Regulation and reimbursement of CLI CELL Therapy

REGULATION and REIMBURSEMENT

of CLI CELL THERAPY

Václav Procházka

Fakultní nemocnice Ostrava

Regenerative medicine

The subject of our activities are autologous

and allogeneic cells of human body tissue, and

products of materials engineering.

Cancer,#28%#

Cardiovascular,#12%#

NonPhealing#wounds,#

8%#

Musculoskeletal,#8%#

AutoImmune,#7%#

Ocular,#5%#

Stroke,#5%#

Diabetes,#4%#

Spinal#Cord#Injury#,#3%#

Skin,#2%#

Other,#18%#

!#

Research Pre-Clinical Early-Stage (Ph. I) Mid-Stage (Ph. II) Late-Stage (Ph. III)

58 Trials 245 Trials 70 Trials 174 Trials 24 Trials

ARM Database

! 185 Therapeutic Companies

! 320 Regen Med Products

Ongoing Industry-Sponsored RM Trials by Stage

Late&Stage!Industry&Sponsored!RM!Trials! Early&to&Mid!Stage!Industry&Sponsored!RM!Trials!

Cancer, 32%

Musculoskeletal

, 28%

Non-healing

wounds, 15%

Cardiovascular,

11%

AutoImmune,

4%

Ocular,

4%

Stroke, 2% Skin, 2% Other, 2%

Goal of stem cell therapy

• Regeneration (916)

•Cell therapy (nonregenerative) (126)

•Gene therapy (96)

•Stem cell collection/mobilization (30)

•Bioscaffold (15)

•Immunotherapy (13)

Target of stem cell therapy

• Immune system (260)

• Heart (197)

• Marrow (157)

• CBS (125)

• Vascular system (90)

Mechanism of disease being treated

• Injury or degeneration (400)

• Ischemia (274)

• Drug – (chemotherapy) or radiation-

induced damage (224)

• Immune attack (142)

• Congential or inherited disease (79)

• Neoplasia (52)

• Infection (10)

• Healthy volunteers (10)

Stem cell tissue source

• Bone marrow (439)

•Peripheral blood (170)

•No sampling (112)

•Umblical cord (99)

•Unspecified (95)

•Adipose tissue (92)

•Eye (16)

•Brain (12)

•Placenta (9)

•Heart (6)

•Embryo (6)

Stem cell manipulation

•Cultured (441)

•Purified (236)

•Drug treatment (95)

•Gene modified (79)

•None (115)

•Other (49)

•Unspecified (43)

Graft donor source

•Autologous (594)

•Allogeneic (305)

•Autologous and allogeneic

•No stem cell graft (118)

•Nospecified (33)

Principle disease/condition targeted

•Cardiovascular disease (278)

•Neurological disease (169)

•Cancer (97)

•Liver disease (67)

•Bone condition (65)

•Other (56)

•Immunodeficiency and other

nonmalignant hematologic condtitions

(49)

•Gastrointestinal disease (46)

•Systemic rheumological disease (45)

•Diabetes (43)

•Eye disease (39)

•Skin condition (19)

•Organ transplant-associated (18)

•Lung disease (15)

•Kidney condition (8)

Stem cell type

•Hematopoietic (432)

•Mesenchymal (432)

•Endothelial progenitor cells (69)

•Other (69)

•Neural (22)

•Unspecified (20)

•Limbal (16)

•Embyronic (6)

•Cardial (6)

Two Type of Stem Cells

EMBRYONIC SC

Totipotent

They can create all kind

s of human cells

They survive in tissue

Cultures

Easily accessible

ADULT SC

Organ-specific

They can create a several

cell types

Limited survival

Difficult isolation

Embryonic SC are totipotent

Adipocytes PericytesAstrocytes NeuronsNeurons

ADULT SC - multipotent

Tepper O, et al; BLOOD: 2005

Vasculogenesis

Bone Marrow Endothelial Progenitor Cells (EPC) produce new blood vessels

(de novo) in HYPOXIC conditions via localized recruitment, proliferation and

differentiation of cells.

