requirements to enter first-in-human studies manufacturing ... · regulation 536/2014 (2019)...
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www.pei.de Requirements to enter first-in-human
studies
Manufacturing, quality assurance, non-
clinical data
Regulatory Workshop on the Development of CAR T cells 30.1.2020
Martina Schüssler-Lenz, M.D.
Paul Ehrlich Institute
Chair, Committee for Advanced Therapies, EMA
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Disclaimer
The views expressed in this presentation are the personal views of the
author and may not be understood or quoted as being made on behalf
of the European Medicines Agency or the Paul-Ehrlich-Institut
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Advanced Therapy Medicinal Products (ATMP)
Regulation (EC) No 1394/2007
Martina Schüssler-Lenz
http://www.biotechnologie.dehttp://www.authormapper.com
Recombinant nucleic acid Pharmaco-immunological… Regeneration, repair….
ATMPs are medicinal products
Are authoriszed in EU via the centralized procedure
Are assessed by the Committee for Advanced Therapies (CAT)
GMP, GLP, GCP adapted to ATMPs
Gene therapye.g.CAR T cells Somatic cell therapy Tissue engineered product
Dt. Ärzteblatt 11.2018
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Differential responsibilities
Clinical Trial Authorisation vs. Marketing Authorisation
National vs centralized
Clinical Trial Authorisation
Member states (national)
PEI, BfArM, AEMPS,
ANSM….
Ethics Committees
Competent authorities for
Environmental Risk
Assessment
Marketing Authorisation
European Medicines Agency
Committees
CAT, CHMP, PRAC, PDCO,
COMP……
Martina Schüssler-Lenz
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EMA Committee for Advanced Therapies (CAT)Quality, Safety, Efficacy -> benefit-risk assessment –> Marketing authorisation
Page 5
CAT
Draft opinion Final opinion
CHMP*
European Commission
Authorisation for placing
ATMPs on the market in the
European Union
*Committee for Medicinal Products for Human Use4
CAT rapporteurs CHMP coordinators
Martina Schüssler-Lenz
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Two CAR Tcell products have been authorised (8.2018)
Axicabtagene ciloleucel, Yescarta®
Tisagenlecleucel, Kymriah®
Seven CAR Tcell products are receiving enhanced EMA support in
the PRIority MEdicines Scheme
Cluster around CD19 and BCMA targeting CAR T cells
436 ongoing trials world wide
49 registered in EU (10.2019, ClinicalTrials.gov)
CAR Tcell developments in the European Union
Geographical Distribution of CAR T cell trials
Updated from as of 30.10.2019 :
Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ, EMBO Mol Med , 8 2017.
436 ongoing trials world wide ←w/o LFU→
• including 31 multi-national trials (≥2 countries)
• Europe is counted as one country
• for some trials no information on trial sites exist
49 registered trials in Europe
• including 25 multi-national trials (≥2 countries)
LFU = long-term follow-up
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Clinical Trial Application
The current process - multinational
Assessment
traditional
ValidationEudraCT
SponsorSubmits
Decisions
Non-harmonized
Separate procedures
Submissions to National Competent Authorities of member states
Courtesy Dr. Reischl
ATMPs
Germany (Paul-Ehrlich-Institut)
90 days - NCA assessment
90 days – Sponsor`s answers to questions (grounds for non-acceptance)
Martina Schüssler-Lenz
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Clinical Trial Application
The current process - multinational
Voluntary Harmonisation Procedure (VHP)
ValidationSponsorSubmits Joint decision
VHP
Courtesy Dr. Reischl
ATMPs
56 - NCA assessment
10 days – Sponsor`s answers to questions (grounds for non-acceptance)
Simplified and harmonized
Single procedure
Submission to [email protected] (Paul-Ehrlich-Institut
Coordinating entry point)
Joint multinational assessment (rapporteur)
Martina Schüssler-Lenz
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Clinical Trial Application
The future process
Regulation 536/2014 (2019)
ValidationEU Database
SponsorSubmits Decision
general
national
Harmonized
Single procedure
Submission to EU Portal
Joint multinational assessment (rapporteur)
ATMPs
45 plus 50 days - NCA assessment
12 days – Sponsor`s answers to questions (grounds for non-acceptance)
Martina Schüssler-Lenz
Courtesy Dr. Reischl
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Clinical Trial ApplicationExample Paul-Ehrlich-Institut
Martina Schüssler-Lenz
Documentation required for:
Quality and manufacturing data
Non-Clinical data
Environmental risk assessment
Clinical Trial documentation
Benefit-risk assessment
Scientific
assessment
Approval includes
authorisation for deliberate release
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Defines scientific principles and provides guidance for the
development and evaluation of CAR Tcells, marketing authorization
and clinical trials
Adresses quality, non-clinical, clinical aspects, pharmacovigilance
and Environmental Risk Assessment (ERA)
End of external consulation phase 31.7.2019
CAT review and finalisation in 2020-> CAT work plan
Guideline on quality, non-clinical and clinical aspects of
medicinal products containing genetically modified cells
https://www.ema.europa.eu/en/quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically-modified-cells
Martina Schüssler-Lenz
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Guideline on quality, non-clinical and clinical aspects of
medicinal products containing genetically modified cellsQuality aspects
Martina Schüssler-Lenz
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Manufacturing and control of CAR-T cells
Transfer via
• retro/lentiviral vector, AAV
• mRNA
• transposons
• gene editing
Matthias Renner
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Primary starting material considerations
Donor testing
• for cell starting material (Directive 2004/23/EC and 2006/17/EC or 2002/98/EC based, but different requirement in EU Member States possible)
• data are mandatory, even in autologous setting, to be aware of cross-contamination risks and safety concerns for operators
• infection-positive material is not excluded from manufacturing.
