Drugs for children

Irja LutsarTallinn 2007

Pediatrics does not deal with miniature men and women, with reduced doses the same class of disease in smaller bodies, but ….. has its own independent range and horizon

Abraham Jacobi rohkem kui 100 aastat tagasi

Problem statement: child vs adult

• The effectiveness and tolerabily is likely to be different– Neonates (premature and full-term) - < 28 days– Infants – 1 mo - < 2years– Children – 2 years – 11 years– Adolescents – 12 years – 16 (-17) years

• Dose cannot be directly extrapolated from adults– Different pharmacokinetics

• absorption• distribution• elimination

• Many agents used in paediatric are never tested in children

Pharmacokinetics of pencillin G

T1/2 Cmax

Premature < 1200 g

30 mg/kg 3,8 h 145,5 mcg/ml

15 mg/kg 4,6 h 58,9 mcg/ml

Full-term baby

15 mg/kg 3,4 h 22,0 mcg/ml

adult

600 mg/dosi 0,5 h 45 mcg/mlMetsvaht et al. AAC 2007; 51: 1995-00

Mean voriconazole plasma concentrations after IV and POS

administration

0

2000

4000

6000

8000

10000

12000

0 2 4 6 8 10 12

Time postdose (h)

Mea

n p

lasm

a vo

rico

naz

ole

co

nce

ntr

atio

n (

ng

/mL

)

6 mg/kg IV (120 min infusion) 8 mg/kg IV (160 min infusion) 6 mg/kg POS

upper limit of SD: 19,030

Walsh et al. AAC 2007

BA in adults 96%

Formulations not suitable for children

• IV formulation toxic or too concentrated– Cyclodextran & nephrotoxic– Quinolones are reconstituted in acids– Not suitable presentations (too large or too small vials)

• Oral formulations– Capsules and film-coated tablets (children cannot

swallow)– Crushed tablets vs whole tablets– How to give bitter tablets?– Solution and suspensions

• Better solubility worse taste• What is a good taste?• Should a medicine have a good taste?• Too large amounts• Bioavailability

Slow release tablet Crushed tablet

History

• 1937 – 107 people with streptococcal infection died (mainly children) – All were treated with a sulphonamide that was

diluted in diethylglycole (antifris)• 1956 – neonates who received

sulphonamides had more often kernicterus than those receiving tetracycline

• Chloramphenicol & “gray baby syndrome” (enzyme immaturity)

• “Gasping syndrome”– Agents that are reconstituted in benzylalcochol

(IV clindamycin)• Antidepressants

How common is off-label use

Years >1 unlicenced or off-label

drug (%)

off-label (%)

Children (hospitalised)

1985-99 36-92 7-60

Neonates (hospitalised)

1998-02 80-97 14-63

Outpatient 1978-01 16-56 9-33

Eur J Pediatr 2005; 164: 552-558

Then younger the child then lower number of studies Then sicker the child the less studies

Studies in children: statistics

• 1997 – FDA 33 new drugs licenced – 27 potentially used for children – 9 had some information on use in children

• Neonates use a lot of medicines– Detroit (USA) 1997-2004 NICU 3,6/per

child– ELBW - 11,7/per child– Australia 93% ELBW at least 1 untested

drug will be used

FDA: paediatric studies

• FDAMA Pediatric Exclusivity 1997 (voluntary)• Pediatric Rule Regulation 1998 (enjoined

2002)• January 2002

- FDAMA Exclusivity Sunsets• January 2002 (compulsary)

- Best Pharmaceuticals for Children Act (BPCA)

• December 2003- Pediatric Research Equity Act (PREA)

• October 2007: Sunset for BPCA & PREA

FDA: stick (WR) & carrot (PE)

• All new drugs ned to be tested in children

• Industry initiated (WR)• waivers

– Disease does not exsist in children

– Drug is too toxic for children

• Deferral until more data on adults are available

• Patent prodection for 6 months– Fluconazole 600 mill $– Sildenafil 1 bill $

Priotrity list of medicines

Pediatric Drug Development

12 17 23 20 23 17 15 18

1112 19 15 25 25 14

98

45

69

21 24 1910 22

3

0

60

120

1999 2000 2001 2002 2003 2004 2005 2006

Calendar year

Nu

mb

er

Pediatric exclusivity determinations Pediatric exclusivity labeling changes

Written requests issued

FDA: results (March 2007)

• FDA issued 341 WR

• 150 new medicines were tested in children

• 128 labelling changes were made

Benefits of WR (FDA)

