mino s 1018 Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Table 1 The In o med Consen and Assen Tool Ki —in o med consen equi emen s o paedia ic clinical ials in Eu ope Consen /assen om child* Consen om pa en (s)/gua dian(s) Gene al in o med consen in o ma ion Coun y Legal age o consen † Manda o y/sugges ed age anges de ined o assen (o consen i assen no used)‡Numbe o equi ed signa o ies O icial language equi emen s Consen empla e(s)/guidelines/in o ma ion sou ces Aus ia No speci ied P ac ice–– 14 yea s 8–13 yea s EC may equi e younge assen s Bo h pa en s Ge man h p://www.medunig az.a /e hikkommission/Fo um/index.h m h p://www.e hikkommissionen.a / h p://www.uibk.ac.a /s a ech /scheil/ scheil-ein ueh ung-in-die-a zneimi elp ue ung-bei-kinde n-und-jugendlichen---kks--kids-ip.pd Belgium 18 yea s 4–11 yea s (some si es do no use unde 12 yea s) 12–14 yea s 14–17 yea s One pa en a ec ui men , bu bo h pa en s a some poin o signa u es Du ch, F ench; Ge man a si e eques h p://www. agg-a mps.be/en/human_use/medicines/medicines/ esea ch_de elopmen /e hic_ commi ee/ empla es_in o med_consen / Do no ha e paedia ic empla es Bulga ia 18 yea s 6–11 yea s 12–14 yea s 14–17 yea s—use own consen +pa en al signa u e also equi ed Bo h pa en s Bulga ian No na ional EC websi es a ailable in English Bulga ian D ug Agency -> clinical ials h p://en.bda.bg/index.php?op ion=com_ con en & iew=ca ego y&layou =blog&id=14&I emid=34 C oa ia No hing speci ied No hing speci ied No hing speci ied C oa ian Agency o Medicinal P oduc s and Medical De ices o C oa ia -> Cen al E hics Commi ee -> h p://www.almp.h /?ln=en&w=o_SEPu In o ma ion on clinical ials no a ailable in English. Czech Republic 18 yea s 7–11 yea s 12 yea s—own consen 12–14 yea s 15–17 yea s Bo h pa en s. Only by one pa en i he o he pa en is no lis ed in he child’s bi h ce i ica e, has died o is younge han 18 yea s. Czech. Whe e he child’s pa en s (o one o hem) a e o eign na ionals, he in o ma ion shee shall be p esen ed in bilingual o ma . S a e Ins i u e o D ug Con ol -> De ails o clinical ials / Guidelines and Fo ms / KLH-22 V.1: h p://www.sukl.eu/medicines/klh-22- e sion-1 Denma k 18 yea s 15–17 yea s––p oxy consen Bo h pa en s Excep ion—no pa en s i aged 15–17 and non-in e en ional no- isk s udy (EC dispensa ion equi ed) Danish The Na ional Commi ee on Heal h Resea ch E hics -> Guidelines abou no i ica ion h p://www.c k.sum.dk/CVK/Home/English.aspx h p://c k.sum.dk/English/guidelinesabou no i ica ion.aspx -> 4.4. Medicinal p oduc ials and clinical in es iga ions o medicinal de ices in ol ing legally incompe en subjec s; 4.4.1 T ials wi h child en and young people unde he age o 18 h p://c k.sum.dk/English/guidelinesabou no i ica ion.aspx#A sni %205.0 Ac on Resea ch E hics Re iew o Heal h Resea ch P ojec s Es onia 18 yea s 0–7 yea s 7–17 yea s––manda o y Bo h pa en s Es onian S a e Agency o Medicine -> Clinical ials -> Condi ions and p ocedu e o conduc ing clinical ials o medicinal p oduc s h p://www. a imiame .ee/en/clinical- ials-medicinal-p oduc s-es onia Finland 15 yea s W i en sepa a e consen as soon as child is li e a e; unde 15 yea s––own consen +pa en al consen ; 15–17 yea s––own consen +pa en al no i ica ion i mino can unde s and he signi icance o esea ch+di ec heal h bene i is expec ed Pa en o legal gua dian and he child, when hey a e li e a e, need o sign he consen . One pa en by he law, bu he o he one can be in o med (bo h can