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Citation: 66 Food & Drug L.J.

479 2011
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The Food and Drug Administration, Regenerative Sciences,
and the Regulation of Autologous Stem Cell Therapies
BARBARA VON TIGERSTROM
INTRODUCTION
For several years, the United States Food and Drug Administration (FDA) has
been engaged in a dispute with Regenerative Sciences, a company that provides stem
cell treatments for orthopaedic applications at a clinic in Colorado. According to
FDA, these treatments are drugs and biological products that must comply with
regulatory requirements, including the need for pre-market approval; Regenerative
Sciences disagrees and its doctors say their practice of medicine is beyond FDA's
jurisdiction. This is not the first time FDA has warned a clinic about its use of
stem cell treatments as unlicensed biologicsI but the current dispute is noteworthy
because of the defendant's persistent and open resistance to FDA regulation and
the strong response by some members of the public to FDA's assertion of authority.
The dispute seems to have become something of a lightning rod for opposition to
FDA regulation and polarized views on access to experimental therapies.
These events are also taking place at a critical time in the development of stem
cell-based therapies, as more therapies are making the transition from laboratory
research into clinical application. This dynamic phase has seen the rise of concerns
about "stem cell tourism," the phenomenon of patients travelling to other countries
to seek novel, often unproven, therapies which are not available in the United States
or other jurisdictions with strong regulatory oversight. These concerns have been
extensively discussed,
2
but until recently, less attention has been focused on clinics
that are operating at - or outside - the margins of approved practice within the
United States itself Both of these developments raise important issues about how
best to regulate novel medical technologies and how to allow regulatory space for
legitimate innovation to serve the needs of patients and advance scientific progress,
while adequately protecting patients from exploitation or physical harm.
As will be seen below, the outcome of the dispute between FDA and Regenera-
tive Sciences should not be much in doubt, but that is only part of the story. The
case and some of the responses to it raise questions that will remain regardless of
the Court's ruling. This article uses the dispute as an opportunity to examine an
area of the law that will be critical to the development of promising new therapies,
and as an illustration of the complex dynamics involved in attempting to regulate
new medical technologies.
* BA (Alberta), MA (Toronto), LLB (Toronto), PhD (Cambridge); Associate Professor, College
of Law, University of Saskatchewan, Canada. Research for this article was supported in part by a
Public Policy Impact Grant from the Stem Cell Network (Canada) and assisted by Adryan Toth (LLM
Candidate, University of Saskatchewan).
I United States of America v. Loran Medical Systems, Inc., et al., 25 F. Supp. 2d 1082 (C.D. Cal.
1997); Letter from MARY A. MALARKEY, OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY, U.S. FooD
AND DRUG ADMIN., to Stem Cell Pharma Inc., (Nov. 22, 2006), available at http://www.fda.gov/Biolog-
icsBloodVaccines/GuidanceCompliance Regulatorylnformation/ComplianceActivities/Enforcement/
UntitledLetterslucm091930.htm.
2 E~g COMMITTEE FOR ADVANCED THERAPIES AND CAT SCIENTIFIC SECRETARIAT, Use of Unregulated
Stem-Cell Based Medicinal Products, 376 LANCEr 514 (2010) [ hereinafter CAT, Use of Unregulated Stem-Cell];
Jane Qiu, Trading on Hope, 27 NATURE BIOTECHNOLOGY 790 (2009); Ole Lindvall & Insoo Hyun, Medical
Innovation Versus Stem Cell Tourism, 324 SCIENCE 1664 (2009); Darren Lau et al., Stem Cell Clinics Online:
The Direct-to-Consumer Portrayal of Stem Cel Medicine, 3 CELL STEM CELL 591 (2008); Charles E. Murdoch
& Christopher Thomas Scott, Stem Cell Tourism and the Power of Hope, 10(5) AM. J. Brognicrs 16 (2010).
479
480 FOOD AND DRUG LAW JOURNAL VOL.66
I. REGENERATIVE SCIENCES AND REGENEXXTM
Regenerative Sciences, LLC (also known as Regenerative Sciences, Inc.) is a Colo-
rado company, the majority shareholders of which are Dr. Christopher Centeno and
Dr. John Schultz. Drs. Centeno and Schultz operate the Centeno-Schultz Clinic in
Broomfield, Colorado.
3
They offer a treatment known as "Regenexx
Tm
" which is
now available in several forms.
4
The form that gave rise to the dispute with FDA was
the original Regenexx treatment, now called "Regenexx-C" (Cultured).I It involves
removing bone marrow from the patient's hip using a needle, as well as taking blood
from the patient's arm. These are sent to the Regenerative Sciences lab where mesen-
chymal stem cells (MSCs) are isolated from the bone marrow. The lab then uses growth
factors from the patient's blood, as well as reagents and culture media, to expand the
MSCs in a cell culture. The expanded MSCs are then mixed with other drug products
and injected into the injured site in the patient, where it is claimed that the MSCs will
help to repair the injury.
6
The process takes about 7 weeks.
7
The Clinic charges $200
to review a prospective patient's films and $250-315 for a consult.
8
The treatment is
reported to cost approximately $7000-9000,9 and is not covered by insurance.
0
The
providers suggest that two to four injection cycles will normally be needed."
Mesenchymal stem cells (MSCs, also referred to as mesenchymal stromal cells'
2
)
are a type of adult stem cell. The main source of MSCs is bone marrow, although
they are also found in other body tissues.
3
In contrast to embryonic stem cells, which
are pluripotent (meaning they can form any type of cell in the human body), adult
stem cells like MSCs are multipotent (meaning they can form only certain types of
cells).1
4
MSCs can form several cell types, including bone, cartilage or fat cells.'
5
They
3 Plaintiff's Motion for Summary Judgment at 19, United States of America v. Regenerative Sci-
ences, LLC, et al (2011) (No. 1:10-CV-01327-RMC) (filed Jan. 7, 2011) (U.S. Dist. Ct. D.C.), available
at HYMAN, PHELPS & MCNAMARA PC http://www.hpm.com/pdfll%2019%20Plaintiff's%20Motion%20
for%20Summary/o20Judgment% 20010711 .pdf.
4 Regenexx Procedures Family of Stem Cell and Platelet Procedures, REGENExxTM, http://www
regenexx.com/ regenexx-procedures-family/ (last visited Jun. 23, 2011) [hereinafter Regenexx Procedures
Family]. (Regenerative Sciences and the Clinic refer to the "Regenexx procedure" while the Food and
Drug Administration refers to it as a product, reflecting the difference of views between them. This
article will use "treatment" or "therapy" as neutral terms, although this is not meant to imply any
conclusion about the clinical benefit of Regenexx for any condition).
Id.
6 This description is summarized from court documents, including: Order of Dismissal, Regenerative
Sciences, Inc. v. United States Food and Drug Administration, et al., (Mar. 26, 2010) (No. 09-cv-0041I-
WYD-BNB) 2WL 1258010 (U.S. Dist. Ct, D. Colo.) and Plaintiff's Motion for Summary Judgment, supra
note 3, at 10-12.
1 Regenerative Sciences, LLC, Regenexx Procedure: Imaging Case Reports and Medical Provider
Information, REGENExxTM, available at http://www.regenexx.com/wp-content/uploads/2008/12/Regenexx-
physician-oriented-V6.pdf at 8 (last visited Jun. 23, 2011) [hereinafter Regenerative Sciences, Regenexx].
FAQ's, REGENExxTM, http://www.regenexx.com/common-questions/ (last visited Jun. 23, 2011).
David Cyranoski, FDA Challenges Stem-Cell Clinic, 466 NATURE 909, 909 (2010) [hereinafter
Cyranoski, FDA Challenges].
10 FAQ's, supra note 8.
11Regenexx-SD Procedure, REGENEXXTM, available at http://www.regenexx.com/wp-content/
uploads/ 2009/09/Regenexx-SD-Brochure.pdf at 2 (last visited Jun. 23, 2011).
12 The terminology has been the subject of some debate, and other names have also been proposed:
see Arnold 1. Caplan, What's in aName?, 16(8) TISSUE ENGINEERING: PART A 2415 (2010); Paolo Bianco,
Pamela Gehron Robey & Paul J. Simmons, Mesenchymal Stem Cells: Revisiting History Concepts, and
Assays 2(4) CELL STEM CELL 313. 314 (2008). In all of its literature, Regenerative Sciences uses the term
"mesenchymal stem cell." This article will use the acronym MSC which can refer to either mesenchymal
stem cell or mesenchymal stromal cell.
13 Ignacio Garcia G6mez et al., Mesenchymal Stem Cells: Biological Properties and Clinical Ap-
plications, 10(10) EXPERT OPINION ON BIOLOGICAL THERAPY 1453, 1453-54 (2010).
14 NATIONAL INsTITUTES OF HEALTH, STEM CELL BAsics, at 12-13 available at http:llstemcells.nih.
govlstatic resources/infolbasics/SCprimer2009.pdf (last visited Jun. 24, 2011) This is unless they are
genetically reprogrammed to be pluripotent (known as induced pluripotent stem cells or iPSCs).
15 Garcia G6mez et al, supra note 13,.at 1453.
2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
are being studied for a range of potential clinical uses, including bone and cartilage
repair as well as possible applications in neurological and autoimmune disorders.
16
The therapeutic effects of MSCs and the mechanisms by which they achieve these ef-
fects are currently being investigated and are not yet fully understood." Regenerative
Sciences appears to claim that in the Regenexx treatment, the MSCs differentiate into
the desired cell type after implantation. In its brochure for physicians, Regenerative
Sciences asserts that: "MSCs receive differentiation cues from their environment.
For example, stretching or pulling forces can cause MSCs to become tendon cells.
Compressive loading like walking can pushes [sic] MSCs towards cartilage lineage."'
8
Regenexx is offered as a "non-surgical treatment option" for "moderate to severe
joint or bone pain" in the hand, hip, knee, shoulder, back, or ankle, or for chronic
bursitis or non-union fractures." A patient brochure lists osteoarthritis, tendon
injuries and avascular necrosis among the conditions treated.
20
Case reports and
MRI images are posted on the Regenexx website claiming to show that the treatment
has been effective.
2
1 Two case reports have been published in medical journals.
22
A
brochure designed for physicians also contains case reports as well as summaries of
preclinical and animal studies relating to the treatment's potential effectiveness.
23
It
also reports the results of surveys of former patients, which are offered as support
for the conclusion that Regenexx significantly reduces pain, compared to standard of
care.
24
In regards to the safety of Regenexx, Dr. Centeno and colleagues published an
article in 2010 reporting the results of a study in which they followed up 227 former
patients. In this sample there were seven probable procedure-related adverse events,
including three possible complications from stem cells.
25
No tumours were found at
the sites where the stem cells were injected.
26
Other experts believe the tumorigenic
potential of MSCs should be low, provided the expansion in culture meets certain
conditions, although there are other risks such as infection.
27
Pending resolution of the litigation, the Clinic is no longer offering Regenexx-C,
although it has licensed the technology to clinics offering it in China and Argen-
16 E.g id at 1457-58; Ivan Martin et al., A Survey on Cellular and Engineered Tissue Therapies in
Europe in 2008, 16(8) TISSUE ENGINEERING: PART A 2419. 2420-21 (2010); Stefan Bajada et al., Updates
on Stem Cells and their Applications in Regenerative Medicine, 2 J. TISSUE ENGINEERING AND REGENERA-
TIVE MED. 169, 175-79 (2008).
'7 E.g. Garcia G6mez et al., supra note 13, at 1462-63; Em Horwitz & M Doninici, How do
Mesenchymal Stromal Cells Exert their Therapeutic Benefit?, 10(8) CYTOTHERAPY 771 (2008).
" Regenerative Sciences, Regenexx, supra note 7, at 6.
19 Conditions Treated, REGENExxTM http://www.regenexx.com/the-regenexx-procedures/ (last
visited Jun. 23, 2011).
20 Regenexx-SD
Procedure,
supra note 11.
21 Case Studies, REGENNExTM, http://www. regenexx.com/the-regenexx-procedures/case-studies/
(last visited Jun. 23, 2011): see also Regenexx Blog, REGENExxTM, http://www.regenexx.com/global-
navigation/regenexx-blog/ (last updated Jun. 24, 2011) (This is a blog found on the Regenexx website,
which contains stories about patients treated with Regenexx).
22 Christopher J. Centeno et al., Partial Regeneration of the Human Hip via Autologous Bone
Marrow Nucleated Cell Transfer: A Case Study, 9 PAIN PHYSICIAN 253 (2006); Christopher J. Centeno
et al., Regeneration of Meniscus Cartilage in a Knee Treated with Percutaneously Implanted Autologous
Mesenchyman Stem Cells, 71 MEDICAL HYPOTHESES 900 (2008); Christopher J. Centeno et al., Increased
Knee Cartilage Volume in Degenerative Joint Disease using Percutaneously Implanted, Autologous Mes-
enchymal Stein Cells, 11(3) PAIN PHYSICIAN 343.
23 Regenerative Sciences, Regenexx, supra note 7.
24 7 Id Al I,21I
25 Christopher J. Centeno et al., Safety and Complications Reporting on the Re-implantation of
Culture-Expanded Mesenchymal Stein Cells using Autologous Platelet Lysate Technique, 5(1) CURRENT
STEM CELL RESEARCH AND THERAPY 8 1(2010).
26 Id
27 Darwin J. Prockop et al., Defining the Risks of Mesenchymal Stromal Cell Therapy, 12(5) Cv-
TOTHERAPY 576. 578 (2010).
48 1
FooD AND DRUG LAW JOURNAL
tina, and is opening a stem cell culture lab in the Cayman Islands." It now offers
"Regenexx-SD" (Same Day) which involves processing the bone marrow and
injecting the cells later the same day.
29
Other variations include "Regenexx-AD"
(Adipose Derived), which combines Regenexx-SD with a structural fat graft,
0
and
"Regenexx-SCP" (Stem Cell Plasma) for meniscus tears.
3
' Case studies reporting
on the use of Regenexx-SD and Regenexx-AD began to be added to the Regenexx
website in early 2011.32 Another page on the website states that "[w]hile Regenexx-
SD does rely on the same stem cell type that was used to treat [the patients in the
case studies] and other clinics have reported good results using similar procedures
that don't rely on stem cell culturing, Regenexx-SD clinical effectiveness has not
yet been established."
33
Scientific literature (including an earlier article by Centeno
himself3
4
) raises some questions as to whether without culturing, the number of
cells would be sufficient to have a significant therapeutic benefit.
35
H. OVERVIEW OF THE DISPUTE
The dispute between Regenerative Sciences and FDA has been ongoing for several
years. In July 2008, FDA sent a letter to Regenerative Sciences stating that, based on
the way the use of MSCs was being promoted on the Regenexx website, it considered
those cells to be drugs and biological products. As such, a valid biologics license or
investigational new drug application (IND) was required and implanting the cells
without a license or IND appeared to violate the applicable legislation. The letter
concluded by requesting Regenerative Sciences to notify FDA of the steps taken or to
be taken to remedy these violations.
36
Regenerative Sciences submitted a response in
which it denied that Regenexx was a drug or biological product." In February 2009,
FDA began an inspection of the Regenerative Sciences facilities.
8
This inspection
found numerous violations of "current Good Manufacturing Practice" (cGMP)."
28 Regenexx Procedures Family, supra note 4; StematixTM Obtains Exclusive License to Regen-
exxTM Stem Cell Procedure Treating Musculoskeletal Diseases in Latin America, REGENEXxTM (Oct.
23, 2009), http://www. regenexx.com/2009/10/stematixE2%84%A2-obtains-exclusive-license-to-
regenexx%E2%84%A2-stem-cell-procedure-treating-musculoskeletal-diseases-in-latin-americal [here-
inafter StematixTM Obtains Exclusive License to RegenexxTM; Local Chinese Government Authorities
Approve Pricing and Reimbursement for Neostem's Licensed Adult Stem Cell Treatments for Orthopedic
Applications in China, NEOSTEM (Nov. 2, 2010). http://www.neostem. com/news/ocal-chinese-government-
authorities-approve-pricing-and-reimbursement-for-neostem-s-licensed-adult-stem-cell-treatments-for-
orthopedic-applications-in-china.html; Centeno-Schultz Clinic Opening a State of the Art Stem Cell
Culture Lab in the Cayman Islands, REGENExxTM (Aug. 17, 2011), http://www.regenexx.com/2011/08/
centeno-schultz-clinic-opening-a-state-of-the-art-stem-cell-culture-lab-in-the-cayman-islands/.
29 Regenexx Procedures Family, supra note 4.
30 Regenexx-AD (Adipose Derived), REGENExxTM (Nov. 27, 2010, 1:35pm), http://www.regenexx.
com/2010/11!regenexx-ad-adipose-derived/.
" Regenexx-SCP (Stem Cell Plasma), REGENExxTM (Nov. 27, 2010., 1:55pm), http://www.
regenexx.com/2010/1 1/ regenexx-scp-stem-cell-plasma/.
32 See Regenexx Blog, supra note 21.
11 Case Studies, supra note 21.
- Centeno et al., Regeneration of Meniscus, supra note 22, at 902-903.
1 E.g Garcia Gomez et al., supra note 13, at 1461.
36 Letter from MARY A. MALARKEY, OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY, U.S. FOOD
AND DRUG ADMIN., to Regenerative Sciences, Inc., (Jul. 25, 2008), available at http://www.fda.gov/Bio-
logicsBloodVaccines/ GuidanceComplianceRegulatorylnformation/ComplianceActivities/Enforcement/
UntitledLetters/ucm091991.htm.
n Order of Dismissal, supra note 6, at 5.
3Id. (Regenerative Sciences also sought a protective order alleging that FDA's inspection was an
attempt to conduct unsupervised discovery, which was denied: id).
SPlaintiff's Motion for Summary Judgment at 14-15, United States of America v. Regenerative
Sciences. LLC. et al (2011) (No. 1: 10-CV-01 327-R MC) (filed Jan. 7, 2011) (U.S. Dist. Ct. D.C.) available
at HYMAN. PHELPS & MCNAMARA PC http://www hpm.com/pdfll%2019%20Plaintiff's%20Motion%20
for%20iSummary%/20Judgment% 20010711 .pdf.
482 VOL. 66
2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES 483
Before the inspection could be completed, Regenerative Sciences filed an applica-
tion for a declaration and injunction to prevent FDA from regulating Regenexx as
a drug or biological product. FDA argued that this application was premature, as
it had not taken any regulatory action against Regenerative Sciences; the July 2008
letter was a preliminary step and not a final administrative action that was open to
review.
40
The Court agreed and dismissed the action as not ripe and fit for review.
4
'
FDA inspected the Regenerative Sciences lab again in 2010, and found that it still
was not compliant with cGMP.42 It warned Regenerative Sciences about cGMP
violations in June 2010.43 In June 2010, Regenerative Sciences applied for an order
"to prompt FDA to take 'final agency action' or leave its medical practice alone."44
The following month, the United States Government, on behalf of FDA, applied for
an injunction against Regenerative Sciences (along with Drs. Centeno and Schultz
and the Regenerative Sciences lab director Michelle Cheever), arguing that Regenexx
was "adulterated" within the meaning of the legislation because of lack of compli-
ance with cGMP and "misbranded" because the product was not properly labelled.
45
Regenerative Sciences agreed to cease offering the cultured cell product (Regenexx-C)
pending resolution of the case.
46
In January 2011, the U.S. Government filed a motion for summaryjudgment
47
and
a motion to dismiss the counterclaims put forward by the defendants (Regenerative
Sciences, Centeno, Schultz, and Cheever), which challenge FDA's authority to regulate
Regenexx.48 The motion for summary judgment asserts that since there is no dispute
as to any material fact, summary judgment would be appropriate.
49
In addition, a
permanent injunction is sought because the defendants have refused to comply with
the law.
50
Further, it is argued that the defendants' counterclaims should fail as a
matter of law and that some of them are barred by the statute of limitations, since
they challenge rules made by FDA more than six years before the claims were made.
5
As of June 2011, no decision on these motions had yet been reported.
52
40 Order of Dismissal, supra note 6, at 1.
41 Id.,
at 15.
42 Plaintiff's Motion for Summary Judgment, supra note 3, at 15-16.
43 U.S. DEP'T OF HEALTH & HUMAN SERVICES, U.S. FOOD AND DRUG ADMIN., News & Events: FDA
Seeks Injunction Against Colorado Manufacturer of Cultured Cell Product, F.D.A. (Jun. 6,2010), http://
www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm221656.htm (last updated Jun. 8.
2010) [hereinafter FDA SEEKS INJUNCTION].
I Regenerative Sciences, Inc., Colorado Medical Clinic Welcomes Opportunity to Fight FDA in
Court, PR NEWSWIRE (Aug. 9, 2010), http://www.prnewswire.com/news-releases/colorado-medical-clinic-
welcomes-opportunity-to-fight-fda-in-court-100247969.html [hereinafter RSI Welcomes Opportunity
to Fight].
" FDA SEEKS INJUNCTION, supra note 43.
* Regenerative Sciences and FDA - FAQs, REGENExxTM (2010), http://www.regenexx.com/wp-
content/uploads/ 2010/08/Regenerative-Science-FAQs-8.211. 10.pdf at 2-3.
47 Plaintiff's Motion for Summary Judgment, supra note 3.
* Plaintiff's Motion to Dismiss Defendants' Counterclaims, United States of America v. Regenera-
tive Sciences, LLC, et al, (2011) (No. 1:10-CV-01327-RMC) (Filed Jan. 7, 2011) (U.S. Dist. Ct. D.C.),
available at HYMAN, PHELPS & MCNAMARA PC http://www.hpm.com/pdfll%2020%20Plaintiff's%20
Motion%20to%20Dismiss%2ODefs'%20Counterclaims%2001071 1.pdf.
9 Plaintiff's Motion for Summary Judgment, supra note 3, at 2.
~' Plaintiff's Motion to Dismiss Defendants' Counterclaims, supra note 48, at 3.
52 At the end of August 2011, the District Court issued an Order to Show Cause, asking for
submissions from the U.S. on the interpretation of the definition of "drug" in 21 U.S.C. §§ 321(g)
(1)(B)&(C): Order to Show Cause, United States of America v. Regenerative Sciences, LLC, et al,
(2011) (No. 1 :10-CV-01327-RMC) (Filed Aug. 29, 2011) (U.S. Dist. Ct. D.C.), available at http://app4.
websitetonight.comprojects2/7075/815S707/uploadsl2Ol11-09-USAvsRSIOrderToShowCause.pdf.
The Order compares the definition of "drug" with the definition of "device" in 21 U.S.C. §4 32 1(h),
which includes an article that "does not achieve its primary intended purposes through chemical
continued
FOOD AND DRUG LAW JOURNAL
m. MAIN POINTS OF CONTENTION IN TIE DISPUTE
A. Is Regenexx a Drug and Biologic or a Human Cellular and
Tissue-based Product?
The central issue in this dispute is the legal characterization of Regenexx, that
is, whether it is a drug and biological product, as claimed by FDA, a human cel-
lular and tissue-based product which is subject to different regulations, or merely a
form of medical practice, as claimed by Regenerative Sciences. If it is a drug and
biological product, then it follows that certain legal requirements under U.S. federal
laws, such as the need for approval and compliance with cGMP, apply to Regenexx.
FDA's position throughout these proceedings has been that Regenexx falls within
the definition of a drug and biologic, and thus must comply with the regulatory
requirements for these categories. A drug is defined in the federal Food, Drug,
and Cosmetic Act (FDCA) to include "articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease in man or other animals" and
"articles ... intended to affect the structure or any function of the body of man
or other animals."" Articles "intended for use as a component" of either of these
are also defined as drugs.
54
The cells (and other components) that are injected into
the patient as part of the Regenexx treatment could certainly be considered to be
"articles." The therapeutic purpose of injecting this substance is also clear from
the promotional material that appears on the Regenexx website." Whether or not
Regenexx actually does have the effects that are claimed, it is certainly intended
to mitigate or treat disease or affect the structure of function of the human body
and is marketed as such. The substance that is injected therefore does fall within
the definition of a drug.
A biological product is defined as "a virus, therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or derivative, allergenic product, or analogous
product ... applicable to the prevention, treatment, or cure of a disease or condi-
tion of human beings."
6
FDA gave notice as early as 1993 that it intended to treat
manipulated cells for use in cell therapy as drugs and biological products." This
action ... and which is not dependent upon being metabolized for the achievement of its primary
intended purposes." The Order states that the definitions "immediately raise the question of why
the Court should not interpret the meaning of the word 'drug' to include not only an article for use
in diagnosis, etc., and intended to affect the structure or function of a patient, but also an article
that 'achieve[s] its primary intended purposes through chemical action' and which is 'dependent
upon being metabolized for the achievement of its primary intended purposes."' The United States
therefore is ordered to show cause why the definition of "device" should not inform and restrict the
definition of "drug." This line of questioning raises broader questions about whether cell therapies,
and indeed all biologics, fall within the definition of a "drug." This is an unexpected approach to
the dispute with potentially "far reaching implications" which are not yet clear: Suzan Onel, Michael
H. Hinckle & Karl M. Nobert, Culture Stem Cells for Autologous Use: Practice of Medicine or FDA
Regulated Drug and Biological Product? (Sep. 19, 2011), http://www.klgates.com/cultured-stem-cells-
for-autologous-use-09-19-2011.
5 21 U.S.C. §§ 321(g)(1)(B), 321(g)(1)(C).
SIt. at§( 321(g)(1)(D).
5 REGENEXXTM. http://www.regenexx.com (last visited Jun. 23. 2011).
56 Public Health Service Act, 42 U.S.C. § 262(i) [emphasis addedl.
*' U.S. DEP'T OF HEALTH AND HUMAN SERVICES , U.S. FOOD AND DRUG ADMIN., APPLICATION OF
CURRENT STATUTORY AUTHORITIES To HUMAN SOMATIC CELL THERAPY PRODUCTS AND GENE THERAPY
PRODUCTS. 58(197) Fed. Reg. 53248-51. 53249 (1993) [hereinafter FDA. APPLICATION OF CURRENT STATU-
ToRY AUTHORITIES].
484 VOL. 66
2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
has been confirmed on several subsequent occasions.
8
The cell preparation used
in Regenexx would therefore also be considered a biological product. In order for
a biologics license to be approved, it must be demonstrated that the "biological
product ... is safe, pure, and potent" and that "the facility in which the biological
product is manufactured, processed, packed, or held meets standards designed to
assure that the biological product continues to be safe, pure, and potent."
59
An alternative classification that would allow Regenexx to escape regulation as a
drug and biological product is the class known as "Section 361" human cellular and
tissue-based products (HCT/Ps), after the section under which they are regulated.6
This category of HCT/Ps is believed to require less extensive regulation because
although these products would qualify as drugs and biological products, they have
distinct characteristics that justify a lower risk classification.
61
The regulations for
HCT/Ps focus on preventing contamination and communicable disease, and are
not concerned with establishing efficacy or other aspects of safety.
62
They require
establishments that manufacture HCT/Ps to be registered, impose requirements
with respect to screening and testing of donors" and set standards for current Good
Tissue Practice (cGTP), addressing issues such as environmental and processing
controls, process validation, labeling controls and record-keeping.
65
If HCT/Ps
meet certain criteria, they are only subject to these regulations.
66
If they fail one or
more of the criteria, they will be subject to the usual drug and biological product
requirements, in addition to the establishment registration, donor eligibility and
cGTP requirements.
7
In order to be regulated solely as a Section 361 HCT/P, a product must be minimally
manipulated, be intended for homologous use (i.e. intended to perform the same func-
tion after transplantation), and not involve combination with another article (with
some exceptions, such as water or preserving agents that do not raise "new clinical
safety concerns with respect to the HCT/P").
6
8 It also must not have a systemic effect
* United States of America v. Loran Medical Systems, Inc., et al., 25 F. Supp. 2d 1082 (C.D. Cal.
