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
1Ethical, Social, and Good Clinical Practice (GCP)
Aspects Of Drug Development In Children And In
Paediatric Clinical Trials Klaus Rose,
klausrose Consulting Pediatric Drug Development
More klaus.rose_at_klausrose.net
2- Labels A Century Ago
- 918.
-
- Source www.wellcomecollection.org
3Modern 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
4 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
klausrose Consulting
- 6 -
5EU Pediatric Regulation
- In force since January 2007
- Combines mandatory development with
reward - 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
deferrals - Reward of six months SPC prolongation
- SPC Supplementary Protection Certificate
klausrose Consulting
- 7 -
6EU Pediatric Regulation Core Elements
- FDA started with looking for some pediatric
data - EU wants, as far as possible, full pediatric
indication(s) - Want the necessary data as soon as possible for
marketed drugs and as early as possible for new
drugs - Expect each company to be knowledgeable up to
date - EMEA / PDCO style has evolved since 2007. Claim
to be science-driven, but have developed a tough
attitude - Some requests can be perceived as exaggerated.
Dictate clinical trials even if they do not make
sense
klausrose Consulting
- 9 -
7Regulatory Scientific Challenge Earlier
Inclusion of Children In Drug Developemnt
Basic Research
Entry into Man
Proof of Concept (PoC)
Phase IIIII
Registration 1st Country
Patent-protected Market
Patent Expiry ? Generic Competition
klausrose Consulting
- 10 -
8(No Transcript)
9Pediatric Homework
- Does the same indication exist in children?
- Diagnostics which other diseases might be
diagnosed? - 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
klausrose Consulting
10PIP 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
b
klausrose Consulting
11PDCO Oral Explanation Room Sitting
15 m
PDCO Chairman
Applicants Speaker
PDCO Members
EMA Representatives
Applicant Representatives
12Case 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,
cardiomyopathies) - 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
development. -
13EMA 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.
http//www.ema.europa.eu/docs/en_GB/document_libra
ry/PIP_decision/WC500005753.pdf - 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)
http//www.ema.europa.eu/docs/en_GB/document_libra
ry/PIP_decision/WC500107411.pdf
14EU 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//curia.europa.eu/juri
s/document/document.jsf?textdocid73453pageInde
x0doclangENmodelstdiroccfirstpart1cid
327397 - Judgment Of The General Court (Third Chamber) 14
December 2011. http//curia.europa.eu/juris/docume
nt/document.jsf?textdocid116583pageIndex0doc
langENmodedocdiroccfirstpart1cid234507
15PIP Decisions
- So far gt 1000 PIPs have been submitted
- The key elements are published, but not the
details - 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
16Melanoma
- Class waiver for melanoma was revoked
- Justification 1.7/ 100000 15-19ys olds in US
statistics Surveillance, Epidemiology End
Results (SEER), www.seer.cancer.gov - 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
2) - 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
17Ipilimumab (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
evaluation. - 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.
18Does This Make Sense?
- Obviously, PDCO wants to do something for
children with melanoma. No doubt about their good
intentions. - It would be unethical to disallow adolescents or
children with melanoma participation in adults
trials. - 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
treatments
klausrose Consulting
19Societal 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
company - 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
institutions - Takes decision power away from originating
companies - Does not contribute to pharmaceutical innovation
in Europe - Has increased the weight of academic pediatrics
- Many clinicians still have a generally positive
view - Assessment of relation of resources assigned to
resulting clinical benefit for children almost
impossible due to confidentiality -
klausrose Consulting
20Light at The End of The Tunnel?
- EMA report to EU Commission emphasizes need for
penalties - 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
expected?
21Conclusions
- 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
22Thank You For Your Attention!
klausrose Consulting
23klausrose Consulting
24Better 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
market - 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
25Age 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
klausrose Consulting
26klausrose Consulting
27Will be released May 2010
klausrose Consulting
28PDCO 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
klausrose Consulting
29EMA/ 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)
klausrose Consulting
30 Waivers
- 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
klausrose Consulting
31 Deferrals
- 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
klausrose Consulting
32Melanoma 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
33Cartilage 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,
Italy) - 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
34More 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
helpful. - 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
35Dosing In Adolescents
- In an FDA hearing 2012 12 of 13 clinicians voted
for the routine acceptance of adult doses in
adolescents - Was based on an FDA report on adolescent PK
Studies - Discussion is ongoing in the pediatric scientific
press - FDA publications and massive advances in
pediatric dosing in pharmaceutical companies
36EU Ombudsman
- Two companies complained against EMA/PDCO _at_ EU
ombudsman - The EU ombudsman concluded that in contrast to
EMAs position the complaint fell within the
scope of maladministration and hence, under his
mandate. - 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
37Resources
- 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
company - 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
klausrose Consulting
38PIP 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
klausrose Consulting