Ethical, Social, and Good Clinical Practice (GCP) Aspects Of Drug Development In Children And In Paediatric Clinical Trials Klaus Rose, klausrose Consulting Pediatric Drug Development - PowerPoint PPT Presentation

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Ethical, Social, and Good Clinical Practice (GCP) Aspects Of Drug Development In Children And In Paediatric Clinical Trials Klaus Rose, klausrose Consulting Pediatric Drug Development


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Title: Ethical, Social, and Good Clinical Practice (GCP) Aspects Of Drug Development In Children And In Paediatric Clinical Trials Klaus Rose, klausrose Consulting Pediatric Drug Development

Ethical, Social, and Good Clinical Practice (GCP)
Aspects Of Drug Development In Children And In
Paediatric Clinical Trials Klaus Rose,
klausrose Consulting Pediatric Drug Development

  • Labels A Century Ago
  • 918.
  • Source

Modern Drugs Therapeutic Potential Dangers
  • 1937 a liquid anibiotic was introduced
  • Solvent Ethylen Glycole highly toxic no
    toxicity testing. gt 100 deaths, 1/3 children
  • Led to revision of FDA legislation
  • Next catastrophe Thalidomide1962
  • Ten cases in the USA by clinical studies
  • Led to the Kefauver-Harris amendments
  • Was the birth of modern labels

US Legislation Triggered Modern Drug Labels
  • Date back to US legislation 1962 enforced proof
    of efficacy.
  • Use in children mostly off-label since then.
  • Voluntary Pediatric Exclusivity (PE) BPCA 2007
    after first laws 1997 2002. Biologics excluded.
  • Mandatory ped development PREA 2003. All age
    groups. Biologics included. Applies to same
    indication as in adults only.
  • Re-authorized 2012 as FDASIA
  • BPCA PREA resulted in multiple pediatric
    research on patented drugs. Both seen by FDA as
    major success
  • BPCA Best Pharmaceuticals for Children Act
  • PREA Pediatric Research Equity Act
  • FDASIA FDA Safety Innovation Act

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EU Pediatric Regulation
  • In force since January 2007
  • Combines mandatory development with
  • Pediatric Investigation Plan (PIP) mandatory end
    of human PK
  • Without approved PIP Marketing Authorisation
    Application (MAA) is blocked
  • PIP must cover all age groups
  • Pediatric Committee (PDCO) assesses PIPs, waivers
  • Reward of six months SPC prolongation
  • SPC Supplementary Protection Certificate

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EU Pediatric Regulation Core Elements
  • FDA started with looking for some pediatric
  • EU wants, as far as possible, full pediatric
  • Want the necessary data as soon as possible for
    marketed drugs and as early as possible for new
  • Expect each company to be knowledgeable up to
  • EMEA / PDCO style has evolved since 2007. Claim
    to be science-driven, but have developed a tough
  • Some requests can be perceived as exaggerated.
    Dictate clinical trials even if they do not make

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Regulatory Scientific Challenge Earlier
Inclusion of Children In Drug Developemnt
Basic Research
Entry into Man
Proof of Concept (PoC)
Registration 1st Country
Patent-protected Market
Patent Expiry ? Generic Competition
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Pediatric Homework
  • Does the same indication exist in children?
  • Diagnostics which other diseases might be
  • Drugs which other pediatric diseases might be
    qualified as being within the condition the
    drug is developed in?
  • PDCO view potential future use in children. May
    be different from future adult use.
  • Which therapeutic alternatives exist in children?
  • Risk/benefit assessment of ped development