sign i hey wan ). Finnish, Swedish Medicines Resea ch Ac 488/1999 Medical Resea ch Dec ee 986/1999 Addi ional in o: FinPedMed guidelines; legal and e hical egula ion— empla es o age g oups 6–17 and pa en s Regula o y equi emen s o clinical ials in Finland Pic u e ca ds o suppo IC p ocess Con inued Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 1019 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Table 1 Con inued Consen /assen om child* Consen om pa en (s)/gua dian(s) Gene al in o med consen in o ma ion Coun y Legal age o consen † Manda o y/sugges ed age anges de ined o assen (o consen i assen no used)‡Numbe o equi ed signa o ies O icial language equi emen s Consen empla e(s)/guidelines/in o ma ion sou ces F ance 18 yea s Based on EC—usually wo o h ee age g oups 4–6 yea s 7–12 yea s 13–17 yea s Pic u e ICFs o young child en Bo h pa en s F ench Comi é de P o ec ion des Pe sonnes Sud-Médi e anée II : h p://www.cpp-sudmed2. / In o ma ion-e -au o isa ion-des?lang= Na ional Consul a i e E hics Commi ee o Heal h and Li e Sciences: h p://www.ccne-e hique. /en Ge many 18 yea s 7–11 yea s 12–16 yea s 17 yea s––own consen +pa en al consen equi ed Bo h pa en s Ge man Ge man E hics Council; h p://www.e hik a .o g/—no in o ma ion o clinical ials Landesä z ekamme B andenbu g—in o ma ion a ailable ONLY in Ge man. h ps://www.laekb.de/ ICF Guidance h ps://www.laekb.de/ iles/146A97FF999/AMG_Pa ien enin o_Kinde _7bis11.pd Hunga y 18 yea s Unde 6 yea s 6–10 yea s 11–14 yea s 15–17 yea s One pa en Hunga ian Na ional Ins i u e o Pha macy and Nu i ion -> Laws and egula ions (only a ailable in Hunga ian) -> Minisz e i endele ek h p://ogyei.go .hu/sea ch/index.php?sea chPh ase=dec ee& om=10 h p://www.ogyei.go .hu/magya _jogszabalyok/ -> Dec ee 35/2005 (VIII. 26.) o he Minis e o Heal h on he clinical ial and applica ion o co ec clinical p ac ices o in es iga ional medicinal p oduc s in ended o use in humans 7§ Clinical ials conduc ed on mino s h p://ne .jog a .hu/j /gen/ge doc.cgi?docid=A0500035.eum Iceland 18 yea s Unde 12 yea s One pa en — he EC can eques bo h pa en s’signa u es in some cases. Icelandic o English. The s udy objec i e in Icelandic. Ma e ials in Icelandic. (Fo s udies in ol ing g oups o o he e hnici y, an app op ia e language is equi ed.) The Na ional Bioe hics Commi ee (h p://www. sn.is/en/node/189) The Pa liamen ; h p://www.al hingi.is/english -> h p://www.al hingi.is/lagasa n/ log-sam hykk -a-al hingi/ -> The Ac o Law, No. 44/2014, on scien i ic esea ch wi hin he heal h sec o de ines he condi ions o biomedical esea ch and he ole o he bioe hics commi ees h p://www.al hingi.is/lagas/nuna/2014044.h ml Se e al laws and egula ions on da a p o ec ion, medicines, biobanks and heal h in o ma ion collec ions (2014), e c I eland 16 yea s (clinical ials) 18 yea s (all o he esea ch) 7 yea s, o acco ding o capaci y o child One pa en English Lis o Resea ch E hics Commi ees o clinical ials o IMP: h p://heal h.go .ie/ eu opean-communi ies-clinical- ials-on-medicinal-p oduc s- o -human-use- egula ions-2004/ Resea ch E hics Commi ee S anda d Applica ion Fo m: h p://www.molecula medicinei eland.ie/ esea ch_e hics Na ional Consen Policy: h p://www.hse.ie/eng/abou /Who/quali yandpa ien sa e y/Na ional_ Consen _Policy/consen aine esou ce/ aine iles/Na ionalConsen PolicyDOC.h ml Clinical T ial Regula ion: S.I. No. 190/2004—Eu opean Communi ies (Clinical T ials on Medicinal P oduc s Fo Human