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.

!# Ongoing

ARM Database

Industry-Sponsored RM Trials by Stage

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

Late&Stage!Industry&Sponsored!RM!Trials!

Stroke, 2%

Skin, 2%

! 185 Therapeutic Companies ! 320 Regen Med Products

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

Other, 2%

Ocular, 4% AutoImmune, 4%

Other,#18%# Skin,#2%# Cancer, 32%

Cardiovascular, 11%

Cancer,#28%#

Spinal#Cord# Injury#,#3%# Diabetes,#4%# Stroke,#5%#

Non-healing wounds, 15%

Ocular,# 5%# Musculoskeletal , 28%

AutoImmune,#7%# Musculoskeletal,# 8%#

Cardiovascular,# 12%# NonP healing# wounds,# 8%#

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 radiationinduced damage (224) • Immune attack (142) • Congential or inherited disease (79) • Neoplasia (52) • Infection (10) • Healthy volunteers (10)

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)

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)

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

Astrocytes

Neurons

Neurons

Adipocytes

Pericytes

ADULT SC - multipotent

Vasculogenesis ď †

Bone Marrow Endothelial Progenitor Cells (EPC) produce new blood vessels (de novo) in HYPOXIC conditions via localized recruitment, proliferation and differentiation of cells.

Tepper O, et al; BLOOD: 2005

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 Point-of-Care in the same OR procedure

15 Min.

Aspirate

Aspirate the desired volume of Bone Marrow

Process

Place into the SmartPReP System

Utilize

Bone Marrow Aspirate Concentrate [BMAC]

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

Stem cell therapy Time line of RM product

Approvals and reimbursemenet of 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

Clinical translational research

Harvesting, manufacturing, Package, Labeling and transfer

Facility certification (cGMP)

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 testing Company Logo

Source tissue for regenerative medicine 1

Bone marrow

2

Adipose tissue, ASC-SVF, ASC-CM

3

Cord blood & tissue, placenta, amniotic tissue

4

Autologous cultered bioptic samples

5

Reprogramed cells-iPSc

6

Peripheral blood – APC, fPRP

7

Limbal cells, Beta cells, etc.

21 October 2013

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.

High

Low

Primary SC (HSC, MSC, MNC)

Expanded (Cell Lines, SC’s (MSC)

Manipulated / Preconditioned SC’s (HSC, MSC)

Genetically Manipulated SC’s (HSC, MSC)

Adult SC’s (intrinsic SC Pool): Multipotent Source: EU ATMP Position Reflection Paper

inVitro Reprogammed SC’s

iPSC (Pluripot ent)

inVitro Established Cell Lines

ESC (Pluripotent)

When to think about reimbursement ?

Reimbursement Clinical Research Phase III

Basic research

Preaclinical research

Clinical Research Phase I-II

1

2

3

4

5

Academic research & Comercial Institutional research

Clean rooms, GMP facility & SOPs for Quality control

Clinical studies & Partnering with Universities and comercionalisat ion

Marketing & Production Commercial transfer & Inovations

Knowledge Transfer

Inovations

Basic Research

Knowledge generation

Animal testing of hypothesis

Safety and efficacy testing

Clinical Transfer

Hind-limb ischemia projects FN Ostrava

1. Preclinical rat model of hind-limb ischemia

28

Hind-limb ischemia projects FN Ostrava

1. Preclinical rat model of hind-limb ischemia

29

Hind-limb ischemia projects FN Ostrava

2. Preclinical diabetic rabbitt model of hind-limb ischemia

30

Clinical Trials of Cell Therapy in CLI A Decade of Experience To Date: 45 Clinical Trials (7 RCT) including 1272 Patients.

Author

Year

Trial Type

N Total

Benoit (6) Idei (32) Lu (42) Madaric (44) Murphy (51) Perin (55) Powell (56) Ruiz-Salmeron (58) Subrammaniyan (65) Walter (69) Burt (8) Higashi (26) Horie (27) Lara-Hernandez (38) Mizuno (48) Prochazka (57) Amann (1) Franz (19) Kawamoto (36) Moriya (49) Chochola (9) Cobellis (10) De Vriese (11) Matoba (46)

2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2010 2010 2010 2010 2010 2010 2009 2009 2009 2009 2008 2008 2008 2008

RCT Cohort RCT Case series Case series Case series RCT Case series Case series RCT w cross Case series Case series Case series Case series Case series RCT Case series Case series Case series Case series Case series Case series Case series Case series

48 97 82 31 30 10 46 20 6 40 9 16 162 28 8 96 51 9 17 42 24 10 16 115

Benoit: Cell Transplantation (2013)

N N Treated Control 34 51 41 31 30 10 32 20 6 19 9 16 162 28 8 42 51 9 17 42 24 10 16 115

