SLIDE 1 Biomarkers in the new European Biomarkers in the new European regulatory environment regulatory environment
Bruno FLAMION, MD, PhD Bruno FLAMION, MD, PhD Chair, Scientific Advice Working Party (SAWP) Chair, Scientific Advice Working Party (SAWP) CHMP CHMP -
EMEA
. .be be
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EMEA Scientific Advice EMEA Scientific Advice Working Party Working Party
Spiros VAMVAKAS, MD, PhD Spiros VAMVAKAS, MD, PhD Acting Deputy Head of Sector Acting Deputy Head of Sector
Organiser Organiser
Secretaries Secretaries Andrea Davies Andrea Davies Sarka Davis Sarka Davis Sandra Gogo Sandra Gogo Merja Heikkurinen Merja Heikkurinen Scientific administrators Scientific administrators Giulio Bognolo Giulio Bognolo Marco Cavaleri Marco Cavaleri Francesca Cerreta Francesca Cerreta Maria Isaac Maria Isaac Maria d. M. Llosas Maria d. M. Llosas Constantinos Ziogas Constantinos Ziogas
SLIDE 4 SAWP composition SAWP composition
Clemens Mittmann Clemens Mittmann Christine Gispen Christine Gispen-
de Wied Sif Ormarsd Sif Ormarsdó óttir ttir Stefano Vella Stefano Vella Hans Hans-
Georg Eichler COMP members COMP members Rembert Elbers Rembert Elbers Kate Kateř řina Kub ina Kubá áč čkov ková á Kerstin Westermark Kerstin Westermark Observers Observers Dobrin Svinarov Dobrin Svinarov Andrea Laslop Andrea Laslop Minne Casteels Minne Casteels Christian Schneider Christian Schneider Jens Ersb Jens Ersbø øll ll Fernando de Andrés Trelles Fernando de Andrés Trelles Mira Pavlovic Mira Pavlovic Sheila Killalea Sheila Killalea John Warren John Warren Simon Day Simon Day Bertil Jonsson Bertil Jonsson Cristina Sampaio Cristina Sampaio Beatriz Silva Lima Beatriz Silva Lima Markku Pasanen Markku Pasanen
SLIDE 5 New SAWP (1) New SAWP (1)
New Framework for Scientific Advice New Framework for Scientific Advice
Regulation (EC) 726/2004 Regulation (EC) 726/2004
SAWP SAWP
- Modernised operative methods and composition (21
Modernised operative methods and composition (21→ →24 members) 24 members)
Broader and more in-
depth advices
- Enlarged field of activities
Enlarged field of activities – – Advices for companies, especially Advices for companies, especially SMEs SMEs – – Cooperation with WHO Cooperation with WHO
Improved follow-
up requests
- Increased transparency and communication
Increased transparency and communication – – Contacts with patient and HCP organisations Contacts with patient and HCP organisations
SLIDE 6 Final report Final report 63 60 50 70
Joint Report Discussion mtg SAWG debriefing SA Meeting 3 Additional experts Other WP Final Letter Revised Joint Report CHMP & COMP CHMP – SAWP EMEA Peer review
40 30
Pre-submission phase
Clock Clock start start First reporting First reporting
EMEA Validation SA Meeting 1 EMEA QUALITY assurance
20
EMEA REVIEW
SA Meeting 2 Additional experts Other WP Other WP Appointment of 2 coordinators LOI EMEA Validation Revision of request Presentation of new request Additional expert appointment Pre-submission meeting With the coordinators
Letter of intent SA Meeting 1
The The New New Scientific Scientific Advice Advice Trail Trail
SLIDE 7 Scientific advice and protocol assistance finalised (including follow-up) 97 109 191 58 69 88 50 100 150 200 2000 2001 2002 2003 2004 2005
All SA-PA
EMEA Scientific Advice is blooming ! EMEA Scientific Advice is blooming !
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Special emphasis will be given to: Special emphasis will be given to:
Products intended for the new mandatory centralised procedure Emerging and new therapies Safety aspects → RMP (insufficient advice so far) Conditional approval : a complex challenge Significant clinical benefit (Protocol Assistance for designated Orphan Medicinal Products)
New SAWP (2) New SAWP (2)
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- more opportunities for hearings / discussion meetings
more opportunities for hearings / discussion meetings with Companies with Companies
increased collaboration with patients and HCP with patients and HCP
- rganisations,
- rganisations, academia and Learned Societies
academia and Learned Societies
workshops and think-
tank meetings on rapidly evolving meetings on rapidly evolving topics topics
SAWP transparency & communication SAWP transparency & communication Workshop on Biomarkers (16-12-2005)
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Biomarkers are a tool for focusing Biomarkers are a tool for focusing drug development programs drug development programs
SLIDE 11 1.
- 1. Efficacy Working Party (
Efficacy Working Party (EWP EWP) guidelines ) guidelines
- specific therapeutic areas (e.g., osteoporosis)
specific therapeutic areas (e.g., osteoporosis)
statistics: Guideline on Small Populations, on : Guideline on Small Populations, on Flexible Designs (TBA) Flexible Designs (TBA) 2.
Pharmacogenetics Working Party ( Working Party (PGWP PGWP) Briefing ) Briefing Meetings with companies Meetings with companies 3.
Scientific advices (SAWP SAWP) ) 4.
CHMP Decisions Decisions 5.
- 5. (future) Conditional Approvals
(future) Conditional Approvals 6.