Use) Regula ions, 2004 h p://www.i ishs a u ebook.ie/2004/en/si/0190.h ml Con inued 1020 Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Table 1 Con inued Consen /assen om child* Consen om pa en (s)/gua dian(s) Gene al in o med consen in o ma ion Coun y Legal age o consen † Manda o y/sugges ed age anges de ined o assen (o consen i assen no used)‡Numbe o equi ed signa o ies O icial language equi emen s Consen empla e(s)/guidelines/in o ma ion sou ces I aly 18 yea s 6–10 yea s 11–14 yea s 15–17 yea s––wi h own signa u e No o icial manda o y age(s) o assen . Di e en age- ailo ed assen s a e submi ed olun a ily, and a e e alua ed by he ECs Bo h pa en s I alian The I alian Medicines Agency h p://www.agenzia a maco.go .i /en/con en /clinical- ials he I alian egula ion on CTs include he ollowing: D.lgs 211/2003 h p://www.agenzia a maco.go .i /si es/de aul / iles/dec e o_24062003_inglese. pd DM 21/12/07 h ps://www.agenzia a maco.go .i / icclin/si es/de aul / iles/ iles_wysiwyg/ iles/ No ma i a/MD_21_Decembe _2007_CTA o m_English.pd La ia 18 yea s 0–7 yea s 7–17 yea s One pa en o legal ep esen a i e La ian S a e Agency o Medicines o he Republic o La ia -> Clinical ials and non-in e en ional ials -> legisla ion h p://www.z a.go .l /?se lang=en -> h p://www.z a.go .l /?id=396&sa=396& op=386 -> h p://www.z a.go .l /index.php?id=381&sa=381& op=333&lang h p://www.z a.go .l /doc_upl/MK_no _289_English_02062010.pd Li huania 18 yea s No se ages Bo h pa en s Li huanian The Li huanian Bioe hics Commi ee -> Biomedical Resea ch -> a ou able opinion on clinical d ug ial h p://bioe ika.sam.l /index.php?3202747546 In o med Consen h p://bioe ika.sam.l /index.php?3221858831 -> h p://bioe ika.sam.l /index.php?577320631—in o ma ion a ailable only in Li huanian h p://bioe ika.sam.l /index.php?3202747546 Mal a 18 yea s 6–17 yea s Pa en s o legal ep esen a i e P ac ice—bo h pa en s One o he o icial languages o Mal a (eg, Mal ese) o in a language unde s andable o he clinical ial subjec and/o his legal ep esen a i e. Mal a Heal h E hics Commi ee h ps://heal h.go .m /en/appbodies/hec/Pages/Links.aspx Mal ese Clinical T ials Regula ions 2004 (LN490 o 2004) MEDICINES ACT, 2003 (ACT NO. III OF 2003); h p://jus icese ices.go .m /DownloadDocumen .aspx?app=lp&i emid=16860&l=1 The Ne he lands 18 yea s 12–17 yea s Bo h pa en s. I pa en s a e di o ced and hey bo h ha e pa en al igh s, hey bo h ha e o sign. Fo a single pa en , wi hou ano he pa ne wi h pa en al igh s, one signa u e is enough. Du ch Cen al Commi ee on Resea ch In ol ing Human Subjec s (CCMO) -> Human Subjec -> In o med Consen —in o ma ion a ailable only in Du ch. h p://www.ccmo.nl/en/ -> h p://www.ccmo.nl/en/mino s Con inued Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 1021 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Table 1 Con inued Consen /assen om child* Consen om pa en (s)/gua dian(s) Gene al in o med consen in o ma ion Coun y Legal age o consen † Manda o y/sugges ed age anges de ined o assen (o consen i assen no used)‡Numbe o equi ed signa o ies O icial language equi emen s Consen empla e(s)/guidelines/in o ma ion sou ces No way 18 yea s 16–17 yea s––wi h own signa u e 12–16 yea s––in special ci cums ances Main ule: bo h pa en s sign he consen o m i hey ha e pa en al esponsibili y o he child. Requi ed o all child en unde 12 yea s old. No wegian The No wegian Na ional Resea ch E hics Commi ees -> Clinical T ials -> Regula ions