• 1998- 2004 – 253 studies in children with new agents – 125 (50%) – efficacy– 51 (20%) – MD PK– 34 (13%) – SD PK– 43 (17%) – safety & tolerability

• 127 (50%) new information• 113 (45%) published• Net economic return - -8,9 mil....507.9

mil $JAMA 2006; 296: 120-123JAMA 2007; 297: 480-8

FDA: 127 changes in drug information

• New dose or changes in exsisting dose (n = 25)

• New data on tolerability (n = 35)

• “No data in children” added into label (n = 28)

• New dosing recommendations for infants or neonates (n = 83)

We got know what we do not know

Many questions were answered but many mopre questions

raised

Deficiencies in the FDA regulations

• Industry might not be interested– Pediatric market is small– Studies in children are complicated– Long-lasting negotiations

• No procedure to study off patent drugs

• No paediatric trial registry

European Union

The same issues

Paediatric regulation: entered into force 26 January

2007

• Improve the health of children– Increase high quality, ethical research into

medicines for children– Increase availability of authorised

medicines for children– Increase information on medicines

• Achieve the above– Without unnecessary studies in children– Without delaying authorisation for adults

Main pillars of the Regulation

• New EMEA Committee: the Paediatric Committee

• An agreed (evolutive) paediatric development: the Paediatric Investigation Plan (PIP)

• A mix of rewards and incentives– For on-patent products– For off-patent products

• A series of other tools for information, transparency, and stimulation of research

Paediatric Committee (PDCO)

+ alternates

to be established by 26 July 2007

Paediatric committe: objectives

• Paediatric scientific advice– Free of charge– Not binding

• Review of PIPs (+waivers & deferrals)• Member States Survey of all existing

uses of medicinal products in children, including off-label within 2 years, final EMEA inventory in third year (2009)

• Update of Paediatric needs by Paediatric Committee on basis of inventory

Currently unauthorised products

18 months after entry into force of the Regulation, 26.07 2008

• Stick– Obligation to submit results of agreed

PIP at time of marketing authorisation application

– If not: Invalid application for MA– Results reported in SmPC– Authorisation in all Member States

• Carrot– 6-month extension of the Supplementary

Protection Certificate

Patent-protected authorisedproducts

24 months after entry into force of the Regulation, 26.01 2009

• Stick– Obligation to submit results of agreed PIP at

time of change (variation/extension) for new indication, route of administration, or pharmaceutical form

– Results reported in SmPC– Authorisation in all Member States

• Carrot– 6-month extension of the Supplementary

Protection Certificate

For off-patent products

• Paediatric Use Marketing Authorisation (PUMA)

New type of MA• Covers exclusively paediatric

indication(s) and formulation(s)• Optional but need for PIP and compliance• No need for MA in all Member States• Brand name may be retained

Carrot• 10 years of data protection: (8+2) +1

Paediatric Investigation Plan

• General strategy of paediatric studies– Epidemiology, pathophysiology, indications,

target population, doses• New formulations (needs & technology)• Preclinical studies (toxicity, effect on

pregnancy, young animals)• Clinical studies (PK studies,

efficacy/safety studies, strategy, time-table)

• Waivers and deferrals

1

Time-table for paediatric studies

Non-clin Phase 1 Phase 2 Phase 3 Post approval

Paediatric invest. plan (PIP)

Compliance

Deferral (annual report on progress)

Waiver

MA

Amendments

PDCO

Scientific adviceCHMPNCA

Waivers

• Product likely to be ineffective or unsafe in all or part of the paediatric population

• Disease occurs only in adults• No significant therapeutic

benefit over existing treatments for children→ for one or more subgroups of the

paediatric population→ for one or more specified indications

Deferrals

• Request to defer initiation or completion of some or all the measures set out in the PIP

• On initiative from applicant or Committee

• For all or part of Paediatric Investigation Plan

• Annual report to monitor deferred studies

A European Network

EMEA paediatric research network• To link together existing networks,

investigators and centres with specific paediatric expertise

• Build up competences at a European level

• Facilitate the conduct of studies• Avoid duplication of studiesPreparatory work at EMEA over 2005-6

Paediatric studies are not the private business of

the pharmaceutical industry

Types of paediatric studies• Direct clinical studies

– PK studies– Efficacy and toleration studies– Preclinical and non-clinical studies

• Indirect studies– Assessment of paediatric standards

• Growth and development

– Epidemiological studies• Prevalence of the disease in children• Pathomechanism of the disease

– Investigations on growth, development & maturation

Who should conduct studies in children

• Pharmaceutical industry• Universities, research institutes,

medical schools• All paediatricians – why not?

