Perspectives from a Regulator

Accessing new drugs:
A regulator's perspective
International Society of Paediatric Oncology 2012 congress
Presented by: Ralf Herold
Scientific Administrator, Paediatric Medicines Section, Human Medicines Special
Areas, Human Medicines Development and Evaluation
An agency of the European Union
"Access to new drugs"
• Access = To study new
drug in non-clinical test
and in clinical trial
• Scientific steps to
accumulate evidence
• This is an experiment,
not medical care
Accessing new drugs - a regulator's perspective
• Access = to make sure
high-quality medicines
are developed and
available for authorised
use and reimbursement
• To advance medical
care, which then can be
used in clinical trials
Regulatory perspective: to safeguard
and to improve public health in Europe
• Protect population and ensure safety of medicines
• European population in its diversity
• Neglected subsets in frequent conditions
• Respond to global needs
• Neglected diseases
The choice of the
endpoint determines
which patient subset
is addressed.
(after S Hirschfeld)
Accessing new drugs - a regulator's perspective
General tools of regulators to support
the development of medicines
• Scientific guidelines
• Orphan designation (incentives during and after development)
• Paediatric investigation plan (incentives)
• Needs lists (Paediatric medicines EMA; WHO Essential medicines)
• Continuous exchange with other institutions (e.g., ECDC, FDA)
• Collaboration with scientific societies
• Consultations in public
• High level of transparency
Accessing new drugs - a regulator's perspective
Scientific Committees at the EMA
• Delegates from the
27 EU Member States + NO + IS
• Health professional representatives
• Patient organisation representatives
• Work to achieve scientific consensus
Accessing new drugs - a regulator's perspective
Paediatric Regulation (EC) No. 1901/2006
• Relevant for you as medical doctors and investigators
• Comprehensive framework of paediatric expertise in EU established:
– Paediatric Committee (PeeDeeCeeOh) with EMA secretariat created
– European paediatric research network at the EMA (Enpr-EMA) created
• Activities and achievements (end 2011*) under Regulation:
– PIP / Waiver for all new and (many) authorised medicines mandatory:
in total 476 PIP Decisions (33 anti-cancer substances, each 1 or 2 PIPs)
– First 43 paediatric indications authorised (1 anti-cancer, more in 2012)
– Assessment of completed studies and reports on medicines in children
• Difficulties and limitations
Accessing new drugs - a regulator's perspective
Bevacizumab SmPC: timely update (03/2012),
reference to authorised indications,
concerns based on results of paediatric trials
Paediatric population
The safety and efficacy of bevacizumab in children and adolescents have not been established. There
is no relevant use of bevacizumab in the paediatric population in the granted indications. Currently
available data are described in sections 5.1, 5.2 and 5.3 but no recommendation on a posology can be
Avastin should not be used in children aged 3 years to less than 18 years with recurrent or progressive
high-grade glioma because of efficacy concerns (see 5.1 for results of paediatric trials).
Method of administration
The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is
well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is
well tolerated, all subsequent infusions may be administered over 30 minutes.