h ps://www.e ikkom.no/en/e hical-guidelines- o - esea ch/ h p://www.legemiddel e ke .no/English/Clinical_ ials/Regula ions/Documen s/No wegian% 20 egual ion%20 o %20Clinical%20T ials.pd Na ional da abase o Laws and Ac s -> Lo om medisinsk og helse aglig o skning (helse o skningslo en)—in o ma ion a ailable only in No wegian. h ps://lo da a.no/dokumen /NL/lo /2008-06-20-44?q=helse o skning Ac on medical and heal h esea ch (Helse o sknings-lo en) Guidance o Helse o sknings-lo en (in No wegian only) Addi ional in o: No wegian Medicines Agency: Websi e on clinical ials. Poland 18 yea s 6–11 yea s 12–15 yea s 16–17 yea s One pa en P ac ice—bo h pa en s Polish h p://www.eu ecne .o g/in o ma ion/poland.h ml No na ional EC websi es a ailable in English Po ugal 18 yea s 0–8 yea s 8–12 yea s 12–17 yea s Bo h pa en s Po uguese h p://www.eu ecne .o g/in o ma ion/po ugal.h ml CEIC—Na ional E hics Commi ee o Clinical Resea ch h p://www.in a med.p /po al/page/po al/CEIC/English No na ional egula ions/ac s a ailable in English Romania 18 yea s Unde 6 yea s 6–10 yea s 11–14 yea s 15–18 yea s Bo h pa en s Romanian Na ional E hics Commi ee o Romania h p://www.adsm. o/ o/comisia+na ionala+de+bioe ica+a+medicamen ului+si+a+dispozi i elo +medicale# No in o ma ion a ailable in English Sco land (UK) 16 yea s 0–5 yea s 6–10 yea s 11–15 yea s Consen wi h own signa u e unde 16 yea s, i hey a e compe en o do so One pa en English NRES Guidance h p://www.h a-decision ools.o g.uk/consen /p inciples-child en.h ml and h p://www.ukc g.nih .ac.uk/de aul .aspx Slo akia n.a. n.a. n.a. Slo akian The S a e Ins i u e o D ug Con ol (SIDC) -> Clinical ials -> Ins uc ions h p://www.sukl.sk/en?page_id=256 -> h p://www.sukl.sk/en/clinical- ials/ins uc ions?page_id=2821 No na ional egula ions/ac s a ailable in English Slo enia 18 yea s 9 yea s—assen 15 yea s—wi h own signa u e One pa en Slo enian Republic o Slo enia Na ional Medical E hics Commi ee -> h p://kme-nmec.si/—only on page No addi ional in o ma ion a ailable. Spain 18 yea s 0–11 yea s 12–17 yea s––wi h own signa u e One pa en Spanish The Agencia Española de Medicamen os y P oduc os Sani a ios (AEMPS); A s a e agency wi hin he Spanish Minis y o Heal h, Social Se ices and Equali y -> Medicines o Human use—> Clinical esea ch wi h medicines h p://www.aemps.gob.es/en/in es igacionClinica/medicamen os/home.h m The Minis y o Heal h, sec ion abou egula ion o clinical ials: h p://www.aemps.gob.es/en/legislacion/espana/in es igacionClinica/ensayos.h m The Spanish Regula ion abou Clinical ials: he ROYAL DECREE 223/2004-sec ion 7.3 (English e sion is a ailable by eques ) Con inued 1022 Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om Table 1 Con inued Consen /assen om child* Consen om pa en (s)/gua dian(s) Gene al in o med consen in o ma ion Coun y Legal age o consen † Manda o y/sugges ed age anges de ined o assen (o consen i assen no used)‡Numbe o equi ed signa o ies O icial language equi emen s Consen empla e(s)/guidelines/in o ma ion sou ces Sweden 18 yea s W i en sepa a e consen as soon as child is li e a e 6–10 yea s 11–14 yea s 15–17 yea s––wi h own signa u e Bo h pa en s and he child, when li e a e, need o sign he consen Swedish The Cen al E hical Re iew Boa d -> Documen s -> In o ma ion o Resea ch Pa icipan s h p://www.epn.se/en/s a / he-o ganisa ion/ -> h p://www.epn.se/en/s a / cen al-e hical- e iew-boa d-documen s/ -E ikp ö ningslagen 2008. Regula o y equi