Who should fund paediatric studies

• Pharmaceutical industry• Pharmaceutical industry + private funds• EU governmental funds (research councils,

science boards)• EU grants

– EU 7FP specific call for paediatric studies for off-patent used drugs

– Priority list

• Paediatric Societies• Charities

– Bill & Melinda Gates foundation

Other Measures:Funding of studies into off-

patent medicines for children• Community funding• Liaison with EC (DG Research) for calls for

proposals under the 7th framework programme (special programme for off-patent drugs)

• Priority list of off-patent medicinal products for paediatric studies (published in December 2006 for comments till 31 January 2007- Finalisation at the March Paediatric Working Party)

Paediatric studies – how to start?

Questions to answer first?• Does the disease occur in paediatrics? • How common is the disease in paediatrics?

– Common → continue– Rare → ???

• Is there an unmet medical need?– Yes → continue

• Which are the potential paediatric indications?– Similar to adults– Different of adults

• Is the disaese process in children and adults similar?– Infections – yes– Fever – yes– Seizures – unknown– HIV - no

Planning is the key• Which studies when and how• Non-clinical studies (toxicity, juvenile

animals)• Formulation issues –child friendly

– suspension, solution – Taste and amount– IV formulation (concentration??)

• Veins are narrow• Limited amount of fluid could be given

– Bioavailability

• Safety/efficacy in all paediatric populations

Reasonable to assume (pediatrics vs adults) similar disease progression? similar response to intervention?

Pediatric Study Decision Tree

NO

Is there a PD measurement**that can be use to predictefficacy?

NO

•Conduct PK studies•Conduct safety/efficacy trials*

NO

•Conduct PK studies to achieve levels similar to adults•Conduct safety trials

YES

Reasonable to assume similarconcentration-response (C-R)in pediatrics and adults?

YES TO BOTH

•Conduct PK/PD studies to getC-R for PD measurement•Conduct PK studies to achievetarget concentrations based on C-R

YES

•Conduct safety trials

An ideal drug

• PK established in all paediatric populations

• Safety well described• Efficacy can be

extrapolated from adults

• Child-friendly formulation available

• Post-marketing experience

• No need for further paediatric studies

• Studies with new formulation could be performed in adults

Unmet medical need & some paediatric data

• Pharmacokinetic studies– Linear pharmacokinetics – SD studies– Non-linear pharmacokinetics – MD studies– Target concentration

• Safety studies if efficacy can be extrapolated from adults

• Efficacy studies if efficacy cannot be extrapolated from adults

• Step-down timing– Studies in adults and in older children first

• Do not forget neonates, if there is a need

3mg/kg 4mg/kg Medians *Paed. **Adults *Paed. **Adults

Cave (ng/ml) 889 1155 1186 3217 AUC (ngh /ml) 10, 670 13, 855 14, 227 38, 605

* 35 subjects from SD and MD PK studies** 236 healthy volunteers from SD and MD PK studies

2.78 fold

1.33 fold dose inc.

1.33 fold

PK Exposures in Paediatrics and Adults

Ethical issues

• Is it ethical to conduct studies in children?• Is it ethical not to conduct studies in

children?• Points to consider

– Sample size– Pain and dyscomfort– Informed consent and assent– Blood loss– No investigations for study purposes only– Effect on growth and development– Is there a benefit (for this child, for the group of

children with similar disease)– Healthy volunteers are not accepted

Kuidas Eesti saaks osaleda laste uuringutes

• Kui palju Eestis kasutatavaid ravimeid omab andmeid kõigi eagruppide kohta?

• Uuringute register lastearstide seltsi juures– Farmaatsiatööstuse poolt läbiviidavad uuringud

pole ainukesed kliinilised uuringud lastel

• EU grandid koos kolleegidega Euroopast• EV valitsus - ETF, sihtfinatseerimine• Heategevuslikud fondid (nt. Lastefond jne)• Rahva teavitamine

– Miks ja kuidas teostatakse uuringuid lastel

Summary

• Political decision - there is a need for more paeditaric data

• Each day new paediatric data will be released

• Future - All medicines used in children should have paediatric data

Pediaatrilised uuringud on globaalsed

• Luua sidemed 3-ndate riikide andmebaasidega

• Lasteuuringute andmebaas kõigile veebis kättesaadavaks

Compliance check:Possible scenarios (new

products)Deferral

MA

PIPDecision Completion of

Measures at MAA

MAMAvalidationvalidation

Reward : If compliant+ Results in SPC+ Authorisation in all MSs

Waiver

Completion Completion measuresmeasuresAnnual reports

on deferral

Partial deferral

Compliance check

Completion Completion measuresmeasuresPartialPartial

completion completion measuresmeasures

Annual reports on deferral

Other Measures: Paediatric Scientific

Advice• Free of charge from entry into force

• Prior to submission of a PIP or during PIP implementation process

• Including advice on pharmacovigilance and risk management systems

• Not binding on Paediatric Committee

• Link Paediatric Committee / Scientific Advice Working Party

Other Measures: Provision of InformationPaediatric clinical trials requiring EUDRACT Modification

