ARETE-ZOE, LLC 1334 E Chandler Blvd 5A-19, Phoenix 85048, Arizona, USA

STEM CELL REGISTRY

Alternative way of generating data from stem cell interventions performed under 21 CFR part 1271 (CGTP)

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

NAP: Stem cell therapies (Nov 2014)

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

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

Issues relating to truthfulness of commercial speech are not unique to stem cells

Corporate freedom of speech

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

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

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

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

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)

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

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

Information in public domain

Clinical Trial Registries

Biomedical Literature

Professional Societies

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

All stem cell trials ClinicalTrials.gov March 22, 2016

Autologous stem cell trials ClinicalTrials.gov March 22, 2016

0

500

1000

1500

2000

2500

Conditions studied

ClinicalTrials.gov August, 2015

805 1 12

1730

81

249

7 2

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

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

0100200300400500600700800

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

4680

596

22

Interventional

Observational

Expanded access

All SC trials: funding

ClinicalTrials.gov January 7, 2016

2907

836

588

528 356

OtherNIH & OtherIndustryIndustry & OtherNIHIndustry & Other & NIHOther & U.S. FedIndustry & NIHU.S. FedIndustry & U.S. FedOther & NIH & U.S. FedU.S. Fed & NIH

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 Oncology Group|National Cancer Institute (NCI) 59 St. Jude Children's Research Hospital 57 Baylor College of Medicine 53 Mayo Clinic 51

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

0200400600800

10001200140016001800

0 1 1 & 2 2 2 & 3 3 4 notstated

402; 8%

4896; 92%

Has results

No results available

All SC trials: results

ClinicalTrials.gov January 7, 2016

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

Multiple publication bias: ALS

0

1

2

3

4

5

6

7

8Additional publicationsidentified by NIH

Publications provided

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

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

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.”

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

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

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

Questions?