1997); U.S. DEP'T OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMIN., CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH, GUIDANCE FOR INDUSTRY: GUIDANCE FOR HUMAN SOMATIC CELL THERAPY
AND GENE THERAPY (Mar. 1998), available at http:// www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatory Information/Guidances/CellularandGeneTherapy/ucm081670.pdf
[hereinafter FDA, GUIDANCE FOR HUMAN SOMATIC CELL THERAPY]; Dina Gould Halme & David A.
Kessler, FDA Regulation of Stem-Cell-Based Therapies, 355(16) NEw ENG. J. MED. 1730 (2006); Donald
W Fink, et al., FDA Regulation of Stem Cell Based Products, 324 SCIENCE 1662 (2009).
1 42 U.S.C. § 262(a)(2)(C); see also Food and Drugs, 21 C.F.R. pts. 600, 601, 610.
6 42 U.S.C. § 264(a).
61 U.S. FOOD AND DRUG ADMIN., PROPOSED APPROACH TO REGULATION OF CELLULAR AND TISSUE-
BASED PRODUCTS, 62 Fed. Reg. 9721, (Feb. 28, 1997), available at http://www.fda.gov/downloads/Bio-
logicsBlood Vaccines/GuidanceComplianceRegulatorylnformation/Guidances/Tissue/UCM062601.
pdf [hereinafter FDA, PROPOSED APPROACH To REGULATION].
62 Id
63 21 C.F.R. § 1271 subpt. B.
6 Id, at § 1271 subpt. C.
65 Id, at § 1271 subpt. D.
6 HCT/Ps are exempt from these regulations if they are removed from an individual and im-
planted "into the same individual during the same surgical procedure": id at § 1271.15(b). Regenerative
Sciences asserts that the same-day version of the Regenexx treatment, Regenexx-SD, is exempt from
regulation under this provision: FAQs, supra note 8. This seems to be stretching the plain meaning of
"same surgical procedure" given that the process involves harvesting the sample in the morning, taking
the sample to the lab for processing, then the patient returning to the Clinic in the afternoon for the
injection procedure: Regenexx-SD Procedure, supra note I1. For the time being, however FDA does
not appear to be challenging this claimed exemption.
67 21 C.F.R. § 1271.20.
485
FOOD AND DRUG LAW JOURNAL
or depend on "the metabolic activity of living cells for its primary function," unless
it is for autologous use (use in the same individual), allogeneic use (use in a different
individual) in a first- or second-degree blood relative, or for reproductive use.
69
In this dispute, the key consideration is whether Regenexx-C is minimally manipu-
lated. In the regulations, "minimal manipulation" is defined with respect to cells
or non-structural tissues as "processing that does not alter the relevant biological
characteristics of cells or tissues." The position of Regenerative Sciences is that
expansion of MSCs in culture should be considered only minimal manipulation.
FDA contends, however, that Regenexx-C is more than minimally manipulated be-
cause it is expanded in culture, and therefore cannot be regulated solely as a Section
361 HCT/P but is also subject to the drug and biological product requirements.
72
In fact, it submits that this is "beyond dispute."" As explained by FDA, expanding
cells in culture, as in the process for preparing Regenexx-C, changes their relevant
biological characteristics because "culturing results in the selection and alteration
of the original bone marrow (or synovial) cells, ... because cells grow and respond
to the tissue culture flasks and the composition of the media and other conditions
under which they are grown. ... The remaining cells would expand in number and
change so they are different from the original cells in the bone marrow."
74
Cultur-
ing causes "changes in the proteins and the genes expressed by the cells, as well as
changes in the shape of the cells.""
The position of FDA that culturing (expansion of cells in culture) constitutes
more than minimal manipulation has been consistent throughout the development
of its approach to regulating cell therapy,
6
despite its having reconsidered the status
of other forms of processing in light of evolving scientific evidence.
7
Sterilization,
cell separation, centrifugation or freezing are considered to be minimal manipulation,
but cell expansion, along with encapsulation, activation, and genetic modification,
are more-than-minimal manipulation." An agency's interpretation of its own regu-
lations is not definitive, but it should generally be given deference by the courts.
79
69 Id, at § 1271.L0(a)(4).
70Id, at § 1271.3(f)(2).
7 See Plaintiff's Motion to Dismiss Defendants' Counterclaims at 24, United States of America
v. Regenerative Sciences, LLC, et al, (2011) (No. 1:10-CV-01327-RMC) (Filed Jan. 7, 2011) (U.S. Dist.
Ct. D.C.), available at HYMAN, PHELPS & MCNAMARA PC http://www.hpm.com/pdf/I%2020%20Plain-
tiff's%20Motion%20to%20Dismiss %20Defs'%20Counterclaims%20010711I.pdf (The legal status of
FDA's interpretive statements and the effect of the statute of limitations on this counterclaim are also
at issue (see id, at 24-36) but discussion of these points is beyond the scope of this article).
72 Plaintiff's Motion for Summary Judgment at 21-22, United States of America v. Regenerative
Sciences, LLC, et al (2011) (No. 1:10-CV-01327-RMC) (filed Jan. 7,2011) (U.S. Dist. Ct. D.C.) available
at HYMAN, PHELPS & MCNAMARA PC http://www.hpm.com/pdf/1%2019%20Plaintiff's%20Motion%20
for%20Summaryo20Judgment% 20010711 .pdf
7 Id, at 22.
74 Id, at 21-22.
" Id, at 22.
76 A Gee, Mesenchymal Stem-Cell Therapy in a Regulated Environment, 3(5) CYTOTHERAPY 397, 397
(2001); e.g FDA, APPLICATION OF CURRENT STATUTORY AUTHORITIES, supra note 57, at 53249 (somatic
cell therapy products to be regulated as biological products include "cells that have been propagated,
expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics"); FDA,
PROPOSED APPROACH To REGULATION, supra note 61, at 17 ("Examples of more-than-minimal manipula-
tion of cells and tissues include cell expansion, encapsulation. activation, or genetic modification").
n' FDA, PROPOSED APPROACH TO REGULATION, supra note 61. at 17-It8 (regarding cell selection).
*' Id, at 17; DEP'T 01F HEALTH AND HUMAN SERVICES. U.S. FOOD AND DRUG ADMIN., HUMAN CELLS,
TISSUE, AND CELLULAR AND TISSUE-BASED PRODUCTS; ESTABLISHMENT REGISTRATION AND LISTING (FINAL
RULE) 66 Fed. Reg. 5447. 5457 (Jan. 19. 2001) (to be codified at 21 C.F.R. pt. 1271) [hereinafter FDA,
HCT/P FINAL RULE].
" For example. see the cases cited in Plaintiff's Motion for Summary Judgment, supra note 3, at 22,
n. 20.
486 VOL. 66
2011 REGULATION OF AUTOLOGOUS STEM CELL THERAPIES
Ultimately, the question of whether culturing cells changes their relevant biological
characteristics is one to be resolved by scientific evidence. FDA's position is supported
by current scientific literature, which suggests that culture conditions influence the
biological properties of MSCs in ways that can affect both safety and efficacy.
8 0
It
is also consistent with approaches taken in the EU,' Canada
82
and Australia, none
of which consider expansion in culture to be only minimal manipulation.
This point is critical to FDA's position, because it is only more-than-minimally
manipulated or non-homologous cell therapies that will be regulated as drugs and
biological products. If Regenexx-C does fall to be regulated as a drug/biologic, the
regulatory requirements that would normally follow are not a matter of debate, such
as the need to get FDA approval (either approval of an investigational new drug ap-
plication, or a biologics licence) and to comply with cGMP and labelling requirements.
A final point to consider is whether these requirements might not apply because the
product had not moved in "interstate commerce." The prohibitions on adulterating
or misbranding drugs apply only where the drugs are in or introduced into interstate
commerce,
84
or "after shipment in interstate commerce."
85
Regenerative Sciences
states that it does not sell any cell products in interstate commerce." However, FDA's
position, supported by several authorities cited in its motion, is that the provisions
nevertheless apply because components of the product, in particular the drugs added
to the cultured cells, have been shipped in interstate commerce."
B. Does FDA Lack Authority to Regulate Regenexx-C?
Despite the fact that Regenexx-C, as a cultured cell product, falls within the defi-
nition of a drug and a biologic, Regenerative Sciences questions FDA's authority
to regulate it.
88
There are two branches to this argument. The first is that FDA
does not have the jurisdiction to regulate with respect to autologous therapies; the
second is that the Clinic is not manufacturing drugs but simply practicing medicine.
Regenerative Sciences challenges the jurisdiction of FDA to regulate stem cells
for autologous use. Autologous use refers to use of a cell or tissue product in the
same individual from which it was derived. The source of authority for the HCT/P
regulations, as mentioned earlier, is Section 361 of the PHSA, which authorizes
the making and enforcement of regulations "to prevent the introduction, transmis-
sion, or spread of communicable diseases from foreign countries into the States or
8 E.g Horwitz & Dominici, supra note 17, at 773; Prockop et al., supra note 27.
81 Regulation (EC) 1394/2007 of the European Parliament and of the Council of 13 November
2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation
(EC) 726/2004, 2007 O.J. (L324), 132 (Annex 1) (Due to the way the Regulation is drafted, forms of
manipulation equivalent to minimal manipulation (manipulation not considered to be "substantial")
are listed in the Annex).
82 HEALTH CANADA, GUIDANCE DOCUMENT FOR CELL, TISSUE AND ORGAN EsTABLISHMENTs: SAFETY
OF HUMAN CELLS, TISSUES AND ORGANS FOR TRANSPLANTATION, 15 (2009).
83 AUSTRALIAN Gov'T, DEPART. OF HEALTH AND AGEING THERAPEUTIC GOODS ADMIN., Regulatory
Framework for Biologicals, TGA (Jun. 8, 2011), http:l/www.tga.gov.aulindustry/biologicals-framework.
htm.
4 21 U.S.C. § 331(a),(b).
85 Id., at § 331(k).
86 Regenerative Sciences and FDA -FAQs, supra note 46.
87 Plaintiff's Motion for Summary Judgment at 23-25, United States of America v. Regenerative
Sciences, LLC, et at (2011) (No. 1 :10-CV-01327-RMC) (filed Jan. 7, 2011) (U.S. Dist. Ct. D.C.) available
at HYMAN, PHELPS &C MCNAMARA PC http://www.hpm.com/pdf[I%2019%20Plaintiff's%20Motion%20
for%20Summaryo20Judgment% 20010711 .pdf.
88 E~g RSI Welcomes Opportunity to Fight, supra note 44; Regenerative Sciences andEFDA -.FAQs,
supra note 46.
487
FOOD AND DRUG LAW JOURNAL
possessions, or from one State or possession into any other State or possession.""
Regenerative Sciences has taken the position that autologous cell therapy "cannot
possibly cause communicable diseases" and that, therefore, the regulations that
define HCT/Ps to include autologous cells and tissues are ultra vires."
This argument should be dispensed with quite easily, since any processing of cells
and tissues carries a risk of contamination or infection." Experts in the field state
that strict controls are necessary in processing MSCs to manage the risk of microbial
contamination.
92
The HCT/P regulations contain an exemption for cells and tis-
sues removed and then implanted into the same individual during the same surgical
procedure," reflecting that fact that when cells are removed and reinserted within
the same procedure, this will "pose no greater risk of disease transmission than the
surgery itself."
94
Whenever cells and tissues undergo other processing, however, the
possibility of communicable disease transmission exists, regardless of whether the cells
are for autologous or allogenic use. The risk of direct transmission of disease between
donor and recipient does not exist for autologous therapies, since these are the same
person, and the requirements imposed on HCT/Ps for autologous use reflect that
fact.
95
Nevertheless, infectious agents could be introduced into the product at some
point between removal and implantation, and it is certainly not inconceivable that
this could result in the transmission of communicable disease across state boundaries.
As a related point, Regenerative Sciences has challenged FDA's authority to regu-
late autologous products as HCT/Ps, because the definition of HCT/Ps was changed
in 2005 without providing the public with notice or an opportunity to comment.
96
The definition of HCT/Ps, which now reads "articles containing or consisting of
human cells or tissues that are intended for implantation, transplantation, infusion,
or transfer into a human recipient,"
97
previously referred to transplantation "into
another human."
98
The change in wording brought autologous products into the
scope of the HCT/P regulation in addition to allogeneic products. Regenerative
Sciences has alleged that the amendment was unlawful because it did not follow
the required notice and comment rulemaking procedures.
99
However, the allega-
tion that a substantive change was made with this amendment is implausible if
one considers the context. FDA had indicated in several earlier documents that
its proposed approach to regulating cell and tissue products included autologous
89 42 U.S.C.
§ 264(a).
90 Order of Dismissal, supra note 6,; see also Plaintiff's Motion to Dismiss Defendants' Counter-
claims, United States of America v. Regenerative Sciences, LLC, et al, (2011) (No. 1:10-CV-01327-RMC)
(Filed Jan. 7, 2011) (U.S. Dist. Ct. D.C.), available at HYMAN, PHELPS & MCNAMARA PC http://www.hpm.
com/pdf/I%2020%20Plaintiff's%20Motion%20to%20Dismiss%2ODefs'%20Counterclaims% 20010711.
pdf
91 FDA, PROPOSED APPROACH To REGULATION, supra note 61, at 12: Halme & Kessler, supra note 58,
at 1732.
92 Garcia Gomez et al., supra note 13, at 1462; Shane M. Ward, Global Harmonization of Regulatory
Requirements for Premarket Approval of Autologous Cell Therapies, 55 FOOD & DRUG L.J. 225-43, 231
(2000).
9 21 C.F.R. § 1271.15(b)
Halme & Kessler, supra note 58, at 1732.
9 21 C.F.R. § 1271.90(a)(1) (exempting autologous cells and tissues from donor eligibility and
screening requirements).
96 Plaintiff's Opposition to Defendants' Motion to Dismiss Pursuant to Rules 12(b)(1) and 12(b)
(6) of the Federal Rules of Civil Procedure, Regenerative Sciences, Inc. v. United States Food and Drug
Administration, et al.. (May 11, 2009) (No. 109CV0041 1) 2009 WL 2956106 (U.S. Dist. Ct, D. Colo.)
[hereinafter Plaintiff's Oppositionj.
*' 21 C.F.R. § 1271.3(d) [emphasis added].
