Guideline on Pharmaceutical Development of Medicines for Paediatric Use

Transcription

1 May 2011 EMA/CHMP/QWP/180157/2011 Cmmittee fr Medicinal Prducts fr Human Use (CHMP) Guideline n Pharmaceutical Develpment f Medicines fr Paediatric Use Draft Draft Agreed by QWP February 2011 Draft agreed by SWP March 2011 Adptin by CHMP fr release fr cnsultatin May 2011 End f cnsultatin (deadline fr cmments) 31 December Cmments shuld be prvided using this template. The cmpleted cmments frm shuld be sent t qwp@ema.eurpa.eu Keywrds Nte: child, pharmaceutical develpment, quality CHMP wuld like t bring t yur attentin the three pints belw fr which further input (specific attentin) is particularly awaited: 6. Rute f administratin and dsage frm 6.2.1: Pwders, granules, pellets and tablets: Acceptability: tablet size and yung children, Sub-divisin f tablets: Use f scre lines t administer lwer dses 9. Excipients in the frmulatin: 9.1 General cnsideratins: Safety f excipients Westferry Circus Canary Wharf Lndn E14 4HB United Kingdm Telephne +44 (0) Facsimile +44 (0) inf@ema.eurpa.eu Website An agency f the Eurpean Unin Eurpean Medicines Agency, Reprductin is authrised prvided the surce is acknwledged.

2 Guideline n Pharmaceutical Develpment f Medicines fr Paediatric Use Table f cntents Executive summary Intrductin (backgrund) Scpe Legal basis General cnsideratins Characteristics f the active substance Rute f administratin and dsage frm General cnsideratins Oral administratin Pwders, granules, pellets and tablets Capsules Oral liquid preparatins Medicines fr rmucsal administratin Medicines fr nasal administratin Orally inhaled (pulmnary) medicines Rectal administratin Cutaneus administratin Preparatins fr administratin in the eye and ear Parenteral administratin Administratin thrugh feeding tubes Fixed dse cmbinatins Dsing frequency Mdified release preparatins Excipients in the frmulatin General cnsideratins Cluring agents Flavurs Preservatives Sugar versus sweeteners Patient Acceptability Cntainer clsure system, dsing device and administratin device General cnsideratins Cntainer size Dsing device Other devices /23

3 User infrmatin (Summary f Prduct Characteristics and Patient Infrmatin leaflet) Definitins /23

4 Executive summary Children can neither be regarded as small adults nr as a hmgeneus grup in themselves. As a cnsequence, paediatric medicines shuld be apprpriately designed fr the target age grup(s). In January 2007 Regulatin EC N 1901/2006 (the Paediatric Regulatin ) entered int frce. As a result f this Regulatin, the number f paediatric frmulatins that the pharmaceutical industry will have t develp t supprt their clinical trials will increase. It is expected that the number f medicines applying fr a marketing authrisatin fr paediatric use will increase as a result. Therefre, the existing regulatry dcuments need t be supprted by specific regulatry guidance n the pharmaceutical develpment f medicines fr use in children between birth and 18 years f age. 1. Intrductin (backgrund) The physical, metablic and psychlgical prcesses peculiar t grwth frm birth int adulthd reveal that children can nt be regarded as small adults nr can they be regarded as a hmgeneus grup in themselves. As a cnsequence, clinical studies in adults are nt necessarily predictive fr children. Thus, clinical trials may be needed in children f different ages in rder t demnstrate that a medicine is safe and effective in all f the indicated target age grup(s). In additin, the treatment f children with medicines pses specific pharmaceutical prblems which have nt been seen t the same extent in adults and which ccurrence may be age dependent. Fr example, yung children are simply unable t swallw cnventinally-sized tablets whereas tablets are a favurable dsage frm fr elder children and adults. Especially nenates pse specific characteristics and needs. They may fr example require very small vlumes f a parenteral medicine in rder t avid a vlume verlad. Therefre, children shuld be treated with medicinal prducts f which the pharmaceutical design is tailred fr use in the target age grup i.e. age apprpriate medicines. Knwledge n the critical t quality aspects f paediatric medicines is still limited, especially when cnsidering these aspects in a multidimensinal apprach t the best attainable and affrdable paediatric medicinal prducts. As a cnsequence, the usefulness (practicality) f sme f the currently paediatric medicines might be questinable / based n minimum standards and culd cnsequently be subject t further ptimisatin in the interest f parents, ther caregivers and children. On the 26th f January 2007, the Paediatric Regulatin entered int frce (Regulatin EC N 1901/2006 f The Eurpean Parliament and f the Cuncil, amending regulatin EEC N 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulatin EC N 726/2004). This regulatin aims t facilitate the develpment and accessibility f medicinal prducts fr use in the paediatric ppulatin, t ensure that medicinal prducts used t treat the paediatric ppulatin are subject t research f high quality and are apprpriately authrised fr use in the paediatric ppulatin, and t imprve the infrmatin available n the use f medicinal prducts in the varius paediatric ppulatins. As a result f this Regulatin, bth the number f paediatric frmulatins that shuld be develped by the pharmaceutical industry and the knwledge n the critical t quality aspects f paediatric medicines is expected t increase rapidly. Bearing the afrementined in mind, the current regulatry dcuments need t be supprted with guidance n the pharmaceutical develpment f paediatric medicines. Therefre, this guideline aims t prvide additinal tls fr the ratinale pharmaceutical develpment f medicines fr children between birth and 18 years f age t thse already described in the current CHMP and ICH guidelines. The guideline intends t balance between predictable and cnsistent regulatry assessments f paediatric medicines (either generic, innvative, existing r new), the speed f develpment, industrial feasibility and the need t develp medicines that are better tailred fr use in children than the 4/23