To include third countries trials linked to a PIP To include results of all trials and of other trials ‘submitted to

competent authorities’ Paediatric information to be made public

Proposal made by EMEA to EC on the data fields to be included in EudraCT and those to be published on paediatric medicinesFor discussion at the Ad Hoc Group for the development of implementing guidelines for Directive 2001/20/ECFollowed by Release for consultation

Public access to paediatric information for authorised products (EudraPharm)

New EMEA Committee: the Paediatric

Committee

• An agreed (evolutive) paediatric

development: the Paediatric Investigation

Plan (PIP)

• A mix of rewards and incentives

– For on-patent products

– For off-patent products

• A series of other tools for information,

transparency, and stimulation of research

• New EMEA Committee: the Paediatric• Committee• • An agreed (evolutive) paediatric• development: the Paediatric Investigation• Plan (PIP)• • A mix of rewards and incentives• – For on-patent products• – For off-patent products• • A series of other tools for information,• transparency, and stimulation of research

BPCA: Pediatric Exclusivity Stats

(As of December 2006)

• Number of patients requested for studies N= 45,700

• Products with Safety Reviews Presented to PAC N= 65

http://www.fda.gov/oc/opt/pediatricsafety.html

• Summaries of Medical/Clinical Pharmacology – Summaries on fda.gov/cder/pediatrics N=73– www.fda.gov/cder/pediatric/summaryreview.htm

BPCA: Pediatric Exclusivity Stats

(As of December 2006)

• 65 products had safety reviews presented to Pediatric Advisory Comm.

• 73 summaries of Medical/Clinical Pharmacology posted on web.

• 56 products placed on the BPCA off-patent priority list

BPCA vs. PREAPREA

• Studies are required

• Orphan drugs designated exempt

• Biologics and Drugs• Studies limited to

drug/indication under development

• No focused post-marketing safety review

• No central review • 10-1-07 Sunset

BPCA• Studies are voluntary• Includes orphan drugs

and orphan drug indications

• Drugs only• Studies on whole moiety• 1 year safety reviews• Summary posted on Web• Central review=PDIT• 10-1-07 Sunset

BPCA: Before a Written Request (WR) is issued, we

answer these questions.• Public Health Benefit – yes• Risk/Benefit appropriate -- yes

Then we ask …

• What information do we need?• In what age groups do we need the

information?• What studies are needed to obtain

this information

Process: BPCA

1. Sponsor makes proposal for WR. Division rejects, accepts, or modifies. OR

2. Division develops WR independent of sponsor

3. Division presents WR to PDIT(Pediatric Team)

4. Office Director signs off on WR to sponsor5. Sponsor accepts or declines.6. If sponsor declines, may be sent to FNIH7. There is tracking of applications submitted

for an exclusivity determination8. A summary of the studies is posted for all

studies9. There is a 1 year post exclusivity safety

review

Process: PREA

1. Sponsor submits an IND for an adult indication

2. Division must decide if pediatric studies are needed and if they can be deferred or if pediatric studies can be waived.

3. If studies are required the time table and general outline are decided before an action is taken on the application.

4. There may or may not be involvement of the pediatric staff. There is no central process.

5. There is no tracking of outcomes except as Phase 4

6. Only approved applications have studies posted

7. There is no mandatory post approval safety review

Selected Pediatric Ethics Activities

• Pediatric Ethical Consults– Sept 2003 – July 2006: approx. 80 consults– Topics: pediatric safety, compliance with

Subpart D, parental permission and child assent, exception from informed consent applied to parents, use of “healthy” children, international studies

• Subpart D (additional protections for children) Referrals under 21CFR§50.54– Pediatric Ethics Subcommittee of Pediatric AC:

FACA review of protocols referred by local IRBs for approval by FDA Commissioner and/or HHS Secretary

– Since 2004: 3 reviews (prior OHRP non-FACA reviews=14)

Subpart D Pediatric Advisory Committee and Ethics

Subcommittee meetings• September 2004: Effects of single dose

Dextroamphetamine in ADHD and functional imaging

• June 2005: Precursor Preference in Surfactant Synthesis of Newborns

• November 2005: Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty