Alternative way of generating data from stem cell interventions performed under 21 CFR part 1271 (CGTP)
STEM CELL REGISTRY ARETE-ZOE, LLC 1334 E Chandler Blvd 5A-19, Phoenix 85048, Arizona, USA
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
Knowns and unknowns
Improved information environment is essential for sound decision-making by all stakeholders
Objective outcome measures needed for assessment of the effectiveness of stem cell therapies
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. •
NAP: Stem cell therapies (Nov 2014)
Corporate freedom of speech Issues relating to truthfulness of commercial speech are not unique to stem cells
Stakeholders Patients Physicians (regular healthcare providers) Manufacturers of HCP/Ts, clinics
Information Reliable Accurate Timely
Producers of mass produced treatments Regulators Insurers, payers Investors
Safety Efficacy Cost-effectiveness ROI
Regulations In the U.S. Section 505
International
of the FD&C Act
Section 351 of the PHS Act
DRUGS
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.
FACILITIES
ENVIRONMENT
EQUIPMENT
RECOVERY
REAGENTS
PROCESS
LABELLING
DISTRIBUTION
SUPPLIES
STORAGE
DONORS
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, reestablishing 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 Systematic review of available information in specialized databases Resource intensive, expensive, mandatory / driven by business need Articles reports datasets
Industry Insurers Healthcare providers Professional societies Academic research
All stem cell trials ClinicalTrials.gov March 22, 2016
Autologous stem cell trials ClinicalTrials.gov March 22, 2016
Conditions studied 2500 2000 1500 1000 500 0
ClinicalTrials.gov August, 2015
All SC trials: recruitment ClinicalTrials.gov January 7, 2016 137
43
Active, not recruiting
373
805
1 12
Approved for marketing Available Recruiting
1858 1730
Enrolling by invitation Not yet recruiting No longer available
249
Temporarily not available Completed
27
81
Suspended
All SC trials: enrollment ClinicalTrials.gov January 7, 2016 800 700 600 500 400 300 200 100 0
All SC trials: Type of trial ClinicalTrials.gov January 7, 2016 22 596 Interventional Observational
4680
Expanded access
All SC trials: funding ClinicalTrials.gov January 7, 2016
528
356
588
2907 836
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
All SC trials: sponsors “Other� means: Fred Hutchinson Cancer Research Center National Cancer Institute (NCI) M.D. Anderson Cancer Center Memorial Sloan Kettering Cancer Center National Heart, Lung, and Blood Institute (NHLBI) Masonic Cancer Center, University of Minnesota City of Hope Medical Center Children's Oncology Group|National Cancer Institute (NCI) St. Jude Children's Research Hospital Baylor College of Medicine Mayo Clinic
ClinicalTrials.gov August, 2015 Trials 192 177 148 100 91 80 72 59 57 53 51
ClinicalTrials.gov January 7, 2016
All SC trials: phases 1800 1600 1400 1200 1000 800 600 400 200 0 0
1
1&2
2
2&3
3
4
not stated
All SC trials: results ClinicalTrials.gov January 7, 2016
402; 8%
Has results No results available
4896; 92%
Scientific publications PubMed
CT Registries vs. publications
> 250,000 hits “stem cells”
Publication bias
>4,200 human clinical trials
Multiple publication bias
~140,000 animal studies
Link between publications
and CT# Non-human experience
Multiple publication bias: ALS 8 7
6 5 4 3
2 1 0
Additional publications identified by NIH Publications provided
Current situation Patient demand
Offered unproven therapies
Untreatable conditions
Cutting edge innovation
Alternative to invasive
Innovative surgery
treatments QoL (orthopedic injuries) Cosmetic procedures Medical tourism
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
Response
Draft Guidances Relating to the Regulation of Human Cells, Tissues, or Cellular or Tissue-Based Products
600 registered attendees
Regulations.gov
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
Current standard of care
Wide variety of approaches SC types Harvest site SC Manipulation SC Reintroduction Imaging technologies Follow-up, rehabilitation
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?