Advanced Therapy Medicinal Products (ATMP)

Transkript

1 Avanserte terapier Regulatorisk høstmøte, 7. oktober 2009 Marit Hystad, PhD Medlem av Committee for Advanced Therapies (CAT) Seniorrådgiver, Statens legemiddelverk

2 Advanced Therapy Medicinal Products (ATMP) Gene therapy medicinal products Somatic cell therapy medicinal products Tissue engineering products Genetically modified cells Nat Biotechnol 2005, 23(7)

3 Regulation (EC) No 1394/2007 Ny EU-forordning Gjeldene fra 30. desember Vedtatt i EU-kommisjonen: For å møte behovet for et bedre regelverk for forskning og utvikling av ATMP Hensikt: Sikre at pasienter i hele EU/EØS-området får tilgang til nye, sikre ATMP er gjennom et felles regelverk

4 Regulation (EC) 1394/2007 Viktigste punkter Dannelsen av Committee for Advanced Therapies (CAT) ved det Europeiske legemiddelverket (EMEA) Sentralisert godkjenning av ATMP Prinsippene for eksisterende lovgivning for medisiner skal også gjelde for ATMP Markedsføringstillatelse Kvalitet, effekt & sikkerhet Overvåkning av produktet etter markedsføring Vitenskapelig rådgiving på et tidlig stadium til små og mellomstore bedrifter som utvikler ATMP

5 Sammensetning av CAT Chair: Dr. C. Schneider

6 Ekspertise i CAT CAT dekker de vitenskapelige områdene som er relevant for ATMPer PhVig 5% Med Dev 5% surgery 1% Gene Therapy 19% Ethics 8% Biotech 24% Tissue Engineering 17% Cell Therapy 21%

7 Oppgaver for CAT 1. Evaluering av markedsføringstillatelse for ATMP Kvalitet, effekt, sikkerhet, Phvg, miljøsikkerhet Første MT er gitt: CondroCelect. Flere produkter under evaluering 2. Klassifisering av ATMP Fjorten produkter vurdert, flere under vurdering 3. Sertifisering av kvalitet/pre-kliniske data (small and medium-sized entreprises (SME)) Første prosedyre starter i oktober Vitenskapelig rådgiving (samarbeid med Scientific Advice Working Party (SAWP)) Rådgivning til tolv produkter, flere under vurdering

8 ATMP med nasjonal tillatelse i et medlemsland Må søke om markedsføringstillatelse sentralt i EMEA ( i hht den nye forordningen Reg. 1394/2007) Genterapi Celleterapi MA klar innen slutten av 2011 Tissue engineering MA klar innen slutten av 2012

9 Survey on ATMP 2009 On member states market/under clinical evaluation Number of medicinal products on market under evaluation 0 Tissueengineered Celltherapy Gene therapy Combination Medicinal products

10 Utfordringer med ATMP? Utviklere Myndighetene

11 Challenges with cell-based medicinal products Cells are complex systems Cells are dependent on their (micro-)environment - Species-specificity - Disease-specificity Cells are reactive to their environment Cell cultures can become heterogeneous Cells might de-differentiate (e.g. during longer cell culture) Cells might migrate ( biodistribution ) => Regulatory consequences: Need for adequate characterization but also necessity to accept limitations

12 Challenges with cell-based medicinal products Non-clinical evaluation A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies)*. *NfG on preclinical safety evaluation of biotechnology derived pharmaceuticals (CPMP/ICH/302/95; ICH S6) - Cell surface molecules (receptors, integrins, ) - Secreted factors like cytokines

13 Challenges with cell-based medicinal products Example: Adult human stem cells for tissue repair (in-vitro expanded, non-modified) in an autoimmune disease - Stem cells grow exponentially - Stem cells can differentiate to different pathways (e.g., osteogenic, myogenic, adipogenic, neurogenic) dependent on microenvironment Problem: Can (theoretically) transform to malignant clones

14 Challenges with cell-based medicinal products What toxicology to expect? - Behaviour at site of injection (De-differentiation / wrong differentiation) - Behaviour at distant sites (e.g. after migration to unwanted sites) Limitations of non-clinical models - Cells react species-specifically (nothing might happen in animals when no interaction) - Cells are immunogenic Immune response of animal might cause immunotoxic effects that would not happen in patients in an autologous setting (=> artifacts) -Immune response of animal could eliminate cells => masking of adverse events

15 Challenges with cell-based medicinal products Possible ways out: Use of immunoincompetent animals (e.g. BALB/C SCID mice) Advantage: Cell-based product can be tested including impurities etc. Disadvantage: Relevance of the data? Toxicology data might not be predictive / informative at all Use off a homologous model (e.g. mouse adult stem cells

