ORTHOBIOLOGICS AND CARTILAGE REPAIR NEW BUSINESS AND REGULATORY CHALLENGES

Transcription

1 ORTHOBIOLOGICS AND CARTILAGE REPAIR NEW BUSINESS AND REGULATORY CHALLENGES RALPH A. GAMBARDELLA, M.D. CHAIRMAN & PRESIDENT KERLAN-JOBE ORTHOPAEDIC CLINIC LOS ANGELES, CALIFORNIA

2 Outline Review FDA regula0ons and environment PRP Stem cells Cell therapies and allogra=s Trends Current challenges and the future of Orthobiologics regula0on Car0lage Coding and reimbursement issues General Insurance Criteria for repair

3 What are Orthobiologics? Orthobiologics are biological based 0ssues or substances used to repair or enhance the healing of orthopedic injures or condi0ons Tissues e.g. Allograft Cells e.g. Autologous Chondrocyte Implantation, BMAC Growth factors e.g. PRP 3

4 FDA Regula6ons The FDA by law does not regulate or assert legal jurisdic0on over the prac0ce of medicine. State law provides the authority and legal standards for the prac0ce of medicine.

5 FDA Regula6ons The FDA regulates the marke0ng approval or clearance, labeling, and promo0on of pharmaceu0cal, medical device, and biologic products in the United States. These products may only be labeled, promoted, and adver0sed for the uses that the FDA has approved or cleared.

6 Human Cells, Tissues, and Cellular and Tissue Based Products (HCT/P) regula6ons ü Category 1: No HCT/P Oversight (prac%ce of medicine) ü Category 2: Sec0on 361 Products with Minimal Oversight (%ssue processing) ü Category 3: Sec0on 351 s Extensive Regula0on of HCT/Ps as Biologics and Drugs (Therapeu%c, FDA approval required) 6

7 Category 1: No HCT/P Oversight Products in this category are not regulated by HCT/P because they are deemed to be of low risk. Examples 1- Vascularized whole human organs for transplanta0on 2- Whole Blood 3- Blood Derived Products MA Chirba et al. FDA Regula0ons: Stem Cells. Jr of Knee Surg. Vol 28 No

8 Category 2: Sec0on 361 Products with Minimal Oversight No Pre-marke6ng Approval is necessary The FDA views Sec0on 361 products as posing a greater risk with regards to safety and regulates them more extensively to prevent contamina0on, infec0on and disease transmission compared to category 1 products To fall within a 361 category, these products must be: 1- No more than minimally manipulated:* 2- Used for homologous purposes 3- Combined with no other cells or 0ssues 4 Autologous or non sysytemic effects Minimally Manipula.on has been defined by the FDA (Centrifuge; Lyophiliza.on Cell-separa.on MA Chirba et al. FDA Regula0ons: Stem Cells. Jr of Knee Surg. Vol 28 No

9 Category 2: Sec0on 361 Products with Minimal Oversight No Pre-marke6ng Approval is necessary Title 1 of the Code of Federal Regula0ons, Part 1271 (21 CFR Part 1271) Examples of category 2 products Ø Platelet Rich Plasma (PRP) Ø Bone Marrow Aspirate Concentrate (BMAC) Ø Allogra=s e:g Biocar0lage, Car0form, DeNovo

10 Platelet Rich Plasma (PRP) PRP comes from a pa0ent's own blood. PRP is a concentrated source of growth factors studies show that PRP treatment may improve healing in many 0ssues. Ø 361 product Ø No premarke0ng approval needed Ø 510 K required for processing device

11 Bone Marrow Concentrate 361 product Harvested from iliac crest and other loca0ons Bone marrow aspirate contains few progenitor cells = 0.01% or 1 in 100,000 cells Centrifuge used to increase MSC numbers and produce bone marrow concentrate There are several commercial systems available for concentra0ng bone marrow; Each system produces different cell composi0on and concentra0on of cells 11 Dragoo, TOBI 2015