Vessel wall stabilisation

LEGAL ASPECTS of

NO-CLI Cell Therapy

Legislation before 2008

Cells and their preparations regulated by law 285/2002 Sb.

„Transplantation law“

Legislation after 2008

The harmonization of Czech law with legislation of EU-EMA (CAT)

From 2008 active two laws

296/2008 Sb. "The law of human tissues and cells "

378/2007 Sb. „The law on Pharmaceuticals“

BMMNC harvesting and application

Aspirate the desired volume of

Bone MarrowAspirate

Place into the SmartPReP

SystemProcess

Bone Marrow Aspirate

Concentrate [BMAC]

Utilize

15 Min.

Point-of-Care in the same OR procedure

The Law 296/2008

Regulates tissue transplants

Regulates cell transplants

Decree no. 422/2008 Coll.

establishing detailed requirements for ensuring the quality

and safety of human tissues and cells intended for use in

humans

Minimal handling allowed for

transplants

Cutting

Comminution

Shaping

Centrifugation

Soaking in antibiotic or antimicrobial solutions

Sterilization

Irradiation

Separation, concentration or purification of cells

Filtering

Lyophilisation

Freezing

Cryopreservation

Vitrification

Law 378/2007

Regulation of the European Parliament and Council Regulation ( EC)

no. 1394/2007 of 13 November 2007 on medicinal products for

advanced therapy and amending Directive 2001 /83 / EC and

Regulation ( EC ) no. 726/2004

Advance Therapy Medicinal Products (ATMPs)

Somatocellular therapy

Tissue engineering products

Gene therapy

Advance Therapy Medicinal Products

(ATMPs) – NATIC Brno

22

Approvals and reimbursemenetof final products for clinical care

Aplication area - SOPs, Clinical research

Harvesting area –Clean room GMP

SOPs - GMP SUKL –Tissue center

EMA/SUKL/Min.of Health/ Insurance comp-VZP

Harvesting, manufacturing, Package, Labeling and transfer

Facility certification (cGMP)

Clinical translational research

Stem cell therapy

Time line of RM product

Regulatory requirements for

ATMP - Cell Therapy Products

Viability testing

Bacteriology and Virology testing

Imunephenotyping

Replication activity testing – CFU

Proteomics

Final product cell profiling

MSI – Microsatelite stability

Aray based Gene Expression

Telomerase testingCompany Logo

21 October 2013

Source tissue for

regenerative medicine

Bone marrow1

Cord blood & tissue, placenta, amniotic tissue

2 Adipose tissue, ASC-SVF, ASC-CM

3

Autologous cultered bioptic samples4

Reprogramed cells-iPSc5

Peripheral blood – APC, fPRP6

Limbal cells, Beta cells, etc.7

Development of Stem Cell Preparations

Risk Based Approach

Stem Cell-Type, Degree and Type of Manipulation

Autologous vs. Allogenic concept and intended use

determine risk assessment.

Source: EU ATMP Position Reflection Paper

Primary SC (HSC, MSC, MNC)

Expanded(Cell Lines, SC’s (MSC)

Manipulated / PreconditionedSC’s (HSC, MSC)

GeneticallyManipulatedSC’s (HSC, MSC)

inVitroReprogammedSC’s

inVitroEstablishedCell Lines

Adult SC’s (intrinsic SC Pool): Multipotent

iPSC (Pluripotent)

ESC(Pluripotent)

Low

High

When to think about reimbursement ?