- 6. Innovative Medicine Think
Innovative Medicine Think-
Tank group
EMEA EMEA
Biomarkers Biomarkers / / surrogate surrogate markers are markers are involved involved in: in:
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EWP guidelines (1) EWP guidelines (1)
CPMP/EWP/197/99
Endpoints in clinical studies with haematopoietic growth factors for mobilisation of autologous stem cells
Ph II primary endpoint & Ph III secondary endpoint Percentage of patients achieving the minimal amount of 2.106/kg CD34+ cells (or an optimal amount) before autotransplantation
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EWP guidelines (2) EWP guidelines (2)
CPMP/EWP/552/95 Rev. 2 for consultation
Evaluation of new medicinal products in the treatment of primary osteoporosis
Ph II primary endpoint & endpoint for Ph III bridging studies BMD and/or biochemical markers (osteocalcin, BSAP, N- or C- telopeptide of type I collagen) For bridging studies, « the time-course of changes in biomarker should recapitulate the time-course observed for the original dosing regimen »
SLIDE 14 EWP guidelines (3) EWP guidelines (3)
CPMP/EWP/83561/05 for consultation
Clinical trials in small populations
Covariate adaptive allocation methods (incl. minimisation)
- Ex. [Falk 2002, immediate vs delayed radiotherapy in SCLC]:
minimisation procedure stratified by (1) clinician - 24 strata, (2) histology - 4 strata, (3) presence of M+ - 2 strata, (4) WHO performance status - 4 strata; → 768 strata. Sequential designs often reduce the size of populations needed n-of-1 trials : the unit of randomisation is the intervention rather than the patient ; possible crossover at end of treatment
SLIDE 15 Main topics of discussions
- 1. Chosen design and rationale
- 2. Population selected for PG studies (variables related to
phenotype)
- 3. Size of selected population ; power to detect association
- 4. Statistical methodology ; correction for multiple testing
- 5. Positive and negative predictive values of PG biomarkers
(clinical trials experience)
- 6. Assumptions on clinical utility (benefit in using predictive PG
testing vs other predictive biomarkers ; use of PG biomarker as segregation marker)
PGWP PGWP – – Briefing Meetings Briefing Meetings
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e.g. Oncology products CHMP decision making CHMP decision making – – B/R assessment B/R assessment
SLIDE 17 SAWP SAWP -
recent scientific advice in Prostate cancer
A phase III, randomized, double blind and placebo controlled trial
- f […] in men with progressive (defined as two consecutive PSA
rises of more than 1 ng/mL and at least 90 days between measurements), high risk (defined as PSA ≥ 8 ng/mL or PSA doubling time of ≤ 10 months) hormone refractory prostate
- cancer. The proposed primary endpoint is […]
CHMP agrees with the proposed study design, including patient selection, choice of endpoints, dosing regimen and statistical
- approach. In case of clinical significant superiority and beneficial
toxicity profile of […] versus placebo CHMP supports its approval for the target indication (PC at high risk of bone M+).
SLIDE 18 Conditional approval (1) Conditional approval (1) Regulation Regulation EC 726/2004, Art. 14(7) EC 726/2004, Art. 14(7) « « conditional conditional approval approval » »
« « following following consultation consultation with with the the Applicant Applicant an an authorisation authorisation may may be be granted granted subject subject to certain to certain specific specific obligations
, to be be reviewed reviewed annually annually by by the the Agency Agency. . The The list list of
these obligations
shall be be made made publicly publicly accessible [ accessible [indicated indicated in in the the SmPC SmPC]. ]. » » → → If If the the Obligations are Obligations are not not fulfilled fulfilled, marketing , marketing authorisation authorisation will will be be withdrawn withdrawn
SLIDE 19 Conditional approval (2) Conditional approval (2) Clinical Clinical criteria criteria inclusively inclusively required required to to grant grant conditional conditional approval approval (Art. 4) (Art. 4)
1. 1. Demonstration Demonstration of
public health health interest interest of
product, , including including unmet unmet medical medical need need 2.
- 2. Demonstration of positive B/R balance, based on
Demonstration of positive B/R balance, based on evidence but pending completion of further studies evidence but pending completion of further studies → → presumed presumed positive B/R balance positive B/R balance → → Specific Specific Obligations = Obligations = further further studies studies
SLIDE 20 Conditional approval (3) Conditional approval (3) Presumed Presumed positive B/R balance positive B/R balance based based on
either/or: /or:
1.
(Reasonably Reasonably) ) likely likely surrogate surrogate endpoint endpoint if if validated validated surrogate surrogate (effect on surrogate predicts (effect on surrogate predicts the desired clinical benefit) the desired clinical benefit): : → → this this is is not not conditional conditional approval approval but normal M.A. but normal M.A. 2.
Interim data data ( (planned planned analysis analysis): ):
primary or
secondary endpoint endpoint
likely surrogate surrogate or on hard
endpoint 3.
Selective approval approval (in a (in a smaller smaller population) population) based based on
biomarker reflecting reflecting activity activity of
the product product
SLIDE 21 Innovative drug development Innovative drug development
- Review Strategic Research Agenda (EC 7
Review Strategic Research Agenda (EC 7th
th Program)
Program)
- Hearings with big and small
Hearings with big and small pharma pharma (12 (12-
2005 to 06-
- 2006) on evolving science, new technologies, new
2006) on evolving science, new technologies, new methodologies methodologies
Hearings with academia
Review of guidelines
EMEA think EMEA think-
tank group
SLIDE 22 Word of conclusion Word of conclusion Introduction to the workshop Introduction to the workshop
Decisions taken during the process of marketing Decisions taken during the process of marketing authorisation authorisation of medicinal products are always
- f medicinal products are always
- uncertain. Evidence that is “beyond doubt” never
- uncertain. Evidence that is “beyond doubt” never
- exists. Long life to the biomarkers.
- exists. Long life to the biomarkers.