* Plaintiff's Opposition, supra note 96; Mary Ann Chirba & Stephanie M. Garfield, FDA Over-
sight of Autologous Stem Cell Therapies: Legitimate Regulation of Drugs and Devices or Groundless
Interference with the Practice of Medicine?, VII J. HEALTH & BIOMED. L. 233. 253-54 (2011).
* Plaintiff's Opposition. supra note 96.
488 VOL. 66
2011 REGULATION OF AuTOLOGOUs STEM CELL THERAPIES
as well as allogeneic therapies." The amendment of the definition provision was
simply part of the process of phasing in the HCT/P regulations,o'
0
and could thus
be seen as a procedural rather than a substantive change.'
02
The second jurisdictional argument, though also likely to fail, is more interest-
ing. This is the claim that Regenexx is not a drug product but simply part of the
practice of medicine, which FDA does not have the authority to regulate.
03
In
response to FDA's application for an injunction, Regenerative Sciences stated: "we
are not a drug manufacturer, but simply a medical practice."14 Regenerative Sci-
ences argues that the "FDA is seeking to enjoin the clinic physicians from practic-
ing medicine using patients' own stem cells."
05
In this view, the processing that is
undertaken to prepare the Regenexx treatment is not the manufacture of a drug,
but a medical procedure that manipulates part of the patient's body. Regenerative
Sciences compares Regenexx to the use of in-vitro fertilization by a lab or fertility
clinic, which is not regulated by FDA.'
06
An obvious difference, of course, is that
the product of in-vitro fertilization (a human embryo) is not an "article" that fits
the definition of a drug under a reasonable interpretation of the FDCA provisions.
As an analogy, then, this is not particularly useful.
Distinguishing between regulation of medical products and medical practice is
not a new issue. It has been extensively discussed in the context of off-label use of
pharmaceuticals. The legal position in the U.S. (similar to other countries, such as
Canada" and the UK'
08
) is that although a drug's label includes the specific indica-
tions for which it is approved, this does not prevent a physician from using it for a
purpose or in a population beyond what was approved (i.e. off-label) in order to treat
a patient.'
1
Thus, FDA has authority over the marketing approval and labeling of
a product, but not over how that product is actually used in clinical practice. FDA's
direct role is limited to restricting the manufacturers' efforts to promote off-label
use.
0
Physicians' activities are regulated by the professional bodies responsible for
medical practice and indirectly by the potential for malpractice litigation.
100 Eg FDA, APPLICATION OF CURRENT STATUTORY AUTHORITIES, supra note 57; U.S. FOOD AND
DRUG ADMIN.. GUIDANCE ON APPLICATIONS FOR PRODUCTS COMPRISED OF LIVING AUTOLOGOUS CELLS
MANIPULATED Ex VIVO AND INTENDED FOR STRUCTURAL REPAIR OR RECONSTRUCTION; AVAILABILITY,
61(103) Fed. Reg. 26523-24 (1996) [hereinafter FDA, GUIDANCE ON APPLICATIONS].
101 See Chirba & Garfield, supra note 98, at 266 (note 208).
02 But see id. at 267, arguing that the change should be seen as substantive rather than procedural.
Although it is true that the change did substantively affect the regulatory categorization of autologous
cell therapies, again it must be appreciated that FDA had already made it clear, prior to the public
consultations on the HCT/P framework, that autologous products would be included in its scope.
103 RSI Welcomes Opportunity to Fight, supra note 44; Regenerative Sciences and FDA - FAQs,
supra note 46.
'1 RSI Welcomes Opportunity to Fight, supra note 44.
105 Id
106 Id; Regenerative Sciences and FDA - FA Qs, supra note 46.
107 See Goodridge v. Pfizer Canada Inc., 2010 O.N.S.C. 1095, 101 O.R. (3d) 202 (Can.); HEALTH
CANADA, HEALTH PRODUCTS AND FOOD BRANCH, RESPONSE To RECOMMENDATIONS TO HEALTH CANADA
OF THE CORONER'S JURY INTO THE DEATH OF ASHLEY MARIE ATKINSON, (2003), available at http:f/www.
hc-sc.gc.calahc-asc/pubs/hpfb-dgpsa/death-deces-atkinson-eng.php.
1os See MEDS. AND HEALTHCARE PRODS. REG. AGENCY, Drug Safety Update: Off-Label or Unli-
censed Use of Medicines: Prescribers' Responsibilities, MHRA (Apr. 2009), http://www.mhra.gov.uk/
Safetyinformation/ DrugSafetyUpdate/CON087990.
10 United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978) ; U.S. DEP'T OF HEALTH & Hu-
MAN SERVICES, U.S. FOOD AND DRUG ADMIN., 'Off-Label' and Investigational Use of Marketed Drugs,
Biologics, and Medical Devices - Information Sheet, (Oct. 18, 2010), available at http://www.fda.gov/
Regulatory~nformation/Guidancesl ucml26486.htm.
110 U.S. DEP'T OF HEALTH & HUMAN SERVICEs, U.S. FOOD AND DRUG ADMIN., GUIDANCE FOR INDUS-
TRY: GOOD REPRINT PRACTICES FOR THE DISTRIBUTION OF MEDICAL JOURNAL ARTICLES AND MEDICAL OR
SCIENTIFIC REFERENCE PUBLICATIONS ON UNAPPROVED NEW USES OF APPROVED DRUGS AND APPROVED OR
CLEARED MEDICAL DEVICES, (Jan. 2009). available at http://www.fda.gov/Regulatoryinformation/Guid-
ances/ucm 125126 .htm; John E. Osborn. Can I Tel You the Truth? A Comparative Perspective on Regulating
Off- Label Scientifc and Medical Information, 10 YALE J. HEALTH PoL'Y L. & ETHICS 299. 308-12 (2010).
489
FOOD AND DRUG LAW JOURNAL
The regulation (or lack thereof) of off-label use has been a matter of debate, since
some experts believe more stringent regulation is necessary to prevent potentially
harmful uses, while others are concerned with protecting physicians' freedom to
resort to off-label uses, which may be the only viable treatments available for some
patients.I' The extent to which FDA can lawfully limit manufacturers' expression in
regulating the promotion of off-label use is also a point of contention."
2
However,
these controversies do not fundamentally call into question the distinction between
products, which are properly the subject of FDA regulation, and physicians' judgments
about the use of those products, which fall within the domain of medical practice.
Clearly, FDA, by controlling the set of products that are lawfully available for use,
has a significant impact on medical practice, but this does not amount to regulating
medical practice per se. If anything, then, the position regarding off-label use tends to
undermine the argument of Regenerative Sciences that FDA is attempting to regulate
its medical practice by subjecting Regenexx to regulation. It illustrates the distinction
between the regulation of products and the regulation of their use in practice. What
FDA is claiming authority to do in this case is the former, not the latter.
The distinction between products and practice has also arisen previously in the
context of FDA regulation of cell and tissue therapies. This issue was raised in
consultations on the HCT/P regulations."
3
FDA's response was that while HCT/
Ps fell within its jurisdiction, it was "not attempting to govern practitioners' use of
HCT/P's [sic], but rather that HCT/P's that would be used by practitioners in their
treatment of patients are in compliance with applicable regulations.""l
4
Essentially,
HCT/Ps - and, for that matter, cell and tissue products that are classified as biologics
and drugs - are no different from other regulated products in this respect, in that FDA
regulation will focus on their manufacture or processing and sale, but not their use
in clinical practice. In a 1997 case, defendants faced with a similar assertion of FDA
authority with respect to their use of a combination of neonatal rabbit and human
fetal cells made the same argument that FDA was attempting to regulate their medical
practice. The Court quickly rejected this argument and found that the mixture of
cells was a drug and biological product over which FDA had regulatory authority."
5
Autologous cell therapies like Regenexx, in which the "manufacturer" and practi-
tioner are closely related, perhaps come closer to challenging the distinction between
product and practice than do any other regulated products. Nevertheless, as long as
there is a distinct product that can be identified as a target for regulation - in this case
the mixture of cells and other substances that is implanted into the patient - this can
be regulated by FDA under current law. Whether this is the most appropriate way to
regulate autologous cell therapies is a broader question which will be considered below.
IV. THE BROADER CONTEXT AND SIGNIFICANCE OF THE DISPUTE
It seems fairly clear given the above analysis that on the legal issues raised in
this dispute, FDA's position is the stronger one and should prevail when and if the
court rules on its merits. Such a ruling would be useful in several respects. The
"IE.g Rebecca Dresser & Joel Frader, Off- Label Prescribing: A Callfor Heightened Professional
and Government Oversight, 37(3) J. L. MED. & ETHICS 476 (Fall 2009); Randall S. Stafford, Regulating
Off-Label Drug Use Rethinking the Role of FDA, 358 NEW ENG. J. OF MED. 1427 (2008).
12 Dresser & Frader, supra note 111, at 478; Jacob Rogers, Freedom of Speech and FDA's Regula-
tion of Off- Label Drug Uses, 76 Gao. WASH. L. REv. 1429.
" FDA, HCT/P FINAL RULE, supra note 78, at 5452.
115 United States of America v. Loran Medical Systems, Inc., et al., 25 F Supp. 2d 1082 (C.D. Cal.
1997).
490 VOL. 66
2011 REGULATION OF AuTOLOGOUS STEM CELL THERAPIES
specific point of the classification of cultured autologous stem cell products is in
itself important, since there are reportedly a number of other U.S. clinics besides
the Regenerative Sciences facility that are offering various types of autologous adult
stem cell therapies.'
16
Clear and authoritative guidance as to the legal status of these
treatments would be useful."' Significant questions and challenges also surround
the regulation of autologous and personalized therapies that are currently being
developed, such as those derived from induced pluripotent stem cells."'
However, a court's decision on these issues would not be the end of the matter,
since the arguments made by Regenerative Sciences and some of the responses to
this dispute illustrate that there are broader questions at stake not only about what
the legal position is in this case but what it should be. This dispute links into several
larger debates about the role of FDA and the appropriate frameworks for regulating
innovations in regenerative medicine. Some of the key themes in these debates will
be explored in this section, in particular: the impact of FDA regulation on access
to new stem cell therapies, the role of FDA regulation in relation to other oversight
mechanisms, the challenges of FDA regulation of autologous cell therapy products,
and the scope of exceptions and flexibility in the regulatory process.
A. The Impact of FDA Regulation on Access to New Therapies
There seems to be general agreement that the court's decision in this case could
significantly affect the availability of stem cell-based therapies in the United States,
but there are widely divergent views on what outcome is desirable. Centeno predicts
that if Regenerative Sciences is successful in this litigation, "the entire regulatory
structure for autologous cell processing, with or without culture, will be rewritten
such that any physician using good practices and treating patients responsibly can
use stem cells as part of his or her medical practice."' Obviously, this is the outcome
that Centeno and Regenerative Sciences - and others offering similar treatments
- would prefer. However, according to Douglas Sipp, an expert commentator on
experimental stem cell treatments, this would be a negative outcome: "Companies
would likely feel empowered to ignore requirements for demonstrable safety and
efficacy of autologous medicinal products, creating an 'anything goes' atmosphere,"
which "would be, as they say, a bad thing."'
20
Amidst growing concerns about "stem
cell tourism,"21 Regenerative Sciences is an example of a U.S. company that has
been identified as offering unproven stem cell-based treatments,1
22
but unlike foreign
16 Elie Dolgin, Survey Details Stem Cell Clinics ahead of Regulatory Approval, 16 NATURE MEDI-
CINE 495, 495 (2010); David Cyranoski, Texas Prepares to Fight for Stem Cells, 477 NATURE 377, 377
(2011) [hereinafter Cyranoski, Texas Prepares to Fight]; see also Cultured Autologous Stem Cell Therapy:
Medical Procedure Or Drug?, STEMCELLDIGEST.NET (Aug. 22, 2010), http://www.stemcelldigest.net/
stemcell/2010/08/cultured-autologous-stem-cell-therapy-medical-procedure-or-drug.html (naming two
other companies that use cultured autologous mesenchymal stem cells in patients).
"' Editorial, Regulators Must Step Up Stem Cell Oversight, 16 NATURE MEDICINE 492 (2010)
[hereinafter Regulators Must Step Up].
"1 See Maureen L. Condic & Mahendra Rao, Regulatory Issuesfor Personalized Pluripotent Cells,
26 STEM CELLs 2753 (2008); Amy Zarzeczny et al., iPS Cells: Mapping the Policy Issues, 139 CELL 1032
(2009) [hereinafter Zarzeczny et al., iPS]; Melissa K. Carpenter & Larry A. Couture, Regulatory Con-
siderations for the Development of Autologous Induced Pluripotent Stem Cell Therapies, 5 REGENERATIVE
MEDICINE 569 (2010).
119 Cyranoski, FDA Challenges, supra note 9, at 909 (quoting Christopher Centeno).
120 Id (quoting Douglas Sipp).
21 E.g CAT, Use of Unregulated Stem-Cell, supra note 2; Qiu, supra note 2; Lindvall & Hyun,
supra note 2.
122 Doug Sipp, The Rocky Road to Regulation, NATURE REPORTS STEM CELLS (Sep. 23, 2009), http://
www nature. com/stemcells/2009/09O9/09O923/full/stemcells.2009. 125.htmi [herein after Sipp, Rocky
Roadj; Regulators Must Step Up, supra note 11 7
491
FOOD AND DRUG LAW JOURNAL
clinics, falls within the authority of the U.S. government to regulate directly. Some
would welcome stricter regulation,'
23
but this view is not unanimous.
The dispute has received little attention from the mainstream media to date, but
there is a substantial body of internet material commenting on the case, includ-
ing online media reports, blogs, and comments from patients and members of
the public.
124
The majority these report the views of Centeno and colleagues and
those who support their position. They cannot be assumed to be representative of
public views, but the recurring themes in these comments are indicative of concerns
and perceptions held by some groups. In many cases, they also illustrate common
misconceptions, since, as will be seen in the discussion below, many of the online
reports and commentaries misstate and exaggerate FDA's position in ways that tend
to portray its actions as extreme and unreasonable, presumably thus generating
more support for the position of Regenerative Sciences.