5 currently authrised, but questinable paediatric medicines r the currently applied ff-label r pharmacy cmpunded medicines. The utcme f this balanced apprach shuld nt necessarily result in a gld standard paediatric medicine. 2. Scpe The principles f this guideline are t be applied during the pharmaceutical develpment f all paediatric medicines as prpsed in Marketing Authrisatin Applicatins (MAA) r applicatins t extend r vary the marketing authrisatin t the paediatric ppulatin (MAVs). As clinical evidence and pharmaceutical knwledge increase ver time, the cntext f the pharmaceutical design f the paediatric medicine in an early clinical trial may differ frm the cntext in the final trials fr marketing authrisatin. In early develpment, it is imprtant t fcus n the suitability and safety f the prpsed frmulatin. If the cmpany is nt yet able t prpse a paediatric medicine, at least the cnsideratins fr the chice f the rute(s) f administratin, dsage frm(s) and excipients in the frmulatin and administratin devices shuld be discussed, including palatability. The use f preliminary (als called enabling) paediatric frmulatins in the early clinical trials may be cnsidered acceptable if apprpriately justified, hwever it is nt exempting frm the requirement t develp a frmulatin which will be industrially-manufactured and cntrlled. Thus, preliminary frmulatins which are based n instructins fr the manipulatin f an authrised medicine will nrmally nt be cnsidered acceptable fr marketing authrisatin. A switch frm a preliminary frmulatin t a cmmercial frmulatin shuld be supprted by relevant bridging studies between different frmulatins used thrughut the develpment, including biequivalence studies if necessary. Paediatric medicines shuld cmply with all the relevant prvisins in the Eurpean Unin. Therefre this guideline shuld be read in clse cnjunctin with all the relevant Cmmissin, ICH and CHMP guidelines. Hwever, the current quality prvisins f existing guidelines may require further justificatin r adaptatin in view f the specific needs f children. This guideline intends t prvide guidance n such adaptatin r justificatin. As a cnsequence, this guideline will nt describe any aspects f the pharmaceutical develpment f a paediatric medicine that equally applies t medicines fr adult use. Pharmaceutical cmpanies shuld have a re-evaluatin f all their prducts n the market. They shuld ensure that their prducts are state f the art i.e. meeting the requirements as described in this guideline within a perid f 5 years fllwing the date f cming int peratin f this guideline. This guideline shuld nt be regarded as prviding exhaustive infrmatin and des nt preclude the existence f ther aspects relevant t the pharmaceutical develpment f paediatric medicines. 3. Legal basis This guideline shuld be read in cnjunctin with Directive 2001/83 f the Eurpean Parliament n the cmmunity cde relatin t medicinal prducts fr human use as amended (further referred t as the Medicines Directive), Directive Regulatin 1901/2006/EC f the Eurpean Parliament and f the Cuncil n medicinal prducts fr paediatric use as amended (further referred t as the Paediatric Regulatin) and the Eurpean Pharmacpeia. In additin, this guideline shuld be read in cnjunctin with all ther relevant directives and regulatins (e.g. n the establishment f the EMA), and the relevant cmmissin, ICH and CHMP dcuments with a special emphasize n: 5/23

6 Ethical Cnsideratins Fr Clinical Trials On Medicinal Prducts Cnducted With The Paediatric Ppulatin Recmmendatins Of The Ad Hc Grup Fr The Develpment Of Implementing Guidelines Fr Directive 2001/20/EC Relating T Gd Clinical Practice In The Cnduct Of Clinical Trials On Medicinal Prducts Fr Human Use (2008, Eudralex Vl. 10 Chapter V) Excipients In The Label And Package Leaflet Of Medicinal Prducts Fr Human Use (Eudralex 3BC7A) 147 ICH Q8(R2) On Pharmaceutical Develpment (EMEA/CHMP/ /2004-ICH Q8 R2) ICH E11 Clinical Investigatin Of Medicinal Prducts In The Paediatric Ppulatin (CPMP/ICH/2711/99) Excipients In The Dssier Fr Applicatin Fr Marketing Authrisatin Of A Medicinal Prduct (CHMP/QWP/396951/06) Guideline On The Rle Of Pharmackinetics In The Develpment Of Medicinal Prducts In The Paediatric Ppulatin (CHMP/EWP/147013/04) Guidelines On Cnduct Of Pharmacvigilance Fr Medicines Used By The Paediatric Ppulatin (EMEA/CHMP/Phvwp/235910/2005- Rev.1) Guideline On The Investigatin Of Medicinal Prducts In The Term And Preterm Nenate (EMEA/536810/08) 158 Guideline On The Summary Of Prduct Characteristics September 2009, Revisin Guideline On The Pharmaceutical Quality Of Inhalatin And Nasal Prducts (EMEA/CHMP/QWP/49313/2005 Crr) Reflectin Paper On Frmulatins Of Chice Fr The Paediatric Ppulatin (EMEA/196218/05) Eurpean Cmmissin Guideline Entitled 'Guideline On The Frmat And Cntent Of Applicatins Fr Agreement Or Mdificatin Of A Paediatric Investigatin Plan And Requests Fr Waivers Or Deferrals And Cncerning The Operatin Of The Cmpliance Check And On Criteria Fr Assessing Significant Studies' (Cmmissin Cmmunicatin 2008/C 243/01). CHMP Scientific Article 5(3) Opinin On The Ptential Risks Of Carcingens, Mutagens And Substances Txic T Reprductin When These Substances Are Used As Excipients Of Medicinal Prducts Fr Human Use General cnsideratins The pharmaceutical design f a medicinal prduct relates t all aspects as described in Mdule 3.2.P., the SmPC sectin 1-3 and 6.0 and the crrespnding parts f the PIL, e.g. the cmpsitin f the prduct, the chice f the dsage frm, the selected primary and secndary packaging etc. All aspects f the pharmaceutical design f a medicinal prduct shuld be justified, where relevant als in relatin t the indicated target age grups. Depending n the aspects t be studied, the ICH classificatin grups fr age may either be divided in smaller grups r cmbined. In deciding n the apprpriateness f the pharmaceutical design f a paediatric medicine, the fcus f attentin shuld nrmally be placed n: the minimum age f the target age grup(s) and the relevant develpmental physilgy; the behaviural age characteristics f children in the target age grup(s); 6/23