emen o clinical ials LVFS 2011:19 Läkemedelslagen—1992 Biobank law––2002 Pe sonal Da a Ac 1998 Na ional Medicines Agency -> Legisla ion -> Codes o S a u es -> 1996:17 Clinical ials o medicinal p oduc s h ps://lakemedels e ke .se/english/ -> h ps://lakemedels e ke .se/english/o e iew/Legisla ion/ Codes-o -s a u es/ UK 16 yea s 0–5 yea s 6–10 yea s 11–15 yea s One pa en English NRES Guidance; h p://www.h a-decision ools.o g.uk/consen /p inciples-child en.h ml and h p://www.ukc g.nih .ac.uk/de aul .aspx © Eu opean Medicines Agency, 2015. Rep oduced wi h pe mission *Consen /assen om child: his in o ma ion has been mainly collec ed ia he no mal daily wo k and no es o he CRO Company, PRA Heal h Sciences (UK), when p epa ing EC submissions o na ional au ho i ies. Some o his in o ma ion is no a ailable in English, no publicly a ailable in egula o y au ho i y’s web pages. In addi ion, some English- ansla ed ex e sions may include inaccu a e e ms o explana ions, which could gi e ise o di e en in e p e a ions. The e o e, he au ho s canno gua an ee 100% accu acy o all na ional equi emen s. In addi ion, his able is a snapsho o he da a ga he ed in 2014, which migh ha e subsequen ly changed. †Legal age o consen : legal age o consen means he age om which a child is able o gi e and sign hei own independen legally alid consen acco ding o he na ional law/ac / egula ion. Child en below his age limi a e incapable o gi ing legal in o med consen and need pa en al/legally au ho ised gua dian’s in o med consen wi h a signa u e o pa icipa e in a clinical s udy. Pa en al/legally au ho ised gua dian’s in o med consen may be ob ained/sough in addi ion o he child’s own consen / assen , o when he child abo e he age limi is incapable o sign consen due o a di icul physical condi ion. ‡Manda o y/sugges ed age anges de ined o assen (o consen i assen no used): hese manda o y o sugges ed age anges a e de ined in na ional egula ion/law/ac , o a child below he legal age o consen and o own in o med consen o assen (depending on he e minology used in legal ex s). This consen o assen is ob ained in addi ion o he legally alid pa en al/legally au ho ised gua dian’s signed in o med consen . This ype o child’s own assen /consen suppo s he child’s in eg i y and igh s, c ea es he oppo uni y o hea hei own opinion, supposed will and possible dissen , hus espec ing he child’s au onomy in he in o med consen p ocess. Lepola P, e al.A ch Dis Child 2016;101:1017–1025. doi:10.1136/a chdischild-2015-310001 1023 O iginal a icle g oup.bmj.com on No embe 30, 2016 - Published by h p://adc.bmj.com/Downloaded om (olde child en below legal adul age) and pa en s (legal gua - dians). Usually, he e m assen e e s o a child’s o mino ’s ag eemen o he ial (no legally alid on i s own), while consen is documen ed h ough legal signa u e(s) by he pa en s (gua dians) o he child, when he child is abo e he legal age. The e a e mo e han 1000 ECs in Eu ope, 35 which esul in subs an ial a iabili y o EC composi ions and p ac ices, 36–38 wi h consequen ly a ce ain deg ee o inconsis ency in he equi ed consen and assen documen a ion o mul ina ional and mul icen e ials. Mo eo e , much ime and esou ces may be needed o ob ain app o als. To manage hese inconsis encies and o educe he duplica i e wo kload, sponso s a e ecom- mended o pe o m an i e a i e o sequen ial e iew a each pa - icipa ing ins i u ion o coun y. The Eu opean Medicines Agency (EMA) has e alua