The central argument opposing FDA's position from a broader policy perspec-
tive is that FDA regulation of therapies like Regenexx will increase costs, cause
delays, and impede access. Several articles refer to FDA attempting to "ban" or
"block" autologous stem cell therapies.' It has been suggested that FDA regula-
tion would increase costs "dramatically" and delay the availability of therapies by
fifteen to twenty years, though the basis for these estimates is not clear.'
26
FDA
regulation is seen by many of these commentators as a negative and unnecessary
barrier preventing access to promising new therapies. This is perhaps not surpris-
ing, given that media portrayals of unproven stem cell treatments are "largely and
increasingly positive," and few media reports discuss risks or evidence of efficacy
beyond anecdotal evidence or testimonials.'1
27
Some perceive autologous adult stem
cell treatments as comparatively "safe" because they use parts of one's own body'1
2t
This may reflect the growing phenomenon of stem cell treatments being marketed
as "natural" products, "distinct from 'artificial' drugs and devices."'
29
Others
claim that the treatments have already been proven to be safe.' Therefore, some
123 Regulators Must Step Up, supra note 117.
124 One legal academic article discussing the case was published shortly before this article went to
press: Chirba & Garfield, supra note 98.
125 E.g Delia Wilder, Potential Arthritis Treatment Advance Blockedby FDA, LIFEEXTENSION (January
2011), http://www.lef.org/magazine/mag201 1/jan2011Potential-Arthritis-Treatment-Advance-Blocked-by-
FDA Ol.htm; FDA Stops Stem Cells in USA, POLITICOL NEWS (Aug. 7, 2010), http://www.politicolnews.
corn/fda-stops-stem-cells-in-usa/ (last updated Mar. 18, 2011); Heidi Stevenson, FDA Bans Stem Cell
Therapy That Saved UK Boy's Life & Man's Leg, GAIA HEALTH (Aug. 14, 2010), http://www.gaia-health.
com/articles251/000288-uk-boys-life-and-mans-leg-saved-by-stem-cell-therapy-that-fda-bansshtml.
126 Regenerative Sciences and FDA - FAQs, supra note 46; Jeff Morris & L. Stephen Coles, Will
FDA Kill Adult Stem CellMedicine?, h+ MAGAZINE (May 1, 2009), http://hplusmagazine.com/2009/05/01/
will-fda-kill-adult-stem-cell-medicine/; Barbara Hanson, Autologous Stem Cells-Hope for the Future,
GAlA HEALTH (Jun. 12, 2009), http://www.gaia-health.com/articles51/000055-Stem-Cell-Advocacy.shtml.
127 Amy Zarzeczny et al., Stem cell Clinics in the News, 28 NATURE BIOTECHNOLOGY 1243, 1245 (2010).
128 Patient Voices, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY, http://cellmedicinesociety.
org/patients/ patient-voices (last visited Jun. 25, 2011); FDA Stops Stem Cells in USA, supra note 125.
12 Douglas Sipp, Stem Cell Stratagems in Alternative Medicine, 6(3) REGENERATIVE MED. 407, 411
(2011).
10 E.g American Doctors Form Group to Oppose FDA's Stance on Adult Stem Cells, ADULT STEM
CELL THERAPY BLOG (Mar. 27, 2009), http://stem-cell-therapy blogspot.com/2009/03/american-doctors-
form-group-to-oppose.html [hereinafter American Doctors Form Group to Oppose FDA]; FDA Stops Stem
Cells in USA, supra note 125; FDA Blunders Stein Cell Research, POLITICOL NEWS (Aug. 9, 2010), http:ll
www.politicolnews.com/fda-blunders-stem-cell-research/ (stating that there is "proof" that Regenexx
"works and is harmless with no side effects"); Patient Voices, supra note 128 (The well-established use
of adult stem cell transplants in cancer treatment is sometimes cited as evidence that treatments like
Regenexx. without acknowledging the differences between them - most notably that Regenexx. unlike
those established treatments, is more than minimally manipulated); Hanson, supra note 126; A. Rahman
Ford, Why Libertarians should Care about Autologous Stem Cells. BUREAUCRASH (Mar. 14, 2011). http://
bureaucrash.com/20 11 /03/14/why-libertarians-should-care-about-autologous-stem-cells/. Centeno also
points to the many published studies reporting use of MSCs for many different conditions: see Morris
& Coles, supra note 126.
492 VOL. 66
2011 REGULATION OF AurOLOGOUs STEM CELL THERAPIES 493
members of the public seem to reject safety concerns as a justification for FDA
regulation. Regenerative Sciences has encouraged this view by dismissing FDA's
stated concerns about safety and public health as "litigation posturing.""' Centeno
has been quoted as stating that FDA regulation would result in significantly higher
costs without any measurable increase in safety.'
32
Alternatively, some accept that
safety issues may exist, but believe that where new stem cell therapies are offered
for serious diseases, patients should have the choice to weigh this risk against the
effects of the disease.
3 3
Regenerative Sciences claims that there has been "literally an outcry by patients
with chronic diseases that FDA would stand in their way of getting safe stem
cell work performed by their doctors."
1 34
It quotes two of its patients describing
FDA's position as "closed-minded" and "short-sighted," suggesting that it shows
"disregard for patients who need pain relief" and will prevent others from getting
useful treatment.
35
Other comments refer to FDA's actions as "inhumane,"; "ir-
responsible" and "uncaring."
36
Many criticize FDA for slowing down progress in
the United States
137
and forcing people to leave the country to get access to new
treatments.
38
One article goes so far as to blame FDA and its attempt to regulate
stem cells as drugs for the deaths of patients who have attempted or been unable
to seek treatment outside the U.S.
139
In attempting to regulate new stem cell-based
therapies, FDA is alleged to be acting contrary to patients' interests, and catering
instead to the interests of "Big Pharma."
40
Two reasons are given for this: first,
that large pharmaceutical companies are the only ones that would be able to afford
to develop new therapies if they are subject to regulation,141 and second, that block-
ing access to new, effective therapies would protect those companies' profits from
current products.1
42
The parallels being drawn between regulation of Regenexx,
a commercially marketed treatment for orthopaedic applications, and access to
experimental treatment for critically ill individuals, are questionable, but they show
how the dispute has been taken up by a larger community advocating in favour of
freer access to novel treatments. These commentaries generally do not mention or
take into account existing mechanisms to provide flexibility and allow early access
to unapproved treatments, such as the "expanded access" regime by which FDA can
13 RSI Welcomes Opportunity to Fight, supra note 44; see also Jack Minor, Under Obamacare
FDA Considers Person's Body a Drug, GREELEY GAZETrE (Sep. 30, 2010), http://www.greeleygazette.com/
press/?p= 5826 (citing Centeno as saying "FDA's issue has never been about the safety of the procedure.").
32 E.g Ryan Abbott, Feds Challenge Stem-Cell Treatment, COURTHOUSE NEWS SERVICE (Aug. 10,
2010), http://www.courthousenews.com/2010/08/10/29439.htm; Wilder, supra note 125.
E Kg Patient Voices, supra note 128; Hanson, supra note 126.
'4 Adult Stem Cells Now!, REGENEXXT (Mar. 31,2009,12:40 PM), http://www.regenexx.com/2009/03/
adult-stem-cells-now.
11Regenerative Sciences and FDA - FA Qs, supra note 46.
136 Wilder, supra note 125; Patient Voices, supra note 128; Hanson, supra note 126.
"I Hanson, supra note 126; FDA Stops Stem Cells in USA, supra note 125; FDA Blunders Stem
Cell Research, supra note 130; FDA Tries to Shut Down Regenerative Sciences, FIir AGING (Aug. 9,
2010) http://www.Fight aging.orglarchives/2010/08/fda-tries-to-shut-down-regenerative-sciences.php;
Ford, supra note 121.
131 E~g Patient Voices, supra note 128; FDA Stops Stem Cells in USA, supra note 125; FDA Blunders
Stem Cell Research, supra note 130.
"' Hanson, supra notc 126.
140 E.g RSJ Welcomes Opportunity to Fight, supra note 44; Morris & Coles, supra note 126 (quot-
ing Christopher Centeno); see also FDA Stops Stem Cells in USA, supra note 125; FDA Blunders Stem
Cell Research, supra note 130.
141 Morris & Coles, supra note 126.
142 Wilder, supra note 125; FDA Stops Stem Cells in USA, supra note 125; Stevenson, supra note
125.
FOOD AND DRUG LAW JOURNAL
authorize use of an investigational (unapproved) drug or biologic where no other
effective therapy is available for a patient with a serious disease or condition.'
43
Another prominent theme in responses to the dispute, in line with Regenerative
Sciences'legal argument that FDA is attempting to regulate the practice of medicine,
is that FDA regulation of stem cell therapies would interfere with the doctor-patient
relationship and therefore encroach on state jurisdiction.1
44
Regenerative Sciences
has stated this case "will decide, once and for all, if the government has the right
to restrict a patient and their doctor from using a person's own stem cells to treat
disease."
45
Centeno has framed this as a question of doctors' and patients' rights,
stating: "we ... believe a physician has the right to use stem cells or other body parts
to help heal the patient,"1
46
and as a patient you have "the right to go to a doctor
and have stem cells taken out and put back in your body[;] that's between you and
me, it's not the business of the federal government."
47
The language of patients'
rights has clearly resonated with some advocates and members of the public.1
48
Some of the predictions about the potential impact of the decision seem clearly
overstated. For example, as discussed above, FDA regulates products, giving approval
after reviewing sufficient evidence to demonstrate safety, efficacy and quality, but
does not regulate how those products are used in practice. Therefore, to state that the
federal government would "dictate how, when, where, and why" stem cell treatments
are used
49
is not correct, nor is it correct to suggest that if FDA's position prevails, it
would mean that physicians would not be able to recommend an alternative remedy
that is not an FDA-approved drug,' or to prescribe compounded drugs (drugs
that are custom made for individual patients when approved formulations cannot
be used)."' These and other comments make connections between this dispute and
larger debates about the extent of federal government influence over medical care.
A few online commentators, and Centeno himself, have linked FDA's actions with
the introduction of the Obama administration's health care plan, alleging that this
litigation and FDA's claim to regulate Regenexx are part of a plan to assert federal
control over medical decision making.'
52
Centeno has stated that: "This is a move
by the federal government to regulate medicine ... That move is consistent with
Obamacare where patients are treated according to strict guidelines."'
143 21 C.F.R. pt. 312, subpt. I; U.S. DEP'T OF HEALTH AND HUMAN SERVICES, U.S. FOOD AND DRUG
ADMIN., EXPANDED ACCESS TO INVESTIGATIONAL DRUGS FOR TREATMENT USE: FINAL RULE, 74(155) Fed.
Reg. 40900 (2009) [hereinafter FDA, EXPANDED ACCESS TO INVESTIGATIONAL DRUGs]; see also 21 C.F.R.
pt. 312, subpt. E, which provides for expedited ("fast-track") review for drugs for life-threatening and
severely debilitating illnesses.
1"Eg Ford, supra note 130.
145 RSI Welcomes Opportunity to Fight, supra note 44.
146 Abbott, supra note 132 (quoting Christopher Centeno).
147 Minor, supra note 131 (quoting Centeno).
148 E.g Patient Voices, supra note 128; Ford, supra note 130.
149 Regenerative Sciences and FDA - FA Qs, supra note 46.
" Minor, supra note 131 (quoting Centeno as stating that if FDA is successful, a doctor would
not be able to recommend fish oil to a patient with high cholesterol because it is not an approved drug).
Is Christopher J. Centeno, Our Patients' Autologous Stein Cells are Drugs: FDA Moving Down a
Dangerous Slippery Slope, AGE MANAGEMENT MEDICINE GROUP (Apr. 2010), http://www.agemed.org/
AMMGejournal/April 2010/RegenerativeMedicineApril2010.aspx [hereinafter Centeno, FDA Slippery
Slope].
85 Minor, supra note 131: Bob Unruh, It's Begun: Obamacare Shutters Pain Treatment, WORLD-
NETDAILY (Aug. 16. 2010, 9:13 PM). http://www.wnd.com?pageld=l191177.
15 Minor, supra note 131: see also Unruh, supra note 152, (Centeno is quoted as saying that FDA's
position is part of a "massive federalist move" and that "Obamacare" requires "a lot of infringement"
of state authority over the practice of medicine).
494 VOL. 66
2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
Many of the themes seen in these comments are familiar ones in the larger debates
about access to experimental therapies. However, autologous stem cell therapies
also give rise to distinct concerns. Some individuals take particular exception to
the government trying to control what is done with a part of their own body; the
assertion of regulatory authority is thereby linked to deeper concerns about au-
tonomy and control over one's body. One recent commentary suggests that FDA
regulation of autologous therapies would be "an unlawful infringement upon the
fundamental individual liberty of the person."
1 54
The discourse of ownership or
property rights is also invoked. A press release issued in August 2010 states that
"Regenerative Sciences believes that stem cells are body parts and not the property
of the government or big pharma."1'
5
Objections to FDA trying to "own" or con-
trol one's own stem cells form a prominent theme in online comments.
156
Again,
these are partly based on misconceptions, first, that FDA regulation involves some
assertion of ownership, and second, that FDA is claiming authority over parts of
the body in their natural state; it is repeatedly stated that FDA is trying to regulate
a person's own cells, body parts, or body as a drug,' usually with no mention of
the fact that only cells and tissues that have been more than minimally manipu-
lated would be defined as a drug. Nevertheless, it appears that some members of
the public believe there should be less government interference with autologous
therapies because they involve the use of one's own biological material.
It would be difficult to deny that FDA regulation of a processed autologous stem
cell therapy like Regenexx would restrict its availability to some extent, since the
expense and time entailed in complying with the regulatory requirements would
likely increase its cost and delay its routine availability - assuming, of course, that
the therapy is, in fact, safe and effective, as its proponents claim. However, many
of the critics' predictions seem to be based on a rather weak understanding of the
regulatory system and may well have been exaggerated to gain public support. Some
of the more extreme views, claiming that FDA is attempting to block access to these
therapies and control people's bodies, should be rejected as having no basis in the
current facts. They do, however, illustrate the type of concerns and values that certain
members of the public believe are at stake when regulating new medical technologies.