7 the age assciated activities f children in the target age grup(s) (e.g. schl, nursery); the envirnment where the prduct is t be used (e.g. hspital r cmmunity); the cnditin t be treated; the cnditin related characteristics f the child (e.g. likely disabled, aggressive, fluid restrictin, high degree f c-medicatin including inability t swallw due t centrally nervus system diseases (e.g. epilepsy) r t critical illnesses); the criticality f the dse (i.e. steep dse/pharmacdynamic respnse curve, narrw therapeutic windw) and hw the dse is t be calculated; the maximum duratin f therapy which can be freseen; the availability f relevant safety data fr the active substance, excipients and the finished medicinal prduct; the pharmaceutical prperties f the drug substance (e.g. slubility, taste); patient acceptability i.e. child friendliness On this basis, the mst sensitive develpment aspects are likely t arise in paediatric medicines fr lng term use in nenates, infants and yung children, particularly when the excipients used are knwn t have their wn undesirable prperties, r when the safety data relevant t the target age grup(s) may nt be as cmprehensive as in adults. 5. Characteristics f the active substance The characteristics f a particular active miety may be desirably mdified by the chice in which the active miety is manufactured int the paediatric medicine as the active substance. Fr example the manufacture f a liquid medicine may require a substance with imprved slubility i.e. a different salt, r a salt instead f the base. Als, child acceptability may be favured by the selectin f a less sluble frm f the active substance, e.g. the base instead f the salt. Mrever, patient safety in children may be imprved by aviding a particular inrganic cunter-in r rganic salt structure. Therefre, the chice f the frm f the active substance in the paediatric medicine shuld be based n its use in the indicated target age grup. The selected frm may differ frm the frms that are emplyed fr the ther target age grups r fr adults. 6. Rute f administratin and dsage frm 6.1. General cnsideratins The advantages and disadvantages assciated with the administratin f a particular paediatric dsage frm via a particular rute f administratin shuld be discussed and justified fr children in each f the indicated target age grups and, where applicable, f different health cnditins. Different rutes f administratin and/r dsage frms may be needed fr the same active substance in rder t allw adequate treatment f children in all the indicated target age grups, and with a different health cnditin r disease develpment. The justificatin fr the chice f the rute f administratin and dsage frm shuld include user aspects as e.g. adequate palatability, tablet size etc. The advantages and disadvantages f a particular rute f administratin and dsage frm shuld als be cnsidered taking accunt f their inherent cnsequences fr the ther pharmaceutical aspects. Fr example, the chice fr a liquid frmulatin 7/23

8 nrmally requires a dsing device and preservatin unless the cmpany has adpted ther measures t guarantee adequate micrbilgical quality. Fr example, the chice fr an inhalatin medicine will require a dedicated medical device Oral administratin Oral administratin can be achieved via several types f dsage frms. In general, the main chice is between the applicatin f an ral liquid preparatin, an ral slid unit dsage frm (e.g. nrmal sized tablet, capsule) r an ral flexible slid dsage frm (e.g. pwder, granules, pellets). Children may be unable t swallw slid unit dsage frms. Oral slid unit dsage frms will als result in a decreased dsing flexibility as cmpared t ral liquid preparatins and ral flexible slid dsage frms. This may be a prblem in case dsing is weight dependent. Bth disadvantages can be vercme by the applicatin f an ral liquid preparatin r an ral slid flexible dsage frm. Hwever, the applicatin f a large range f dses with an ral slid flexible dsage frm may necessitate the need fr a dedicated device in rder t avid dsing errrs. Slid ral dispersible tablets will als enable dsing flexibility, if parts f the dispersed slutin are taken. Hwever, crrect dsing will then require a fully disslved slutin r a hmgeneus dispersin, the crrect vlume f water t be added and the crrect vlume f the disslved slutin r dispersin t be taken. Such handling is prne t errrs and nrmally nt cnsidered acceptable. Oral administratin will usually ccur via nrmal swallwing and drinking, hwever, feeding tubes may be applied where relevant, see Pwders, granules, pellets and tablets Acceptability Pwders, granules and pellets may be given t children frm birth when administered as a slutin. If apprpriately justified, the applicatin f a liquid dispersin may be acceptable frm birth as well. If pwders, granules r pellets are administered in their slid frm, they will nrmally be cnsidered acceptable frm the mment the infant is able t accept slid fd. This is usually arund six mnths age. The risk f aspiratin, chking and where relevant chewing shuld be cnsidered depending n the target age grup, size, shape, quantity (vlume) and the type f the active substance and dsage frm (e.g. gastr-resistant and mdified release). The tablet size is fundamental t the ability f a child t swallw a tablet. Yung children may be able t accept small tablets, but nt large tablets. Unless therwise justified by apprpriate studies r clinical evidence, small tablets (i.e. tablets frm 3 t 5 mm diameter, width r length whichever is the lngest) will nt be cnsidered acceptable fr children belw the age f 2 years, medium sized tablets (i.e. tablets frm 5 t 10 mm) fr children belw the age 6 years; large tablets (i.e. tablets frm 10 t 15 mm) fr children belw the age f 12 years and very large tablets (i.e. tablets frm 15 mm) fr children belw the age f 18 years. Fr chrnic diseases, tablet size acceptability in children may be imprved by adequate training techniques. Such training may allw a larger size fr age grups than nrmally cnsidered acceptable. Tablet size acceptability may als be imprved by adequate instructins fr jint intake with semi slid fd. In rder t avid a wide range f strengths, a single dse may nrmally invlve several small sized tablets. The suitability f tablets in children shuld be further justified in relatin t the disease and the risks assciated t under-dsing, chking and aspiratin. Any identified risks shuld be carefully balanced against the risks assciated with the applicatin f an alternative dsage frm. 8/23

