Alternative way of generating data from stem cells interventions performed under 21 CFR part 1271 (CGTP) https://www.aretezoe.com/stem-cells

1. ARETE-ZOE,LLC
1334 E ChandlerBlvd5A-19, Phoenix85048,Arizona,USA
STEM CELL REGISTRY
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)
Improved information environment is essential for sound decision-makingby all stakeholders
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. •
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.
ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION

8. HCT/Ps under section 361 of the
PHSAct 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
TEDTalks on Astroturf
How patients search for
medical information online

12. Information in public domain
ClinicalTrial
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. 0
500
1000
1500
2000
2500
Conditions studied ClinicalTrials.gov
August, 2015

17. 805 1 12
1730
81
249
72
1858
43
373
137 Active, not recruiting
Approved for marketing
Available
Recruiting
Enrolling by invitation
Not yet recruiting
No longer available
Temporarily not available
Completed
Suspended
All SC trials: recruitment
ClinicalTrials.gov
January 7, 2016

18. All SC trials: enrollment
ClinicalTrials.gov
January 7, 2016
0
100
200
300
400
500
600
700
800

19. All SC trials: Type of trial
ClinicalTrials.gov
January 7, 2016
4680
596
22
Interventional
Observational
Expanded access

20. All SC trials: funding
ClinicalTrials.gov
January 7, 2016
2907
836
588
528
356
Other
NIH & Other
Industry
Industry & Other
NIH
Industry & Other & NIH
Other & U.S. Fed
Industry & NIH
U.S. Fed
Industry & U.S. Fed
Other & NIH & U.S. Fed
U.S. Fed & NIH

21. All SC trials: sponsors
ClinicalTrials.gov
August, 2015
“Other” means: Trials
Fred Hutchinson Cancer Research Center 192
National Cancer Institute (NCI) 177
M.D. Anderson Cancer Center 148
Memorial Sloan Kettering Cancer Center 100
National Heart, Lung, and Blood Institute (NHLBI) 91
Masonic Cancer Center, University of Minnesota 80
City of Hope Medical Center 72
Children's OncologyGroup|National Cancer Institute (NCI) 59
St. Jude Children's Research Hospital 57
Baylor College of Medicine 53
Mayo Clinic 51

22. All SC trials: phases
ClinicalTrials.gov
January 7, 2016
0
200
400
600
800
1000
1200
1400
1600
1800
0 1 1 & 2 2 2 & 3 3 4 not
stated

23. 402; 8%
4896; 92%
Has results
No results available
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
0
1
2
3
4
5
6
7
8
Additional publications
identified by NIH
Publications provided

26. Current situation
Patient demand Offered 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 orTissue-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?