Importantly, critics of FDA's position tend to argue not only that it would restrict
access to therapies, but that it would do so in a way that is unnecessary or inap-
propriate. If true, this would be a serious and important critique of FDA regula-
tion. In order to assess this critique, it is necessary to consider the advantages and
disadvantages of FDA regulation and alternative forms of oversight.
B. The Regulatory Framework for Innovative Stem Cell Therapies
A central point in the dispute is the assertion by Centeno and Regenerative Sci-
ences that autologous cell therapies are not or should not be subject to regulation
as products by FDA. Even though it was concluded above that according to the
154 Ford, supra note 130.
55 RSI Welcomes Opportunity to Fight, supra note 44.
56 For example, see the comments posted in response to Ed Silverman, FDA Seeks Injunction
Against Stein CellCompany, PHARMALOT (Aug. 6,2010,I4:12 PM), http://www.pharmalot.comI2010/08/
fda-seeks-injunction-against-stem-cell-company/; Patient Voices, supra note 128; Hanson, supra note
126; Wilder, supra note 125. (One article goes so far as to compare FDA regulation of autologous
therapies with slavery, apparently on the basis that it would involve the "commodification" of human
beings: Ford, supra note 130).
'"' E.g Minor, supra note 131; Patient Voices, supra note 128; RSI Welcomes Opportunity to Fight.
supra note 44.
495
FOOD AND DRUG LAW JOURNAL
current regulatory provisions, these therapies do fall within the definition of drugs
and biological products (if more than minimally manipulated) or of Section 361
HCT/Ps, the question remains whether this should be the case. This is part of a
broader question about the appropriate regulatory framework for emerging stem
cell-based therapies.
Regulation by FDA (or its equivalent in other jurisdictions) obviously does not
operate in isolation. Other forms of oversight, including the regulation of medi-
cal professionals and the potential for civil liability, also contribute to protecting
patients and enforcing standards for those who offer novel stem cell treatments.'
5 8
A commentary on the Regenexx website states that "the appropriate place for this
type of cell therapy to be regulated" is "local medical boards and the courts."
15 9
Few would question whether these bodies should play some role in oversight, but
this role needs to be examined more carefully before we can conclude that it would
be sufficient in the absence of FDA regulation.
Professional regulatory bodies, such as state medical boards or their equivalents
in other jurisdictions, set and enforce standards for entry into the profession, com-
petence and professional conduct. Competence and discipline proceedings could be
used to sanction practitioners who show a lack of knowledge and skill or who act
unethically in offering novel stem cell treatments. Examples of such proceedings
already exist. For example, the General Medical Council in the United Kingdom
ordered in 2010 that a doctor be removed from the Medical Register (thus barring
him from practice) as a result of numerous findings of misconduct.'6 The Fitness
to Practise Panel had found that this doctor had provided stem cell treatments
to several patients that were inappropriate, unjustifiable, and "without scientific
or other clinical/medical basis," and in doing so had exploited these patients and
acted contrary to their best interests. The Panel also found that the doctor had
misled patients and failed to obtain informed consent.
16
' In the United States, the
Florida State Medical Board issued an emergency license restriction in February
2011 preventing a doctor from providing any stem cell treatment after a patient
died following a procedure in which the doctor injected bone marrow aspirate into
her carotid artery, a procedure which is alleged to have no medical justification and
"no substantiated medical and/or scientific value."
62
While certainly important, these proceedings have significant limitations, includ-
ing, most notably, that they are retrospective in nature, typically responding to a
complaint after a patient has allegedly been injured or exploited by a practitioner's
conduct. They do not generally include an a priori evaluation of the safety or
efficacy of the treatment that is offered. Many patients may be injured or may
consent to (and pay for) treatments of dubious effectiveness before any action is
'1 Barbara von Tigerstrom, Product Regulation and the Clinical Translation of Stem Cell Research,
5 STEM CELL REVS. & REPS. 135, 137 (2009).
'1 Shaker Kits and Stem Cells in a Grocery Bag, REGENEXxTM (Mar. 26, 2011, 6:34 AM), http:/
www regenexx. com/20111/03/shaker-kits-and-stem-cells-in-a-grocery-bag/.
160 Fitness to Practice Panel re: Dr. Robert Theodore Henri Kees Trossel, (GEN. MED. COUNCIL,
U.K.) (Sep. 29, 2010), available at http://www.gmc-uk.org/static/documents/content/Trossel.pdf.
161 Id.,
at 35.
162 Administrative Complaint at paras, 19-20, Department of Health v. Zannos 0. Grekos (D.O.H.
Case No. 2010-14317) (Mar. 14, 2011). available at http://www.circare.orglpd/grekos_201 10314.pdf; see
Liz Freeman, Bonita Doctor Seeks State Hearing on Stem Cell Therapy, Bone Marrow Practice, NAPLES
NEWS (Mar. 20. 2011, 6:30 PM), http:f/www.naplesnews.conlnews/20l11/mayl20/Zannos-Grekos-stem-
cell-Regenocyte-Therapeutic-lee/; Doug Sipp, Regenocyte s Grekos' License Restrict ed over Patient Death,
STEM CELL TREATMENT MONITOR (Apr. 30, 2011, 2:26 AM), http://sctmonitor.blogspot.com/2O011041
regenocytes-grekos-loses-medical html.
496 VOL. 66
2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
taken. It may be especially challenging to address questionfs of efficacy in such
proceedings, since lack of efficacy may be difficult to establish and action may not
be taken unless the practitioner can be shown to be incompetent or to be exploiting
patients by offering a patient he or she knows is not effective (which is difficult to
prove). This means that only the more egregious cases are likely to be dealt with
under these processes.
Similarly, civil litigation can be used to seek compensation for injured patients
and to punish and deter negligent conduct by medical practitioners offering stem
cell treatments, but also has limitations. Failure to obtain adequately informed
consent or negligence in providing treatments could provide a basis for liability.
However, this too is retrospective in nature (albeit with a potential deterrent effect),
and in addition, requires that plaintiffs have both the means and the motivation to
pursue lengthy and expensive civil claims. Ethical review by hospital ethics boards
or institutional review boards (IRBs) can also play a useful role and could provide
prospective review of proposed treatment or research. However, there may not
always be formal mechanisms in place to review proposed innovative treatment,
which is outside the scope of IRBs whose role is to approve research protocols.
Professional regulatory bodies, such as state medical boards, or national pro-
fessional associations could take a more proactive role in providing more specific
guidance to practitioners wishing to offer novel stem cell therapies. This guidance
could then provide the basis for disciplinary proceedings against members who
disregard the accepted standards, as well as playing a role in negligence proceedings
by informing the courts' interpretation of the standard of care to which defendants
should be held. To date, however, these standards have not emerged, and profes-
sional bodies appear to have taken an essentially reactive approach to regulating
this emerging field.'
63
In the absence of such professional standards, a number
of competing guidelines, standards and policies have been formulated by various
organizations. These could also play a valuable role in the governance of novel
stem cell treatment providers, adding sector-specific self-regulation to the formal
regulatory structures.'"' Presently, however, their effectiveness is undermined by
fragmentation and conflicts of interest.
Regenerative Sciences has asserted that FDA regulation of Regenexx is unnec-
essary because its lab "has strictly adhered to the International Cellular Medicine
Society's (ICMS) strict, professional guidelines and has been audited three times
by independent third parties with no safety concerns," and that "ICMS lab guide-
lines are the best fit for autologous cell processing and provide strong patient
protection."l
65
To the casual reader this statement gives the impression that the
Regenerative Sciences lab is complying with independent external standards, but
this is not really the case. The auditor does appear to be independent, but its role
was to evaluate the lab's compliance with the guidelines formulated by the ICMS.1
66
There are significant ties between Regenerative Sciences and the ICMS. Centeno
163 However, it was reported recently that the Texas Medical Board is considering the adoption of
a policy on stem cell treatments: see Cyranoski, Texas Prepares to Fight, supra note 116, 378.
E.g Alessandro Blasimme, Panel Presentation at Bringing Regenerative Medicine to the Clinic:
Trials and Tribulations in Europe and Beyond. Regenerative Medicine in Europe (REMEDiE) Clos-
ing Conference. Stem Cells in Translation. Self-Governance and Public Accountability in the Quest for
Regenerative Medicine, (Apr. 19, 2011) (a copy of the presentation is on file with the author).
165 RSJ Welcomes Opportunity to Fight, supra note 44.
166 Regenerative Sciences and FDA - FAQs, supra note 46; INT'L CELLULAR MED. SOCIETY, LAB
PRACTICES GUIDELINES: VERSION 1.0. (Apr. 15, 2009), available at http://www cellmedicinesociety org/
attachments/055_ICMS %20Lab%20Practices%20Guidelines.pdf.
497
FOOD AND DRUG LAW JOURNAL
was a founding member of the ICMS, and remains a member of its Board of Di-
rectors.'
67
Another Board member
68
is a vice-president of Stemantix, the company
that holds the rights to Regenexx in Latin America.'
9
The 5-member committee
responsible for the ICMS lab guidelines included both Centeno and the Regenera-
tive Sciences lab director.' Drs. Centeno and Schultz are both members of the
ICMS Institutional Review Board."'
The ICMS describes itself as a "patient safety advocacy organization" that
provides "peer oversight."'
2
Its precursor organization,"' the American Stem
Cell Therapy Association, "was formed in opposition to FDA's position that adult
stem cells are drugs."'
74
The ICMS maintains a web page encouraging individuals
to support its position by joining the organization and sending emails to FDA
ombudsman."' Part of the purpose of the organization is to "value a physician's
right to innovate through the practice of everyday medicine and encourage them
[to] embrace the power of responsible observational study and peer oversight."'
7 6
In order to be eligible to serve on the Advisory Board or any Council of the
ICMS, a member must "affirm that minimally culture expanded stem cells are
1) Part of the practice of medicine ... 2) Do not constitute the creation of a new
biologic drug or product that would fall under any part of FDA regulation on new
drugs or biologics and 3) Exempt from any US Food and Drug Administration
regulations.""' Thus the ICMS explicitly operates as both an advocacy organiza-
tion, promoting a position against FDA regulation and a voluntary self-regulatory
body. Self-regulation in this context appears to be part of a strategy to resist and
avoid government regulation.
In addition to formulating guidelines and standards, the ICMS maintains a
patient registry and a clinic accreditation program. The ICMS Treatment Registry
is part of the "responsible observational study" promoted by the organization. It
is a web-based registry that "tracks outcomes and complications from cell based
medical treatments," using data collected from patients for up to 20 years following
treatment.
7 6
This information is shared by clinics that have been "approved" by
ICMS,'
79
but patients must pay to have their information in the registry'
8
s
0
Registry
data is confidential and may not be shared or used by any ICMS member or reviewer
167 ICMS Board of Directors, ICMS: INTERNATIONAL CELLULAR MEDICINE SocrETY, http://www.
cellmedicine society.org/home/boards-and-councils/board-of-directors> (last visited Jun. 25, 2011).
168 Id.
169 StematixTM Obtains Exclusive License to RegenexxTM, supra note 28.
17 LAB PRACTICEs GUIDELINES: VERSION 1.0, supra note 166.
171 ICMS Institutional Review Board (IRB), ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY,
http://www.cell medicinesociety org/home/boards-and-councils/irb (last visited Jun. 25, 2011).
172 ICMS Frequently Asked Questions, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY, http://
www.cell medicinesociety.org/home/faqs (last visited Jun. 25, 2011).
" Sipp, Rocky Road, supra note 122.
174 Adult Stein Cells Now!, supra note 134; American Doctors Form Group to Oppose FDA, supra
note 130.
" About the International Cellular Medicine Society, INTERNATIONAL CELLULAR MEDICINE SOCIETY,
http://www.safestemcells.org/ (last visited Jun. 25, 2011).
176 ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY, http://cellmedicinesociety.org/ (last visited
Jun. 25, 2011j.
177 Boards & Councils, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETYr, http://www.cellmedi-
cinesociety orgl home/boards-and-councils (last visited Jun. 25. 2011).
178 ICMS Treatment Registry, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY, http://cell-
medicinesociety org/ clinics/registry (last visited Jun. 25, 2011).
498 VOL. 66
2011 REGULATION OF AuToLoGous STEM CELL THERAPIES 499
except with permission.'
8
' The Registry currently contains over 750 patient cases.'
The "Stem Cell Clinic Accreditation Program" allows clinics to be evaluated by
the ICMS and "accredited."' The process includes approval by the Society's own
Institutional Review Board, analysis of cell samples, site audits, laboratory audit by
an ICMS-authorized organization, and self-assessment of compliance with ICMS
guidelines.'
84
To date there are two clinics participating in the ICMS accreditation
program, the Regenerative Medicine Institute in Tijuana, Mexico' and World Stem
Cells, LLC's Advanced Cellular Medicine Clinic in Cancun, Mexico.'
The ICMS is not the only organization promoting a self-regulatory approach.
For example, a company called "Repair Stem Cells Institute" has formulated its
own standards and advertises a process to become an "RCSI approved treatment
center."' At the same time, scientific organizations like the International Society
for Stem Cell Research (ISSCR) and the National Institutes of Health' have been
actively seeking to educate the public about stem cell treatments and clinics. The
ISSCR has published Guidelines for the Clinical Translation of Stem Cells (ISSCR
Guidelines)'
89
and a Patient Handbook on Stem Cell Therapies.'
90
It also launched a
website for the public with information about stem cell treatments.'
9
' Initially it of-
fered to review clinics upon request by patients, to determine, based on information
supplied by the clinic, whether its treatments had been approved by an independent
ethics committee and the appropriate regulatory authorities;' this function is not
currently active, however. ' Although there may be some superficial resemblance
between the activities of organizations like the ICMS, on one hand, and the ISSCR,
on the other, in reality their nature and orientation are very different. The ICMS
was formed by and brings together practitioners who offer stem cell treatments in
for-profit clinics, and is promoted as an alternative to government regulation. The
181 Id
182 ICMS Press Releases: International Stem Cell Society Announces Over 750 Adult Stem Cell
Patient Cases Trackedin Treatment Registry, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY (Mar.