14 46 41 0 0 0 14 0 0 21 0 0 0 0 0 54 0 0 0 0 0 0 0 0

Author

Year

Trial Type

N Total

Motukuru (50) Napoli (52) Van Tongeren (68) Wester (70) Zhang (72) Bartsch (5) Hernandez (24) Huang (31) Saito (60) Arai (2) Durdu (12) Koshikawa (37) Miyamoto (47) Huang (29) Ishida (33) Lenk (39) Higashi (25) Huang (30) Saigawa (59) Esato (14) Tateishi-Yuyama (66)

2008 2008 2008 2008 2008 2007 2007 2007 2007 2006 2006 2006 2006 2005 2005 2005 2004 2004 2004 2002 2002

Case series Cohort Case series Case series Case series Cohort Case series Case series Case series RCT Case series Case series Case series RCT Case series Case series Case series Case series Case series Case series Case series

36 36 27 8 15 25 12 150 14 25 28 7 8 28 6 7 7 5 8 8 45

N N Treated Control 36 18 27 8 15 13 12 150 14 13 28 7 8 14 6 7 7 5 8 8 45

0 18 0 0 0 12 0 0 0 12 0 0 0 14 0 0 0 0 0 0 0

NO-CLI Trial Results

New England Medical Center Boston, USA

Fransizkus Hospital Berlin, Germany

Sri Ramachandra Chennai, India

University Bratislava Bratislava, Slovakia Studie 4 National Grant, Slovakia

13 %

Cell Transplantation, Vol. 19, pp. 1413–1424, 2010 Printed in the USA. All rights reserved.

Copyright Ó 2010 Cognizant Comm. Corp.

0963-6897/10 $90.00 + .00 DOI: 10.3727/096368910X514170 E-ISSN 1555-3892 www.cognizantcommunication.com

Cell T herapy, a New Standard in M anagement of Chronic Critical L imb I schemia and Foot Ulcer V. Procha´ zka,* J. Gumulec,† F. Jalu˚ vka,‡ D. Sˇ alounova´ ,§ T. Jonszta,* D. Czerny´ ,* J. Krajcˇ a,* 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, VSˇ B-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

Amputation rate 50% 45%

44%

40%

35% 30% 25% 20% 15% 10%

Fifty percent of diabetics (7% of general population) suffer from peripheral arterial occlusive disease, which may lead to amputation due to critical limb ischemia (CLI). The aim of our study was to prevent major limb amputation (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 I and II. Patients in group I (n = 42, 36 males, 6 females, 66.2 ± 10.6 years) underwent local treatment with ABMSC while those in group II (n = 54, control, 42 males, 12 females, 64.1 ± 8.6 years) received standard medical care. The frequency of major limb amputation in groups I and II was 21% and 44% within the 120 days of follow up, respectively (p < 0.05). Only in salvaged limbs of group I both toe pressure and toe brachial 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 (correlation, p = 0.024) with age, even 21% though there was no correlation between age and healing. An unexpected finding was made of relative, bone marrow lymphopenia in the initial bone marrow concentrates in patients who failed ABMSC therapy (21% of MLA). This difference was statistically significant (p < 0.040). We conclude ABMSC therapy results in 79% limb salvage in patients suffering from CLI and FU. In the remaining 21% lymphopenia and thrombocytopenia were identified as potential causative factors, suggesting that at 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

5% 0% Control

I NT RODUCT I ON BMAC

In diabetic patients, nonhealing cutaneous ulcers are a significant clinical, social, and healthcare problem.

Based on more than 10 million diabetic patients in the

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).

Standard treatment of chronic wounds, and especially those secondary to CLI, includes surgical revasculariza-

BEFORE PŘED

AFTER PO

BEFORE PŘED

AFTER PO

BEFORE PŘED

AFTER PO

BEFORE PŘED

AFTER PO

BEFORE PŘED

AFTER PO

BEFORE PŘED

AFTER PO

Results of 5 Meta-analysis for Amputation and Wound healing 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] 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 Marrowâ&#x20AC;&#x201C;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.