12 Marketed 361 Products Products Company Regulatory Pathway Biocartilage Arthrex HCT/P 361 Allograft Material MOA BMS Augmentation Micronized Matrix acts as internal scaffold Level of Evidence No Published Data: Animal Studies Cartiform Arthrex HCT/P 361 Allograft Material DeNovo NT Chondrofix Zimmer Biologics Zimmer Biologics HCT/P 361 Allograft Material HCT/P 361 Allograft Material Performation of OCA disk. Controlled Cryopreservation Juvenile Particulated Cartilage Photofix Processing with Methylene Blue Single Case Study < 12mths One two year study 72% failure rate 2 of the 4 centers in their study Morselized car0lage 0ssue is considered minimally manipulated and is required regulated as a gra= 0ssue and not a biologic. The American Associa6on of Tissue Banks, the AATB, regulates the procurement, handling, and tes6ng of donor 6ssues. 12

13 361 Products under Inves0ga0on Products Company Regulatory Pathway Car0stem Adiopse- Derived Stem Cells Medipost Co Ltd. Stanford University J. Dragoo HCT/P 361 Allogra= Material HCT/P 361 Allogra= Material MOA Human umbilical cord blood-derived mesenchymal stem cells ADSCs on a collagen scaffold: delivery of more specific progenitor cells Level of Evidence Phase III Trial in Korea Data: Phase II in the US Phase II ADDSC vs MFX 13

14 Category 3: Sec0on 351 Extensive Regula0on of HCT/P as Biologics and Drugs The FDA views Sec0on 351 much more stringent and concentrates on both safety and efficacy. To fall within a 351 category, these products must be: 1- More than minimally manipulated: (Changing the cells morphology, func0on, expression during culturing; Can not take them out of the OR) 2- Used for nonhomologous purposes 3- Combined with other cells, 0ssues or ar0cles that could increase the risk of safety 4 Have a systemic effect or otherwise rely of the metabolic ac0vity of other cells to perform its primary func0on MA Chirba et al. FDA Regula0ons: Stem Cells. Jr of Knee Surg. Vol 28 No

15 High Risk : Sec0on 351 In vitro and preclinical animal study Small pilot human study (Phase I) Small ini0al randomized controlled study (Phase II) Large mul0center randomized controlled study (Phase III)

16 High Risk: Sec0on 351 Requires the establishment of an IND (Inves0ga0onal New Drug program) Requires a BLA (Biologic License Applica0on) Product Classifica6on Clinical Study Applica6on Type Review Center Biologic Inves0ga0onal New Drug Biological Licensing Applica0on Center of Biologics Evalua0on and Research Device Inves0ga0onal New Drug 510(K) or premarket approval Center for Devices and Radiological Health Drug Inves0ga0onal New Drug New Drug Applica0on Center for Drug Evalua0on and Research

17 Cost of Bringing a New Biological Product to Market 351 Regula0ons Requires the Cost of Conduc0ng Phase I, II and III Clinical Studies Clinical Trial in a Nut Shell Clinical Trials for Car6lage Repair: to 30 Million Dollars 17

18 Cost of Bringing a New Biological Product to Market 351 Regula0ons Requires a Standard of Compliance and Performance from the Company 18 18

19 Cost of Bringing a New Biological Product to Market 351 Regula0on Requires Hurdles of Manufacturing and Distribu0on Process Controls & Product Characteriza%on Final Product Release: Process Controls: Environmental Controls Raw Materials Tes0ng Lot Segrega0on Equipment Calibra0on Personnel Training Records and Documenta0on Validated Shipping Process Monitoring & Valida0on Sterility Endotoxin Mycoplasma Cell Number Proprietary Product Release VIP Assays : Viability Iden0ty Potency Validated Manufacturing Process 19

