Ibc cell therapy clinical development conference (arlington va september 10 11 2012)v.4
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Ibc cell therapy clinical development conference (arlington va september 10 11 2012)v.4
- 1. Cell Therapy Clinical Trials: Why They Fail IBC Inaugural Cell Therapy Clinical Development Conference Arlington, Virginia Gregory A. Bonfiglio Proteus Venture Partners September 10, 2012
- 2. Agenda I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies I. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory Hurdles IV. Case Studies Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 2
- 3. RM Has Entered A New ERA RM Market is Maturing: Key Metrics Rapidly Expanding Market: • $1.6B in 2010 Commercial Products • $20.0B in 2025 • 400 on Market (Mostly Skin, Tools Media, & Devices); • CAGR of 18.34% – 900+ in Development Dramatic Revenue Growth • $130M in 2001 1.2M+ Patients Treated with RM Products. • $1.6B+ in 2010 Worldwide funding for research RM Companies Increasing • 700+ Co’s involved in RM • $2.5B Now • 60+ Public Co’s; • $14B in 10 Years – $8.7B Total Market Cap Clinical Programs • 225+ Private Co’s • Over 4100 Clinical Trials • Over In 650 Late Stage Trials CONFIDENTIAL 3
- 4. Global Company Distribution Canada UK 133 firms Europe 24 firms (ex. UK) 3% 19% 14% 93 firms Asia 56% 2% 32 firms 5% Middle East 17 firms USA 386 firms 700+ RM companies worldwide! CONFIDENTIAL 4
- 5. The Role of Cell Therapy: 1st Regenerative Medicine Cell Therapy: Key Metrics Established Technology : • 40+ Years in Clinical Practice 320,000+ Patients Treated • 1st Bone Marrow Transplant: 1968 – Acute Lymphoblastic Commercial Products Leukemia (ALL) • 44 Cell Therapies on Market • 1st Cord Blood Transplant: 1988 – $1B Revenues – Fanconi Anemia Dramatic Revenue Growth Clinical Programs • 22,500+ Clinical Trials (Cell • $410M in 2008 Therapy) • $5.1B+ in 2014 – Vast Majority are HSCs in Oncology • 52.22% CAGR – 2800+ “New” Cell Therapies – 560+ in PIII/Pivitol Trials CONFIDENTIAL 5
- 6. The Role of Cord Blood: Fastest Growing Segment of CT Market Cord Blood Key Metrics Market Size: Fastest Growing Segment of Cell • $3.4B (2010) Transplant Market • $14.9B (2015) • 22% of All Cell Transplants in 2010 • CAGR: 27.9% • 40% by 2015 Cord Blood Banks: Total Cord Blood Transplants: 25,000 • 150+ Private Banks in 43 Countries • 44 Public Banks • 1,500 per year (2005) • 26 Countries • 3,000 per year (2010) Total Cord Blood Units Stored • 10,000 per year (2015) • 500,000 Units in Public Banks • 1M+ Units in Private Banks Therapeutic Applications • 60+ in Clinical Practice Clinical Trials • Leukemia; Lymphoma; Blood • Over 650 FDA Clinical Trials Disorders; Hematopoietic – 450+ New Therapies Restoration – 96 Pivotal/PIII Trials CONFIDENTIAL 6
- 7. Cell Therapy Market: Expanding Rapidly (50%+ CAGR) Dramatic Cell Therapy Revenue Growth CTI Revenues: $410M (2008) - $5.1B (2014) Cell Therapy Industry: Billion Dollar Global Business With Unlimited Potential; Regenerative Medicine; Chris Mason, David Brindley, Emily J Culme-Seymour & Natasha L Davie CONFIDENTIAL 7
- 8. Agenda I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies I. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory Hurdles IV. Case Studies Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 8
- 9. “Cell Therapies” in Clinical Development: 19,430+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 9
- 10. “New” Cell Therapies In Clinical Trials 2,800+ FDA Trials Involve “New” Cell Therapies Refining the Data • Remove Oncology Trials o Bone Marrow/Cord Blood/ Mobilized Blood Progenitor Cells • Remove Tissue Engineering Trials • Result: 2,800+ “New” Cell Therapy Trials Open Studies, Without Results: 1,360 Late Stage Trials: 560+ • Phase III: 460+ Trials • Phase IV: 90+ Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 10
- 11. FDA Cell Therapy Clinical Trials by Phase Vast Majority of Cell Therapy Trials Are in “Early Stage” 40% 49% Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: A decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012); CONFIDENTIAL 11 ClinicalTrials.gov (www.clinicaltrials.gov)
- 12. FDA Cell Therapy Clinical Trials by Cell Origin No Clear Preference for Autologous or Allogeneic Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: A decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012); CONFIDENTIAL 12 ClinicalTrials.gov (www.clinicaltrials.gov)
- 13. FDA Cell Therapy Clinical Trials MOA: Engraftment vs. Transient Most of the Cell Therapies Are Transient 9% 5% 37% 50% Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: A CONFIDENTIAL 13 decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012); ClinicalTrials.gov (www.clinicaltrials.gov)
- 14. FDA Cell Therapy Clinical Trials by Cell Type (2010) The Top 5 Cell Types Make Up 88.6% Of All Studies CONFIDENTIAL 14
- 15. FDA Trials Involving MSCs (2010) MSCs in Wide Range of Therapeutic Applications Source: Alan Trounson et al. BMC Medicine 2011 9:52 doi:10.1186/1741- 7015-9-52 CONFIDENTIAL 15
- 16. Agenda I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies I. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory Hurdles IV. Case Studies Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 16
- 17. FDA Clinical Trial Process CONFIDENTIAL 17
- 18. FDA Clinical Trials: Key Metrics (2012) Overall Failure Rate (2012): 84.7% Size Failure Length Purpose (# Pts.) Rate 6-9 Phase I 20–100 Months Primarily Safety 53% Up To Short Term 9 Months Phase II Several -2 Years Safety; Mainly 77% 100 Effectiveness 100s – Safety, Dosage & Phase III Several 1-4 Years Effectiveness 41% 1000 Source: PARAXEL Biopharmaceutical R&D Statistical Sourcebook (2012/2013); Tufts Center for the Study of Drug Development, http://csdd.tufts.edu (Tufts CSDD) CONFIDENTIAL 18
- 19. FDA Approval Rates for All Compounds (1993-2004): 16% Overall Failure Rate (1993-2004): 84% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295 CONFIDENTIAL 19
- 20. Approval Rates Vary Substantially By Therapeutic Application CNS Approval Rate: 8.2% vs. Anti-Infective: 23.9% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295 CONFIDENTIAL 20
- 21. Large Molecule Approval Rates Are @3X Higher Than Small Molecules Overall Success Rate (1993-2004): 32% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295 CONFIDENTIAL 21
- 22. Key Reasons for Late Stage Failures: Efficacy; Safety; Finances Failures in Phase II Failures in Phase III Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083 CONFIDENTIAL 22
- 23. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Technology Failures 1. Efficacy FDA Trials: 50%+ Efficacy Related Failures Cell Therapies Efficacy Rates Should Be Better o Significant Pre-Clinical Data Developed in Academic Settings o Often Have Patient Data o Expect “Large Molecule” Approval Rates: 34% 2. Safety FDA Trials: 30-40% Safety Related Failures Cell Therapies Do Not Present the Same Risk Profile o Limited Risk of Systemic Toxicity o But GvHD; Tumorgenicity; Arrhythmias (Cardio) Are Safety Failure Modes CONFIDENTIAL 23
- 24. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Clinical Trial Design 1. Poorly Chosen Endpoints Primary & Secondary o E.g.: Disease Progression vs. Overall Survival Difficult To Measure Clinical Benefit Objectively 2. Inappropriate Patient Population Broad Patient Base vs. Targeted Application 2. Discontinuity b/w Research & Commercial Processes • Lose “Magic” When Manufacturing Process Is Optimized for Commercial Production 2. Control Group Issues Failure to Anticipate Benefit in Clinical Setting Bias CONFIDENTIAL 24
- 25. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Clinical Trial Management 1. Lack of Clinical Operations Experience Most CT Trials Conducted by Start Ups or Academics Limited Pharma Involvement 2. Patient Enrollment Inappropriate Inclusion/Exclusion Criteria Inadequate Supply of Patients 80% of Clinical Trials Fail to Meet Their Enrollment Goals 3. Data Management Poor Data Capture/Entry 3. Bias Investigator Bias; Reporting Bias CONFIDENTIAL 25
- 26. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Funding 1. Very Challenging Funding Environment 2. Limited Capital Available 3. Inadequate Resources To Correct For Errors, or Re-Design Trials Regulatory Hurdles 1. Regulatory Framework Evolving 2. Some Key Parameters Unclear e.g. Data Necessary to Establish Safety 3. Regulatory Agencies Climbing Learning Curve CONFIDENTIAL 26
- 27. Agenda I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies I. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory Hurdles IV. Case Studies Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 27
- 28. Geron’s hESC Spinal Cord Trial November 14, 2011 Geron Halting Stem Cell Research, Laying Off Staff, Stem Cell Pioneer Exits Field Geron exiting such research, laying off staff, to focus on cancer drug tests MENLO PARK, Calif. (AP) -- Money troubles have forced the first company doing a government- approved test of embryonic stem cell therapy to discontinue further stem cell programs and lay off much of its staff. >>>>>>> In a statement, the company said the decision to narrow its focus "was made after a strategic review of the costs, ... timelines and clinical, manufacturing and regulatory complexities associated with the company's research and clinical-stage assets.". CONFIDENTIAL 28