9 Appearance Overly attractive ral slid dsage frms shuld be avided. Every effrt t differentiate the appearance f tablets frm cnfectinary shuld be made. Sub-divisin f tablets It is highly likely that every line n a paediatric tablet will be used in daily practise as a scring line t lwer the dse, either within r ff-label. Therefre, every line n a tablet fr paediatric use shuld result in equal tablet parts accrding t the criteria f the Ph. Eur. mngraph n sub-divisin f tablets. Thus, it is nt cnsidered sufficient t state in the SmPC and PIL that the scring line is nly meant t facilitate the administratin f bth halves at the same time and nt t divide the tablet in tw halves. Crushing tablets Unless therwise justified, crushing f a tablet prir t administratin shuld nt be the standard prcedure t treat children in the indicated target age grups. Any justificatin shuld at least include: the pssibility t market the (tablet) granules in a single dse sachet r a capsule that shuld be pened prir t use; the impact f crushing n palatability; patient acceptance; bi-availability and the risk fr the persn wh shuld be crushing the tablets Dispersible tablets The minimum vlume fr dispersin shuld be described and justified in relatin t the indicated target age grup(s). Fr well palatable slutins, the vlume shuld nt exceed 20 ml including any rinsing where relevant fr children belw the age f 4, and 50 ml including any rinsing where relevant fr children frm 4 years. The minimum vlume fr dispersin shuld als be stated in the SmPC and PIL. Parents may wish t administer dispersible tablets by ther means as intended i.e. as a nrmal tablet withut any prir dispersin. At the same time, children may nt directly swallw any given tablet, but decide t keep the tablet in their muth fr a perid f time thereby using it as an rdispersible tablet. The impact f these tw alternative administratin methds n the safety and efficacy f the medicine shuld be discussed. The issue shuld be clarified t the users in the SmPC and PIL. Ordispersible tablets Children may take rdispersible tablets by ther means than intended i.e. the tablets may be swallwed withut dispersin in the muth. Caregivers may als wish t disperse the medicine in a liquid prir t giving it t the child because they are afraid that the child will swallw the intact medicine. The impact f thse tw alternative means n the safety and efficacy f the medicine shuld be discussed. The SmPC and PIL shuld clarify whether r nt the rdispersible tablet may be used as a dispersible tablet. The direct swallwing f an rdispersible tablet withut prir dispersin in the muth shuld nt result in relevant safety and efficacy prblems. 9/23

10 Capsules Hard and sft capsules may be taken intact. They may als be pened and their cntents taken as such. The suitability f bth appraches shuld be discussed and justified fr all the indicated target age grup(s). If a hard capsule is t be pened prir t use, its cntents shuld meet the same requirements as stated fr pwders, pellets r granules where relevant. If a sft capsule is t be pened prir t use, its cntents shuld meet the same requirements as ral liquid preparatins where relevant. Instructins fr remval f small amunts f liquid frm a sft capsule and then subsequently administratin by the ral rute can result in dsing errrs and this apprach is nrmally nt cnsidered acceptable. Only if capsules are t be taken intact, the dimensins f the capsule shuld be justified in relatin t the target age grup(s), child health cnditins, inter patient differences and the risks assciated t accidental chking r chewing. Nrmally, the smaller hard capsules are nly cnsidered acceptable frm the age f 6 years if t be taken intact Oral liquid preparatins General cnsideratins Oral liquid dsage frms are nrmally cnsidered acceptable fr children frm full term birth. Oral multi-dse liquid dsage frms will nrmally need t be preserved (see sectin 9.4), whereas ral slid dsage frms will nrmally nt. This wuld favur the use f ral slid dsage frms ver the use f ral liquid dsage frms in children. Nevertheless, preserved slutins will generally be cnsidered as an acceptable dsage frm fr children frm birth. Oral liquid dsage frms fr children shuld be packaged tgether with an apprpriate dsing device. If dsing t the indicated target age grups requires multiple deliveries f the mst apprpriate strength f the liquid preparatin with a device (e.g. when dsing ranges frm 0.5 t 15 ml), then preferably multiple devices with a different dsing cntent shuld be prvided with the packed medicine in rder t assure the availability f an apprpriate device t the patient (fr this example e.g. bth a 3 ml device and 15 ml dsing device). Further instructins n the dsing device are prvided in sectin The risks f incrrect r accidental verdsing with the dsing device shuld be discussed and justified in relatin t the criticality f the dse fr children in the target age grup(s) and the ptential fr dsing errrs when measuring the medicine. Adequate measures shuld be undertaken in cases where incrrect dsing is likely t result in a ptential serius risk t public health. Such measures may e.g. invlve the applicatin f unit dse packagings as pre-filled ral syringes r cups fr single use r the selectin f anther dsage frm. Fr ral liquid slutins and dispersins, the maximum recmmended single dsing vlume is 5 ml fr children aged belw 4 years and 10 ml fr children aged between 4 and 12 years. The minimum dsing vlume will be determined by the accuracy f the dsing device. Oral suspensins The ptential fr dsing errrs f the minimum and maximum recmmended dses in the relevant target age grups shuld be discussed with regard t sedimentatin and sticking f the suspended active substance t the primary cntainer and t the dsing device. 10/23