31, 2011), http:flwww. cellmedicinesociety org/home/news/press-releases.
'1 Clinic Accreditation Program, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY, http://
cellmedicinesociety org/clinics/accreditation (last visited Jun. 25, 2011).
184
Id.
'11 ICMS Press Releases: ICMS Announces First Participant in Stem Cell Clinic Accreditation
Program, ICMS:INTERNATIONAL CELLULAR MEDICINE SOCIETY (Mar. 15, 2011), http://www.cellmedici-
nesociety.org/homelnews/ press-releases.
186 ICMS Press Releases: World Stem Cells Second Participant in ICMS Stem Cell Clinic Ac-
creditation Program, ICMS: INTERNATIONAL CELLULAR MEDICINE SOCIETY (May 10, 2011), http://www.
cellmedicinesociety.org/home/ news/press-releases.
'18 RCSJ Standards, REPAIRSTEMCELLS.ORG, http://www.repairstemcells.org/Treatment/RSCI-
Standards.aspx> (last visited Jun. 25, 2011).
" Stem Cell Information: The National Institutes of Health Resource for Stem Cell Research ,
NAT'L INSTS. OF HEALTH, http://stemcells.nih.gov/ (last modified April 29, 2011).
18 INT'L SOC'Y FOR STEM CELL RESEARCH, GUIDELINES FOR THE CLINICAL TRANSLATION OF STEM
CELLS, (Dec. 3, 2008), available at http://www.isscr.org/clinical trans/pdfs/ISSCRGLClinicalTrans.pdf
[hereinafter ISSCR GUIDELINES].
190 INT'L Soc'Y FOR STEM CELL RESEARCH, PATIENT HANDBOOK ON STEM CELL THERAPIES: APPENDIX
I OF THE GUIDELINES FOR THE CLINICAL TRANSLATION OF STEM CELLS, (Dec. 3, 2008), available at http://
www isscr.org/ clinical trans/pdfs/ISSCRPatientHandbook.pdf.
191 Considering Stem Cell Treatment?, A CLOoSER LOOK AT STEM CELL TREATMENTS: INT'L Soc'Y FOR
STEM CELL RESEARCH, http://www.closerlookatstemcells.org (last visited Jun. 25, 2011).
192 Additional lnformation about the ISSCR Clinic Review Process, A CLOSER LOOK AT STEM CELL
TREATMENTS: INT'L Soc'Y FOR STEM CELL RESEARCH, http://www.closerlookatstemcells.org/Addition-
alinfo_lSSCRReview Process.htm (last visited Jun. 25, 2011).
19 Submit a Clinic for Review. A CLOSER LOOK AT STEM CELL TREATMENTS: INT'L Soc'Y FOR STEM
CFLL RFSEARCH, http://ww~w clnserlonkatstemcells.orgSubmit aClinic.htm (last visited ,Jun. 25, 2011).
FOOD AND DRUG LAW JOURNAL
ISSCR is a large multinational scientific association with an interest in stem cell
research and clinical translation, and has been a prominent critic of commercial
providers of unproven stem cell therapies.'
94
This patchwork of self-governance initiatives contains some useful elements, but
its effectiveness is undermined by fragmentation of the various efforts and by the
conflicts of interest inherent in organizations like the ICMS that have significant
ties with clinics profiting from the treatments they purport to regulate. Even if the
guidelines and standards promulgated by such an organization are in fact adequate
to ensure patient safety, public confidence in them will be undermined unless they
are formulated and monitored by an arm's-length body. The value of a registry
is also limited if its data are under the exclusive control of an organization whose
members have a financial interest in continuing to provide the treatments being
followed. Finally, the self-governance mechanisms developed to date are voluntary
schemes without any credible means of enforcement.
A key element missing from this framework is a consistent, rigorous and in-
dependent evaluation of the evidence relating to safety and effectiveness of new
treatments. The importance of independent evaluation is highlighted by the
weaknesses in some of the evidence that has been forward in support of Regenexx:
the sample sizes are quite small;' there do not appear to be any controls (either
placebo controls or controls for other interventions which may also be provided
to Regenexx patients"'); and claims of efficacy are largely based on self-reported
pain levels,' which are notoriously unreliable and susceptible to placebo effects.'
9 8
This is not to say that the evidence collected thus far is not useful, but especially
where significant commercial interests are at stake, the importance of thorough
and independent evaluation of the evidence cannot be overstated.
The obvious mechanism to provide this independent evaluation is regulation
by FDA, which has been entrusted with the task of evaluating the safety, efficacy,
and quality of new products. Even if new oversight mechanisms could help to ad-
dress the issues raised by novel stem cell-based therapies,'
99
it makes sense to allow
this existing body to continue with its mandate unless a clear justification can be
articulated for creating a new specialized regulatory structure for stem cell-based
therapies. However, regulation by FDA is exactly what is resisted by Regenera-
tive Sciences and those who support its position. As discussed above, in part this
is because of fundamental differences in perspective about who should have the
authority to make judgments about the risks and benefits of new treatments, but
in addition, Centeno and his supporters have advanced a very specific argument
194 ISSCR GUIDELINES, supra note 189; Insoo Hyun et al., New ISSCR Guidelines Underscore
Major Principles for Responsible Translational Stem Cell Research, 3 CELL STEM CELL 607 (2008).
19 For example, one report is based on 28 patients with hip injuries followed for 6 months and 12
followed for 12 months: see Regenerative Sciences, Regenexx, supra note 7 at 21.
96 The Clinic also provides other types of treatment: see the Clinic's website at CENTENO-Sc-ULTZ
CLINic, http://www.centenoschultz.com/ (last visited Jun. 25, 2011). Information on the Regenexx
website indicates that physical therapy or other "conservative care" will often be recommended: FAQ's,
supra note 8.
1" Regenerative Sciences, Regenexx, supra note 7, at 13-14, 21.
98 See the recent review by Irene Tracey, Getting the Pain You Expect: Mechanisms of Placebo,
Nocebo and Reappraisal Effects in Humans, 16 NATURE MED. 1277 (2010) (Notably, "More expensive
placebo treatments produce significantly more placebo analgesia than less expensive ones" id, at 1282).
19 See Jonathan Kimmelman, Francoise Baylis & Kathleen Cranley Glass, Stem Cell Trials: Lessons
from Gene Transfer Research, HASTINGS CENTER REPORTs 23, 25-26: Insoo Hyun, Allowing Innovative
Stem Cell-Based Therapies Outside of Clinical Trials: Ethical and Policy Challenges, 38(2) J. L. MED. &
ETHICS 277, 281(2010).
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2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
that FDA regulation is inappropriate or unsuitable specifically for autologous
stem cell therapy. This argument is of particular interest as more stem cell-based
therapies - many of them autologous - are moving toward clinical applications.
C. FDA Regulation of Autologous Stem Cell Therapies
In Centeno's opinion, applying FDA regulations to autologous stem cell thera-
pies is inappropriate because of their individualized nature. He draws a distinction
between a "one-on-one" risk, such as is posed by autologous stem cell therapy or a
medical procedure, and a "one-on-many" risk, such as from a "bad batch of mass
produced drugs" that could "make many patients ill in 50 states."
2
" He questions
whether an autologous treatment can ever have "the same widespread public health
impact as drug production,"
201
A Regenerative Sciences document also suggests
that cGMP guidelines enforced by FDA are designed for mass drug manufacture,
whereas guidelines like the ICMS lab guidelines are more appropriate for process-
ing one patient's tissue at a time.
202
Regulating an emerging field is always difficult; with new technology, the "bullseye
of appropriate regulation is small and ever-changing" and "there are likely to be
periods of over- and under-regulation."
203
The language, structure, and concepts
of the regulatory framework fit uneasily with the new generation of cell and tissue
therapies in many respects.
2
0 Especially to a lay person, and even to some profes-
sionals in the field, it may seem very odd to use the language of "manufacturing"
and "drugs" to refer to a process that involves manipulating human biological
material, especially the patient's own cells and tissues. However, what is impor-
tant is whether the substance of the regulatory requirements and the way they are
administered are appropriate and fulfil the twin purposes of FDA to protect and
advance public health.
2 05
It is widely recognized that FDA regulations and guidelines, originally developed
for mass-produced pharmaceutical drugs and devices, need to be adapted in the
context of cell and tissue therapies, and that there are challenges associated with
this. For example, "principles of conventional pharmacokinetics" (e.g. absorp-
tion and excretion) are "not applicable" to stem cell-based products
206
and quality
testing requirements such as purity or potency need to be reinterpreted in ways
that are appropriate to products composed of living cells.
207
The timelines for the
processing and administration of stem cell products can present challenges for
quality control testing.
2 08
Furthermore, determining what animal models to use
200 Centeno, FDA Slippery Slope, supra note 151.
201 Id
202 Regenerative Sciences and FDA - FAQs, supra note 46.
203 Karinne Ludlow, Diana M. Bowman & Dwayne D. Kirk, Hitting the Mark or Falling Short
with Nanotechnology Regulation?, 27(11) TRENDS IN BIOTECHNOLOGY 615, 615 (2009).
204 Karen Martell, Alan Trounson & Elona Baum, Stem Cell Therapies in Clinical Trials: Workshop
on Best Practices and the Need for Harmonization, 7(4) CELL STEM CELL 451, 451 (2010); Sebastian C.
Sethe, The Implicationsof "Advanced Therapies" Regulation, 13 REJUVENATION RESEARCH 327,327 (2010).
205 U.S. DEP'T OF HEALTH & HUMAN SERVICES, U.S. FOOD AND DRUG ADMIN., STRATEGIC PRIORITIES
2011-2015: RESPONDING To PUBIC HEALTH CHALLENGES IN THE 21sT CENTURY, at 2 (2011), available at
http:I/www.fda.gov/ downloadslAboutFDA/ReportsManualsForms/Reports/UCM252o92.pdf.
206 Fink et al., supra note 58, at 1662.
207 Id.; Jeffrey L. Fox, FDA Scrutinizes Human Stem Cell Therapies, 26(6) NATURE BIOTECHNOLOGY
598, 599 (2008); Robert A. Preti, Bringing Soft and Effective Cell Therapies to the Bedside, 23(7) NATURE
BIOTECHNOLOGY 801, 802 (2005).
200 Preti, supra note 207, at 802.
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FOOD AND DRUG LAW JOURNAL
in preclinical testing and evaluating the results of this testing are much more dif-
ficult for cell therapies than conventional pharmaceuticals.
2 09
FDA has made some
progress in formulating guidance
2 10
and engaging in dialogue with stakeholders to
explore and address outstanding issues.
21
'
What, then, of autologous stem cell therapies? Throughout the development
of FDA's approach to regulating cell and tissue products, the relevant regulations
were intended to be applied to autologous as well as allogeneic cell therapies.
212
Is there some reason why this should not be the case? There are two key charac-
teristics of autologous therapies to consider. First, because the same person is
both donor and recipient, the donor screening and testing requirements that are
applicable to allogeneic products obviously would not be appropriate; there is no
need to worry about transmission of disease or genetic conditions from donor to
recipient. The regulatory process already takes this into account, because donor
eligibility and screening requirements do not apply where cells and tissues are for
autologous use." As discussed above, the risks of disease transmission through
contamination or cross-infection between laboratory samples still remain, as do
other potential safety, efficacy and quality issues, so other regulatory requirements
are equally relevant to autologous as to allogeneic products.
The second important characteristic is that autologous products are made for
and administered to one individual. This means that they are made in small quanti-
ties and are individualized or custom-made products. In fact, this characteristic is
not unique to autologous cell therapy products, because some allogeneic products
may be individualized or custom-made as well. The important distinction here is
therefore between custom-made products and "off-the-shelf" products. The latter
are more like conventional pharmaceutical products in the sense that they can be
mass-produced and then used in any of a large number of patients. At the other
extreme, products are prepared in small quantities - as small as a single dose - for
specific patients. Both of these models - as well as variations along a spectrum
between them - are likely to be important in the development of stem cell-based
therapies, each having advantages and disadvantages, and being appropriate for
different applications.
214
Therefore, it is important to understand the distinct
regulatory challenges that apply to autologous or other individualized therapies.
209 Fink et al., supra note 58, at 1663; Fox, supra note 207, at 599; COMMITTEE FOR ADVANCED
THERAPIES AND CAT SCIENTIFIC SECRETARIAT, Challenges with Advanced Therapy Medicinal Products
and How to Meet Them, 9 NATURE REVS. DRUG DEV. 195, 197 (2010).
210 Eg U.S. DEP'T OF HEALTH AND HUMAN SERVICES, U.S. FOOD AND DRUG ADMIN., CENTER FOR
BIOLOGICs EVALUATION AND RESEARCH, GUIDANCE FOR INDUSTRY: POTENCY TESTS FOR CELLULAR AND GENE
THERAPY PRODUCTS, (Jan. 2011), available at http://www.fda.gov/downloads/BiologicsBloodVaccines/
Guidance ComplianceRegulatorylnformation/Guidances/CellularandGeneTherapy/UCM243392.pdf
[hereinafter FDA, GUIDANCE ON POTENCY TESTS]; U.S. DEP'T OF HEALTH AND HUMAN SERVICES, U.S.
FOOD AND DRUG ADMIN., CENTER FOR BIOLOGICS EVALUATION AND RESEARCH, GUIDANCE FOR FDA RE-
VIEWERS AND SPONSORS: CONTENT AND REVIEW OF CHEMISTRY, MANUFACTURING, AND CONTROL (CMC)
INFORMATION FOR HUMAN SOMATIC CELL THERAPY INVESTIGATIONAL NEW DRUG APPLICATIONS (INDs)
(Apr., 2008), available at http://www.fda.gov/ downloads/BiologicsBloodVaccines/GuidanceCompli-
anceRegulatorylnformation/Guidances/Xenotransplantation/ucm092705.pdf; FDA, GUIDANCE FOR
HUMAN SOMATIC CELL THERAPY, supra note 58.
211 Fink et al., supra note 58, at 1663.
212 E~g FDA, APPLICATION OF CURRENT STATUTORY AUTHORITIES, supra note 57; FDA, GUIDANCE
ON APPLICATIONS, supra note 100.
