Regulatory Science leading into the future of medical product innovation the role of research and academia. Beatriz Silva Lima

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2 Regulatory Science leading into the future of medical product innovation the role of research and academia Beatriz Silva Lima University oj Copenhagen November 2016

3 My own History as a Science-Regulator Hybrid Experimental & Lecturing Pharmacology: MoA, therapeutic applications PhD Pharmacology Cellular mechanisms of smooth muscle contractility Role of calcium Modelling replacement of calcium with strontium IP3 as second messenger. Nonclinical Assessor at Infarmed/PT on Pharmacotoxicology (learning by doing!)

4 A Life Long progress: Trainning - Science - Regulation Academia Towards full professorship Towards Full Professor -Since 1997: Trannings - Pharmacotoxicology - Regulatory Masters: -EUDIPHARM (FR) -RAMPS (PT) -MIND (DK) -SafeSciMet (EU) -ECMDC (EU) Regulatory Ftox Assessor Safety Working Party -Chair -CHMP member -SAWP member -CAT member Guidelines: -ICH, Pediatrics, FIH

5 Towards Regulatory Science REGulations SCIence

6 Towards Regulatory Science REGulations SCIence

7 J Young Pharm Vol 2 / No 3; DOI: /

8 TAB08: TGN 1412 BACK ON TRACK "One of the reasons that no good dose determination had been possible was that there was no in vitro assay available where soluble TGN1412 would stimulate PBMCs, Thomas Hu nig, University of Wu rzburg 8

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10 TAB08: TGN 1412 BACK ON TRACK "We've since had the opportunity to use the system to look for a window of concentration where we would not get proinflammatory cytokine release, but we would get the desired effect of regulatory T cell activation, and we found it,. Thomas Hu nig, University of Wu rzburg "At 0.05 μg/ml you can start to detect a low percentage of occupied receptors, and that's also where we can begin to detect the biological response, 10

11 TAB08: TGN 1412 BACK ON TRACK "We took an extra safety measure by not just starting at what we found would be the lowest dose of Treg activation, but going even much lower, going 1,000-fold less than what was used in London in the 2006 study," the team progressively increased TAB08 delivery in volunteers under clinical surveillance until it reached the dose recommended by the RESTORE and receptor occupancy assays: 20-fold lower than the dose from

12 Bial Case: what was missed?

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15 ICH S1 Guidelines under Revision Possible to anticipate results of rodent studies based on Pharmacological classes plus weight of evidence (from literature) plus more inteligent studied (eg in vitro, omics, etc)? (big) regulatory change in carcinogenicity testing requirements!!

16 Innovation-driven Regulatory Chalenges Last 20 Years Biopharmaceuticals: (ICH S6 R1) species relevance challenged Immunogenicity driven limitations Biosimilars : molecualr attributes for immunogenicity Cell and Gene Therapies (ATMPs) Cell and Gene Therapies (ATMPs) species relevance challenged in vivo studies challenged Immunogenicity driven limitations Risk-based approach implemented platform concept under discussion (eg for vectors)

17 Drug Development Success (Arrowsmith, 2012) J Arrowsmith(2012),Nature Reviews Drug Discovery, vol 11: 17 17

18 Search for Causes and Solutions for Attrition Better Science (eg MoA, disease mechanisms) Modified Development Paradigms Better Training (Regulators, Scientists, PATIENTS?) Stronger Dialogue along Development Process Pharmacologists / Toxicologists Preclinical Scientists / Clinical Scientists More Pre-competitive Stakeholders Collaboration: IMI / PSTC

19 Innovative Medicines Initiative The Transformative Platform for Science and Regulations Academia - SMEs - Public Institutions Patients-Regulators

20 Pre-competitive Collaborations: THE TRANSFORMATION? Stakeholders Redefined : - Regulators - Industry (Big & SMEs) - Academics - PATIENTS

21 Molecular databases In silico systems (QSARs) Modelling In vitro systems Imaging Animal / Human Computer Science and Systems etechnologies Patient follow up (eficacy/safety) Patient databases: patient stratifications ipscs Technologies Microphysiological systems Human body on a chip? Omics Innovation Outputs from Pre-competitive Collaborations Human / animalpredictive biomarkers BANKING

22 T R A I N N I N G Discovery Design PK Pharmacodynamics Toxicology Clinical European Lead Factory Open PHACTS K4DD (kinetics for drug discovery) DDmore StemBanCC EBISC etox Liver Toxicity: MIP-DILI Carcinogenicity (MARCAR) EHR4C SAFE-T WEB-RADAR GETREAL REAL LIFE

23 Discovery Design PK Toxicology Clinical T R A I N N I N G Pharmacodynamics European Lead Factory Open PHACTS K4DD (kinetics for drug discovery) DDmore StemBannC EBISC etox Liver Toxicity: MIP-DILI Carcinogenicity (MARCAR) EHR4C SAFE-T Disease specific Diabetes Oncology Autism Alzheimer Asthma Pain Osteorartritis Tuberculosis Product specific WEB-RADAR GETREAL REAL LIFE

24 Pre-competitive Collaborations: Guiding THE Transformation? Dedicated Guidances Needed - for validation of new technologies and tools - for validation of new tests - for samples managing - for managing electronic data - for innovative clinical trials designs To Make Innovation Usable & Accessible Towards Transformed Paradigm?

25 Consequence(s) From Regulatory Reaction into Pro-action

26 Academia: Where are We in this Process? EVERYWHERE!! Research identify disease mechanisms Identify and characterise targets generate and design hits Generate models for research Tgs / disease models/ Human-based models Provide Science and Tools for Regulatory Purposes Contribute for Regulatory Assessments Review /Research on Regulatory Tools and Outcomes Trainning Medicines scientists Regulators PATIENTS

27 BUT: Regulation (slowly) Meets Science Action is needed! Basic Research to take into consideration subsequent regulatory needs eg Interspecies comparisons (Human) Data Collection and Use Data Quality Data reproducibility Data / Samples preservation Tools characterization/validation Applied Research to be compliant with regulatory requirements GMP/GLP principles to be know, understood and applied as possible GRegSciPractice!!

28 Regulatory Agencies: Fundamental Partners in Research AND Strong Alliance with EMA/ National Agencies As Partners in Research is fundamental!

29 Towards the Future of Regulatory Science in Academia To be Widely Recognised To be widely Implemented accross Academia To be made accessible to all disciplines and Society To incorporate Students, Researchers and Patients as ultimate beneficiaries. Academic Reg Sci Centers: To Become Rule Rather than Exception?

30 THANK YOU