11 In additin, the risks f under-dsing and ver-dsing t the child shuld be discussed fr the wrst case scenari i.e. nt shaking the cntainer prperly r nt shaking it at all. Adequate measures shuld be undertaken in cases where incrrect shaking will result in a ptential serius risk t public health. Such measures may invlve the applicatin f unit dse packagings as pre-filled ral syringes r cups fr single use r the selectin f a different dsage frm. Drps Oral liquid drps can prvide a means t administer medicines in lw dses r small vlumes. The vlume dispensed (i.e. drp size) will be determined by the design and physical characteristics f the drpper, the physical-chemical prperties f the slutin and the methd f drpping. The maximum number f drps per single intake shuld be stated and shuld nrmally nt exceed 10 drps (i.e. abut 0.5 ml). The accuracy and precisin f the vlume dispensed shuld be justified in relatin t the criticality f the dse. Unless therwise justified, ral liquid drps will nly be cnsidered acceptable fr medicines with a wide therapeutic windw in view f the ptential fr dsing inaccuracies Medicines fr rmucsal administratin The size and shape f rmucsal frmulatins shuld be cnsidered fr each f the target age grups in relatin t the lcal area where they shuld be applied. In rder t avid the risk f swallwing muthwashes r dental gels, these medicines need t be applied using a cttn bud, spnge r similar attribute in yunger children Medicines fr nasal administratin Nasal medicines will nrmally be cnsidered suitable fr children f all ages. The suitability f the nasal rute f administratin fr lcal and systemic treatment a particular medicine shuld be discussed and justified in terms f the likelihd that the active substance (and excipients) will cause pain r irritatin. Als, the patient acceptability in view f palatability and sensatin f the medicine n actuatin shuld be discussed and justified. Fr nasal medicines with a lcal actin, the risks f systemic (adverse) effects due t bth crrect and incrrect applicatin shuld be discussed. Devices fr nasal administratin shuld be adapted t the size f the nstrils/nasal cavity fr the intended target age grup(s) Orally inhaled (pulmnary) medicines The patient acceptability and age-apprpriateness f rally inhaled medicines (including slutins fr nebulisatin) need t be justified. Pressurized metered dse inhalers may be applied t children frm birth if in cmbinatin with a specific spacer system and face mask. Elder children may use the inhaler with r withut a spacer. Dry pwder inhalers can usually nly be applied by elder children because it is the child patient which makes his r her dse by the inspiratry flw. Fr high ptency medicines, multi-dse cntainers with a secure dse cunting, an end f life lck-ut system and measures t prevent inadvertent multiple dsing shuld be develped in rder t reduce the risk f accidental verdsing Rectal administratin Suppsitries 11/23

12 The size and shape f the suppsitry shuld be tailred t the size f the child. Unless suppsitries have been specially designed t deliver smaller amunts f the full dse, they shuld nt be cut in rder t prvide a smaller dse. Liquid rectal preparatins The length f the canule f the enema and any vlume t be administered shuld be tailred t the age and size f the child. The use f scaled devices (pre-filled syringes with a rectal tip) shuld be cnsidered where relevant. Clear instructins shuld be prvided in the SmPC and PIL n the methd fr delivering the required dse t the child by the caregiver Cutaneus administratin The skin underges many changes frm birth int adult hd. These differences shuld be taken int cnsideratin when develping cutaneus medicines fr children. The use f excipients knwn t sensitize the skin shuld be carefully justified. The need r restrictin t use water-impermeable materials as a cating t the cutaneus medicine shuld be stated. Where relevant, the impact f catings, fever r thermal heating n skin permeability and the risk t verdsing shuld be discussed. The size and shape f transdermal patches and medicated plasters shuld be tailred t the size and shape f the child bdy and shuld nt interfere with daily rutines. Applicatin sites which cannt be easily reached by the child shuld are preferred. If ther sites are t be used, the impact f deliberate remval f the patch/plaster n the clinical utcme shuld be discussed. Patches and plasters are preferably develped fr use as a single dse/strength. Hwever, especially fr children, they may be develped t prvide fr a range f dses/strengths by cutting. Cutting will nly be cnsidered acceptable if cutting lines are present and if dse unifrmity and cnsistency have been apprpriately demnstrated Preparatins fr administratin in the eye and ear Preparatins fr the ear and the eye are mstly develped fr a single patient grup, including children, adults and the elderly. Preparatins fr the ear and the eye may be prly accepted by sme children, hwever in lack f better alternatives they shuld be cnsidered acceptable dsage frms fr children f all ages. In rder t avid the use f (ptentially txic) preservatives in multi dse preparatins, single dse preparatins r multi-dse preparatins in a dedicated multi-dse cntainer that des nt require its cntents t be preserved i.e. preservative free cntainers shuld be cnsidered fr children, especially nenates. This is especially imprtant if lng term use may be necessary. Yung children can nt yet be instructed t keep their eyes pen. It is imprtant that the parent is infrmed as t hw t hld cntainer and the child in rder t crrectly administer the medicine Parenteral administratin General cnsideratins Parenteral administratin is the mst cmmnly used rute f administratin fr active substances fr children wh are seriusly ill and fr clinically unstable term and preterm nenates. The chice fr an intravenus, subcutaneus r intramuscular injectin is t be justified in terms f the intended clinical effect, relevant characteristics f the active substance and child acceptance (pain). 12/23

