1. ARETE-ZOE, LLC 1334 E Chandler Blvd 5A-19, Phoenix 85048, Arizona, USA Alternative way of generating data from stem cell interventions performed under 21 CFR part 1271 (CGTP)

2. Problem statement Stem cells have characteristics that distinguish them from drugs, biologics, or medical devices. Considerable body of science has not yet been accumulated to develop and deliver safe and effective treatments. Their regulation remains unclear. Advertising strategies Patient autonomy Regulatory uncertainty Generating evidence Information environment

3. NAP: Stem cell therapies (Nov 2014)Stem cell therapies Improved information environment is essential for sound decision-making by all stakeholders Marketing claims by clinics offering stem cell therapies are not necessarily supported by clinical evidence in the scientific literature Marketing claims by clinics offering stem cell therapies are not necessarily supported by clinical evidence in the scientific literature Unproven stem cell treatments can harm patients by leading to complications such as tumors, meningitis, or even death Patients who have no other treatment options may be willing to take these risks if there is a slight chance of success. • Patients who have no other treatment options may be willing to take these risks if there is a slight chance of success. • Objective outcome measures needed for assessment of the effectiveness of stem cell therapies Objective outcome measures needed for assessment of the effectiveness of stem cell therapies Knowns and unknowns

4. Issues relating to truthfulness of commercial speech are not unique to stem cells Corporate freedom of speech

5. Stakeholders Patients Physicians (regular healthcare providers) Manufacturers of HCP/Ts, clinics Producers of mass produced treatments Regulators Insurers, payers Investors Information Reliable Accurate Timely Safety Efficacy Cost-effectiveness ROI

6. Regulations In the U.S.International Section 505 of the FD&C Act DRUGS Section 351 of the PHS Act BIOLOGICS Device provisions of the FD&C Act DEVICE Section 361 of the PHS Act only Minimally manipulated  Regulations vary widely  Enforcement inconsistent  Offshore clinics  Medical tourism  Patient demand-driven

7. 21 CFR part 1271 Minimal manipulation  (1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement  (2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues. ENVIRONMENT FACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESS RECOVERY LABELLING STORAGE DONORS DISTRIBUTION

8. HCT/Ps under section 361 of the PHS Act and 21 CFR part 1270 Manufactures of HCT/Ps that are: Drugs Medical Devices Biological Products Hematopoietic stem cells from peripheral and cord blood Reproductive cells and tissues Human heart valves Human dura mater

9. Ethical considerations The Helsinki Declaration In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician's judgement it offers hope of saving life, re- establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. (The Helsinki Declaration, Article 37)

10. Information environment How a patient will search for medical information? What a biomedical researcher can find in public domain? Information as paid service: professional specialized databases

11. Sharyl Attkisson TED Talks on Astroturf How patients search for medical information online

12. Information in public domain Clinical Trial Registries Biomedical Literature Professional Societies

13. Information as paid service Industry Insurers Healthcare providers Professional societies Academic research Systematic review of available information in specialized databases Resource intensive, expensive, mandatory / driven by business need Articles reports datasets

14. All stem cell trials ClinicalTrials.gov March 22, 2016

15. Autologous stem cell trials ClinicalTrials.gov March 22, 2016

16. Conditions studied ClinicalTrials.gov August, 2015

17. All SC trials: recruitment ClinicalTrials.gov January 7, 2016

18. All SC trials: enrollment ClinicalTrials.gov January 7, 2016

19. All SC trials: Type of trial ClinicalTrials.gov January 7, 2016

20. All SC trials: funding ClinicalTrials.gov January 7, 2016

21. All SC trials: sponsors ClinicalTrials.gov August, 2015 “Other” means:Trials Fred Hutchinson Cancer Research Center192 National Cancer Institute (NCI)177 M.D. Anderson Cancer Center148 Memorial Sloan Kettering Cancer Center100 National Heart, Lung, and Blood Institute (NHLBI)91 Masonic Cancer Center, University of Minnesota80 City of Hope Medical Center72 Children's Oncology Group|National Cancer Institute (NCI)59 St. Jude Children's Research Hospital57 Baylor College of Medicine53 Mayo Clinic51

22. All SC trials: phases ClinicalTrials.gov January 7, 2016

23. All SC trials: results ClinicalTrials.gov January 7, 2016

24. Scientific publications PubMed CT Registries vs. publications  > 250,000 hits “stem cells”  >4,200 human clinical trials  ~140,000 animal studies  Publication bias  Multiple publication bias  Link between publications and CT#  Non-human experience

25. Multiple publication bias: ALS

26. Current situation Patient demandOffered unproven therapies  Untreatable conditions  Alternative to invasive treatments  QoL (orthopedic injuries)  Cosmetic procedures  Medical tourism  Cutting edge innovation  Innovative surgery  But also widespread fraud  Difficult to distinguish  Outside FDA jurisdiction to limit risk to business

27. The Letter outlines three major areas of problems: (1) the adipose stem cell product (stromal vascular fraction or SVF) is an unapproved biological drug (2) non-homologous use of the product (3) more than a dozen specific problems related to the production of the stem cell product SVF

28. Change in approach Request for comments Draft Guidances Relating to the Regulation of Human Cells, Tissues, or Cellular or Tissue-Based Products Regulations.gov Response  600 registered attendees  100 speaker requests  Hearing delayed “The agency intends to schedule a scientific workshop to gather information from manufacturers of cell based products, clinical researchers, and other stakeholders regarding the generation of scientific evidence to facilitate the development of safe and effective cell based therapeutics.”

29. Information gap: solution Unproven to proven therapies Comparison to defined standard  Wide variety of approaches  SC types  Harvest site  SC Manipulation  SC Reintroduction  Imaging technologies  Follow-up, rehabilitation  Current standard of care  Datasets from insurers  Big data approach  Patient >> data  Patient vs. statistical pool

30. Technical requirements  Patient anonymity  Indication  intervention  outcome  follow-up  Long-term follow-up & update from clinics  IPR protection  QoL studies, safety and efficacy, cost-effectiveness  Comparison against outcomes on defined standard of care as obtained from insurers

31. Technical requirements  Comparison against current standard of care  Continuous evaluation of coming data  Safety and efficacy, QoL  Benefit-risk assessments  Cost-effectiveness compared to other options  Multiple different PME, and likely evolving  Learning ecosystem  Near real time analytical output

32. Questions?