Preparation and Management of Phase I-Studies in … · 20/20 CABG patients ... derived from...

Preparation and Management of Phase I-Studies in Stem Cell Therapy

Dr. Gudrun Tiedemann, Rostock, Germany

Dr. Dirk Sawitzky, Leipzig, Germany

AGAH – 20th Anniversary, Workshop 5

April 1, 2011

Reference and Translation Center for Cardiac Stem Cell Therapy (RTC)

— Research Center— Translation Center— Study Center

- founded in 2008 at Rostock University by Prof. Gustav Steinhoff

- financed by BMBF, M-V and industrial partners

2© 2011 RTC Rostock

Basic researchstem cell modification (viral/non viral vectors, magnetic nanoparticles)stem cell biology (miRNA)pathomechanisms, myocardial repair

Pre-/non-clinical researchquality/safety/efficacy issues for stem cell-based medicinal products, optimization programs, animal models,administration technologies

RTC – RegMed Research Concept

Clinical researchclinical trials/REGISTRY-programs in cardiovascular indications

different stem cell populations regenerative compoundscombinations


Clinical Trials

Translation

CD133+ MSC Substances(e.g. EPO) Combinations

GLP

GCP

RTC – Development Strategy

ManufacturingGMP

Research4© 2011 RTC Rostock

RTC –Experience with CD133 +-BMSCs (adult, autologous, primary)

Phase I/II clinical feasibility and safety study (6/01-3/03)

15 CABG patients (0,5-5Mio CD133 +-BMSC): no cell-related complications in long-term analysis, cardiac perfusion improvedStamm C et al. Lancet 2003,361:45

Phase II prospective RCT (4/03-7/05)

20/20 CABG patients (1-5Mio CD133+-BMSC): better LVEF and perfusion than CABG only, safety confirmedYerebakan et al, Cell Transplantation 2007, Stamm et al. CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac

Cardiov Surg, 52(3):152-8; 2004, Stamm et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic

ischemic heart disease: safety and efficacy sturdies. J Thorac Cardiov Surg, 133(3):717-25; 2007

Phase III multicenter RCT, double blinded (10/09-ongoing)75/75 CABG patients (0,5-5Mio CD133+-BMSC): better LVEF and perfusion than CABG only, safety confirmed

REGISTRY-program since 2001 (long term safety in humans)

90 patients, different indications, no related AEs, morbidity, QoL

Quality-/safety tests, animal models


Stem cells – source for therapies

definition stem cells (SC) cells with extensive proliferation capacity and self-renewing capacity

capable of proliferation as stem cells in an undifferentiated form

capacity to generate multi-lineage differentiation

various (SC) types

isolated from different tissues of the human body

source for therapies for diseases or repair/ regeneration of damaged or lost tissue

regulated in the EU as Medicinal Products (MPs)

classified mostly as ATMP

inhomogeneous product group with different risks

specific regulatory requirements


Preparation of Phase I-studies in SC-therapy

cell typ• source/procurement• Isolation/processing• expansion/manipulationindication

classification• ATMP• not-ATMPregulatoryrequirements

risk estimationpre-clinical/clinical requirements• quality• safety• efficacy

authorization• clinical trials


authorization• procurement• manufacturing/

processing

SC-types differentiation potential & clinical experience

totipotent ESC (embryonic stem cells): derived from blastocysts, differentiation capacity for every cell typ and for a functional organism (ethically contovers!) ESCs for therapy: in vitro established cell lines (pluripotent!), allogenic concepts, immunogenicity („therapeutic cloning“), teratoma forming high risk, first safety trial in US in paraplegia

pluripotent iPS (induced pluripotent stem cells): derived from reprogrammed somatic cells “artificial stemness”, high differentiation capacity for every cell type but not for a functional organism iPS for therapy: autologous concepts, reprogramming errors and genomic instability/ epigenetic control not yet technically mature, many features like hESC high risk, first trials in planning phase

multipotent „adult SCs”: derived from intrinsic SC-pool (MSC, HSC: lifelong existing), stemness and differentiation capacity for a limited number of cell types (typically nearest relationship) adult SCs for therapy: different types/subpopulations, primary cells/expanded cells/ manipulated cells, autologous/allogenic concepts different (lower) risk, most extensively used for therapeutic purposes, many clinical trials


Adult SC - types

Haematopoietic progenitor/stem cells (HSCs)in bone marrow (BM), circulating blood, also in placental or cord blood,primary cells, mixed cell populations (MNCs), subpopulations (specific marker) many clinical trials, autologous concepts (or careful HLA-matching)

Mesenchymal stromal/stem cells (MSCs)in BM , adipose tissue and other tissues, adherent to plastic, specific surface antigen expression, multipotent differentiation potential, can differentiate towards mesenchymal lineages in clinical trials, generally considered as immune privileged (allogenic concepts possible)

Tissue-specific progenitor cells limited differentiation capacity for few cell types, specific to tissue

In Europe all preparations are regulated as MPs, classified mostly as ATMP!









processing

Advanced Therapy Medicinal Products (ATMP)

SCT (somatic cell therapy medicinal product): treating, preventing or diagnosing a disease

TEP (tissue engineered product): regenerating, repairing or replacing a human tissue (+combination products)

active substance: cells or tissues

substantial manipulated so that characteristics, functions or

structural properties have been altered or

that are not intended to be used for the same essential function(s) in

the recipient and the donor (“not homologous use”)

GT (gene therapy medicinal product): regulating, repairing, replacing, adding or deleting a genetic sequence

active substance: recombinant nucleic acid

11© RTC Rostock

ClassificationAdvanced Therapy Medicinal Products (ATMP)