ed he impac o he Paedia ic Regula ion a e i s fi s 5 yea s o being in o ce. 39 So a , he egula ion has no ye led o mo e paedia - ic CTs in Eu ope, al hough he e a e plans o conduc CTs wi h en olmen o mo e child en. 39 S ill, he ini ia ion o new CTs may be hampe ed by he p ac ical obs acles o complex EC p ocesses. Cu en ly, i is no possible o seek Eu opean-wide legisla i e changes o EC p ac ice ha monisa ion, as he p ac ice o one EC will no necessa ily wo k o ano he wi hou conce ed e o o achie e ha mony. Howe e , an expe g oup has designed model consen and assen o ms o di e en paedia - ic age g oups, 40 which could be applied ac oss Eu ope. Fu he mo e, be e defini ions o he concep s o ‘unde s and- ing’,‘capabili y’,‘capaci y o au onomous decisions’and ‘mo al unde s anding o al uism’could g ea ly suppo a ha - monisa ion p ocess. To sol e hese p oblems, we sugges he ollowing measu es: ▸Uni o m, commonly accep ed s anda ds and guidance ac oss Eu ope/EEA ▸Defini ion o he lowes age limi o consen and assen equi ing own signa u es in addi ion o pa en al (legal) consen un il he legal age o majo i y pe mi s independen consen ▸Fundamen al discussion o c ea e mo e de ailed defini ions o assen and consen and o decide whe he hese e ms could be ha monised and used wi h simila p inciples o paedia ic popula ion ▸S anda dised s uc u e and eading le el equi emen s o consen and assen documen s, including ecommenda ions o legal gua dian’s (pa en al) signa u es ▸A mas e consen /assen empla e in all na ional languages being publicly and eadily a ailable. ‘The In o med Consen and Assen Tool Ki ’was upda ed mainly un il he end o 2014. As na ional-le el egula ions and laws may change o e di e en in e als, he accu acy o he da a and linked documen s a e dependen upon egula e iew. The Enp -EMA’s cen al aim is o enhance and p omo e he conduc o paedia ic CTs in Eu ope. This oolki being publicly a ailable ee o cos on he Enp -EMA websi e mee s his aim. Please go o: h p://www.ema.eu opa.eu/Pa ne s&Ne wo ks/ Ne wo ks/Enp -EMA/Enp -EMA ac i i ies, o di ec ly a : h p:// inyu l.com/h2x l . Wi h his oolki , we hope ha all s ake- holde s will p oac i ely p o ide eedback ia he Enp -EMA, o keep his oolki up o da e and os e ing discussion on ha mon- isa ion o EC p ocedu es needed o paedia ic ials ac oss Eu ope. Acknowledgemen s Special hanks go ou o o he pa ne s o ou o iginal wo king g oup, I ana Sil a (EMA), D Richa d T ompe e (GOSH/IPTA, UK) and D Alan Boddy (p e iously Newcas le Uni e si y/cu en ly, he Uni e si y o Sydney) o hei help in p epa ing he ini ial epo o Enp -EMA. Con ibu o s Li e a u e sea ch was done by PL, AN, JM, PS and DN; da a collec ion and figu es we e done by PL, JM, PS and AN; Da a in e p e a ion, w i ing and app o al o final e sion we e done by all au ho s. Funding This esea ch has ecei ed unding om he Eu opean Union’s Se en h F amewo k P og amme o esea ch, echnological de elopmen and demons a ion unde g an ag eemen no. 261060 (Global Resea ch in Paedia ics—GRiP ne wo k o excellence). Compe ing in e es s None decla ed. P o enance and pee e iew Commissioned; ex e nally pee e iewed. Open Access This is an Open Access a icle dis ibu ed in acco dance wi h he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license, which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p://c ea i ecommons.o g/ licenses/by-nc/4.0/ REFERENCES 1 Eu opean Union. 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