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PIP Structure

Part A Procedure for the assessment of the application
Part B Overall Development Of The Drug Target Disease
Part C Product-Specific Waivers
Part D Pediatric Investigation Plan
D1 Proposed ped dev indication, age grups, existing data
D2 Quality (CMC, technical staff)
D3 Non-clinical aspects
D4 Clinical aspects clinical strategy individual studies
D5 Timeslines of proposesd measures
Part E Applications for Deferrals
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PDCO Oral Explanation Room Sitting
15 m
PDCO Chairman
Applicants Speaker
PDCO Members
EMA Representatives
Applicant Representatives
Case Study Coronary Artery Disease (CAD)
  • Nykomed requested a full waiver for a
    diagnostic agent for coronary artery disease
    (CAD), a disease listed on the class waiver list
  • EMA condition is Visualisation of myocardial
    perfusion for diagnostic purposes. Myocardial
    perfusion deficits exists in children (congenital
    heart defects, coronary anomalies,
  • Negative opinion 2008
  • Applicant took EMA to EU Court of Justice 1st
    instance backed EMA
  • US originator company negotiated a new PIP with
    EMA, agreed 2011
  • Danish company continued law suit . EU General
    Court backed EMA 2011 otherwise it would be too
    easy for companies to circumvent pediatric

EMA Decisions Perflubutane
  • EMA decision of 28 November 2008 on the
    application for product specific waiver for
    perflubutane EMEA-000194-PIP01-08 in accordance
    with Regulation (EC) No 1901/2006 of the European
    Parliament and of the Council as amended.
  • EMA decision of 18 May 2011 on the agreement of
    a paediatric investigation plan and on the
    granting of a deferral and on the granting of a
    waiver for perflubutane (EMEA-000194-PIP03-10)

EU Court of Justice Decisions
  • Order of the President of the Court of First
    Instance of 24 April 2009 Nycomed Danmark v
    EMEA (Case T-52/09 R). http//
  • Judgment Of The General Court (Third Chamber) 14
    December 2011. http//

PIP Decisions
  • So far gt 1000 PIPs have been submitted
  • The key elements are published, but not the
  • Details are always confidential
  • Nevertheless, we can see trends in specific areas
  • Melanoma
  • Joint injuries
  • Vaccines
  • Drugs for preterm newborns
  • Drugs developed only for children
  • Rare diseases

  • Class waiver for melanoma was revoked
  • Justification 1.7/ 100000 15-19ys olds in US
    statistics Surveillance, Epidemiology End
    Results (SEER),
  • 6 PIPs if you search with melanoma Ipilimumab
    (2) MAGE-A3 recombinant protein GSK1120212
    GSK2118436 RO5185426
  • Ipilimumab BMS conditions melanoma (PIP 1) and
    solid malignant tumours excluding melanoma (PIP
  • Mage-A3 recombinant protein Condition melanoma
  • GSK1120212 Condition Melanoma malignant solid
    tumours (excluding melanoma)
  • GSK2118436 Condition Melanoma malignant solid
    tumours (excluding melanoma)
  • RO5185426 Condition Melanoma

Ipilimumab (Yervoy)
  • Condition melanoma and non-melanoma solid tumors
    (2 PIPs)
  • Studies for melanoma
  • i.v. study of pre- and postnatal development in
    cynomolgus monkeys with a 6-month postnatal
  • OL, dose escalation clinical trial of
    intravenously administered ipilimumab in children
    from 2 to less than 18 years (and in young adults
    to 21 years) with untreatable, refractory or
    relapsed solid malignant tumours.
  • OL multi-centre, single-arm i.v. ipilimumab in 12
    to lt18 y with untreated/ previously treated
    advanced/metastatic melanoma.
  • OL randomized active-controlled study adjuvant
    ipilimumab anti-CTLA4 therapy vs. high-dose
    interferon a-2b in kids 12 - lt 18 y (and
    adults) with resected high-risk melanoma.

Does This Make Sense?
  • Obviously, PDCO wants to do something for
    children with melanoma. No doubt about their good
  • It would be unethical to disallow adolescents or
    children with melanoma participation in adults
  • Once an adult melanoma drug is registered in
    adults, of course clinicians will use it in
    children as well. Too few patients for
    statistically significant results
  • As companies have to commit to studies to be
    finished in a defined time horizon, the pediatric
    patients with melanoma are now blocked for
    PDCO-triggered clinical trials.
  • Has started to affect e.g. US children with
    cancer, although the clinical community sees
    other priorities
  • In consequence, danger of blocking promising