213 21 C.F.R. § 1271.90(a)(1).
214 Chris Mason & Peter Dunnill. Assessing the Value of Autologous and Allogeneic Cells for Re-
generative Medicine, 4(6) REGENERATIVE MED. 835 (2009).
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2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
I Given the possibility of cross-contamination or infection, it is not really true that
individualized stem cell-based products present only "one-on-one" risks as opposed
to "one-on-many," as Centeno has suggested.
215
However, these products do present
some distinctive (though not entirely unique) challenges. The difficulties with test-
ing for safety and for quality attributes such as purity and potency are exacerbated
when products are made in small quantities for individual patients
216
and need to be
administered within a short time so that it may be impractical to wait for test results.
217
Regulatory agencies like FDA have therefore been exploring ways to adapt regulatory
requirements to autologous therapies where the usual requirements are not feasible.
21
1
Furthermore, the products may be affected by variation in the source material
(e.g. the number and characteristics of cells from different patients
219
), the processing
(which may be tailored to individual needs or conditions) or both. Depending on the
nature and extent of this variation, at a certain point the question arises whether an
entirely new product is being made for each individual patient, rather than batches
of a single product. For example, it has been suggested that for autologous therapies
using induced pluripotent (iPS) cells (cells reprogrammed to be pluripotent), each
patient-specific iPS cell line would need to be characterized and tested separately
and could be treated as a separate product by regulatory authorities.
220
If and
when this is the case, it would present a significant barrier to the development of
those personalized therapies. The cost of autologous therapies is already relatively
high compared to allogeneic products,
22
1 and the cost associated with individual
approvals could be prohibitive.
222
However, even if this is true for iPS cell thera-
pies - arguably the most complex stem cell-based therapies being developed - it
certainly is not the case that for all autologous stem cell therapies, each individual's
cells are considered to be a separate product needing a new approval, as one critic
has suggested.
223
Recent FDA guidance refers to a dose for an individual patient
as a "lot" of an autologous or "single patient allogeneic" product, not a separate
"product."
224
In addition, several autologous cell and tissue products have already
been approved in the U.S. (autologous cultured chrondrocytes for cartilage repair,
autologous cellular immunotherapy for prostate cancer, and autologous fibroblasts
for nasolabial fold wrinkles),
225
Europe (autologous cultured chrondrocytes for
215 Centeno, FDA Slippery Slope, supra note 151.
216 Ward, supra note 92, at 232.
217 Carpenter & Couture, supra note 118, at 577; Angela Osborne, Overcoming Manufacturing and
Financial Challenges of Personalised Cell Therapies, 4(22) PHARMACEUTICAL TECH. EUROPE 30 (2010).
218 E.g. FDA, GUIDANCE FOR HUMAN SOMATIC CELL THERAPY, supra note 58, at 11.Ward, supra
note 92, at 232-33, 237; R. Botta & G. Migliaccio, Cell-Based Treatments: Advanced Therapies and
Transplants, 43 TRANSPLANTATION PROCEEDINGs 338, 339 (2011).
219 Mason & Dunnill, supra note 214, at 845; Carpenter & Couture, supra note 118, at 570.
220 Condic & Rao, supra note 118, at 2755-56.
221 Mason & Dunnill, supra note 214, at 844.
222 Amy Zarzeczy et al., iPS, supra note 118, at 1036.
223 Stevenson, supra note 125 ("each individual case in which a person's stem cells are used is
considered a different drug. That means... that a full drug approval process must be undergone each
time stem cells are taken and grown for use on that same person.").
224 FDA, GUIDANCE ON POTENCY TESTS, supra note 210, at 3.
225 August 22, 1f997Approval Letter by U.S. FOOo AND DRUG ADMIN. to Tim Surgenor for Carticel
(Aug. 22, 1997), available at http://www fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/
ApprovedProducts/ucm 171702.htm; April 29, 2010 Approval Letter from U.S. FOOD AND DRUG ADMIN.
to Dendreon Corporation for Provenge. (Apr. 29, 2010): http://www.fda.govfBiologicsBloodVaccines/
CellulareneTherapyProducts/Approved Products/ucrn2l0215.htm; June 21, 2011 Approval Letter by
U.S. FOOD AND DRUG ADMIN. to Jeanne M. Novak for Laviv, (June 21, 2011), available at http:l/www
fda.gov[BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducs/ucm260486.htm.
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FOOD AND DRUG LAW JOURNAL
cartilage repair),
226
and Australia (a cultured MSC product for bone repair),
227
all
of which were treated as a single product. However, when approval is sought for
autologous products "there will be considerable regulatory concerns relating ... to
the reproducibility of the manufacturing process" and the extent of variability in the
final product from patient to patient.
228
For some types of therapies, at least (such
as autologous iPS cell therapies), the challenge of generating sufficient evidence
to satisfy these concerns could be a significant obstacle.
229
It can be concluded from this that there are, indeed, particular challenges with
regulatory approval of autologous stem cell-based products, some of which may
require regulatory agencies to develop new approaches or adapt conventional
requirements. However, none of these issues make the product approval process
by FDA less relevant or inappropriate, provided that it is applied in a flexible way.
Given the limitations of the other forms of oversight such as professional regula-
tion and liability, at present the best approach to ensure that patients receive safe
and effective therapies is to continue regulating cell and tissue therapies -including
autologous stem cell therapies - in the way FDA has attempted to do with Regenexx.
D. Is There a Need for Greater Flexibility?
Finally, there are formal exceptions under which products that have not been
approved by FDA can be provided to individual patients. Are these sufficient to
answer legitimate public concerns about access to promising new therapies? The
"expanded access" program allows physicians to apply for permission to use inves-
tigational (unapproved) drugs outside of an approved clinical trial, where patients
have serious or life-threatening conditions and do not have other reasonable options
for treatment.
230
A similar program for Section 361 HCT/Ps allows products to be
used (in this case without prior approval) where there is an "urgent medical need,"
even if the usual standards for donor eligibility have not been satisfied.
3
Physicians
are also permitted to prescribe, and pharmacists to prepare, an unapproved drug
where the approved product is unsuitable for an individual patient.
232
This process,
known as "compounding,"is permitted where the substances used are components
of approved drugs or are listed on an appropriate pharmacopoeia or equivalent.
233
The 2007 European Regulation on Advanced Therapy Medicinal Products (AT-
MPs), which applies to stem cell-based products that are more than minimally ma-
nipulated, contains an additional exemption known as the "hospitals exemption."
234
Whereas most ATMPs require a central marketing authorization from the European
Medicines Agency, products are exempt from this requirement if they are "prepared
on a non-routine basis according to specific quality standards, and used within the
"6 EUROPEAN MEDICINES AGENCY: EVALUATION OF MEDICINES FOR HUMAN USE, ASSESSMENT REPORT
FOR CHONDROCELEcr, (No. EMEA/H/C/00878) (2009), available at http://www.ema.europa.eu/docs/
enGB/document library/EPAR_- _Public assessment report/human/000878/WC500026035.pdf
227 Mesoblast Receives TGA Regulatory Approval to Commercially Manufacture Adult Stein Cell
Products, MESOBLAST (Jul. 21, 2010), http://www.mesoblast.com/download/l78/.
228 Carpenter & Couture, supra note 118, at 577.
229 Id
23o 21 C.FXR. Pt. 312. subpt. I; FDA, EXPANDED ACCESS TO INVESTIGATIONAL DRUGs, supra note 143.
23 Id, at§ 1271.60(d).
2 21 U.S.C. § 353a.
SId., at §353a(b)(l)(A).
23 Regulation (EC) 1394/2007 of the European Parliament and of the Council of 13 November
2007 on Advanced Therapy Medicinal Products and Amending Directive 200 1/83/EC and Regulation
(EC) 726/2004. 2007 0.J. (L324), art. 28.
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2011 REGULATION OF AUTOLOGOUs STEM CELL THERAPIES
same Member State in a hospital under the exclusive professional responsibility of
a medical practitioner, in order to comply with an individual medical prescription
for a custom-made product for an individual patient."
235
However, these prod-
ucts are not exempt from regulation altogether; their regulation is left to national
authorities, but must include at least traceability, pharmacovigilance, and quality
standards equivalent to those imposed on other ATMPs.
36
The U.S. does not have
any equivalent to the hospital exemption in its regulations and it might consider
adding one, though the case for it is less compelling outside of the European context
where centralized marketing authorization operates alongside national regulation.
All of these exceptions provide for additional flexibility while maintaining some
regulatory oversight by FDA or its equivalent. They create space for access and
innovation outside of the formal process of approved clinical trials and marketing
authorizations or licenses. Even among those who are concerned about allowing
novel stem cell treatments to proceed without FDA approval, there is a recognition
that it can sometimes be legitimate for "[r]esponsible clinician-scientists" to attempt
medical innovations with individual patients where there is sufficient justification
for doing so.
237
These exceptions provide the legal framework within which this
can take place.'
None of these exceptions would allow Regenerative Sciences to continue providing
Regenexx-C without FDA approval, however, if the courts support FDA's position in
this dispute that approval is required. The physicians providing this treatment have
not applied for expanded access, and even if they did it is doubtful that their applica-
tion would succeed as it does not meet the necessary criteria. Although Centeno has
compared autologous cell therapy to compounding of pharmaceuticals,
2 3 9
prepara-
tion of Regenexx-C would not fit within the definition of compounding (even if it
were provided by a licensed pharmacist), because not all of its active components are
approved or listed substances. Even if a hospital exemption similar to the European
provision existed, it would not be available because Regenexx-C is prepared on a
routine basis. These exceptions are designed to provide flexibility for innovation on
a case-by-case basis, and to allow access on compassionate grounds for patients with
life-threatening or other serious conditions and no other viable treatment options.
They are not intended to allow unapproved treatments to be provided commercially
on a routine basis. The fact that Regenerative Sciences would not be able to take
advantage of these exceptions does not show that they need to be expanded. Rather,
it illustrates the important distinction between innovative medical practice justified by
patient need, on one hand, and routine commercial provision of new treatments, the
safety and efficacy of which have not been assessed, on the other.
240
The regulatory
framework should ensure that there is enough flexibility to cover the former but not
the latter. The existing framework may not be perfect, but it does give effect to this
distinction in a reasonable way.
CONCLUSION
The legal issues before the court in the litigation between Regenerative Sciences
and FDA may seem narrow and somewhat technical, and resolution of the specific
2" Id, at art. 28(2).
6 Id
23 ISSCR GUIDELINES, supra note 194, at 4-5.
23 Hyun, supra note 199. at 282-83 (also discussing off-label use as another way in which innova-
tive treatment can occur outside clinical trials); von Tigerstrom, supra note 158, at 136-37.
* Centeno, FDA Slippery Slope, supra note 151.
240 Eg. 1SSCR GUIDELINES. supra note 194. at 5.
505
FOOD AND DRUG LAW JOURNAL
questions before the court should not be particularly contentious. FDA's position that
Regenexx should be considered a drug and biological product is eminently reasonable
given the text of the legislation and the ways in which it has been interpreted and ap-
plied to date. The arguments put forward by Regenerative Sciences to contest FDA's
position and challenge its authority in this matter are flawed in important respects.
It has been suggested that the "predicament" in which Regenerative Sciences now
finds itself - having spent considerable time and effort developing and marketing a
product without first securing the necessary approvals - should provide "valuable
lessons" to other companies.
24
1
Looking at the bigger picture, several other lessons emerge. Reactions to FDA's
assertion of authority in this case reveal the complex dynamics underlying the regula-
tion of innovative therapies. They also suggest the need for more public education
both about new stem cell treatments - which has been undertaken by the ISSCR
and others - and about the role and functioning of FDA, since the misconceptions
perpetuated by some of the commentary appear to be contributing to a polarized
and unproductive debate. Careful public scrutiny is also required of claims about
the adequacy of alternative forms of oversight such as voluntary organizations (e.g.
the ICMS). It may be that additional governance mechanisms could play a useful
role, but these should be held to basic standards of independence and rigour in order
to be accepted as credible.
It is not surprising that a dispute about the nature and limits of regulatory oversight
would involve an autologous stem cell therapy. Autologous cells are more easily used
in "clinician-centered activity in hospitals and clinics,"
242
and therefore autologous
therapies are likely to represent the "front lines" of physician-led innovation, chal-
lenging the traditional model of multi-phase clinical trials and regulatory approvals.
Autologous cell therapy products do also present distinct challenges for regulation,
though the most important of these are not, in fact, the issues raised by Regenerative
Sciences in this dispute. The limited experience of FDA and other agencies to date
suggests that the regulatory requirements can be adapted, and the challenges that
exist do not call into question the appropriateness of regulating these products as
biologics. Given the limitations of other forms of oversight, it would be premature
and unwise to dispense with this form of regulation, despite its difficulties.
The nature and extent of flexibility allowed within the regulatory framework will
likely continue to be contentious. The complex tensions between the fundamental
public values at stake are not reducible to a simple trade-off between access and pro-
tection.
243
The exceptions that are currently built into the system are reasonably well
aligned with the distinction - which may not always be as clear as we would like - be-
tween responsible case-by-case innovation to meet the urgent needs of patients, on the
one hand, and commercial enterprises that profit from routinely providing unproven
treatments, on the other. Few would deny that there is still room for improvement,
both in adapting the regulatory requirements to new categories of products as our
scientific knowledge evolves, and in implementing a balanced, risk-based approach
to innovative therapies.
244
Though the outcome in this dispute should be clear, the
regulation of autologous stem cell therapies will remain a work in progress.
241 Chad A. Lan dmon & Tara R. Rahemba, Human Tissue and Stem Cell Therapies Revolutionary
New Therapies that Face Increasing FDA Scrutiny, 2010(6) UPDATE 16, 19 (2010).
24 Mason & Dunnill, supra note 214, at 848.
243 Alex John London, Jonathan Kimmelman & Marina Elena Emborg, Beyond Access v. Protec-
tion in Trials of Innovative Therapies. 328 SCIENCE 829 (2010).
24 See e~g Martell. Trounson &Baum, supra note 204, at 451; Sethe, supra note 204, at 328: Preti,
supra note 207, at 803.
506 VOL. 66