Impact Of The EU Pediatric Regulation: Assessing The First 3 Years

Klaus Rose, M.D., M.S. Principal ConsultantGranzer Regulatory Consulting

22nd AnnualEuroMeeting

March 8-10, 2010Monaco

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These slides are the intellectual property of Klaus Rose and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

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EU Regulation: A Changed Environment

• Few pharma decision boards without PIP debate

• Industry slides start no longer with A&E

• Sometimes clinicians & regulators do

• Emphasis on ‘nuts & bolts‘ of PIPs

• Background knowledge remains desirable & essential

*Lucas Cranach, The Fall of Man

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Impact On What?

• Child health • Pharmaceutical industry: PIP costs per department/

per company/ across industry • EMA• Academia • Pediatric Learned Societies • Reimbursement institutions• Service providers• Emerging new business

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Child Health

• FDA 2001 Status Report to Congress*: “Superior drug treatment information is expected to permit quicker recoveries from childhood illnesses, with fewer attendant hospital stays, physician visits and parental work days lost.“

• No such statistics so far • FDA& EMA statistics on new trials, label changes etc. • Points missing: QoL endpoints, child survival Not all improvements are measurable

*www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM049915.pdf

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Capturing PIP Costs Across A Company

• Flexible time usually booked ‘somewhere‘ • Few companies have dedicated pediatric FTE• Learnings from pediatric theme # across projects:

- Usually, themes are abandoned if below threshold- Even if maintained, of limited value

High costs where large programs reach execution Underreporting of early PIP brainstorming & preparingDiscrepancy:workload seen by individuals vs.numbersIn comparison to overall costs PDD planning costs lowEven semi-precise cost estimate will take years

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PIP Costs: Regulatory Consulting

• One consulting company so far charged 200 – 300 working hours for ‚ordinary‘ regulatory PIP preparation

• Was regulatory consulting only and depended of clinical + other input from requesting company

• With deeper clinical input requested by company can easily be three to five times these hours

• Fees depend of seniority of consultant involved

• Does still not include efforts of sponsoring company and specifically not PIP execution, i.e. performing of studies etc.

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PIP Costs: Execution

• With 20 – 30 thou € / patient real costs, a study with 100 adult subjects costs 2 – 3 Mio €

• Multiply that with factor P in trials in children

• Higher number of subjects correspond to higher costs

• Potential additional costs: Juvenile Animal studies, developing a pediatric formulation, establish of a registry, etc.

• Rule of the thumb for BD&L, e.g. for a product without pediatrics done so far: 20 Mio €

• This money needs to be invested today. Reward will come somewhen between 2020 and 2030

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• Lack of preparedness & disbelief • Handling of different child diseases by adult teams, e.g.

oncology: demanding, complex, • Rare & ultra-rare pediatric target disease outside adult use

for ½y SPC prolongation: challenging • Initial disregard of functions, e.g. preclin tox & s; tech dev;

resulted in suboptimal handling higher EMA demands • Territorial fighting: who coordinates pediatrics? – Could be

regulatory, clinical, project management, marketing, others

Initial Internal Barriers

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• Disbelief has disappeared in big pharma • Smaller EU & non-EU-companies continue learning: regula-

tory lone warriors bring the bad news to the CEO‘s attention• Technical Development: EUPFI

www.pharmacy.ac.uk/fileadmin/documents/Practice_and_Policy/EuPFI_European_Paediatric_Formulation_Initiative.pdf

• Preclin Tox&Safe/ Juv Animals: ILSI HESI 5/6th May Wash DC• Rare & ultra-rare pediatric diseases: Parties still struggling • Many invisible, small-scale changes

The Landscape Today

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One PIP Or Several PIPs

• When company devops consecutively new indications for one product & indication not covered by class waivers, company can choose to submit new PIP of modify old PIP

• Modification process is faster • New PIP doesn‘t jeopardize ongoing PIP negotiation

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EU Rewards Are Possible

• Studies that were concluded (last patient last visit) before January 2007 can be included in the PIP

• However, no rewards will be granted • For a reward: significant new measure required • Could be any contribution • Granted rewards are not published. But: look @ product

specific decisions + when studies must be done.

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Decision 1st Instance of EU Court of Justice (EuCJ)

• Company submitted contrast medium for CAD• PDCO: heart malperfusion exists in kidsask deferral • Company didn‘t negative PDCO opinion no MAA

validation sued @ 1st instance EuCJ • APR2009 1st instance EuCJ rejected (i) request to

suspend EMEA decision to deny waiver (ii) interim measures

• Main case still pending • http://curia.europa.eu/jcms/jcms/j_6/home and search for • Case T-52/09 R

siness Development & Licensing (BD&L)

g pharma‘s productivity is not sufficient art-ups replenish the pipe lineed to consider pediatrics in BD&L

U: BD&L package without PIP 20 Mio € worth less company that licenses in and receives negative MA opinion(s) damages its attractivity MA/PDCO role includes performing quality checks BD&L capabilities

P Withdrawal

ong as no PDCO decision you can withdraw PIP h a PDCO opinion it‘s out the company‘s hands ject abandonded after PDCO positive opinion: ify & inform

ropean Pediatric Research Networks

ltitude of EU pediatric research networks exists ey continue to expandEA plans to coordinate network of networks

cus of national networks still on clinical studies ustry has good experience record with disease-

ecific networkse of national networks still open

obably Europe will not need 27 national pediatric earch networks

w Pediatric Companies

h growing market & funding, medicines for dren will attract inventive personalities

amples: TherakindO4CP l be interesting to follow

arned Societies

crepancy enthusiasm from top representatives & atively low interest of practicing pediatriciansl limited interest for pediatric clinical trials

multitude of subliminal changes is evolving ny more changes will take a lot of more time

mbursement Institutions & Prices

far children‘s pharmaceutical treatment is strongly sed on generics mmercials in pediatric journals focus on generics mbursement institutions have so far scarcely ed the discussionMA medications will be much more expensive mbursement institutions will have to adapt

Os

ny PIPs are reaching execution phasest trials are executed by CROsropean CRO Federation (EUCROF) has created a diatric working group (PWG) CROF PWG has performed 2 ped surveysnclusion: Much space for improvement in EU

gulatory Consultancies

h need for regulatory & clinical consultingjority of clients: Small EU companies and all sizes m outside of EU ality will drive selection of the fittest

nclusions

legislation increased pediatricians‘ armamentariumgoes much further: proper pediatric indication andin of ped consideration as early as possiblecan be bottleneck or roadblock for new drugs

sts are considerable but not negotiables are best handled by knowledgabe person /team

ose who do not want to learn are punishede legislation will certainly not go away

all of its outcomes are easy to measurentinuing dialogue between the partners essential

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Thank You For Your Attention!