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Societal Impact of EU US Pediatric Legislation
  • Increases cost of drug development
  • For large companies costs are still marginal.
  • Can be different for an individual small / medium
  • SME office _at_ EMA offers help, but PDCO treat all
    applicants equally
  • Higher costs for pediatric medicines have not yet
    reached calculations of insurers / reimbursement
  • Takes decision power away from originating
  • Does not contribute to pharmaceutical innovation
    in Europe
  • Has increased the weight of academic pediatrics
  • Many clinicians still have a generally positive
  • Assessment of relation of resources assigned to
    resulting clinical benefit for children almost
    impossible due to confidentiality

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Light at The End of The Tunnel?
  • EMA report to EU Commission emphasizes need for
  • EMA 5 years report July 2012 to EU Commission
    EU Parliament Work is well advanced to promote
    less detailed PIP proposals, including the key
    elements in PIP opinions. The simplification of
    applications and subsequently of PDCO opinions
    should benefit early PIP applications
  • First changes were presented by EMA at the
    EFGCP/DIA/EMA pediatric conference September 2012
    in London, UK
  • General revocation of class waivers in pediatric
    oncology was announced a few days ago
  • Revision of pediatric regulation in 2018
    reasonable modification of the regulation to be

  • Drug development no longer possible without
    considering children
  • Increases cost complexity of drug development
  • Mosaic of goodwill, scientific input, bureaucracy
    without checks balances, disproportionate use
    of resources, limited clinical benefit
  • PIP skills needed intimate knowledge of PDCO,
    EMA procedures
  • Potential for saving resources is highest during
    early PIP preparation
  • Aim for individual company negotiate PIP that
    will serve child health in the far future and
    lets company survive
  • Revision 2018 divergent proposals will be made
  • EU Councils Lisbon strategy 2000 EU by 2010 to
    become the most competitive and dynamic
    knowledge-based economy in the world
  • EU pediatric legislation should be seen in this
    framework. Is one of many EU challenges. Good
    intentions are not enough
  • Legislation will stay ? no alternative than to
    continue the dialogue

Thank You For Your Attention!
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  • Back-Ups

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Better Medicines for Children or Better Use of
Adult Medicines in Children?
  • EU US pediatric pharmaceutical legislation
    tries to close a gap - in the use of existing
    adult drugs in children
  • So far, there is no industry that develops drugs
    for children
  • Such an industry could exist if there would be a
  • There are enough rare diseases to keep thousands
    of researchers busy but somebody has to pay
  • Today, not even a straw facilitating intake of
    antibiotics is reimursed in Germany formulation
    was abandoned
  • We talk about two issues (1) Handling additional
    pediatric requests in adult development, and (2)
    nice wording better medicines for children

Age Groups (ICH E 11)
Preterm newborn infants(0 - 27 days)
ICH E 11
Term newborn infants(0 - 27 days)
Infants and toddlers(28 days to 23 months)
Children (2 - 11 years)
Adolescents (12 to 16-18 years) US 16 y / EU 18 y
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Will be released May 2010
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PDCO Summary Report Template D.1.b
The Regulation considers the need for data in
the paediatric use. This can be based on the
potential for off-label use in children. The
Regulation does not require that the PIP is
limited to the proposed wording of the adult
indication, but it is assumed that there should
be some relationship
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EMA/ PDCO Feedbacks Reports
  • Requests for modification for validation
  • Day 30 report no action required from applicant
  • Day 60 report lists requested modifications
    must be answered
  • Day 90 report lists requested last modifications
  • Day 120 Showdown AND only chance for F2F Oral
    Explanation (OE)

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  • Waivers are given for all children or specific
    age groups
  • Age classifcation based on ICH E 11
  • Waivers only for 3 conditions
  • Drug probably ineffective or unsafe
  • Disease doesnt exist in children
  • No significant therapeutic benefit

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  • Allows company to perform pediatric measures
    (studies, technical development etc.) at a later
    defined time point
  • Only concrete measures can be deferred
  • Basic framework outlined in ICH E 11
  • Will for most new drugs be granted as long as
    there are not sufficient safety efficacy data
    in adults
  • Will for marketed drugs with off-label pediatric
    use be very difficult to obtain