13 The site f injectin, the injectin vlumes and, if relevant, the needle thickness and needle length shuld be described and justified twards the characteristics f the parenteral preparatin, the age and weight f the child, the maximum number f injectins per day and the duratin per treatment. Where apprpriate, needle free injectrs shuld be cnsidered, especially fr medicines requiring frequent r lng treatment perids. Serial dilutins (in rder t achieve the required dse) are nt acceptable as they are prne t errrs and can be avided by prviding apprpriate cncentratins f the parenteral medicine. The minimum dsing vlume f a medicine will depend n the accuracy f the relevant dsing device. Where relevant, the size f the syringe and the graduatin that permits accurate administratin shuld therefre be described as well. Fr the currently available 1-ml syringes, the smallest vlume fr parenteral administratin is set at 0.1 ml. Unless therwise justified, subcutaneus and intramuscular injectin vlumes shuld nt exceed 1 ml. Sme parenteral preparatins may be intended fr emergency situatins where venus access may nt be easily established (e.g. resuscitatin and intensive care). The suitability f medicines which are cmmnly used in emergency situatins fr intra sseus administratin shuld be discussed and relevant infrmatin shuld be prvided in the SmPC and PIL. Nenates may nly accept very small vlumes f medicatin in rder t avid vlume verlad and t allw sufficient rm fr essential fluid nutritin. This aspect shuld be cnsidered when develping parenteral medicines fr pre-term and full term nenates, in particular t medicines intended t be administered as a cntinuus infusin. Out-patient use In cases where parenteral administratin is required fr children in ut-patient settings, it shuld be demnstrated that the presentatin f the parenteral medicine is sufficiently tailred t the administratin by the child itself r its adult caregiver. This is especially imprtant in cases where administratin may als be necessary in situatins where a trained caregiver is nt present Administratin thrugh feeding tubes Fr ral medicines fr which the administratin via a feeding tube cannt be regarded as an exceptin but rather as the rule (e.g. in pre-term nenates), the particle size, viscsity, dsing vlume and cmpatibility f the ral medicine with the tube material shuld be discussed and justified. Dse recvery after extrusin thrugh the nasgastric tube shuld be demnstrated using rinse vlumes relevant t the target age grup. In additin and if relevant depending n the lcatin f the tube, the risks assciated t the accidental aspiratin f the medicine shuld be discussed. The impact f the administratin f an ral medicine thrugh a feeding tube n bi-availability shuld be discussed. The afrementined requirements als apply fr medicines where the SmPC and PIL state that the medicine may be administered thrugh a feeding tube Fixed dse cmbinatins Fixed dse cmbinatins are ften develped as an alternative substitutin therapy fr patients already treated with the individual cmpnents, especially fr chrnic diseases. They may be f value fr patients t simplify therapy and imprve adherence. When clinically relevant, the cmpany shuld make effrts t cnsider all pssible ptins fr develping an age-apprpriate fixed dse cmbinatin 13/23

