.be be . 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 - - EMEA EMEA CHMP
Organiser Organiser 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 Scientific administrators Scientific administrators Giulio Bognolo Giulio Bognolo Secretaries Marco Cavaleri Secretaries Marco Cavaleri Andrea Davies Francesca Cerreta Andrea Davies Francesca Cerreta Maria Isaac Sarka Davis Maria Isaac Sarka Davis Maria d. M. Llosas Sandra Gogo Maria d. M. Llosas Sandra Gogo Merja Heikkurinen Constantinos Ziogas Merja Heikkurinen Constantinos Ziogas
SAWP composition SAWP composition Clemens Mittmann Andrea Laslop Clemens Mittmann Andrea Laslop Christine Gispen- -de Wied de Wied Minne Casteels Christine Gispen Minne Casteels Sif Ormarsdó óttir ttir Christian Schneider Sif Ormarsd Christian Schneider Stefano Vella Jens Ersbø øll ll Stefano Vella Jens Ersb Hans- -Georg Eichler Georg Eichler Fernando de Andrés Trelles Hans Fernando de Andrés Trelles Mira Pavlovic Mira Pavlovic COMP members Sheila Killalea COMP members Sheila Killalea Rembert Elbers John Warren Rembert Elbers John Warren Kate ř ř ina Kub ina Kubá á č č kov ková á Simon Day Kate Simon Day Kerstin Westermark Bertil Jonsson Kerstin Westermark Bertil Jonsson Cristina Sampaio Cristina Sampaio Observers Beatriz Silva Lima Observers Beatriz Silva Lima Dobrin Svinarov Markku Pasanen Dobrin Svinarov Markku Pasanen
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 → 24 members) Modernised operative methods and composition (21 → 24 members) � � Broader and more in- -depth advices depth advices Broader and more in � � 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 up requests Improved follow � � Increased transparency and communication Increased transparency and communication � � – Contacts with patient and HCP organisations Contacts with patient and HCP organisations –
Clock Clock Pre-submission First reporting First reporting Final report Final report start start phase Joint Discussion mtg Final Presentation of new request LOI Report SAWG debriefing Letter Additional expert appointment Revised Joint Revision of request Report -30 -30 0 0 -5 -5 20 30 40 50 60 70 63 SA SA Additional SA SA Additional Meeting 1 Meeting 1 experts Meeting 3 Meeting 2 experts Other Other Other WP WP WP EMEA REVIEW EMEA EMEA CHMP – SAWP EMEA QUALITY of evidence Validation Validation assurance EMEA Peer review Pre-submission meeting With the coordinators CHMP The The New New Scientific Scientific & Appointment of COMP Advice Advice Trail Trail 2 coordinators Letter of intent
EMEA Scientific Advice is blooming ! EMEA Scientific Advice is blooming ! Scientific advice and protocol assistance finalised (including follow-up) 2005 191 2004 109 2003 97 2002 88 2001 69 2000 58 0 50 100 150 200 All SA-PA
New SAWP (2) New SAWP (2) 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)
SAWP transparency & communication SAWP transparency & communication � more opportunities for hearings / discussion meetings more opportunities for hearings / discussion meetings � with Companies with Companies � increased collaboration increased collaboration with patients and HCP with patients and HCP � organisations, academia and Learned Societies academia and Learned Societies organisations, � workshops and think workshops and think- -tank tank meetings on rapidly evolving meetings on rapidly evolving � topics topics Workshop on Biomarkers (16-12-2005)
Biomarkers are a tool for focusing Biomarkers are a tool for focusing drug development programs drug development programs
EMEA EMEA Biomarkers / / surrogate surrogate markers are markers are involved involved in: in: Biomarkers 1. Efficacy Working Party ( Efficacy Working Party (EWP EWP) guidelines ) guidelines 1. • specific therapeutic areas (e.g., osteoporosis) • specific therapeutic areas (e.g., osteoporosis) • statistics : Guideline on Small Populations, on : Guideline on Small Populations, on • statistics Flexible Designs (TBA) Flexible Designs (TBA) 2. Pharmacogenetics Pharmacogenetics Working Party ( Working Party (PGWP PGWP) Briefing ) Briefing 2. Meetings with companies Meetings with companies 3. Scientific advices ( Scientific advices (SAWP SAWP) ) 3. 4. CHMP CHMP Decisions Decisions 4. 5. (future) Conditional Approvals (future) Conditional Approvals 5. 6. Innovative Medicine Think Innovative Medicine Think- -Tank group Tank group 6.
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 2.10 6 /kg CD34 + cells (or an optimal amount) before autotransplantation
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 »
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
PGWP – – Briefing Meetings Briefing Meetings PGWP 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)
CHMP decision making – – B/R assessment B/R assessment CHMP decision making e.g. Oncology products
SAWP - - recent scientific advice recent scientific advice SAWP in Prostate cancer A phase III, randomized, double blind and placebo controlled trial of […] 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 + ).
Conditional approval (1) Conditional approval (1) Regulation EC 726/2004, Art. 14(7) EC 726/2004, Art. 14(7) Regulation « conditional conditional approval approval » » « « following following consultation consultation with with the the Applicant Applicant an an « authorisation may may be be granted granted subject subject to certain to certain authorisation specific obligations specific obligations , to , to be be reviewed reviewed annually annually by by the the Agency. . The The list list of of these these obligations obligations shall shall be be made made Agency publicly accessible [ accessible [indicated indicated in in the the SmPC SmPC]. ]. » » publicly → If → If the the Obligations are Obligations are not not fulfilled fulfilled, marketing , marketing authorisation will will be be withdrawn withdrawn authorisation
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