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Melanoma PIP Considerations
  • Classification as adolescent disease refers to US
    data 15-19ys olds. Ovarial carcinoma, 1.4/100000
    in 15-19y class waiver stays.
  • Deducing 2/5 from 1.7 (18/ 19 y old are adults)
    2/5 of 1.4 ? lower limit 1.02 - 0.84/ 100000 as
    limit for ultra rare disease? Not official
  • Melanom ist rare lt 18 most are detected without
    metastases. With these case numbers no
    statistically significant results possible
  • Separate clin studies in adolescent melanoma
    ethically questionable
  • Adolescents should have the right to participate
    at adult studies, but
  • No PIPs for more frequent pediatric cancer types
    because they dont exist in adults hence no
    business case for drug development
  • Starts to negatively impact pediatric cancer
    research worldwide as PDCO decisions block
    pediatric patients

Cartilage Disorders
  • ACT (autologous chondrocyte transplantation)
    routine in treating cartilage injuries. Belated
    registration required by German law ? PIP.
  • Two published chondrocyte PIPs
  • Autologous cartilage derived cultured
    chondrocytes (Genzyme)
  • Culture expanded autologous chondrocytes (Fidia,
  • Genzyme Retrospective investigation of S and
    prospective investigation of SE data in ped
    patients treated for cartilage defects with
    autologous cartilage derived cultured
    chondrocytes. Pediatric population from closure
    of femoral epiphyseal growth plate to lt18 y.
  • Fidia Randomized MC SE study of Hyalograft
    autologous chondrocyte implantation compared to
    microfracture in 16-17y olds
  • An adolescents knee is biologically the same as
    a young adults one
  • PDCO uses legal age to order medically
    ethically questionable trials

More Examples
  • Vaccines were developed for decades without PDCO
  • Drugs for preterm newborns development teams
    competence is sufficient to develop drug from
    research to registration for which CHMP is
    responsible. Addition input from PDCO not
  • Drugs developed only for children there are a
    few companies who dare. Addition input from
    PDCO not helpful.
  • Rare diseases starting in childhood. Drug
    development requires very special knowledge. MAA
    is discussed with CHMP. Mandatory additional PDCO
    discussion perceived as waist of time resources
    by industry

Dosing In Adolescents
  • In an FDA hearing 2012 12 of 13 clinicians voted
    for the routine acceptance of adult doses in
  • Was based on an FDA report on adolescent PK
  • Discussion is ongoing in the pediatric scientific
  • FDA publications and massive advances in
    pediatric dosing in pharmaceutical companies

EU Ombudsman
  • Two companies complained against EMA/PDCO _at_ EU
  • The EU ombudsman concluded that in contrast to
    EMAs position the complaint fell within the
    scope of maladministration and hence, under his
  • The enquiry resulted in recommending, inter
    alia,EMA guidelines to assist PDCO to follow a
    coherent structure of analysis in future cases.
  • We will later today hear more directly from a
    representative of the EU ombudsmans office!
  • alia, EMA guidelines to assist PDCO to follow a
    coherent structure of analysis in future cases

  • Big companies PIP is one of many many challenges
  • SMEs limited resources. Additional PIP challenge
    is usually much more time consuming than
    originally thought
  • Estimated consulting dimensions
  • Regulatory PIP consulting 200-300 hours
  • Clinical input should come from the sponsoring
  • Deep clinical consulting can increase the effort
    by factor 3 to 5
  • This does not include additional internal costs
    by the sponsor and not the costs of PIP execution
  • Even best external consulting will not allow the
    sponsoring company to just forget pediatrics

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PIP Execution
  • Ca. 20 30000 / costs per patient ? Study 100
    adults 2-3 Mio
  • Multiply with factor P for pediatric studies
  • More patients ? higher costs
  • Additional costs juvenile animal studies,
    pediatric formulation, establish a registry, etc.
  • BDL rough estimate if you buy a product where
    pediatric homework has not been done 20 Mio
    (including study execution, provided your MAA is
    not blocked
  • A part of this money must be invested before MAA,
    a part thereafter

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