Donor to donor variations ?
Impact of patient pre-treatment regimes for cell starting material ?
Standardisation of primary cell collection ? (between centers)
Validation of transportation to the manufacturing site
Pooling of cells derived from multiple, subsequent aphereses
Comparability of fresh and frozen cell material in case of re-production
Pros and cons for introducing acceptance limits for autologous material
Matthias Renner
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Process validation using material from healthy donors
Ethical concerns regarding process validation with patient material
Limited sourcing option from patients (severely ill, pediatric)
But
• could mobilisation be performed in same manner (for stem cell products)?
• potential differences in
Cell type composition before and after expansion
Cell growth potential during expansion phase
Transduction efficiency and transgene expression Impact on
dose
Validation strategy could be based on combination of historical data, process development,
characterization and comparability studies, cells from healthy individuals, and continued
process verification on patient samples
Matthias Renner
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Manufacturing and control of CAR Tcells
Sterility, Endotoxin, Mycoplasma
Appearance
Identity
Number of CD3+, transduced (therapeutically active) cells
Cell viability
Percent transduction (CAR expressing cells)
Biological activity (Inf-g release, cytotoxicity assay)
Average vector copy number/cell
% cell impurities (NK, Monocytes, B-(tumor) cells, CD34+ cells)
Residual beads, media components, (vector particles)
[Absence of RCV or modifying enzymes (CAS nuclease,
TALENs, transposase, ZFNs)]
Absence of insertional oncogenesis
Typical release parameter
Matthias Renner
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Comparability studies
According to ICH Topic Q5E principles
To be assessed for risk to affect quality of final product
Healthy donor material acceptable
Split sample approach favored
Product and process changes -> comparability are one of the main
issues in translating CAR Tcells from bench -> bedside -> marketing
authorisation
Changes to the manufacturing process
Martina Schüssler-Lenz
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Guideline on quality, non-clinical and clinical aspects of
medicinal products containing genetically modified cellsNon-clinical aspects
Martina Schüssler-Lenz
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pharmacodynamic “proof of concept” in relevant non-clinical model(s)
biodistribution of the MP
identification of potential target organs of toxicity
identification of potential target organs of biological activity
identification of toxic effects including immunogenicity and tumorigenicity
recommendation on initial dose and dose escalation scheme to be used in
the proposed clinical trial
identification of parameters to be monitored in the proposed clinical trial
identification of patient eligibility criteria (inclusion/exclusion criteria)
Non-clinical studies
Goals
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Challenges for non-clinical studies with CAR Tcells
Human cell-based IMP with immunological MoA
No suitable animal model available:
xenograft model:
• impact of immune system not analysable
• GvHD reduced observation period
• on-target, off-tumor and off-target reactivity not analysable
• lack of stimulus for T-cell activity / expansion reducedobservation period
syngenic model:
• analysing different CAR/TCR T-cells
human HLA transgenic model:
• different HLA-expression pattern and strength compared to human situation
Matthias Renner
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Pharmacology studies
Non-clinical studies
Efficacy considerations
Matthias Renner
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Non-clinical studies
Safety considerations
Single (or repeated) dose toxicity study in a relevant animal model:
CARs: relevant animal model depends on cross-reactivity of thescFv
Evaluation of antigen expression in non-target human organs and tissues
Relevant clinical experience
On-target/off-tumor toxicity:
Evaluation of cross-reactivity with similar epitopes
Relevant clinical experience
Off-target toxicity:
Matthias Renner
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Points to consider
Use suitable animal models, complement with in vitro data and
provide scientific justification
Use batches that are comparable to clinical batches
Support and justify with data from other CAR Tcells
European public assessment reports (EPARs) of Yescarta and
Kymriah as information source
https://data.europa.eu/euodp/en/data/dataset/epar-human-
medicines
Non-clinical evaluation of CAR Tcells
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EMA scientific guidelines
EMA homepage
Human regulatory
Scientific guidelines
Mulstidisciplinary
General questions
e.g. Paul-Ehrlich-Institut „kick-off“ meetings for early
developments
Product-specific questions
Scientific national advice, face-to-face meetings
EMA written scientific advice
Regulatory and scientific guidance and support
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Last but not least….The Committee for Advanced Therapie`s recent support to developers
Guidelines and other documents related to CAR-Tcells
New: Guideline on requirements for investigational ATMPs
New: Questions and answers on comparability considerations for
advanced therapy medicinal products (ATMP)
New: Questions and answers on use of out-of-specification batches
of authorized cell/tissue-based ATMPs
New: Common application form for GMO related aspects CAR-
Tcells in clinical trials
Revision: Guideline on safety and efficacy FU and risk management
for ATMPs
Revision: Guideline for genetically modified cells incl. Special
considerations CAR-Tcells
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GMP, GLP, GCP for ATMPs,…….
Martina Schüssler-Lenz
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Thank you for your attention
Martina Schüssler-Lenz