Basic

Research

Basic research

1

Knowledge

generation

2

Preaclinical

research

Animal testing

of hypothesis

3

Clinical

Research

Phase I-II

4

Clinical studies

&

Partnering

with

Universities

and

comercionalisat

ion

Knowledge

Transfer

Clinical

Research

Phase III

Clinical

Transfer

Academic

research

&

Comercial

Institutional

research

Safety and

efficacy

testing

Clean rooms,

GMP facility

&

SOPs for

Quality

control

5

Marketing

&

Production

Commercial

transfer

&

Inovations

Inovations

Reimbursement

Hind-limb ischemia projectsFN Ostrava

1. Preclinical rat model of hind-limb ischemia

28

29


1. Preclinical rat model of hind-limb ischemia

30


2. Preclinical diabetic rabbitt model of hind-limb ischemia

Clinical Trials of Cell Therapy in CLI A Decade of Experience

Author Year Trial

Type

N

Total

N

Treated

N

Control

Benoit (6) 2011 RCT 48 34 14

Idei (32) 2011 Cohort 97 51 46

Lu (42) 2011 RCT 82 41 41

Madaric (44) 2011 Case series 31 31 0

Murphy (51) 2011 Case series 30 30 0

Perin (55) 2011 Case series 10 10 0

Powell (56) 2011 RCT 46 32 14

Ruiz-Salmeron (58) 2011 Case series 20 20 0

Subrammaniyan (65) 2011 Case series 6 6 0

Walter (69) 2011 RCT w cross 40 19 21

Burt (8) 2010 Case series 9 9 0

Higashi (26) 2010 Case series 16 16 0

Horie (27) 2010 Case series 162 162 0

Lara-Hernandez (38) 2010 Case series 28 28 0

Mizuno (48) 2010 Case series 8 8 0

Prochazka (57) 2010 RCT 96 42 54

Amann (1) 2009 Case series 51 51 0

Franz (19) 2009 Case series 9 9 0

Kawamoto (36) 2009 Case series 17 17 0

Moriya (49) 2009 Case series 42 42 0

Chochola (9) 2008 Case series 24 24 0

Cobellis (10) 2008 Case series 10 10 0

De Vriese (11) 2008 Case series 16 16 0

Matoba (46) 2008 Case series 115 115 0

To Date: 45 Clinical Trials (7 RCT) including 1272 Patients.

Benoit: Cell Transplantation (2013)

Author Year Trial

Type

N

Total

N

Treated

N

Control

Motukuru (50) 2008 Case series 36 36 0

Napoli (52) 2008 Cohort 36 18 18

Van Tongeren (68) 2008 Case series 27 27 0

Wester (70) 2008 Case series 8 8 0

Zhang (72) 2008 Case series 15 15 0

Bartsch (5) 2007 Cohort 25 13 12

Hernandez (24) 2007 Case series 12 12 0

Huang (31) 2007 Case series 150 150 0

Saito (60) 2007 Case series 14 14 0

Arai (2) 2006 RCT 25 13 12

Durdu (12) 2006 Case series 28 28 0

Koshikawa (37) 2006 Case series 7 7 0

Miyamoto (47) 2006 Case series 8 8 0

Huang (29) 2005 RCT 28 14 14

Ishida (33) 2005 Case series 6 6 0

Lenk (39) 2005 Case series 7 7 0

Higashi (25) 2004 Case series 7 7 0

Huang (30) 2004 Case series 5 5 0

Saigawa (59) 2004 Case series 8 8 0

Esato (14) 2002 Case series 8 8 0

Tateishi-Yuyama (66) 2002 Case series 45 45 0

NO-CLI Trial Results

Sri Ramachandra

Chennai, IndiaFransizkus Hospital

Berlin, Germany

New England Medical

Center

Boston, USA

University Bratislava

Bratislava, Slovakia

Studie 4

National Grant, Slovakia

13

%

44%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Control BMAC

Cell Transplantation , Vol. 19, pp. 1413–1424, 2010 0963-6897/10 $90.00 + .00

Printed in the USA. All rights reserved. DOI: 10.3727/096368910X514170

Copyright Ó 2010 Cognizant Comm. Corp. E-ISSN 1555-3892

www.cognizantcommunication.com

Cell Therapy, a New Standard in M anagement

of Chronic Critical L imb I schemia and Foot Ulcer

V. Prochazka,* J. Gumulec,† F. Jaluvka,‡ D. Salounova,§ T. Jonszta,* D. Czerny,*J. Krajca,* R. Urbanec,‡ P. Klement,¶ J. Martinek,# and G. L. Klement**

*Radiodiagnostic Institute, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

†Hemato-Oncological Center, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

‡Surgery Clinic and Anaesthesiology Department, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

§Department of Mathematical Methods in Economy, VSB-Technical University Ostrava, Ostrava-Poruba, Czech Republic