- 29. Geron’s hESC Spinal Cord Trial Reasons for Failure: Regulatory Hurdles & Finances Geron Finances hESC Clinical Program •Went Public in 1996 •Halted SPI Trial After 4 Patients o Raised Over $500M Treated • 52 Week Market Range: 70% •Also Halted Programs in Drop (2011) Diabetes, Cardio, Cartilage & o Stock Price: $6.12 -- $1.82 Immunotherapy o Market Cap: $790M -- $239M • Cash Position: $142M • Relationship With CIRM o Monthly Burn: $6.5M oTerminated $25M Funding Agreement • Spent Over $200M on hESC oReturned $6.4M to CIRM Programs CONFIDENTIAL 29
- 30. Dendreon’s Provenge: Autologous Dendritic Cell Immunotherapy Recombinant APC takes Antigen is The mature antigen- PAP- up the processed and loaded APCs are the GM-CSF antigen displayed on active component of antigen surface of the sipuleucel-T combines with APC resting APC INFUSE Inactive Active PATIENT T-cell T-cell T-cells Sipuleucel-T proliferate and activates T- attack cells in the prostate cancer body cells CONFIDENTIAL 30 Source: David Urdal (2011)
- 31. Dendreon’s Provenge: Autologous Dendritic Cells for Late Stage Prostate Cancer Death Chemotherapy Castration 1 st targeted Tumor patients volume Local & Therapy activity Asymptomatic Symptomatic Non-Metastatic Metastatic Androgen Dependent Castrate Resistant Time CONFIDENTIAL 31 Source: David Urdal (2011)
- 32. Dendreon’s Provenge: Phase III Clinical Trial Design & Results Reasons for Failure: Poorly Chosen Endpoints Phase III Trial – 3 Arms FDA Action •1st & 2nd Arms: •1st & 2nd Arms: Refused o Patient Population: Asymptomatic, Metastatic to Grant Approval on Prostate Cancer Patients Secondary Endpoints o Endpoints: o Primary: Time to Disease Progression o Secondary: Overall Survival o Results: Failed Primary; Met Secondary •3rd Arm: Granted •3rd Arm: Approval on Primary Endpoint in o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients o Overall Survival o Endpoints: o Primary: Overall Survival o Secondary: Time to Disease Progression o Results: Met Primary; Failed Secondary CONFIDENTIAL 32
- 33. Intercytex Cyzact: Autologous Fibroblasts For Venous Leg Ulcers CONFIDENTIAL 33 Source: Paul Kemp (2010))
- 34. Intercytex Cyzact: Autologous Fibroblasts For Venous Leg Ulcer Reason for Failure: Patient Population; Control Issues Cyzact Phase III Trial FDA Action •Initial Patient Population: Patients With •Refused to Grant Severe Venous Leg Ulcer Approval •Primary Endpoint: Complete Healing At 12 Weeks •Insufficient Showing of •Supplemental Patient Population: Patients Efficacy Against SoC on With Moderate Venous Leg Ulcers Secondary Endpoints from •Control: Traditional Bandage (SoC) 1st & 2nd Arms •Results: Failed To Meet Primary Endpoint o Failed to Properly Account for Efficacy of Traditional Bandage in a Clinical Setting o Expanded Patient Population Diluted Efficacy CONFIDENTIAL 34
- 35. Osiris Prochymal: MSCs For GvHD (and Crohn’s) CONFIDENTIAL 35
- 36. Osiris Prochymal: MSCs For GvHD & Crohn’s Reasons for Failure: Clinical Trial Design Prochymal Trials Regulatory Action •GvHD Trial: •GvHD: FDA Refused to o Patient Population: Asymptomatic, Metastatic Grant Approval (2010) Prostate Cancer Patients o Inadequate Showing o Endpoints: of Efficacy o Primary: Time to Disease Progression o Secondary: Overall Survival •Health Canada Approves o Results: Failed Primary; Met Secondary Prochymal for Pediatric GvHD (May 2012) •Crohn’s Trial o Patient Population: Asymptomatic, Metastatic Prostate •Crohn’s: Trial Suspended Cancer Patients in 2009 o Endpoints: o Resumed Enrollment o Primary: Overall Survival o Secondary: Time to Disease Progression in May 2010 o Issue: Significant “Placebo Effect” – Patient Reporting CONFIDENTIAL 36
- 37. The Final Word CONFIDENTIAL 37 CONFIDENTIAL 37
- 38. APPENDIX CONFIDENTIAL 38
- 39. Proteus: An Investment and Advisory Firm Focused on RM Proteus, Inc. Proteus Proteus Proteus Management, LLC Insights, LLC Advisors, LLC (Fund Management) (Consulting Services) (Investment Banking Services) CONFIDENTIAL 39
- 40. Cell Therapy Products Involve Various Technology Combinations Technology Requirements: Examples CNS Myocardial Cell Orthopaedic Islet Cell Replacement Replacement Replacement Replacement Cells Embryonic Cardiac progenitor cells Chondrocytes Islet cells stem cells Bone marrow cells Bone marrow cells Progenitors Cell harvester Implantation & Device +/- Catheter +/- Catheter & concentrator encapsulation Immunotherapy? Drug / Biologic (for allo cells) Immunotherapy? Immunotherapy? Biomaterials 3D Scaffolds? 3D Scaffolds 3D Scaffolds Scott Bruder, BD; MSC Conference (2011) CONFIDENTIAL 40
- 41. Stem Cells in Clinical Development: 4100+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 41
- 42. Clinical Trials Involving “Stem Cells” and “Cell Therapy” - 3800+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 42
- 43. Cord Blood Therapies in Clinical Development: 600+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 43
- 44. Density Of Clinical Trials Worldwide Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083 CONFIDENTIAL 44
- 45. Phase II & III Failures (2007–2010): “Unsustainably High” Phase II Failures in 2008–2010: 82% Phase III Failures in 2007–2010: @ 50% John Arrowsmith: Nature Reviews Drug Discovery 10, 328-329 (May 2011); doi:10.1038/nrd3439; Nature Reviews Drug Discovery 10, 87 (February 2011) | doi:10.1038/nrd3375 CONFIDENTIAL 45
- 46. FDA Drug Approvals Per Year (1996-2010) Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083 CONFIDENTIAL 46
- 47. FDA Clinical Trials Involving “Cell Therapy” s a r Tl ac nl C l i i i Year CONFIDENTIAL 47 www.ClinicalTrials.gov (excludes cancer studies); Scott Bruder, BD
- 48. FDA Clinical Trials Involving “Stem Cells” s a r Tl ac nl C l i i i Year www.ClinicalTrials.gov (excludes cancer studies); CONFIDENTIAL 48 Scott Bruder, BD
- 49. Key Failure Modes: Lack of Funding Probability: Probability: Probability: Probability 66% 70% 40% of success Steps Basic & Discovery Preclinical Preclinical Clinical Clinical Clinical Market Research Research Development Phase I Phase II Phase III 1-3 years 1.4-1.8 year 2.5-3.8 years Outcome Proof of Concept. Therapeutic IND Safety Efficacy Product Candidate Release Investment PI PII PIII $75=100MM Amount $5-10MM $10-15MM $20-25MM $50-75MM Actors Grants to Universities Venture IPO & Partnering & Research Deals Investments • Average Time to Market: 10-15 Years Institutes, • Average Costs: $1.3B+ Key • Failure Rate: @ 90% • Less than 30% of approved drugs recoup M etrics: development costs CONFIDENTIAL 49
- 50. Key Failure Modes: Lack of Funding Coming Out (?) of the Worst Financial Crisis in 75+ Years CONFIDENTIAL 50
- 51. CT Business Models: Autologous v. Allogeneic Autologous Model Allogeneic Model Patients Own Cells/Tissue Universal Cells in a Bottle • Personalized Medicine • Big Pharma “Drug Model” • Provenge: Autologous Treatment for Advantages: Advantages: Prostate Cancer Using Dendritic Cells • Easier Regulatory Path • Scalable (GTP) - Centralized Processing COGS • Low • No Immune Response • $93K per Treatment Challenges: Challenges: - $350K+ Projected Revenues Regulatory • More Difficult • Difficult to Scale Path • High COGS• $725M Market Cap ($5.0B in 2011) • Immune Response Service vs. Product CONFIDENTIAL 51
- 52. Dendreon’s Provenge: Manufacturing & Treatment Protocol Day 1 Day 2-3 Day 3-4 Leukapheresis Provenge is manufactured Patient is infused Patient Patient Provenge Provenge Apheresis Center Dendreon Doctor’s Office Three Treatments (On Weeks 0, 2, 4) CONFIDENTIAL 52 Source: David Urdal (2011)
- 53. Provenge: Two Phase III Arms Failed To Meet The Primary Endpoint But Showed Improvement In Overall Survival Phase III Targeted Endpoints (Provenge vs Placebo) Patients 127 asymptomatic, 1ary: Time to D9901 D9902A metastatic androgen disease independent prostate progression No statistical significant delay in time to cancer patients 2ary: overall disease progression survival Death Chemotherapy Castration Targeted Endpoints phases Patients Tumor 3 98 asymptomatic, 1ary: Time to Local D9901 volume Therapy and metastatic androgen disease & D9902A activity independent prostate progression cancer patients 2ary: overall Asymptomatic Symptomati c survival Non-Metastatic Metastatic Androgen Castrate Resistant Dependent Time CONFIDENTIAL 53
- 54. Provenge: FDA Refused To Approve BLA Based On Secondary Endpoint (Overall Survival) Phase III D9901 D9902A (1ary endpoint time to (1ary endpoint time to disease progression) disease progression) Submission of the overall survival data for a FDA’s answer in May 2007 BLA • “the lack of pre-specified primary method for survival analysis rendered it impossible to estimate the Type I error (statistical persuasiveness) for this survival difference” • “under-representation of the African American population should be addressed” • “Request of additional clinical data to support the overall survival efficacy claim” CONFIDENTIAL 54