SC preparations that are substantially manipulated and /or intended to be used not for the same essential function in the recipient as in the donor “not homologous use” are regulated since end of 2008 by the Regulation EC 1394/2007

Gustav Steinhoff (Ed): Regenerative Medicine – form Protocol to Patient, Springer 2011, P. 946 (Tiedemann, Sethe)

© 2011 RTC Rostock

EU regulation since 2008


© 2011 RTC Rostock

Integration of ATMP-Regulation into the European regulatory framework


© 2011 RTC Rostock

Germany

PEI, regional authorities (manufacturing), (BfArM)

EMA-CAT

„briefing“

„Classification procedure“

„Scientific Advice“

SME Incentives (Certification)

Regulatory support


SC-MPs: risk-based approach

Degree and kind of manipulation and intended use determine the risk:


adult SCs (intrinsic SC-pool): multipotent

iPSC(pluripotent)

ESC(pluri-potent)

primary SCs (HSC, MSC, MNC)

(may be not ATMP)

expanded (cell lines) SCs (MSC)

manipulated/ preconditioned SCs (HSC, MSC)

genetically manipulated SCs (HSC, MSC)

in vitro reprogrammed stemness

in vitro established cell lines








processing

Pre-/non-clinical requirements for SC

Quality considerations

starting material

manufacturing process/validation

characterisation/QC

Identity

Purity

Potency

Tumourigenicity/genom stability


Pre-/non-clinical requirements for SC

Non-clinical considerations animal models

biodistribution, tumourigenicity, differentiation in vivo,

immune rejection

Clinical considerations pharmacodynamics, pharmacokinetics

dose finding studies

Clinical efficacy

Clinical safety

pharmacovigilance


Pre-/non-Clinical requirements for SC

Guideline on Human cell-based medicinal products (CHMP/410869/06)

Reflection paper on stem cell-based medicinal products (CAT/571134/09)

Guideline on xenogeneic cell-based medicinal products (CHMP/CPWP/83508/09)

Strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (CHMP/SWP/28367/07)

http://www.ema.europa.eu regulatory scientific guidelines cell therapy and tissue engineering









processing

The GxP challenge

development process like every MP

challenge for ATMP:

living cells but regulatory requirements widely adopted from pharma

development in universities or SME without GxP facilities/experience

clinical trials

regulatorypre-clinical

researchmarket

pharma-covigilance

basic research

GCPGLP

trial samples/product manufacturingproduct development

GMP


Regulatory requirements (AMG) in SC-therapy

Exemptions for individual therapies

MA(central Manufacturing)

IMP

ATMP§4 (9)

§4b (Hosp. Exemption)Procurement §20bManufacturing §13 (GMP)„MA“ §21a (2-8)

Procurement §20bManufacturing §13 (GMP)MA §21(1) central procedure

Procurement §20bManufacturing §13(GMP)

GCP-Trials

Not an ATMP

§20d („one-hand-

principle“)No authorization required!

Procurement §20bProcessing §20c (GFP)„MA“§21a(Manufacturing §13GMP)(MA§21)

Procurement §20bProcessing §20c (GFP)

(Manufacturing §13GMP)

GCP-Trials


ppprocurement/manufacturing/clinical trials /application

GMP- „central“ manufacturing ATMP (GCP-trials/central MA for EU)


procurement

GMP-central-manufacturing

Hospital

othersApplication (MA)physician: GCP-trials

Application (MA)physician: GCP-trials

GMP- „Hospital exemption“ for ATMP


GMP-individual-manufacturing,

low numbers

Hospital

applicationphysician

„Point-of care“ (PoC)-manufacturing ATMP


Hospital:own authorization for procurement +PoC-GMP-manufacturing

Hospital

Application (MA)physician: GCP-trials

If not an ATMP: §20d „one-hand-principle“ i.e.

all under responsibility of the physician, no authorization required!

The GxP challenge (AMG) for SC-studies

GMP

procurement, manufacturing-/processing-authorization

(central, PoC, Hospital exemption)

responsibility: regional competent authority (Landesbehörde)

DIR 2003/94/EG (GMP-Directive), D: AMWHV + AMG §13 ff

GLP

for pre-clinical data (needed for clinical trial application)

responsible for establishment: regional competent authority

responsible for monitoring and inspection:

GLP-Bundesstelle beim Bundesinstitut für Risikobewertung (BfR)

Dir 2004/10/EG (GLP-Directive), D: ChemG § 19a Abs.1

© 2011 RTC Rostock





authorization• clinical trials• management



processing

GCP – PEI authorization for clinical study

IIT: sponsor/investigator/financing/ethic

Application by the sponsor: (PEI/BfArm 10.08.2006)„3. Notification on the clinical trial of medicinal products for human use“

indication, mode of application, population, study-design, ...

IMP (IMPD, IB)

manufacturing and quality data, non-clinical pharmacology and

toxicology data, clinical trial and previous human experience data,

risk/benefit analysis, ...

name & address of ethics committee (application EC)

.......


GCP – SC trials: points to consider

evaluation time at PEI: 90 days + 90 days for applicant

management

procurement/manufacturing: contracts & audits, responsibilities,

serology, ...

integration of stem cell trials in clinic routine

logistic: transport/quality controls/release

coordination with OP

documentation: procurement, transport, application

interaction with the patient special need for information, informed consent

Time coordination procurement/OP

cost/benefit

dose/efficacy, additional benefit, reimbursement, ...30© 2011 RTC Rostock

Topics to discuss

SC product classification/certification procedures (EMA)

risk based approach/dialog with the authorities

preclinical quality/safety-testings

authorization for procurement/manufacturing

central manufacturing/PoC-processing

planning/authorization for GCP-conform IITs

specific questions??

© 2011 RTC Rostock www.cardiac-stemcell-therapy.com



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