¶Henderson Research Center, McMaster University, Hamilton, Ontario, Canada

#Clinical Laboratory, J.G. Mendel Cancer Center, Novy Jicin, Czech Republic

**Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical University, Boston, MA, USA

Fifty percent of diabetics (7% of general population) suffer from peripheral arterial occlusive disease, whichmay lead to amputation due to critical limb ischemia (CLI). The aim of our study was to prevent major limbamputation (MLA) in this group of patients using a local application of autologous bone marrow stem cells(ABMSC) concentrate. A total of 96 patients with CLI and foot ulcer (FU) were randomized into groups Iand II. Patients in group I (n = 42, 36 males, 6 females, 66.2 ± 10.6 years) underwent local treatment withABMSC while those in group II (n = 54, control, 42 males, 12 females, 64.1 ± 8.6 years) received standardmedical care. The frequency of major limb amputation in groups I and II was 21% and 44% within the 120days of follow up, respectively (p < 0.05). Only in salvaged limbs of group I both toe pressure and toebrachial index increased (from 22.66 ± 5.32 to 25.63 ± 4.75 mmHg and from 0.14 ± 0.03 to 0.17 ± 0.03,respectively, mean ± SEM). The CD34+ cell counts in bone marrow concentrate (BMC) decreased (correla-tion, p = 0.024) with age, even though there was no correlation between age and healing. An unexpectedfinding was made of relative, bone marrow lymphopenia in the initial bone marrow concentrates in patientswho failed ABMSC therapy (21% of MLA). This difference was statistically significant (p < 0.040). Weconclude ABMSC therapy results in 79% limb salvage in patients suffering from CLI and FU. In the remain-ing 21% lymphopenia and thrombocytopenia were identified as potential causative factors, suggesting thatat least a partial correction with platelet supplementation may be beneficial.

Key words: Critical limb ischemia (CLI); Diabetic foot ulcer; Autologous bone marrow stem cells (ABMSC);Lymphopenia of bone marrow

I NTRODUCTI ON suddenly and causes 50–67% of all nontraumatic lower

extremity amputations. Fifty-two percent of diabetics

with CLI die during the 4.5 year follow up (35,36).In diabetic patients, nonhealing cutaneous ulcers are

a significant clinical, social, and healthcare problem. Standard treatment of chronic wounds, and especially

those secondary to CLI, includes surgical revasculariza-Based on more than 10 million diabetic patients in the

US and an estimated prevalence of 15% for chronic cu- tion (distal crural or pedal bypass), endovascular therapy

(recanalization by percutaneous transluminal angioplasty),taneous ulcers, there are approximately 1.5 million pa-

tients with this problem. Peripheral arterial occlusive or maximum podiatric wound care (hyperbaric oxygen,

antibiotics, vasodilators). Despite the available thera-disease (PAOD) has been recognized as a significant

factor in this population. For example, in European pies, 25% of patients still progress to amputation. The

outcomes are even worse in diabetics, with multicausalStudy Group on Diabetes and Lower Extremity (Eurodi-

ale) 49% of patients presenting with new diabetic foot disease, where neuropathy, poor healing, and peripheral

arterial occlusive disease occur simultaneously. Thirtyulcer had PAOD. Critical limb ischemia (CLI) develops

Received February 1, 2010; final acceptance May 13, 2010. Online prepub date: June 7, 2010.Address correspondence to Vaclav Prochazka, M.D., Ph.D., M.Sc., Interventional Neuroradiology and Angiology, Radiology Department, Ave 17.Listopadu 1790, University Hospital Ostrava, Ostrava-Poruba, 70852, Czech Republic. Tel: 00420 59737 2172; Fax: 00420 59737 2175; E-mail:[email protected]

1413

Amputation rate

PŘED POBEFORE AFTER





PŘED POAFTERBEFORE

Results of 5 Meta-analysis for Amputation and

Wound healing

[1] Wang, Zheng-Xu, et al. "Efficacy of Autologous Bone Marrow Mononuclear Cell Therapy in Patients with

Peripheral Arterial Disease." Journal of atherosclerosis and thrombosis (2014).