- 55. 3rd Phase III With Overall Survival (1ary Endpoint) And With Extension Of Population To More Serious Patients Chemotherapy Phase III Castration Death phases D9901 D9902A 3 D9901 (1ary endpoint time to (1ary endpoint time to Tumor and Local disease progression) disease progression) volume Therapy D9902A & activity IMPAC T Asymptomatic Symptomati FDA refuses BLA c Non-Metastatic Metastatic Phase III Androgen Castrate Resistant Dependent IMPACT Time (1ary endpoint overall survival) Targeted Endpoints Patients 512 Asymptomatic and 1ary: Overall minimally metastatic survival androgen independent 2ary: Time to prostate cancer patients disease progression CONFIDENTIAL 55
- 56. FDA Approved BLA For Provenge Based On IMPACT Trial Results Phase III D9901 D9902A (1ary endpoint time to (1ary endpoint time to disease progression) disease progression) FDA refuses BLA Phase III IMPACT (1ary endpoint overall survival) FDA’s answer in April 2010 Submission of IMPACT data (showing 4.1 • Approval of BLA: IMPACT results met 1ary month overall survival improvement) for a endpoint of overall survival and exhibits BLA safety profile CONFIDENTIAL 56
- 57. Provenge: Primary Reasons For Failure of the 1st & 2nd Arms of the Phase III Trial • Failed To Meet Primary Endpoint (Time To Disease Progression) • Submitted Retrospective Analysis (On Overall Survival Improvement Which Was The 2ary Endpoint And Not The 1ary Endpoint) o FDA Generally Does Not Accept This Retrospective Analysis • Did Not Adequately Select Primary Endpoint And Did Not Explore Endpoint In Early Clinical Trials (E.G. Phase 2 Trial) o FDA Of Prefers Primary Clinical Endpoint Over Seceondary Endpoint • Did Not Target A Representative US Patient Population o Patient Population in the Trial Must Be Sufficiently Large To Represent The US Patient Population Adequately • Poor Choice Of Patient Population (Included Extreme Patients) CONFIDENTIAL 57 Source: Joyce Frey (2011)
- 58. Cyzact : 1st Stage: Intercytex Enrolled Very Ill Patients Phase III Targeted Endpoint Arm 1 Arm 2 Patients Cyzact with Control: • 396 patients with 1ary: complete compression compression venous leg ulcer healing at 12 bandaging bandaging with at least 3 weeks months duration • With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month Intercytex action • Intercytex enrolling extreme cases of venous leg ulcer patients CONFIDENTIAL 58
- 59. Cyzact 2nd Stage: Intercytex Enrolled Moderate Patients, To Increase The Rate Of Healing Phase III Arm 1 Arm 2 Data Safety Monitoring Board said Cyzact with Control: compression compression • “continue the trial and enrol more patients: bandaging bandaging the control arm is achieving a higher rate of healing than expected” Intercytex action • Under the pressure of investors, Intercytex rushed to quickly enroll patients but Intercytex enrolled different type of patients (i.e. not only extreme patients but also easy to heal patients) CONFIDENTIAL 59
- 60. Result: Cyzact Failed To Meet Primary Endpoint Phase III Arm 1 Arm 2 FDA’s answer in 2008 Cyzact with Control: compression compression • Failed to meet primary endpoint: no bandaging bandaging statistical difference between Cyzact (Arm 1) and Control (Arm 2) No statistical difference No further work on Cyzact planned Intercytex thoughts • Should have enrolled only extreme patients (i.e. patient with venous leg ulcers that had decreased in size by less than 10% in one month instead of 30%) and this would have enabled to show difference between Cyzact arm and control arm CONFIDENTIAL 60
- 61. Cyzact: Primary Reasons For Phase III Failure • Did Not Adequately Select Patient Population o Intercytex Selected Both Extreme And Non Extreme Patients Instead Of Only Focusing On Extreme Patients • Rushed To Enroll Patients To Obtain Phase III Results o The Company Enrolled Diverse Type Of Patients Who Were Reacting Differently With The Control • Underestimated The Control Efficacy In A Clinical Trial Setting o The Control With The Compression Bandaging Showed Better Efficacy Results In The Clinical Trial Setting Than In The Usual Setting CONFIDENTIAL 61
Notes de l'éditeur
- Talk to drug developers about clinical trials and one word comes up repeatedly—unsustainable. The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable. What's most distressing is the large number of compounds that earn kudos in phase 2 only to fizzle out in one of those big, outrageously expensive phase 3 trials
- http://clinicaltrials.gov/: “ Stem Cells ” search = 4184 Trials (September 2012) TriMark: $3 billion in 2010; expected to reach $4.5 billion by 2014 = 10.67% CAGR Scientia Advisors: $1.6 billion in 2010; expected to be $15-20 billion by 2025 = 18.34% CAGR Visiongain: $0.82B in 2010; excepted to reach $8.84B in 2021 = 24.13% CAGR Dr. Alain Vertes (Roche) RM Market: $410M (2008); $2.6B (2012); $5.0B (2014) [51.7% CAGR] Chris Mason Cell Therapy Market: $200M (2009); 323,000 Patients treated with Cell Therapies FDA Website (July 2010): 3100 + trials involving “stem cells” Vast majority are in cancer: 2270 lukemia (1129) + lymphoma (1149) 150+ studies in Cardio 2121 involve hematopoietic stem cell transplant
- Cell Therapy Revenues (2008–2014): $410M (2008) -- $5.1B (2014); 52.22% CAGR Chris Mason Cell Therapy Market: $200M (2009); 323,000 Patients treated with Cell Therapies FDA Website (August 2012): 19,450+ + trials involving “Cell Therapy” FDA Website (August 2012): 4172 + trials involving “stem cells” FDA Website (August 2012): 3300 + trials involving “stem cells” & “Cell Therapy” Vast majority are in cancer: 2270 lukemia (1129) + lymphoma (1149) 150+ studies in Cardio 2121 involve hematopoietic stem cell transplant 459 trials in PIII or PIV; Conditions Addressed: Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or before Birth Eye Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Mouth and Tooth Diseases Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Substance Related Disorders Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases Wounds and Injuries
- A September 2012 search for “Cord Blood” on the FDA Website re Clinical Trials (http://clinicaltrials.gov/) nets 667 trials – 450+ involving cord blood therapeutics; 96 trials in Phase III or Phase IV. Average Fees: Private Banks $1,750 Initial Collection & Storage; Range: $890 - $2300 $125 Annual Fee; Range: $85-$150 Average Fee: Public Banks: $35,000 per Unit (US/EU) Public Bank Utilization Rate: 1-3% of Units per year
- Cell Therapy Revenues (2008–2014): $410M (2008) -- $5.1B (2014); 52.22% CAGR Graph showing the estimated CTI revenues from 2008–2014 † , together with the value of the regenerative cell therapy market estimated for 2009–2010, based on actual sales of US FDA/EMA approved products ‡ . † Data taken from: Evers P: Advances in the Stem Cell Industry . Global Business Insights (2009). ‡ Data taken from: Mason C, Manzotti E: Regenerative medicine cell therapies: numbers of units manufactured and patients treated between 1988 and 2010. Regen. Med. 5(3),307–313 (2010).
- Failure Modes Analysis Assumes that the Technology is Safe & Effective Talk to drug developers about clinical trials and one word comes up repeatedly—unsustainable. The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable. What's most distressing is the large number of compounds that earn kudos in phase 2 only to fizzle out in one of those big, outrageously expensive phase 3 trials
- Search of ClinicalTrials.gov: “Cell Therapy”: 19,450+ FDA Clinical Studies Involve Cell Therapies: (by Category) Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or before Birth Ear, Nose, and Throat Diseases Eye Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Mouth and Tooth Diseases Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Occupational Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Substance Related Disorders Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases Wounds and Injuries
- Vast Majority of Trials are in Phase I and Phase II (89%) The other 1% were Phase 0, defined as ‘those trials that were not listed as Phase 1 and described as pre-clinical’ Over 10% are “Late Stage” trials Influenced by large amount of autologous therapies (i.e. high safety data) Early proof of concept often can be demonstrated as Phase 1 secondary end-point – therefore more progress on cf. small molecule drugs/biologics
- Number of trials using each is approximately equal. No clear preference for autologous or allogeneic, despite vastly different processing & regulatory requirements ‘ Auto/Allo’ in the figure used EITHER a combination of autologous and allogeneic cells in a single product, OR trials involved both types of cell Only twelve of the nearly 2000 trials used xenotransplant-based procedures (including the sole administration of xenograft cells as well as human cells grown in association with animal cells). General lack of confidence in developing xenograft products & ethical considerations.
- Most CTs in clinical trial development are products that will elicit a temporary response when given to the patient. 50% of the trials involved cells that are eliminated in typically a number of days/weeks after implantation, i.e., of transient in vivo nature. Conversely, only 5% of therapies were defined as a permanent implantation, where the administered cells or their progeny remain in vivo for over a number of years.
- 2011 Data This captures most all of the cell types in some sort of clinical study But take a look at the top 5 The top 5 88.6% of all ongoing trials and they ’re also the 5 most sponsored by industry. What could this mean? These are targets for co-creation but I ’ll come back to that later
- Diseases being addressed using mesenchymal stem cells (MSC) for clinical trials (n = number of trials) . Trounson et al. BMC Medicine 2011 9 :52 doi:10.1186/1741-7015-9-52 Mesenchymal stem cell (MSC) clinical trials by clinical phase (n = number of trials) . Trounson et al. BMC Medicine 2011 9 :52 doi:10.1186/1741-7015-9-52 The public clinical trials database http://clinicaltrials.gov webcite shows 123 clinical trials using MSCs for a very wide range of therapeutic applications (Figure 1 ), the majority of which are in Phase I (safety studies), Phase II (proof of concept for efficacy in human patients), or a mixture of PhaseI/II studies (Figure 2 ). This includes bone and cartilage repair, cell types into which MSCs readily differentiate, and immune conditions such as graft versus host disease and autoimmune conditions that utilize the MSC's immune suppressive properties. Expectations for patient benefits are high in these therapeutic applications. Nevertheless, there are many prospective applications where the mechanism of action is not obvious and some concerns have been expressed about the likelihood of long-term benefit of these applications. In the case of allogenic MSCs, delivery to an inflamed site can result in gain of immune potency with accelerated damage due to a heightened immune-mediated inflammatory response [ 5 ].
- Failure Modes Analysis Assumes that the Technology is Safe & Effective Talk to drug developers about clinical trials and one word comes up repeatedly—unsustainable. The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable. What's most distressing is the large number of compounds that earn kudos in phase 2 only to fizzle out in one of those big, outrageously expensive phase 3 trials
- FDA Clinical process is Well Known
- Aggregate Data from Several Studies conducted from 2004-2012 Source: PARAXEL Biopharmaceutical R&D Statistical Sourcebook (2012/2013); Tufts Center for the Study of Drug Development, http://csdd.tufts.edu ( Tufts CSDD )
- Phase transition probabilities and clinical approval success probabilities for self-originated compounds by period of first-in-human testing. BLA, biologics license application; NDA, new drug application . Success-rate trends Figure 1 shows estimated phase transition probabilities and the overall clinical approval success rates for the 1993–1998 and the 1999–2004 subperiods. The results do not suggest any trend in the overall clinical approval success rates for new drugs over this period; estimates showed that approximately one in six new drugs that entered clinical testing during each of these subperiods was eventually approved for marketing. However, there were small differences between the two subperiods with respect to the estimated clinical phase transition rates. The results suggest that the failures occurred somewhat earlier in the clinical trial process (phases I and II) for drugs initiated into clinical trials during the later subperiod. There are at least two good reasons for the generally higher clinical approval success rates for licensed-in compounds. First, these compounds have generally undergone some screening or testing prior to licensing and have been shown to be promising candidates for marketing approval. Thus, there may be a screening effect for new drugs that are licensed-in. Second, it is likely that many of these licensed-in drugs were acquired after some clinical testing had been done on them. Although drugs may be licensed-in at any point during the development process, including during the preclinical period, later clinical phases are associated with higher approval rates. We do not have data on when in the development process each of the licensed-in drugs was acquired, but if, for example, the average licensed-in drug was acquired at phase II, then we would expect higher clinical approval success rates for the licensed-in group for that reason alone.
- Table 3. Phase transition and clinical approval probabilities by therapeutic class for self-originated compounds first tested in humans from 1993 to 2004 . Success rates by therapeutic class Prior research has shown that success rates for new drugs vary by therapeutic class. We also found, as we have in the past, that clinical approval success rates differ by therapeutic class in any given period. Our analysis of self-originated drugs found estimated clinical approval success rates that varied from 8% for CNS drugs to 24% for systemic anti-infectives. This variability in success rates by therapeutic class might be explained, at least partially, by differences in the uncertainty (inherent in the differing scientific objectives and underlying science knowledge base) about the regulatory standards that must be satisfied for different drug classes. For example, efficacy end points for antibiotics are often clearly defined and can be assessed in a relatively straightforward way . In contrast, it can often be difficult to prove the efficacy of psychotropic compounds, or to establish causal links between these drugs and side effects. Table 3 shows the estimated phase transition and clinical approval success probabilities for the seven therapeutic classes and one miscellaneous category. There was substantial variability by class for both the phase transition probabilities and the clinical approval success rates. More than 70% of the self-originated drugs in the antineoplastic, musculoskeletal, and respiratory categories moved from phase I testing to phase II testing, whereas fewer than 60% of the self-originated drugs in the systemic anti-infective and central nervous system (CNS) categories did so. One-third or fewer of the self-originated drugs in the respiratory, cardiovascular, and CNS categories proceeded from phase II to phase III testing, but nearly half of the antineoplastic/immunologic drugs moved from phase II trials to much more expensive phase III testing. However, once antineoplastic/immunologic drugs reached phase III, they had a relatively low estimated probability (55%) of having an application for marketing approval submitted to the US Food and Drug Administration. Similarly, only 50% of gastrointestinal/metabolism drugs and 46% of CNS drugs moved from phase III to regulatory review. In contrast, the systemic anti-infective, musculoskeletal, and respiratory drug categories had relatively high estimated probabilities of getting to regulatory review after they had entered phase III (79% or higher). The estimated clinical approval success rates for self-originated drugs varied substantially by therapeutic class. The CNS (8%), cardiovascular (9%), gastrointestinal/metabolism (9%), and respiratory (10%) categories had relatively low estimated approval success rates. In contrast, systemic anti-infectives had a relatively high clinical approval success rate (24%).
- Recombinant Proteins And Monoclonal Antibodies: 32% Approval Rate Phase transition probabilities and clinical approval success probabilities by type of compound, for self-originated compounds first tested in humans from 1993 to 2004. BLA, biologics license application; NDA, new drug application. Figure 3 shows our results for estimated transition and clinical approval success probabilities by product type. Estimated transition probabilities for all phases were higher for large molecules. The estimated clinical approval success rate for large molecules (32%) was much higher than for small molecules (13%). Studies have indicated that success rates differ within the monoclonal antibody class by type of antibody (murine, chimeric, human, or humanized). 20 However, overall, the estimated clinical approval success rates for recombinant proteins and monoclonal antibodies did not differ by much (34% for recombinant proteins and 36% for monoclonal antibodies for self-originated drugs). The large-molecule subtypes, however, did vary somewhat in their estimated phase transition probabilities. Specifically, recombinant proteins had higher phase transition rates for the early clinical phases but a lower estimated phase transition probability for phase III to regulatory review (66% for recombinant proteins and 87% for monoclonal antibodies). We did find substantial differences in clinical approval success rates by product type (large vs. small molecules). The success rate for large molecules (nearly one-third) is consistent with the findings from a study of biopharmaceutical R&D costs covering a somewhat earlier period. 6 We also found higher phase transition rates at all phases for large molecules.
- Picturing the problem According to consultants CMR International (London), there were twice as many development projects halted in phase 3 during 2008–2010 than in 2005–2007 (ref. 1 ). In phase 2, where historically most drugs fail, success rates dropped to a mere 18% in 2008–2009, from 28% in 2006–2007 (ref. 2 ). Closer analysis reveals a lot. Of 108 failed phase 2 trials, more than half the stumbles were due to insufficient efficacy, almost 30% were related to strategy (insufficient consideration to similar drugs in development elsewhere) and another 20% hinged on clinical or preclinical safety ( Fig. 1a ). Commenting on these results, the author pointed to the high number of strategy-related bombs and wondered whether “an increase in collaborative efforts between companies up to the point of proof-of-concept for novel targets or mechanisms might be more cost-and-time effective.” Such a suggestion would have been deemed ridiculously naive just a few years ago. An analysis of 83 failed phase 3 programs revealed that many failed trials involve agents with novel mechanisms addressing high unmet need 3 ( Fig. 1b ). But in his analysis, CMR's science director John Arrowsmith also attributed much of the blame to “wishful thinking,” which is clearly a problem. Experts also point to myriad other factors, including incompetence of those running the trials, poor recruitment practices, variability in diagnostics, inefficient protocol design and patient heterogeneity.
- Should expect LOWER failure rates from Cell Therapy Trials
- Also: Poor Choice of Indication/Sub-Indication Severe Patients vs. Moderately Ill Patients E.g.: Symptomatic Vs. Asymptomatic
- Failure Modes Analysis Assumes that the Technology is Safe & Effective Talk to drug developers about clinical trials and one word comes up repeatedly—unsustainable. The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable. What's most distressing is the large number of compounds that earn kudos in phase 2 only to fizzle out in one of those big, outrageously expensive phase 3 trials
- Geron Dumps Stem Cell R&D Programs, Axes 38% of Workforce Geron, for better or worse, has been the poster child for embryonic stem cell therapies for a decade. And now with a new CEO at the helm, that’s all in the past. Menlo Park, CA-based Geron (NASDAQ: GERN ) said today it is getting out of the business of developing stem cell therapies so that it can concentrate more on developing cancer drugs. As part of the decision, Geron is cutting 66 jobs, or about 38 percent of its workforce. It will now look to unload its stem cell therapies onto partners. The decision was made to conserve cash, the company said. Geron had $180.3 million in cash and investments in the bank at the end of September, and it had a net loss of about $65 million in the first nine months of the year, according to its most recent quarterly report. Shares of the company dropped about 12 percent in after-hours trading, to $1.93, after the announcement. “ In the current environment of capital scarcity and uncertain economic conditions, we intend to focus our resources,” said Geron CEO John “Chip” Scarlett, in a statement. Geron to shut down stem cell programs, shares fall Mon Nov 14, 2011 5:04pm EST (Reuters) - Geron Corp said it will stop development of its stem cell programs to focus more on its cancer drugs, sending its shares down as much as 20 percent in after-market trading. The move will see Geron cut 66 full-time positions, or about 38 percent of its workforce and stop the development of the first U.S.-approved human embryonic stem cell trial. The company expects to take a one-time charge of about $5 million in the fourth quarter and about $3 million in the first half of next year. "In the current environment of capital scarcity and uncertain economic conditions, we intend to focus our resources on advancing our Phase 2 clinical trials of imetelstat and GRN1005," Chief Executive John Scarlett said. "This would not be possible if we continue to fund the stem cell programs at the current levels." Geron expects to end the year with cash and investments in excess of $150 million. Shares of Menlo Park, California-based company were down 20 percent at $1.75 in extended trading. They had closed at $2.20 on Monday on Nasdaq .
- 09/12/12 ISCT FINAL v.2A-- 5-5-09
- Primary Reasons for Failure of 1 st & 2 nd Arm of Phase II Trial: Failed To Meet Primary Endpoint (Time To Disease Progression) Submitted Retrospective Analysis (On Overall Survival Improvement Which Was The 2ary Endpoint And Not The 1ary Endpoint) FDA Generally Does Not Accept This Retrospective Analysis Did Not Adequately Select Primary Endpoint And Did Not Explore Endpoint In Early Clinical Trials (E.G. Phase 2 Trial) FDA Of Prefers Primary Clinical Endpoint Over Secondary Endpoint Did Not Target A Representative US Patient Population Patient Population in the Trial Must Be Sufficiently Large To Represent The US Patient Population Adequately Poor Choice Of Patient Population (Included Extreme Patients)
- 09/12/12 CancerVaccineBio_062910 the leading product of Intercytex, Cyzact (or ICX-PRO), an active allogeneic human dermal fibroblast preparation (embedded in a human fibrin gel matrix), failed to meet its primary end point in a multi-centre phase III clinical trial for the treatment of venous leg ulcers (Intercytex, 2010a), DEFINITIONS “ Human dermal fibroblasts or HDFs are the cells which are responsible for and orchestrate the wound healing process and which may be absent or dysfunctional in chronic wounds. Allogeneic HDFs are derived from the dermis of normal human skin. HDFs are the principal cell type found in the dermal layer of human skin where they secrete collagen, the main component of the dermis” (Intercytex, 2010a). “ Fibrin : an insoluble protein formed during haemostasis or blood clotting, comprising the essential part of a blood clot. In ICX-PRO, the fibrin-based gel matrix maintains the human dermal fibroblasts’ (HDFs) functions and it gradually degrades after it has been applied to the wound - allowing the HDFs to initiate healing” (Intercytex, 2010a). This preparation was designed to stimulate active repair and closure in persistent chronic wounds
- Primary Reasons For Failing The Phase III Did Not Adequately Select Patient Population Intercytex Selected Both Extreme And Non Extreme Patients Instead Of Only Focusing On Extreme Patients Were Under The Pressure Of Investors To Obtain Phase III Results And Rushed To Enroll Patients The Company Enrolled Diverse Type Of Patients Who Were Reacting Differently With The Control Underestimated The Control Efficacy In A Clinical Trial Setting The Control With The Compression Bandaging Showed Better Efficacy Results In The Clinical Trial Setting Than In The Usual Setting
- Phase 2 Crohn's Disease Data Prochymal is currently in clinical trials for the treatment of moderate to severe Crohn's disease, a painful, disabling inflammatory disease that often requires surgery. Osiris is currently conducting a multi-center trial to evaluate the safety and efficacy of Prochymal for Crohn's disease. In previous studies in gastrointestinal graft versus host disease (GvHD), Prochymal has been shown to reduce inflammation and promote crypt regeneration in the damaged intestine. Below is an endoscopic view and corresponding histology in a patient with severe gastrointestinal GvHD before (left) and nine days following Prochymal treatment (right). At the time of Prochymal infusion, this patient was unresponsive to all other modes of intervention. Nine days after treatment with Prochymal, there is a decrease in intestinal inflammation and ulceration as well as corresponding crypt regeneration as depicted by the arrows.
- May 2012 : Osiris Therapeutics said Thursday that Canadian regulators had approved its drug Prochymal, to treat children suffering from graft-versus-host disease , a potentially deadly complication of bone marrow transplantation. Prochymal is a preparation of mesenchymal stem cells, which are obtained from the bone marrow of healthy young adult donors. The stem cells are separated out from the marrow and expanded in culture, so that one donation is enough to make as many as 10,000 doses. Graft-versus-host disease occurs when the immune cells in a bone-marrow transplant see the recipient’s organs as foreign and attack them, causing potentially severe damage to the skin, liver and digestive tract. This happens most often when the donor is not an exact match for the recipient. Doctors try using steroids or other drugs to damp the immune attack, but in many cases those don’t work, and the patient may die. Prochymal is approved in Canada for children whose condition is not controlled by steroids. In a small trial, about 60 percent of such children had a clinically meaningful response to the drug, Osiris said. Osiris is not expected to gain much revenue from patients with a rare disease in Canada. But it is a welcome success for a 20-year-old company that has had its share of failures. In 2009, Prochymal failed in two late-stage clinical trials, showing little to no advantage over placebo in treating graft-versus-host disease. The company is also trying to develop Prochymal as a treatment for Crohn’s disease , diabetes , heart attacks and other illnesses, but has had some failures there as well.
- 19,450+ FDA Clinical Studies Involve New Therapies: (by Category) Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or before Birth Ear, Nose, and Throat Diseases Eye Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Mouth and Tooth Diseases Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Occupational Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Substance Related Disorders Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases Wounds and Injuries
- 19,450+ FDA Clinical Studies Involve New Therapies: (by Category) Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or before Birth Ear, Nose, and Throat Diseases Eye Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Mouth and Tooth Diseases Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Occupational Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Substance Related Disorders Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases Wounds and Injuries
- 400+ FDA Clinical Studies Involve New Therapies: (by Category) Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or before Birth Ear, Nose, and Throat Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Injuries, Poisonings, and Occupational Conditions Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases
- Trial density is indicated by color, with the darker color having higher densities. Annual growth rate is indicated for some countries. Out of country By far the biggest challenge facing clinical trial organizers is patient recruitment , particularly as trial sizes increase. This has led to the rapid and expansive growth of overseas trials, according to Charlene Sanders, vice president of global regulatory affairs at Premier Research Worldwide (Philadelphia; Fig. 4, Table 5). The Associated Chambers of Commerce and Industry of India reports that only a single clinical trial was outsourced to India by US-based drug firms between 1996 to 2000, but in the following five years, >190 such trials were conducted in India 12 . A recent US Department of Health and Human Services report found that in FY 2008 80% of approved drug marketing applications included data from foreign trials and over half of trial subjects and sites were outside the United States 13 .
- Studies conducted by John Arrowsmith at Reuters, published in Nature Reviews Drug Discovery (2011) Phase II Failures in 2008–2010: 82% At present, however, Phase II success rates are lower than at any other phase of development. Analysis by the Centre for Medicines Research (CMR) of projects from a group of 16 companies (representing approximately 60% of global R&D spending) in the CMR International Global R&D database reveals that the Phase II success rates for new development projects have fallen from 28% (2006–2007) to 18% (2008–2009), although these success rates do vary between therapeutic areas and between small molecules and biologics. As the current likelihood of a drug successfully progressing through Phase III to launch is 50 % (Nature Rev. Drug Discov.10, 87; 2011), the overall attrition of late-stage drug development seems to be unsustainably high. Phase III Failures in 2007–2010: @50% There were 83 Phase III and submission failures between 2007 and 2010. As shown in Fig. 1a, the therapeutic areas in which the largest proportions of these failures occurred were: cancer (28%); nervous system, which includes neurodegeneration (18%); alimentary and/or metabolism, which includes diabetes and obesity (13%); and anti-infectives (13%). Almost 90% of the failures across all therapeutic areas were attributable to either lack of efficacy (66%) or safety issues (21%) (Fig. 1b). The efficacy failures can be further broken down into projects that failed to demonstrate a statistically significant improvement versus placebo (32%), an active control (5%) or as an add-on therapy (29%). Of the drugs that failed to show an improvement in efficacy as an add-on therapy, 58% were anticancer drugs, and of those that failed to show an improvement in efficacy versus placebo, 33% were nervous system drugs.
- Figure: FDA Drug Approvals Per Year . Whatever the cause, the rate of new molecular entity (NME) approvals has been falling in the past decade. The FDA approved just 19 NMEs in 2009 compared with 53 in 1996). Thus, even though 2011 has proven to be a banner year for drug approvals, including innovative medicines, the trend over the past decade has been disheartening (Figure). The cost of development for a drug is also now pegged at over $1 billion and estimates run as high 15 years to get a drug candidate from target identification to market 6 . Although R&D budgets grew dramatically over the past decade, beginning in 2009, there has been a downturn in such spending. Some attribute that fall to a growing sense that R&D is not providing sufficient return on investment 1 . Most of the expense in R&D arises during human testing.
- For 40 years Biotech has depended on easy access to cheap capital ; no longer available: Private Equity: VC investments in Early Stage Biotech are down over 40% in last 12 months Public Markets Closed: Only a handful (13) of Biotech IPO in last 24 months Key Metrics Average Time to Market: 10-15 Years Average Costs: $1.3B Failure Rate: @90% Under 30% of approved drugs recoup R&D costs Tufts Center for the Study of Drug Development, http://csdd.tufts.edu (Tufts CSDD) estimates a typical drug development cost at $1.3 billion, and needing 10-15 years to bring it to market. The development of oncologic drugs has a tendency to amass higher costs because of the higher failure rates.
- Dendreon (NASDAQ: DNDN) is a Seattle based biotechnology company. Its lead product, Provenge (known generically as sipuleucel-T), is an immunotherapy for prostate cancer. It consists of a mixture of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) that have been incubated with the Dendreon PAP-GM-CSF fusion protein. Phase III clinical trial results demonstrating a survival benefit for prostate cancer patients receiving the drug were presented at the AUA meeting on 28 April 2009. After going through the approval process, Provenge was given full approval by the FDA on April 29, 2010. Dendreon's name derives from the "Dendritic Cell" which forms a major component of the company's product candidates that use the "Dendreon Cassette Technology" to insert a disease-specific target protein into a general platform. Their lead product, Provenge, is an example of their "rationally designed therapeutic process" intended to break immune tolerance to certain disease specific proteins. It is hypothesized that receptor mediated uptake of antigen by dendritic cells occurs when they are exposed to the Dendreon fusion protein which links the disease specific protein to a recognition protein. This approach is in contrast to other dendritic cell vaccines that use methods such as electroporation to get the DC's to present antigen related epitopes. In the case of Provenge, this disease related protein is Prostatic acid phosphatase and the signalling component is GM-CSF. Initial clinical results for Provenge in 2000 showed immune responses supporting the expected mode-of-action, as well as a PSA reduction which was thought to relate to clinical improvement. In 2006, Dendreon built a manufacturing facility in Morris Plains, New Jersey to accommodate production for a Phase III trial and possible 2007 drug approval by the U.S. Food and Drug Administration (FDA). In January 2007, the FDA accepted Dendreon's Biologic License Application (BLA) filing for Provenge. On March 29, 2007, the FDA Office of Cellular, Tissue and Gene Therapies Advisory Committee voted 17-0 that Provenge is reasonably safe and 13-4 that the trial data showed substantial evidence that it is effective. However, on May 9, 2007, Dendreon received a letter from the FDA demanding more results and information before approval. On April 14, 2009, Dendreon announced that the results for the Phase III trial of Provenge were positive, saying there had been a reduction in the odds of death compared to the use of a placebo. On April 28, 2009, the full details of the study were released. The trial found that patients treated with Provenge lived an average of 4.1 months longer than patients treated with the control (autologous cells without the GM-CSF / PAP fusion protein). On April 29, 2010, the FDA approved Provenge for use in the treatment of advanced prostate cancer.
- 09/12/12 CancerVaccineBio_062910 -On day 1, patient white blood cells are harvested by apheresis. -During day 2-3, the cells are processed at Dendreon (Isolation of the dendritic cells –or antigen presenting cells- +activation of the dendritic cells with the Antigen Delivery Casette specific to prostate cancer developed by Dendreon. -Finally on day 3-4, the Provenge (activated dendritic cells) is delivered as an intravenous infusion given as an outpatient procedure. -The process is repeated 3 times: On weeks 0, 2 and 4.
- -2001: Beginning of the planned D9901 and D9902 clinical trials with asymptomatic, metastatic androgen independent prostate cancer patients and with time to disease progression as a primary endpoint With the positive results from the phase 1 and 2 clinical trials that followed the second dose regimen, Dendreon went to see the FDA to discuss the design of phase 3 (November 1998). Dendreon wanted to execute two identical phase 3 trials (multi-centre, double blind, randomised and placebo controlled trials) to show efficacy and confirm safety (Dendreon, 2001; Dendreon, 2003): (1) D9901 trial with 127 patients and (2) D9902 trial with 125 patients. The targeted patients had asymptomatic, metastatic androgen independent prostate cancer (Dendreon, 2003). Two thirds of the patients would receive Provenge and the other third a placebo. The primary endpoint was the time to disease progression (Dendreon, 2001). As a secondary endpoint, Dendreon decided to follow overall survival for every patient for 3 years. -2002: Preliminary results of D9901 showing no statistical significant delay in the time to disease progression Decision of splitting D9902 in two D9902A with the same patient population and D9902B with less aggressive cancer patients (low Gleason score) -2003:-Initiation of D9902B -2005:-Completion of the entire analysis of D9901 showing survival advantage in patients receiving Provenge -Modifications of the clinical protocol of D9902B which became D9903 or IMPACT trial: Elimination of the patient restriction and extension of patient population to minimally symptomatic patients Elevation of overall survival to the primary endpoint Based on the D9901 data, granting of the Fast Track designation by the FDA for Provenge -2006:-Submission of the D9901 results (in conjunction of those of D9902A) showing overall survival improvement to the FDA for a BLA -2007:-Preliminary positive vote of FDA Refusal of marketing approval with FDA letter and requirement of additional clinical data Concentration of the resources for the development of Provenge and thus reduction of workforce -2009:-Completion of D9902B phase 3. -2010:- Obtainment of D9903 data Submission of D9903 data for MA FDA MA approval (29/4/2010) (Spent about $800 million to developed Provenge)
- Source of quote: http://www.fda.gov/downloads/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm214540.pdf -2001: Beginning of the planned D9901 and D9902 clinical trials with asymptomatic, metastatic androgen independent prostate cancer patients and with time to disease progression as a primary endpoint -2002: Preliminary results of D9901 showing no statistical significant delay in the time to disease progression Decision of splitting D9902 in two D9902A with the same patient population and D9902B with less aggressive cancer patients (low Gleason score) -2003:-Initiation of D9902B -2005:-Completion of the entire analysis of D9901 showing survival advantage in patients receiving Provenge -Modifications of the clinical protocol of D9902B which became D9903 or IMPACT trial: Elimination of the patient restriction and extension of patient population to minimally symptomatic patients Elevation of overall survival to the primary endpoint Based on the D9901 data, granting of the Fast Track designation by the FDA for Provenge -2006:-Submission of the D9901 results (in conjunction of those of D9902A) showing overall survival improvement to the FDA for a BLA -2007:-Preliminary positive vote of FDA Refusal of marketing approval with FDA letter and requirement of additional clinical data In 2006, while Dendreon was still conducting D9903, the company met with the FDA and introduced an initial proposal for its BLA (Dendreon, 2007). This application would be based on the overall survival improvement evidence found in the D9901 study (i.e. 4.5 month improvement in median survival compared to the placebo) in conjunction with the supportive data obtained from D9902A study (Dendreon, 2006). It would also use the data from both clinical trials which showed no toxicity (Dendreon, 2006). Since Provenge had the fast track designation, FDA granted priority review for the Provenge BLA in January 2007 (Dendreon, 2008). The FDA’s Cellular, Tissue and Gene Therapies Advisory Committee reviewed the BLA for Provenge and voted on 29 March 2007 (Dendreon, 2008). The Committee unanimously agreed that the submitted data established that Provenge is reasonably safe for the targeted population. The majority of the committee (13 yes, 4 no) also believed that the submitted data provided substantial evidence of the efficacy of Provenge. However, on 8 May 2007, Dendreon received a complete response letter from the FDA mentioning that the lack of a pre-specified primary method for survival analysis rendered it impossible to estimate statistical error (FDA, 2009). Therefore, FDA requested additional clinical data in support of the efficacy claim of overall survival. The FDA also stated that it would accept and review results of the completed D9902B IMPACT study to support licensure of Provenge (Dendreon, 2008). After the announcement of the negative response from the FDA regarding the BLA, Dendreon’s stock price dropped sharply. Concentration of the resources for the development of Provenge and thus reduction of workforce -2009:-Completion of D9902B phase 3. -2010:- Obtainment of D9903 data Submission of D9903 data for MA FDA MA approval (29/4/2010) (Spent about $800 million to developed Provenge)
- -2001: Beginning of the planned D9901 and D9902 clinical trials with asymptomatic, metastatic androgen independent prostate cancer patients and with time to disease progression as a primary endpoint -2002: Preliminary results of D9901 showing no statistical significant delay in the time to disease progression Decision of splitting D9902 in two D9902A with the same patient population and D9902B with less aggressive cancer patients (low Gleason score) -2003:-Initiation of D9902B -2005:-Completion of the entire analysis of D9901 showing survival advantage in patients receiving Provenge -Modifications of the clinical protocol of D9902B which became D9903 or IMPACT trial: Elimination of the patient restriction and extension of patient population to minimally symptomatic patients Elevation of overall survival to the primary endpoint Based on the D9901 data, granting of the Fast Track designation by the FDA for Provenge -2006:-Submission of the D9901 results (in conjunction of those of D9902A) showing overall survival improvement to the FDA for a BLA -2007:-Preliminary positive vote of FDA Refusal of marketing approval with FDA letter and requirement of additional clinical data In 2006, while Dendreon was still conducting D9903 (IMPACT), the company met with the FDA and introduced an initial proposal for its BLA (Dendreon, 2007). This application would be based on the overall survival improvement evidence found in the D9901 study (i.e. 4.5 month improvement in median survival compared to the placebo) in conjunction with the supportive data obtained from D9902A study (Dendreon, 2006). It would also use the data from both clinical trials which showed no toxicity (Dendreon, 2006). Since Provenge had the fast track designation, FDA granted priority review for the Provenge BLA in January 2007 (Dendreon, 2008). The FDA’s Cellular, Tissue and Gene Therapies Advisory Committee reviewed the BLA for Provenge and voted on 29 March 2007 (Dendreon, 2008). The Committee unanimously agreed that the submitted data established that Provenge is reasonably safe for the targeted population. The majority of the committee (13 yes, 4 no) also believed that the submitted data provided substantial evidence of the efficacy of Provenge. However, on 8 May 2007, Dendreon received a complete response letter from the FDA mentioning that the lack of a pre-specified primary method for survival analysis rendered it impossible to estimate statistical error (FDA, 2009). Therefore, FDA requested additional clinical data in support of the efficacy claim of overall survival. The FDA also stated that it would accept and review results of the completed D9902B IMPACT study to support licensure of Provenge (Dendreon, 2008). After the announcement of the negative response from the FDA regarding the BLA, Dendreon’s stock price dropped sharply. Concentration of the resources for the development of Provenge and thus reduction of workforce -2009:-Completion of D9902B phase 3. -2010:- Obtainment of D9903 data Submission of D9903 data for MA FDA MA approval (29/4/2010) (Spent about $800 million to developed Provenge)
- -2001: Beginning of the planned D9901 and D9902 clinical trials with asymptomatic, metastatic androgen independent prostate cancer patients and with time to disease progression as a primary endpoint -2002: Preliminary results of D9901 showing no statistical significant delay in the time to disease progression Decision of splitting D9902 in two D9902A with the same patient population and D9902B with less aggressive cancer patients (low Gleason score) -2003:-Initiation of D9902B -2005:-Completion of the entire analysis of D9901 showing survival advantage in patients receiving Provenge -Modifications of the clinical protocol of D9902B which became D9903 or IMPACT trial: Elimination of the patient restriction and extension of patient population to minimally symptomatic patients Elevation of overall survival to the primary endpoint Based on the D9901 data, granting of the Fast Track designation by the FDA for Provenge -2006:-Submission of the D9901 results (in conjunction of those of D9902A) showing overall survival improvement to the FDA for a BLA -2007:-Preliminary positive vote of FDA Refusal of marketing approval with FDA letter and requirement of additional clinical data Concentration of the resources for the development of Provenge and thus reduction of workforce -2009:-Completion of D9902B phase 3. -2010:- Obtainment of D9903 data Submission of D9903 data for MA FDA MA approval (29/4/2010) Dendreon, which had concentrated its resources on the development of Provenge, decided to reduce its workforce in 2007 (Dendreon, 2008) (Figure 9). In 2009, the company completed D9902B and submitted the data to the FDA (Dendreon, 2010). The study, which enrolled 512 patients, showed that Provenge extended median survival by 4.1 months compared to the placebo group (Dendreon, 2010; Kantoff et al., 2010). Based on D9902B (IMPACT) evidence, which met the primary endpoint of overall survival and exhibited safety profile, FDA granted a marketing approval on 29 April 2010 for asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer patients (Dendreon, 2011b). (Spent about $800 million to developed Provenge)
- -2001: Beginning of the planned D9901 and D9902 clinical trials with asymptomatic, metastatic androgen independent prostate cancer patients and with time to disease progression as a primary endpoint -2002: Preliminary results of D9901 showing no statistical significant delay in the time to disease progression Decision of splitting D9902 in two D9902A with the same patient population and D9902B with less aggressive cancer patients (low Gleason score) -2003:-Initiation of D9902B -2005:-Completion of the entire analysis of D9901 showing survival advantage in patients receiving Provenge -Modifications of the clinical protocol of D9902B which became D9903 or IMPACT trial: Elimination of the patient restriction and extension of patient population to minimally symptomatic patients Elevation of overall survival to the primary endpoint Based on the D9901 data, granting of the Fast Track designation by the FDA for Provenge -2006:-Submission of the D9901 results (in conjunction of those of D9902A) showing overall survival improvement to the FDA for a BLA -2007:-Preliminary positive vote of FDA Refusal of marketing approval with FDA letter and requirement of additional clinical data Concentration of the resources for the development of Provenge and thus reduction of workforce -2009:-Completion of D9902B phase 3. -2010:- Obtainment of D9903 data Submission of D9903 data for MA FDA MA approval (29/4/2010) Dendreon, which had concentrated its resources on the development of Provenge, decided to reduce its workforce in 2007 (Dendreon, 2008) (Figure 9). In 2009, the company completed D9902B and submitted the data to the FDA (Dendreon, 2010). The study, which enrolled 512 patients, showed that Provenge extended median survival by 4.1 months compared to the placebo group (Dendreon, 2010; Kantoff et al., 2010). Based on D9902B (IMPACT) evidence, which met the primary endpoint of overall survival and exhibited safety profile, FDA granted a marketing approval on 29 April 2010 for asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer patients (Dendreon, 2011b). (Spent about $800 million to developed Provenge)
- The regulators agreed that there was no animal model for human ulcers, and thus Intercytex went directly into clinical studies (Kemp, 2010a). PHASE II In contrast with Apligraf, the FDA classified Cyzact as an HCT/Ps (or biologic) and not as a medical device (Higgins, 2010; Kemp, 2010b; Kemp, 2010a). This FDA decision generated more difficulties for the clinical development of Cyzact. Indeed, this meant that Intercytex had to do cellular controls a three arm clinical trial (Kemp, 2010b). Intercytex conducted a phase I clinical study with 10 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) and this study showed some good results (Higgins, 2010). The Phase II clinical trial involved 19 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) to determine the dosage and show preliminary results of efficacy with histological observation (Kemp, 2010a). The study gave very good results with most of the patients -40% healing completely after 24 weeks (Higgins, 2010). Unfortunately, no control group was used in this phase II trial which would have been useful as a prelude to the phase III clinical trial (Higgins, 2010; Kemp, 2010a). In hindsight this was a mistake (Kemp 2010b). Phase III In 2005, Intercytex started a double-blind randomised controlled study in the US, the UK and Canada with three arms (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 3). Although Apligraf was categorised as a device, it had to do a randomised control clinical trial (Falanga, 2010). An arm is any of the treatment group in a randomised clinical trial. Arms Patients involved and their treatments First arm involving 196 patients 2/4 of the patients; Cyzact with four layer compression bandaging (the current standard of care for venous leg ulcers) Second arm involving 100 patients 1/4 of the patients; the control group (compression bandaging) Third arm involving 100 patients 1/4 of the patients; the vehicle (fibrin) with a compression bandaging (the purpose of this group was to double blind patients but also physicians) Table 3: The composition of the arms in the phase III clinical trial of Cyzact including a total of 396 patients. The inclusion criteria (i.e. which patients could participate into the trial) are given in Table 4 (Kemp, 2010b): Inclusion criteria Venous leg ulcer of at least 3 months duration Non-responsive to conventional therapy With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month Table 4: Inclusion criteria for Cyzact phase III clinical trial. There were two different endpoints for phase III, one stricter than the other: complete healing at 12 weeks (FDA); rate and incidence of closure (MHRA in the UK but which is part of the EMA). Consequently, Intercytex had to deal with two non homogeneous endpoints. At the beginning of phase III progression, in 2007, Intercytex had about 100 patients in the first arm, 50 patients in the second arm and 50 patients in the third arm (Higgins, 2010). The Data Safety Monitoring Board (DSMB) of Intercytex was in charge of monitoring the data (Intercytex had no direct access to the data) and recommended that Intercytex continue the trial but that because the control arm was achieving a higher rate of healing than expected that the trial would need to have a total of about 390 patients (Higgins, 2010; Kemp, 2010b; Kemp, 2010a).Therefore, Intercytex under pressure from the investors, pushed the clinicians to enrol patients quickly (Kemp, 2010a). Intercytex ended up with 196 patients in the first arm, 100 in the second arm and 100 in the third arm (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 5). At the end of the phase III study, in 2008, the study failed to meet its FDA primary endpoint, since there was no statistical difference between any of the groups and especially between the 1 st arm with Cyzact and the 2 nd arm with the control (Intercytex, 2010a). As a result, no further work on Cyzact was planned in any indication (Intercytex, 2010a). According to recent analysis, more extreme cases of venous leg ulcer patients were selected in 2005-2006, which explains why (Table 5), there was a difference between the 1 st arm with Cyzact and the 2 nd arm with the control (Higgins, 2010; Kemp, 2010a). However, later, in 2007 and 2008, physicians enrolled other patients more quickly, that were not extreme patients (i.e. easy to heal patients) and that may explain why no differences were observed at the end of the trial in 2008 (Higgins, 2010; Kemp, 2010a). Therefore, if Intercytex had had stricter inclusion criteria and taken only patients with four layer compression bandaging, whose venous leg ulcers haddecreased in size by less than 10% in one month, and Intercytex may have seen a difference between Cyzact and the control group at the end of the phase III clinical trial (Kemp, 2010a) (Table 6). Hence, it seems sometimes difficult to target the right patients for cell therapies clinical trials. It has been suggested that the difference in environment between the clinical and the normal context was not taken into account enough in the design of the clinical study (Higgins, 2010). Indeed, the nurses applying the control bandage were better trained than they would have been in a normal context (Higgins, 2010). Therefore, because the nurses had to follow a precise monitored protocol to administrate the product or the control (Higgins, 2010) and because Cyzact seemed to rely less on the skill of the nurses, the control arm displayed better results than anticipated (Higgins, 2010). Falanga (2010) added that it is often difficult to select an adequate control for advanced medicinal product, since the gold standard control can vary country by country.
- The regulators agreed that there was no animal model for human ulcers, and thus Intercytex went directly into clinical studies (Kemp, 2010a). PHASE II In contrast with Apligraf, the FDA classified Cyzact as an HCT/Ps (or biologic) and not as a medical device (Higgins, 2010; Kemp, 2010b; Kemp, 2010a). This FDA decision generated more difficulties for the clinical development of Cyzact. Indeed, this meant that Intercytex had to do cellular controls a three arm clinical trial (Kemp, 2010b). Intercytex conducted a phase I clinical study with 10 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) and this study showed some good results (Higgins, 2010). The Phase II clinical trial involved 19 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) to determine the dosage and show preliminary results of efficacy with histological observation (Kemp, 2010a). The study gave very good results with most of the patients -40% healing completely after 24 weeks (Higgins, 2010). Unfortunately, no control group was used in this phase II trial which would have been useful as a prelude to the phase III clinical trial (Higgins, 2010; Kemp, 2010a). In hindsight this was a mistake (Kemp 2010b). Phase III In 2005, Intercytex started a double-blind randomised controlled study in the US, the UK and Canada with three arms (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 3). Although Apligraf was categorised as a device, it had to do a randomised control clinical trial (Falanga, 2010). An arm is any of the treatment group in a randomised clinical trial. Arms Patients involved and their treatments First arm involving 196 patients 2/4 of the patients; Cyzact with four layer compression bandaging (the current standard of care for venous leg ulcers) Second arm involving 100 patients 1/4 of the patients; the control group (compression bandaging) Third arm involving 100 patients 1/4 of the patients; the vehicle (fibrin) with a compression bandaging (the purpose of this group was to double blind patients but also physicians) Table 3: The composition of the arms in the phase III clinical trial of Cyzact including a total of 396 patients. The inclusion criteria (i.e. which patients could participate into the trial) are given in Table 4 (Kemp, 2010b): Inclusion criteria Venous leg ulcer of at least 3 months duration Non-responsive to conventional therapy With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month Table 4: Inclusion criteria for Cyzact phase III clinical trial. There were two different endpoints for phase III, one stricter than the other: complete healing at 12 weeks (FDA); rate and incidence of closure (MHRA in the UK but which is part of the EMA). Consequently, Intercytex had to deal with two non homogeneous endpoints. At the beginning of phase III progression, in 2007, Intercytex had about 100 patients in the first arm, 50 patients in the second arm and 50 patients in the third arm (Higgins, 2010). The Data Safety Monitoring Board (DSMB) of Intercytex was in charge of monitoring the data (Intercytex had no direct access to the data) and recommended that Intercytex continue the trial but that because the control arm was achieving a higher rate of healing than expected that the trial would need to have a total of about 390 patients (Higgins, 2010; Kemp, 2010b; Kemp, 2010a).Therefore, Intercytex under pressure from the investors, pushed the clinicians to enrol patients quickly (Kemp, 2010a). Intercytex ended up with 196 patients in the first arm, 100 in the second arm and 100 in the third arm (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 5). At the end of the phase III study, in 2008, the study failed to meet its FDA primary endpoint, since there was no statistical difference between any of the groups and especially between the 1 st arm with Cyzact and the 2 nd arm with the control (Intercytex, 2010a). As a result, no further work on Cyzact was planned in any indication (Intercytex, 2010a). According to recent analysis, more extreme cases of venous leg ulcer patients were selected in 2005-2006, which explains why (Table 5), there was a difference between the 1 st arm with Cyzact and the 2 nd arm with the control (Higgins, 2010; Kemp, 2010a). However, later, in 2007 and 2008, physicians enrolled other patients more quickly, that were not extreme patients (i.e. easy to heal patients) and that may explain why no differences were observed at the end of the trial in 2008 (Higgins, 2010; Kemp, 2010a). Therefore, if Intercytex had had stricter inclusion criteria and taken only patients with four layer compression bandaging, whose venous leg ulcers haddecreased in size by less than 10% in one month, and Intercytex may have seen a difference between Cyzact and the control group at the end of the phase III clinical trial (Kemp, 2010a) (Table 6). Hence, it seems sometimes difficult to target the right patients for cell therapies clinical trials. It has been suggested that the difference in environment between the clinical and the normal context was not taken into account enough in the design of the clinical study (Higgins, 2010). Indeed, the nurses applying the control bandage were better trained than they would have been in a normal context (Higgins, 2010). Therefore, because the nurses had to follow a precise monitored protocol to administrate the product or the control (Higgins, 2010) and because Cyzact seemed to rely less on the skill of the nurses, the control arm displayed better results than anticipated (Higgins, 2010). Falanga (2010) added that it is often difficult to select an adequate control for advanced medicinal product, since the gold standard control can vary country by country.
- The regulators agreed that there was no animal model for human ulcers, and thus Intercytex went directly into clinical studies (Kemp, 2010a). PHASE II In contrast with Apligraf, the FDA classified Cyzact as an HCT/Ps (or biologic) and not as a medical device (Higgins, 2010; Kemp, 2010b; Kemp, 2010a). This FDA decision generated more difficulties for the clinical development of Cyzact. Indeed, this meant that Intercytex had to do cellular controls a three arm clinical trial (Kemp, 2010b). Intercytex conducted a phase I clinical study with 10 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) and this study showed some good results (Higgins, 2010). The Phase II clinical trial involved 19 venous leg ulcer patients using Cyzact (Higgins, 2010; Kemp, 2010a) to determine the dosage and show preliminary results of efficacy with histological observation (Kemp, 2010a). The study gave very good results with most of the patients -40% healing completely after 24 weeks (Higgins, 2010). Unfortunately, no control group was used in this phase II trial which would have been useful as a prelude to the phase III clinical trial (Higgins, 2010; Kemp, 2010a). In hindsight this was a mistake (Kemp 2010b). Phase III In 2005, Intercytex started a double-blind randomised controlled study in the US, the UK and Canada with three arms (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 3). Although Apligraf was categorised as a device, it had to do a randomised control clinical trial (Falanga, 2010). An arm is any of the treatment group in a randomised clinical trial. Arms Patients involved and their treatments First arm involving 196 patients 2/4 of the patients; Cyzact with four layer compression bandaging (the current standard of care for venous leg ulcers) Second arm involving 100 patients 1/4 of the patients; the control group (compression bandaging) Third arm involving 100 patients 1/4 of the patients; the vehicle (fibrin) with a compression bandaging (the purpose of this group was to double blind patients but also physicians) Table 3: The composition of the arms in the phase III clinical trial of Cyzact including a total of 396 patients. The inclusion criteria (i.e. which patients could participate into the trial) are given in Table 4 (Kemp, 2010b): Inclusion criteria Venous leg ulcer of at least 3 months duration Non-responsive to conventional therapy With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month Table 4: Inclusion criteria for Cyzact phase III clinical trial. There were two different endpoints for phase III, one stricter than the other: complete healing at 12 weeks (FDA); rate and incidence of closure (MHRA in the UK but which is part of the EMA). Consequently, Intercytex had to deal with two non homogeneous endpoints. At the beginning of phase III progression, in 2007, Intercytex had about 100 patients in the first arm, 50 patients in the second arm and 50 patients in the third arm (Higgins, 2010). The Data Safety Monitoring Board (DSMB) of Intercytex was in charge of monitoring the data (Intercytex had no direct access to the data) and recommended that Intercytex continue the trial but that because the control arm was achieving a higher rate of healing than expected that the trial would need to have a total of about 390 patients (Higgins, 2010; Kemp, 2010b; Kemp, 2010a).Therefore, Intercytex under pressure from the investors, pushed the clinicians to enrol patients quickly (Kemp, 2010a). Intercytex ended up with 196 patients in the first arm, 100 in the second arm and 100 in the third arm (Higgins, 2010; Intercytex, 2010a; Kemp, 2010b) (Table 5). At the end of the phase III study, in 2008, the study failed to meet its FDA primary endpoint, since there was no statistical difference between any of the groups and especially between the 1 st arm with Cyzact and the 2 nd arm with the control (Intercytex, 2010a). As a result, no further work on Cyzact was planned in any indication (Intercytex, 2010a). According to recent analysis, more extreme cases of venous leg ulcer patients were selected in 2005-2006, which explains why (Table 5), there was a difference between the 1 st arm with Cyzact and the 2 nd arm with the control (Higgins, 2010; Kemp, 2010a). However, later, in 2007 and 2008, physicians enrolled other patients more quickly, that were not extreme patients (i.e. easy to heal patients) and that may explain why no differences were observed at the end of the trial in 2008 (Higgins, 2010; Kemp, 2010a). Therefore, if Intercytex had had stricter inclusion criteria and taken only patients with four layer compression bandaging, whose venous leg ulcers haddecreased in size by less than 10% in one month, and Intercytex may have seen a difference between Cyzact and the control group at the end of the phase III clinical trial (Kemp, 2010a) (Table 6). Hence, it seems sometimes difficult to target the right patients for cell therapies clinical trials. It has been suggested that the difference in environment between the clinical and the normal context was not taken into account enough in the design of the clinical study (Higgins, 2010). Indeed, the nurses applying the control bandage were better trained than they would have been in a normal context (Higgins, 2010). Therefore, because the nurses had to follow a precise monitored protocol to administrate the product or the control (Higgins, 2010) and because Cyzact seemed to rely less on the skill of the nurses, the control arm displayed better results than anticipated (Higgins, 2010). Falanga (2010) added that it is often difficult to select an adequate control for advanced medicinal product, since the gold standard control can vary country by country.