20 Sec0on 351 Product Example : Autologous Chondrocyte Implanta0on (ACI) Only FDA approved cell therapy for car6lage repair 1996 MAS cell guidelines released by the FDA: Car0cel BLA was submised FDA Accelerated Approval 1997 & Full Approval with updated label in 2006 Biological Treatment op0on developed in Goteburg Sweden by Prof s, Lars Peterson, Anders Lindahl and Mats Brisberg: Using cultured Chondrocytes to develop a durable repair 0ssue to treat large chondral lesions. Brittberg et al. Treatment of Deep Cartilage Defects in the Knee with Autologous Chondrocyte Transplantation, NEJM 1994

21 Sec0on 351 Products under Inves0ga0on Products Company Regulatory Pathway Novocart Aesculap Biologics, LLC HCT/P 351 Combina0on Product Cultured Chondrocytes NeoCart Histogenics HCT/P 351 Combina0on Product Cultured Chondrocytes MOA Cultured Chondrocytes seeded onto the biphasic collagen scaffold. A bio-engineered neocartilage implant Level of Evidence Commercially Available since 2002 in EU. Mul0ple Cohort Case studies Phase I & II Clinical Publica0ons 21

22 Sec0on 351 Culture expanded mesenchymal stem cells from bone marrow and other sources would be required to go through the 351 pathway Example: cells used in this study would need to go through 351 approval process

23 TRENDS & REIMBURSEMENT $$$$$

24 ORTHOPEDIC STEM CELL USE SOARED IN 2012 An es0mated 1 million U.S. pa0ents had been treated with stem cells over the course of the previous 15 years. By the end of 2012, Orthopedics This Week es0mates that that number of pa0ents treated rose by an astonishing 100,000! Physician users now number in the thousands.

25 REGENERATIVE PROCEDURES at KJOC 2013 total: 337 procedures 2015 total: 430 procedures 40 BMAC stem cell procedures for 2015 Trend showing a 33% increase in two years

26 PRP KJOC $1000 per single injec0on site tendon elbow tendon achilles tendon knee $4000 to add stem cells from bone marrow aspirate per single injec0on site

27 PRP PRICING (KNEE GURU) In NYC, I was quoted $ per knee. In Florida I have been charged $800 per knee for PRP In India it is around $125 [8000 INR] In Atlanta I paid $800 per knee Europe the max I found is 200 euros (250 dollars more or less). Birmingham, Alabama I was told last week PRP would be $200

28 Study found over 500 unregulated stem cell clinics in the USA alone 351 U.S. business engaged marke6ng of stem cell interven6ons offered at 570 clinics. Direct-to-consumer marke0ng of unapproved stem cell treatments is a well-known occurrence in other countries with lax medical regula0ons. An examina0on of Internet-based marke0ng claims revealed widespread promo0on of such interven0ons by businesses based in the United States. There is a need for beder FDA oversight in the USA Turner, L. and P. Knoepfler (2016). "Selling Stem Cells in the USA: Assessing the Direct-to- Consumer Industry." Cell Stem Cell 19(2):

29 FDA Involvement & Warning Lesers Regenexx- culture expansion of bone marrow cells: con0nuing point of care treatment s Young Medical Spa Intellicell off site processing and lack of scien0fic valida0on StemProCell- site visit with inquiry on OUS importa0on of lecithin- no ac0on to date Todd Malan, MD- site visit regarding cytori device- no ac0on to date Regenocyte- Theravitae and Intellicell; Violated Board Mandate to discon0nue stem cells while under inves0ga0on Inquiry leders- request for addi0onal scien0fic evidence Dra= Guidance Documents- December 2014 Bioheart TOBI

30 REGROW ACT 2016 The goal is to accelerate the development of biologic therapies in the US Similar to legisla0on passed in Japan Major Change : Condi0onal Use (5 year) Approval a=er Phase I and II Will it pass?