[2] Fadini, Gian Paolo, Carlo Agostini, and Angelo Avogaro. "Autologous stem cell therapy for peripheral

arterial disease: Meta-analysis and systematic review of the literature." Atherosclerosis 209.1 (2010): 10-17.

[3] Liu, F. P., et al. "Autologous bone marrow stem cell transplantation in critical limb ischemia: a meta-analy

sis of randomized controlled trials." Chinese medical journal 125.23 (2012): 4296-4300.

[4] Teraa, Martin, et al. "Autologous Bone Marrow–Derived Cell Therapy in Patients With Critical Limb Ische

mia: A Meta-Analysis of Randomized Controlled Clinical Trials." Annals of surgery 258.6 (2013): 922-929.

[5] Benoit, Eric, Thomas F. O'Donnell, and Amit N. Patel. "Safety and efficacy of autologous cell therapy

in critical limb ischemia: a systematic review." Cell transplantation 22.3 (2013): 545-562.

Meta studies cover clinical trials between the years 2002-2013 and include about 1,500 unique patients. Included rando

mized studies are mainly large proportion of which are controlled studies ( versus placebo or standard care ) .

[1] Amputatiion 1y OR=8.05 CI95% (3.58 - 18.08) P < 0.00001

Amputation 3y OR=22.33 CI95% (4.14 - 120.5) P = 0.0003

[2] Amputation OR=11.11 CI95% (2.27 - 50.00) P = 0.0005

Wound healing OR=3.54 CI95% (1.09 - 11.51) P = 0.032

[3] Amputation OR=2.70 CI95% (1.61 - 4.45) P = 0.0002

Wound healing OR=5.83 CI95% (2.37 - 14.29) P = 0.0001

[4] Amputation RR=0.45 CI95% (0.27 - 0.75) P = 0.002

Wound healing RR=1.87 CI95% (1.49 - 2.36) P = 0.00001

[5] Amputation OR=2.77 P = 0.0004


Wound healing

HARD ENDPOINTS

B) Surrogate Endpoints[1] ABI 12 weeks MD 0.12 CI95% (0.07 - 0.16) P<0.00001

ABI 24 weeks MD 0.14 CI95%(0.10 - 0.17) P<0.00001

ABI 48 weeks MD 0.12 CI95%(0.02 - 0.23) P=0.02

TcpO 12 weeks MD 1.95 mmHg CI95%(−7.41-11.3) P=0.68

TcpO2 24 weeks MD 6.89mmHg CI95%(6.17 -7.62) P＜0.00001

TcpO2 48 weeks MD 20.35mmHg CI95%(12.51-28.19) P＜0.00001

Pain MD −1.37 CI95%(−1.69-−1.04) P < 0.00001

[2] ABI 0.46 ± 0.04 0.63 ± 0.04 P = 0.011

TcpO2 22.8 ± 2.8 35.8 ± 2.9 P = 0.0002

Pain 6.35 ± 0.43 2.11 ± 0.37 p < 0.0001

Claudication interval 75.7 ± 19.4 402.3 ± 70.9 p < 0.0001

[4] ABI 0.12 CI95%(.09,.15) ~+30% P < 0.00001

TcpO2 14.26mmHg CI95%(8.54,20.02) ~+30% P < 0.00001

Pain -1.1 CI95%(-1.37,-.83) ~+25% P < 0.00001

Claudication interval 178.73m CI95%(127.68,229.78) P < 0.00001

[5] ABI Improvement u 24 (studies) z 38 +63.2%

TcO2 Improvement u 20 (studies) z 26 +76.9%

Pain Improvement u 33 (studies) z 37 +89.2%

Claudication interval Improvement u 17 (studies) z 19 +89.5%


Wound healing

Regulatory Status

USA: FDA 510K Cleared, EU: CE Mark with

Expansion Claim

Diabetic foot and amputation rates in Czech republic

0

5 000

10 000

15 000

20 000

25 000

30 000

35 000

40 000

45 000

50 000

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Zdroj: Výkazy o činnosti zdravotnických zařízení pro obor diabetologie (A04), období: 2000 - 2013

Počet případů

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Diabetická

noha37 764 36 725 38 166 37 971 39 753 38 090 41 328 42 337 42 992 43 990 45 118 44 011 43 248 44 657