Results of 5 Meta-analysis for Amputation and Wound healing HARD ENDPOINTS [1]

[2]

[3]

[4]

[5]

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

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

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

Amputation

RR=0.45

CI95% (0.27 - 0.75)

P = 0.002

Wound healing

RR=1.87

CI95% (1.49 -

P = 0.00001

Amputation

OR=2.77

2.36)

P = 0.0004

Results of 5 Meta-analysis for Amputation and Wound healing

B) Surrogate Endpoints [1]

[2]

[4]

[5]

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

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

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

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%

Regulatory Status

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

Diabetic foot and amputation rates in Czech republic 50 000 45 000 Počet případů

40 000 35 000 30 000 25 000

Diabetic foot

20 000

Amputations

15 000 10 000 5 000

Diabetická noha Amputace (%)

13 20

12 20

11 20

10 20

09 20

08 20

07 20

06 20

05 20

04 20

03 20

02 20

01 20

20

00

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

37 764

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

5 865 6 118 6 743 7 029 7 444 7 303 7 834 7 853 8 169 8 439 8 501 10 408 10 425 11 168 (15,53 %) (16,66 %) (17,67 %) (18,51 %) (18,73 %) (19,17 %) (18,96 %) (18,55 %) (19,00 %) (19,18 %) (18,84 %) (23,65 %) (24,11 %) (25,01 %)

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

Diabetic foot and amputation prices in FNO

Souhrn vykázané/uznané péče za pacienty, kteří prodělali amputaci kvůli poruše oběhového systému, kromě horních končetin a prstů u nohy, viz DRG báze 0515 - data za 01/2011 - 10/2014 (hosp. data dle DRG; preskripce a poukazy na zdrav. prostředky; amb. produkce) - zdroj dat: Archív vykázané/uznané péče FNO (datový sklad OSVZP a OFA) HOSPITALIZACE dle DRG Úhrada HOSP. - vše HOSP. přes Případový počet RČ dle výkonově s HB paušál DRG (před i DRG báze 0515 body LP Zum, Zulp ROK 0,90 Kč CM po amputaci) 2011 67 6 694 648 173 570 Kč 1 291 037 Kč 7 489 790 Kč 247,4431 7 988 940 Kč 2012 61 6 277 889 165 970 Kč 1 543 014 Kč 7 359 084 Kč 228,9441 7 727 830 Kč 2013 70 7 075 759 198 465 Kč 1 870 630 Kč 8 437 278 Kč 273,6646 8 706 160 Kč 01-10/2014 52 5 443 352 129 240 Kč 1 351 064 Kč 6 379 320 Kč 185,3878 6 106 743 Kč Celkem 25 491 648 667 245 Kč 6 055 744 Kč 29 665 472 Kč 935,4396 30 529 673 Kč * r. 2011-2013 - výpočet dle vyúčtování zdrav. služeb od jednotlivých ZP - vše Případovým paušálem (jako Alfa DRG); r. 2014 - dle Úhradové vyhlášky - vše Případovým paušálem (jako Alfa DRG)

ROK

prům. HOSP.

prům.

PRESKR.

PRESKRIPCE HVLP, IVLP a ZP na poukaz

AMBULANCE**

počet RČ dle DRG Preskripce Léků a ZP báze 0515 pac. (před i po (před i po amputaci) HVLP IVLP ZP amputaci) 76 708 940 Kč 0 Kč 446 666 Kč 1 155 606 Kč 76 833 484 Kč 0 Kč 507 724 Kč 1 341 208 Kč 68 526 295 Kč 0 Kč 337 734 Kč 864 029 Kč 55 445 878 Kč 0 Kč 267 377 Kč 713 254 Kč 2 514 597 Kč 0 Kč 1 559 501 Kč 4 074 097 Kč

počet RČ dle Úhrada AMB. DRG báze 0515 (před i po (před i po amputaci) body Zum,Zulp amputaci) 97 2 550 391 481 640 Kč 2 536 251 Kč 88 2 791 178 420 305 Kč 2 648 800 Kč 94 2 400 561 685 029 Kč 2 571 565 Kč 73 694 910 118 054 Kč 686 750 Kč 8 437 040 1 705 028 Kč 8 443 366 Kč

** body přepočtené k 1.1.2014; úhrada za body dle HB dle úhradové vyhlášky (HB nesnižována) včetně výkonů: klinické stomatologie; CyberKnife; SDH; lůžek sociální péče; foniatrických pomůcek

Vážená prům. úhrada na RČ (Hosp, Preskr., Amb.)

prům. AMB.

2011

119 238 Kč

15 205 Kč

26 147 Kč

2012

126 686 Kč

17 647 Kč

30 100 Kč

2013

124 374 Kč

12 706 Kč

27 357 Kč

01-10/2014

117 437 Kč

12 968 Kč

9 408 Kč

160 590 Kč 174 433 Kč 164 437 Kč 139 813 Kč

Cena protézy : 85 tis Kč

Mean =Cena 166 vozíku:500 40 tisCZK Kč Prosthesis = 85 000 CZK wheelchair = 40 000 CZK Celkem= 291 500 CZK

Rehabilitation costs Social-economic costs EURODIALE – 500 600 CZK

REIMBURSEMENT

Czech angiology society

Czech society for cardiovascular surgery Czech society for interventional radiology Czech diabetology society Czech haematology society

CODE 12530 CODE 12520

facebook.com/diabetickanoha www.stopamputacim.cz