14 fr all r sme subsets f the paediatric ppulatin, unless such a develpment wuld be prevented by the cmplexity f dses required r by the lack f flexibility t ensure an adequate dse adjustment. 7. Dsing frequency The chice f the dsing frequency shuld be justified in terms f the characteristics f the active substance, the intended clinical effect (immediate release versus prlnged release) and child patient and caregiver cnvenience/therapeutic adherence. Fr paediatric medicines that may be used mre than twice daily, special attentin shuld be given t the suitability f administratin in ut-patient settings where a trained caregiver is nt readily available (kindergarten, schl etc). Prlnged release frmulatins can be useful fr children wh wuld therwise need t take medicatin whilst at schl r during the night. Their use can reduce the dsing frequency significantly and can be beneficial fr cmpliance. 8. Mdified release preparatins Mdified release medicinal prducts shuld be cnsidered fr children when relevant. Depending n the size f the particles, especially multiparticulate systems may be applicable acrss a wide age range. The develpment f mdified release preparatins shuld nt be restricted t the ral rute f administratin. Alternative rutes f administratin culd be applicable depending n the active substance characteristics (eg. transdermal). Fr slid ral mdified release preparatins, the risk f chewing is likely t affect the suitability f the dsage frm. The risk f chewing n the efficacy and safety f the medicine shuld therefre be discussed and shuld, unless therwise justified, nt result in a serius risk t public health. In the develpment f ral mdified-release frmulatins fr paediatric use, special attentin must be given t the physilgical cnditins f the child t be treated, e.g. gastric ph and gastr-intestinal mtility (gastric emptying, transit time) and their variability since these characteristics culd have an impact n the drug absrptin. These aspects shuld als be cnsidered when designing in vitr testing during pharmaceutical develpment. 9. Excipients in the frmulatin 9.1. General cnsideratins The suitability f an excipient in a paediatric medicine is a key element f the pharmaceutical develpment prcess. Althugh any basic cnsideratins regarding the use f a specific excipient in a medicinal prduct will nt be different fr adult and paediatric medicines, the inclusin f any excipient in a paediatric medicine requires additinal cncern in view f the ptential risk f mre prnunced safety implicatins. Overall, the fllwing aspects are t be cnsidered with respect t the selectin f an apprpriate excipient: the pharmaceutical technlgic characteristics f the excipient and ptential alternatives; the safety prfile f the excipient fr children all ver the indicated target age grups n basis f single and daily expsure (and nt the cncentratin r strength f the medicine); the expected duratin f treatment i.e. shrt term versus lng term; the criticality f the cnditin t be treated; 14/23

15 the characteristics f the disease; manufacturability; allergies and sensitizatin The safety implicatins f an excipient fr a specific target age grup and rute f administratin at the prpsed daily intake can range frm absent until fully unacceptable and may include all stages in between e.g. lw risk, mderate risk etc. Althugh the final evaluatin n the acceptability f the excipient in the medicinal prduct shuld be based n an verall risk t benefit evaluatin f the prduct itself, it must be acknwledged that an verall psitive risk t benefit assessment is nt cnsidered an acceptable argument t market prly develped medicines. Thus, in case the use f excipients with an identified risk cannt be avided in the frmulatin f a particular pharmaceutical dsage frm, the added value f the chsen pharmaceutical dsage frm (and rute f administratin) shuld be well balanced against the pssible use f ther pharmaceutical dsage frms and rutes f administratin that d nt require the use f such excipients. In ther wrds, applicants shuld nt cme with a single fait accmpli when excipients with an identified risk are intended t be used. It is expected that a cmprehensive develpment ratinale will be prvided, taking int accunt the relative benefits and risks f a number f pssible and feasible alternatives. This principle is already established in the Cncept Paper fr this guideline. New evidence may suggest that the safety f sme excipients that are cmmnly used in licensed paediatric medicines, may be subject t debate, either as such, abve sme daily intake r in sme target age grups. All this wuld require further research befre a final cnclusin can be drawn. Until then, pharmaceutical cmpanies are recmmended t avid questinable excipients in new paediatric medicines. Whilst it is acknwledged that the use f a new excipient in a paediatric medicine is fundamental t pharmaceutical innvatin and whilst it is acknwledged that the use f such a new excipient may be well justified by apprpriate pre-clinical studies, it must be realized that safety issues may nly becme apparent when the medicine is used n a larger scale. Therefre, the added value f the new excipient in a specific paediatric medicine must be well balanced against the use f ther excipients with a knwn safety prfile and against the use f ther dsage frms r rutes f administratin that d nt require the use f this new excipient. If used, the safety prfile f any new excipient shuld be clsely mnitred pst marketing. Allergies can arise frm early childhd and children may be mre easily sensitized than adults. In rder t avid sensitizatin and t expand treatment pssibilities f allergic children, pharmaceutical industries are encuraged t develp medicines that d nt cntain excipients that are knwn fr their ptential t cause sensitizatin/allergies. The fllwing infrmatin surces shuld be cnsulted in rder t assess the safety prfile f an existing excipient in a paediatric medicine (see Figure 1): The Cmmissin, ICH and CHMP guidelines; CHMP scientific decisins where applicable and as e.g. reflected in Questins and Answer dcuments n the EMA website, pinins, referrals etc; The excipient cmpsitin f currently authrised medicines fr children A reference alne is nt sufficient. Fr each f the relevant target age grups, the indicatin, rute f administratin, treatment duratin, dsage frm, cncentratin, maximum daily excipient intake and expsure shuld be taken int cnsideratin in all r a sample f the licensed medicines. 15/23

16 543 Fd Legislatin This surce f infrmatin pses sme limitatins as it relates t fd nly (i.e. chrnic and lng term use), the data may nt clearly relate t children and the safety margins may be rather wide; All additives, flavurs, preservatives and clrants described in the Fd Legislatin and suitable fr the paediatric ppulatin are nrmally cnsidered acceptable fr use in ral, paediatric medicines, unless there are additinal safety indicatins frm the ther infrmatin surces and unless the wrding in the Fd Legislatin itself causes reasn fr cncern. In case f such additinal cncerns, the excipient shuld either be mitted frm the frmulatin r the applicant shuld justify why the inclusin f the excipient can be cnsidered as acceptable in view f nrmal dietary rutines by the indicated target patients; The afrementined des nt apply t nenates fr which further nn clinical data is required; The safety f additives, flavurs, preservatives and clrants that are described in the Fd Legislatin requires further evaluatin fr use in nn-ral dsage frms; It shuld be remembered that parents r caregivers that need t avid a certain excipient may be able t d s fr fd, but that there may nt be any alternative fr a medicine. Therefre, the justificatin f an excipient in a paediatric medicine by reference t the Fd Legislatin shuld be cnsidered in view f knwn allergies as well. A mre strict apprach may apply. 563 The Eurpean Fd Safety Scientific Opinins (EFSA) This surce f infrmatin pses sme limitatins as it relates t fd nly (i.e. chrnic and lng term use) and the data may nt relate t children. Hwever a warning fr adults may questin the safety f the excipient fr children. 567 Other surces f infrmatin as e.g Expert cmmittee n fd additives (JECFA), which is a mixed cmmittee f the WHO and the Fd and Agricultural Organisatin; Infrmatin in indexed literature; In-huse infrmatin as nn published scientific evidence It is emphasized that it is the respnsibility f the applicant t justify that each excipient in the paediatric medicine is safe fr its intended use and target age grup. New txiclgical studies may be necessary if the use f an existing excipient in a paediatric medicine can nt be justified n basis f the afrementined infrmatin surces. As safety infrmatin n excipients fr use in children is scarce and fragmented, the EMA intends t publish an annex t this guideline prviding an versight f the mst current infrmatin. Hwever, it must be reminded that this annex can nt be used as the sle justificatin and des nt allw applicants t refrain frm the afrementined methdlgy fr justificatin f the safety f an existing excipient fr use in a paediatric frmulatin /23

17 Figure 1: Decisin tree fr the evaluatin f the safety prfile f existing excipients in paediatric frmulatis fr a specific target age grup Is there a CHMP pinin available relating t this excipient? Is the pinin published within the last 5 years? Is the pinin applicable t the relevant target age grup(s)? Is the pinin relevant in view f the indicatin? Is there new evidence available that has nt yet been cnsidered by the CHMP? END Are there Cmmissin/CHMP/ICH guidelines available relating t this excipient? Are these applicable t the target age grup(s)? Are these dcuments still up t date? END Des the excipient in the apprved prducts result in a higher r cmparable daily expsure? Is the excipient apprved in a number f current paediatric medicines? Are the apprved prducts t be administered via a mre risky r cmparable rute f administratin? Are the apprved prducts t be administered during a cmparable r lnger treatment duratin? Are the apprved prducts intended fr a less serius r cmparable indicatin? Are there any new data relevant t safety that have nt been cnsidered previusly? END Is the excipient included in the fd legislatin? Is the infrmatin in the legislatin relevant? END Is there infrmatin available frm EFSA? Is the infrmatin relevant? END Are there any ther surces f infrmatin available? Is the infrmatin relevant? END Cnduct animal studies end i.e. n further need t justify the use f the particular excipient in the paediatric medicine (when the excipient r the medicinal prduct meets the cnditins stated) 17/23

18 Cluring agents Cluring agents allwed in fdstuffs are als allwed in medicines. Hwever, fds fr infants r yung children must nt cntain added clurs except in sme specified cases. Patients that wish r need t avid a certain cluring agent can avid fds cntaining that agent, but fr a medicine there may nt be any alternative. As a cnsequence, paediatric medicines shuld nrmally nt be clured. The use f any specific cluring agent in a paediatric medicine shuld be discussed and justified in terms f allergenic ptential, minimal txiclgical implicatins in the target age grups, child patient and caregiver s acceptability and the need t avid accidental dsing errrs. Where there is a need t differentiate between similar medicines t avid accidental dsing errrs, the use f e.g. shape, size and embssing shuld nnetheless be cnsidered prir t cnsidering the use f cluring agents. The justificatin shuld address bth the necessity t clur the medicine and the selectin f a particular cluring agent. Az-dyes are nt cnsidered acceptable as better alternatives are cmmnly available. In relevant cases the lack f a cluring agent in a paediatric medicine shuld als be discussed and justified in the light f all measures undertaken t avid accidental dsing errrs Flavurs Adequate palatability plays an imprtant rle in patient acceptance. Especially in ral liquid frmulatins, flavurs may be necessary t achieve this gal. The ratinale fr the use f a particular flavur in a paediatric medicine shuld be clearly described and justified accrding sectin 9.1 and 9.5. The use f flavurs shuld be justified by the cmpany, including the chice f natural versus synthetic flavurs. Natural r chemical equivalents f natural flavurs shuld be used if pssible. The qualitative and quantitative cmpsitin f the flavurs shuld be prvided. In additin, safety cncerns shuld be discussed. These cncerns shuld include ptential impurities (i.e. residual slvents) and the risk f allergies and sensitizatin Preservatives Preservatives have a ptential t cause txiclgical prblems, especially in yung children. The need t preserve the paediatric medicine and the chice f the preservative system at the lwest cncentratin feasible shuld be justified in terms f risk t benefit balance. The risk t benefit balance shuld at least take accunt f the facts as described underneath. It is emphasized that the general chapter n excipients als applies t preservatives. The apprpriateness f the preservative system fr the indicated target age grups shuld be discussed. It may becme necessary t use mre than ne preservative in certain circumstances. The individual and cmbined txicity f the preservatives shuld be cnsidered. When the lwest cncentratin feasible t achieve apprpriate micrbilgical preservatin is clse t the level that wuld nt be acceptable frm a safety prspective, applicants shuld cnsider alternative dsage frms Sugar versus sweeteners The imprtance f palatability in paediatric frmulatins is paramunt and sweetness plays an imprtant rle in this. Sweetness can be achieved by the use f natural r artificial (synthetic) sweeteners. Sweetening agents can be categrised as fllws: 18/23