Amputace

(%)

5 865

(15,53 %)

6 118

(16,66 %)

6 743

(17,67 %)

7 029

(18,51 %)

7 444

(18,73 %)

7 303

(19,17 %)

7 834

(18,96 %)

7 853

(18,55 %)

8 169

(19,00 %)

8 439

(19,18 %)

8 501

(18,84 %)

10 408

(23,65 %)

10 425

(24,11 %)

11 168

(25,01 %)

Diabetic foot

Amputations

Souhrnvykázané/uznanépéčezapacienty,kteříprodělaliamputacikvůliporušeoběhovéhosystému,

kroměhorníchkončetinaprstůunohy,vizDRGbáze0515-dataza01/2011-10/2014(hosp.datadleDRG;preskripceapoukazynazdrav.prostředky;amb.produkce)

-zdrojdat:Archívvykázané/uznanépéčeFNO(datovýskladOSVZPaOFA)

ROK

počet RČ dle

DRG báze

0515 body LP Zum, Zulp

HOSP.-

výkonověsHB

0,90Kč CM

ÚhradaHOSP.-vše

přesPřípadový

paušálDRG(předi

poamputaci)

počet RČ

dle DRG

báze 0515

(před i po

amputaci) HVLP IVLP ZP

PreskripceLékůaZP

pac.(předipo

amputaci)

počet RČ dle

DRG báze 0515

(před i po

amputaci) body Zum,Zulp

ÚhradaAMB.(před i po

amputaci)

2011 67 6 694 648 173 570 Kč 1 291 037 Kč 7 489 790 Kč 247,4431 7988940Kč 76 708 940 Kč 0 Kč 446 666 Kč 1155606Kč 97 2 550 391 481 640 Kč 2536251Kč



01-10/2014 52 5 443 352 129 240 Kč 1 351 064 Kč 6 379 320 Kč 185,3878 6106743Kč 55 445 878 Kč 0 Kč 267 377 Kč 713254Kč 73 694 910 118 054 Kč 686750Kč

Celkem 25 491 648 667 245 Kč 6 055 744 Kč 29 665 472 Kč 935,4396 30529673Kč 2 514 597 Kč 0 Kč 1 559 501 Kč 4074097Kč 8 437 040 1 705 028 Kč 8443366Kč

*r.2011-2013-výpočetdlevyúčtovánízdrav.služebodjednotlivýchZP-všePřípadovýmpaušálem(jakoAlfaDRG); **bodypřepočtenék1.1.2014;úhradazabodydleHBdleúhradovévyhlášky(HBnesnižována)

r.2014-dleÚhradovévyhlášky-všePřípadovýmpaušálem(jakoAlfaDRG) včetněvýkonů:klinickéstomatologie;CyberKnife;SDH;lůžeksociálnípéče;foniatrickýchpomůcek

ROK prům. HOSP.

prům.

PRESKR. prům. AMB.

Váženáprům.

úhradanaRČ

(Hosp,Preskr.,

Amb.)

2011 119238Kč 15205Kč 26147Kč 160590Kč

2012 126686Kč 17647Kč 30100Kč 174433Kč

2013 124374Kč 12706Kč 27357Kč 164437Kč

01-10/2014 117437Kč 12968Kč 9408Kč 139813Kč

Cenaprotézy: 85tisKčCenavozíku: 40tisKč

PRESKRIPCEHVLP,IVLPaZPnapoukaz AMBULANCE**HOSPITALIZACEdleDRG

Mean = 166 500 CZK

Prosthesis = 85 000 CZK

wheelchair = 40 000 CZK

Celkem= 291 500 CZK

Rehabilitation costs

Social-economic costs

EURODIALE – 500 600 CZK

Diabetic foot and amputation prices in FNO

Czech angiology society

Czech society for cardiovascular surgery

Czech society for interventional radiology

Czech diabetology society

Czech haematology society

CODE 12530

CODE 12520

REIMBURSEMENT

facebook.com/diabetickanoha

www.stopamputacim.cz

Documents

Regulation and reimbursement of CLI CELL Therapy