Requirements to enter first-in-human studies Manufacturing ... · Regulation 536/2014 (2019)...

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……


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EMA Committee for Advanced Therapies (CAT)Quality, Safety, Efficacy -> benefit-risk assessment –> Marketing authorisation

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


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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)


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The current process - multinational

Voluntary Harmonisation Procedure (VHP)

ValidationSponsorSubmits Joint decision

VHP


ATMPs

56 - NCA assessment


Simplified and harmonized

Single procedure

Submission to [email protected] (Paul-Ehrlich-Institut

Coordinating entry point)

Joint multinational assessment (rapporteur)


mailto:[email protected]

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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




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Clinical Trial ApplicationExample Paul-Ehrlich-Institut


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


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medicinal products containing genetically modified cellsQuality aspects


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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


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medicinal products containing genetically modified cellsNon-clinical aspects


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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


Efficacy considerations

Matthias Renner

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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

https://data.europa.eu/euodp/en/data/dataset/epar-human-medicines

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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

https://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relevant-advanced-therapy-medicinal-products

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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,…….


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Thank you for your attention


Requirements to enter first-in-human studies Manufacturing ... · Regulation 536/2014 (2019)...

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