16 The homologous model Classically used with monoclonal antibodies Human(ized) anti-human-cd28 monoclonal antibody Rat anti-rat-cd28 monoclonal antibody

17 Non-clinical development: Principles How to best test the product in animals? CBMP are complex, relevance includes: Cell surface molecules (receptors, integrins, ) Secreted factors like cytokines Possibility 1: Test the CBMP in animals Advantage The actual MP is tested, including all impurities etc Disadvantage: Not all (if any) interactions are similar to humans Possibility 2: Use a homologous product Advantage All interactions are relevant(?) (pharmacology toxicology) Disadvantage: Not the actual MP is tested

18 Article: Challenges with Advanced Therapy Medicinal Products and how to meet them: The European Committee for Advanced Therapies (CAT). Committee for Advanced Therapy (CAT) and the CAT Scientific Secretariat, European Medicines Agency. Nature Reviews Drug Discovery, oct/nov 2009

19 Advanced Therapies are threesome Quality Non-Clinical - Impurities - Cells: Culture conditions and their impact on differentiation - ( ) - tissue cross-reactivity? - unwanted biodistribution? - toxicity? B R I D G I N G Clinical - additional safety measures required? - immunogenicity

20 Advanced Therapies are doublethreesome Science - (see above) - How to find the correct regulatory routes for guidance documents (e.g. cell-based tumour vaccines) -How to deal with products that have already been used without evidence? - Regulation of long-term follow-up of efficacy Regulation B R I D G I N G Ethics - How to perform first-in-human trials? - How to deal e.g. with the risk of inserational mutagenesis?

21 CAT ønsker å samarbeide Interesserte organisasjoner Møte 2-3 ganger per år - første møte i september på EMEA Eks: German Pharmaceutical Industry Association, Internal Society for Cellular Therapy og Karolinska University Hospital (33 organisasjoner representert) Fokus på Akademia ATMPer utvikles ofte her - behov for bedre tilrettelegging Reflection papers Condrocytes-containing products Stem cell products Ekspertgruppe ved Statens Legemiddelverk Forankring i det vitenskaplige miljøet i Norge

22 Innovation Task Force (ITF) Mandat og Rolle ved EMEA: Gi støtte til medisinsk innovasjon i EU Forum for tidlig dialog med søkere Utveksle informasjon «Briefing meetings» Regulatorisk rådgivning Guiding tidlig i utviklings prosessen Vitenskaplige komiteer (CHMP, CAT) Kvalifiserer produktet for EMEAs prosedyrer?

23 SME Office Small and medium-sized enterprises (SMEs) Rolle ved EMEA: Fremme innovasjon og utvikling av nye medisinske produkter (mennesker og dyr) Ser på de spesielle behov som er aktuelle for mindre firmaer (Ex: Reduksjon i kostnader ved å søke ukike prosedyrer) Ny User Guide for SMEs sendt ut for konsultasjon

24 Challenge: Balanced view Hurdles should neither be too high nor too low. To develop an ATMP is not an excuse for an immature dossier or to neglect regulatory standards.

25 Takk for oppmerksomheten! Marit Hystad

26 Unntak fra Reg. 1394/2007 The hospital exemption : ATMP prepared on a non-routine basis According to specific quality standards Used within the same member state in a hospital Exclusive professional responsibility of a medical practitioner In order to comply with an individual medical prescription for a custom made product for an individual patient Statens legemiddelverk vil avgjøre tillatelser for denne type produkter Regulatorisk krav vil basere seg på EMEAs retningslinjer

27 Representanter for klinikere European Group for Blood and Marrow Transplantations Dietger Niederwieser (Member) Per Ljungman (Alternate) European Society of Gene and Cell Therapy George Dickson (Member) Thierry Van den Driessche (Alternate)

28 Evaluering av ATMP To utrederland utpekes av CAT/CHMP: ASSESSMENT TEAM 1 Rapporteur ASSESSMENT TEAM 2 Co-Rapporteur Eksperter Eksperter Utreder på vegne av fellesskapet Øvrige medlemsland kan kommentere/bidra underveis

29 Europeisk samarbeid Nasjonale legemiddelmyndigheter jobber i nettverk EØS-avtalen 2000: Norge med som nesten EU-medlem European Medicines Agency CHMP Committee for Medicinal Products for Human Use

30 Sentral legemiddelforvaltning i EU European Commission EMEA European Medicines Agency COMP CAT CHMP CVMP PDCO SAWP PhVWP Diverse andre arbeidsgrupper