31 FDA Workshop September 8 th 2016 Public Workshop: Scien6fic Evidence in the Development of Human Cells, Tissues, and Cellular and Tissue-Based Products Subject to Premarket Approval. Purpose: Iden0fy and discuss scien0fic considera0ons and challenges to help inform the development of human cells, 0ssues, and cellular and 0ssue-based products (HCT/Ps) subject to premarket approval, including stem cell-based products.

32 FDA Public Hearing September 12 th &13 th 2016 Purpose and Scope of the Mee6ng The purpose of the public hearing is to obtain comments on the four dra= guidance documents rela0ng to the regula0on of human cells, 0ssues, and cellular and 0ssue-based products (HCT/Ps) from a broad group of stakeholders, including 0ssue establishments, biological and device product manufacturers, health care professionals, clinicians, biomedical researchers, and the public.

33 FDA Guidance's for review at mee0ng September 12 th &13 th 2016 Dra= Guidance for Industry: Same Surgical Procedure Excep0on under 21 CFR (b): Ques0ons and Answers Regarding the Scope of the Excep0on Minimal Manipula0on of Human Cells, Tissues, and Cellular and Tissue-Based Products: Dra= Guidance Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considera0ons; Dra= Guidance Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products Dra= Guidance for Industry and FDA Staff

34 Expecta0ons and discussions during FDA public hearing Interpreta0on of FDA guidance documents including adipose stem cells are a drug and that their use is o=en non-homologous. Stem cell clinics will likely push for less FDA oversight REGROW on stage? Will CIRM advocate for less FDA oversight again? What happens a=er the mee0ng ends? source:

35 Coding and Reimbursement Issues for Articular Cartilage Treatment

36 ARTICULAR CARTILAGE ICD-10 DIAGNOSTIC CODES M M23.92 Internal Derangement Knee M M OCD Knee M M Other Specified Osteochondropathies Lower Leg M94.8X6 Other Specified Disorders of Cartilage Lower Leg

37 ARTICULAR CARTILAGE ICD-10 CODES Unspecified internal derangement Unspecified disorder of joint Osteochonditis Dissecans Disorder of bone and cartilage M (2) Chondromalacia Knee M22.41 (2) Chondromalacia Patella Tear medial meniscus Tear lateral meniscus

38 ARTICULAR CARTILAGE Modifiers CODES 59 is used to identify a distinct procedural service Separate incision or lesion Separate compartment Separate injury 22 is for extraordinary situation ( ie,obesity) Must document with cover letter

39 ARTICULAR CARTILAGE SURGICAL CODES CPT Chondroplasty/Debridement CPT Removal of Loose Body CPT Microfracture CPT Arthroscopic Osteochondral Autograft CPT Arthroscopic Osteochondral Allograft CPT Open Osteochondral Allograft CPT Open Osteochondral Autograft

40 ARTICULAR CARTILAGE SURGICAL CODES CPT OCD drill intact lesion CPT OCD intact lesion with internal fixation CPT OCD with bone graft with or without internal fixation

41 ARTICULAR CARTILAGE SURGICAL CODES CPT Autologous Chondrocyte Implantation CPT Meniscal Transplantation CPT Osteotomy after epiphyseal closure CPT Anterior Tibial Tubercleplasty CPT Arthroscopy with biopsy

42 ARTICULAR CARTILAGE SURGICAL CODES CPT Arthrosurface Trochlea CPT Arthrosurface Patella CPT Unicompartmental Knee

43 ARTICULAR CARTILAGE SURGICAL CODES INVESTIGATIONAL CPT unlisted knee (DeNovo,Biocartilage, Trufit plugs, etc.) CPT open autograft talus CPT unlisted foot or toes CPT arthroscopically aided repair OCD talus CPT unlisted arthroscopy repair of other joints

44 ARTICULAR CARTILAGE SURGICAL CODES HCPCS J7330: Autologous cultured chondrocytes,implant HCPCS S2112: Arthroscopy knee for harvesting of cells

45 ARTICULAR CARTILAGE REIMBURSEMENT FDA approval does not imply payer coverage

46 ARTICULAR CARTILAGE REIMBURSEMENT Hospital or Surgicenter Problems Global Contract for services Differs for different payors Differs for different geographic areas

47 ARTICULAR CARTILAGE REIMBURSEMENT Surgical Implant and Disposable Costs Shaver ( $ ) RF Device ( $ ) Osteochondral autograft kit ( $ ) Osteochondral OBI kit ($225 ) Osteochondral allograft kit (Rental) Chondral pins/screws ( $695 ) Meniscal repair implants ( $ )

48 ARTICULAR CARTILAGE REIMBURSEMENT IMPLANT MATERIALS Osteochondral allografts ($9,950) Meniscal allografts ($4,750) ACL allografts ($2,500) Osteotomy implants ($795) Cell implants Carticel was ($20,000) Carticel now ($0) 3 rd Party Payor Program Denovo ($3,500) Arthrex Biocartilage ($1,000)

49 ARTICULAR CARTILAGE REIMBURSEMENT DME s Braces Cold Therapy Pain pumps Viscosupplementation Medications Physical Therapy

50 General Criteria for Cartilage Repair Age years Disabling localized knee pain for six months which has failed conservative treatment An intact meniscus is present Lesion must be discrete, single and unipolar Lesion is largely contained with near normal surrounding cartilage (Gr 0,1,2)

51 General Criteria for Cartilage Repair A normal joint space is present No active infection No osteoarthritis or inflammation Knee is stable with normal mechanical alignment Patient can comply with postoperative restrictions for wt. bearing

52 General Criteria for Cartilage Repair No history of cancer in bones fat or muscle of affected limb Body Mass Index (BMI) of < or = to 30

53 ACI Criteria Inadequate response to prior surgery Defect size > or = to 1.5cm sq Cartilage only defect No allergy to gentamicin, bovine cultures Focal, full thickness (Gr. III or IV) isolated to MFC,LFC trochlea Defect from acute or repetitive trauma ALL General Criteria met

54 ALL General Criteria met Osteochondral Autograft Criteria Arthroscopic or MRI examination Defect size between 1.0 to 2.5cm sq Focal, full thickness (Gr.III or IV) isolated to MFC,LFC or trochlea Defect from acute or repetitive trauma

55 Osteochondral Allograft Criteria Arthroscopic or MRI examination Defect size = or > 2.0cm sq Focal, full thickness (Gr. III or IV) isolated to MFC,LFC or trochlea Defect from acute or repetitive trauma ALL General Criteria met

56 Investigational Procedures ALL procedures on joints other than the knee ANY procedure that does not meet ALL of the criteria ALL use of non-autologous synthetic bone filler materials ALL use of minced cartilage

57 CONCLUSIONS Get involved early in your career with the business end of what you do Be a leader and embrace industry as your partner to help improve your practice and improve your patients outcomes

58 THANK YOU

59 CURRENT CHALLENGES & FUTURE OF ORTHBIOLOGICS REGULATION

60 Recent Case Study: Perils of Unregulated stem cell therapy

61 Recent Case Study Chief Complaint: Recurrent L knee effusion, swelling HPI: 24 year old male who presents with recurrent knee effusion and swelling. Pa0ent received injec0on in L knee in Gualadajara, Mexico on 2 weeks prior. Past Medical History: has a past medical history of Bipolar disorder (HCC). Past Surgical History: congenital clavicle malforma0on surgery at age 4 Social History: denies tob/etoh

62 Recent Case Study Per pa0ent injec0on contained platelet rich plasma and placental stem cells. Since injec0on pa0ent has complained of recurrent effusions and L knee pain and swelling. Knee has been aspirated mul0ple 0mes with WBC counts ranging from 10-19k, all cultures nega0ve to date. All aspira0ons have yielded blood 0nged fluid. He presented to the ED today with recurrence. Denies fever or chills.

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