Accessing new drugs - a regulator's perspective
Paediatric Investigation Plan agreed by PDCO:
the main tool of the Paediatric Regulation
• Basis for development and authorisation of a medicine for all
paediatric population subsets
• PDCO defines paediatric use to be targeted by the study program
• Mandatory for new medicinal products under development and for
authorised medicines when new indication, route or formulation
• Binding on pharmaceutical companies
• Completion required once "triggered" in a regulatory submission
• Includes studies with details and timing to document
quality, safety and efficacy of the medicine
Accessing new drugs - a regulator's perspective
Regulatory activities in medicine development
Phase 1
Phase 2
Phase 3
in adults
PIP initial submission by
applicant to PDCO
Non-compliance blocks
validation (filing)
Orphan medicine
Accessing new drugs - a regulator's perspective
Procedure for handling applications for
agreement of PIP / waiver (SOP/H/3207)
Day 30 =
First discussion
in the PDCO
60 days
Day 60 =
Second discussion
in the PDCO
Day 90 =
Third discussion
in the PDCO
60 days
Day 120 =
Possible oral
~ 3 months
Day 1 =
After validation,
Summary report
drafted by EMA
Day 60 = Adoption
“PDCO Request for
modification” or
“PDCO Opinion”
Accessing new drugs - a regulator's perspective
Day 61 =
Summary report
updated with
applicant response
Day 120 = Adoption
“PDCO Opinion”
Agreeing / refusing
PIP and / or waiver
Potentially followed by 30-day Re-examination
Difficulties and limitations encountered with
implementing the Paediatric Regulation (I)
• Assessment of old studies and reports inconclusive:
Meaningful paediatric studies difficult to define and conduct
• General considerations and areas for improvement
– Use of new information by health care professionals uncertain
– Variable awareness of need for paediatric clinical research
– Paediatric care based on poor evidence infrequently challenged
– Some paediatric therapeutic areas have been neglected
– Wide-spread off label use not abolished by generating paediatric data
Accessing new drugs - a regulator's perspective
Activities and responsibilities of
regulators and stakeholders
Accessing new drugs - a regulator's perspective
Difficulties and limitations encountered with
implementing the Paediatric Regulation (II)
• Difficulties in paediatric oncology:
– Regulatory system previously solely based on histopathology
– Data not yet available (e.g., biological principle, xenografts, adult studies)
to inform which is paediatric malignancy (if any) that could need medicine
– Difficulties to build success on mechanism of action and biomarker(s)
– Choosing relevant study designs and strategies difficult for all stakeholders
– Inefficiencies of setting up and running studies
– Inspections of paediatric trials show critical and major findings
– Many discussions (e.g., COG, NIH, SIOP) not accessible to EMA
– Paediatric trials for oncology medicines ongoing, but no PIP
Accessing new drugs - a regulator's perspective
Anti-cancer medicines for children:
non-clinical and clinical safety findings
• Results of first completed juvenile animal studies available
– Bone metabolism inhibitor A: effects at all doses, partially reversible,
findings have clinical relevance, putative biomarkers found
– Tyrosine kinase inhibitor B: no unexpected and no more serious findings
compared to clinical profile in adults
– Tyrosine kinase inhibitor C: unexpected kidney toxicity (glomerulopathy),
generally more serious toxicity compared to clinical profile in adults
– Cytotoxic medicine D: no unexpected finding
– Pro-apoptotic medicine E: unexpected finding brain hypoplasia
Accessing new drugs - a regulator's perspective
Anti-cancer medicines for children: difficult
discussions of priorities and paediatric interest
• Interesting data …
• Should blue be a priority?
• What is missing?
• Full transparency necessary
• Data update necessary
• Medical data survivors?
• Review clinical records?
Accessing new drugs - a regulator's perspective
Recent activities for paediatric oncology and
anti-cancer medicines for children
• “Policy on determination of condition for PIP” (EMA/272931/2011)
published: criteria for the PDCO to define the paediatric interest
based on unmet needs, mode of action, MedDRA or biological criteria
• PDCO discusses revoking class waivers, taking into account
the evolution of knowledge and science over the last years
• Model oncology PIPs in the works to attract pharmaceutical
companies, to flag subsets with high unmet needs, to quote priorities
• Paediatric oncology task force with experts from community
• “Involvement of children and young people at the PDCO”
for public consultation (EMA/PDCO/388684/2012 )
• PDCO involved in assessments (CHMP) of paediatric trial results
Accessing new drugs - a regulator's perspective
Regulator's perspective for paediatric oncology:
• Oncology PIPs help paediatric oncologists to get medicines for trials
and help children with cancer to get safe and efficacious medicines
• International scientific exchange collaboration required
in view of difficulties in past and present to generate data
• Regulators (EMA / PDCO) open to implement collaboration
• Need to improve information for high-quality PIPs and priorities
Accessing new drugs - a regulator's perspective
• PDCO: Dobrin Konstantinov, Henk van den Berg, Jacqueline Carleer,
Janez Jazbec, Jaroslav Sterba, Koenraad Norga, Paolo Paolucci
• EMA: Agnès Saint Raymond, Ralph Bax, Francesco Pignatti, Lynley
Marshall, Peter Bauer
Accessing new drugs - a regulator's perspective

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