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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
Memorandum
Date:
12-16-02
From:
Gloria Chang, IDS/Pharmacist, Division of Standards and Labeling Regulations,
Office of Nutritional Products, Labeling and Dietary Supplements, HFS-820
Subject:
75-Day Premarket Notification of New Dietary Ingredients
To:
Dockets Management Branch, HFA-305
New Dietary Ingredient: Astaxanthin (Extract of Haematococcus pluvalis)
Firm:
/
Submitter: Ullman, Shapiro, and Ullman, LLP
Manufacturer: Mica Gaia, Inc.
Date Received by FDA:
90-Day Date: 6/05/02
3/07/02
In accordance with the requirements of section 413(a) of the Federal Food, Drug, and
Cosmetic Act, the attached 75-day premarket notification for the aforementioned new
dietary ingredient should be placed on public display in docket number 953-03 16 after
6/05/02. Hence, it can be displayed now.
Thank you for your assistance.
*gLl t?#fL;{
Gloria Chang, IDS/Pha
acist
Attachments
955oJ/b
&wIP
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
College Park, MD
Marc S. Ullman, Counselor at Law
Ullman, Shapiro & Ullman, LLP
299 Broadway, Suite 1700
New York, NY 10007
Dear Mr. Ullman:
This is in responseto your letter to the Food and Drug Administration (FDA) dated
January 9,2002 and originally filed with FDA on January 15,2002. Your notification
concernsthe new dietary ingredient, astaxanthinextracted from Huematococcuspluvidis
algae and manufactured by Micro Gaia Inc. of Maui, Hawaii. In a subsequenttelephone
conversationon January 24,2002 with you, Mr. Gary Coody of my staff informed you that
the notification did not meet the minimum requirementsof 21 CFR 6 190.6. Mr. Coody
statedthat the 75 day safety review would not commenceuntil the requestedinformation was
submitted and that the date that we received the information would be the new filing date.
Your amendednotification dated March 01,2002 containing the additional information was
received by FDA on March 07,2002 and is the new effective filing date.
The law at 21 USC. 35Ob(a)(2)requires that a manufacturer or distributor submit certain
information to FDA at least 75 days before a new dietary ingredient or a dietary supplement
containing it is introduced or delivered for introduction into interstate commerce. This
information must include the basis on which the manufacturer or distributor has concluded
that the new dietary ingredient or a dietary supplementcontaining it will reasonablybe
expectedto be safe. FDA reviews this information to determine whether it provides an
adequatebasis for such a conclusion. Under 21 U.S.C. 350b(a)(2), there must be a history of
use or other evidence of safety establishing that the dietary ingredient, when used under the
conditions recommendedor suggestedin the product’s labeling, will reasonablybe expected
to be safe. If this requirement is not met, the new dietary ingredient or dietary supplement
containing it is deemedto be adulteratedunder 21 U.S.C. 342(f)(l)(B), becausethere is
inadequateinformation to provide reasonableassurancethat the new dietary ingredient does
not present a significant or unreasonablerisk of illness or injury.
FDA has carefully consideredthe information in your notification that you relied upon to
conclude that astaxanthin extracted from the Haematococcuspluvialis algae and consumedin
the recommendeddose of 1 to 2 mg per day will reasonablybe expected to be safe. Your
notification notes that there were no age limitations or limitations on duration of use. Your
notification statesthat the product will contain a warning that pregnant and lactating women
should consult a physician before use. Becauseyou did not include any long-term human
toxicity studiesin your notification, and there was no safety data on long term or chronic use
in children and infants, we strongly suggestthat you consider excluding use in this vulnerable
subpopulation.
Page2 - Marc S. Ullman
Further, to deter excessive intake, for example from other sources of the carotenoids either
from foods or other dietary supplements, it may be helpful to advise all consumers not to
exceed the recommended daily dose of astaxanthin.
Although we are not finding at this time that the basis on which you have concluded that a
dietary supplement containing astaxanthin will reasonably be expected to be safe is
inadequate, FDA is not precluded from taking action in the future against a dietary
supplement containing astaxanthin if it is found to be adulterated or misbranded. It is the
manufacturer’s or distributor’s responsibility to ensure that any dietary ingredient contained in
a dietary supplement is safe and properly labeled. Importantly, new dietary ingredients for
use in dietary supplements that FDA has reviewed through the premarket notification process
are not “approved” or “authorized” by the agency.
Your notification will be kept confidential for 90 days from the date of its receipt. After
June 52002, your notification will be placed on public display at FDA’s Dockets
Management Branch in docket number 958-03 16. However, any trade secret or otherwise
confidential commercial information in the notification will not be disclosed to the public.
Prior to June 5,2002, you may wish to identify in writing specifically what information you
believe is proprietary in your current notification for FDA’s consideration. Nevertheless, our
Center’s Freedom of Information Officer has the authority to make the final decision about
what information in the notification should be redacted before it is posted at Dockets.
Please contact us at (301) 436-2371, if you have any questions concerning this matter.
Sincerely yours,
Felicia B. Satchel1
Director
Division of Standards
and Labeling Regulations
Office of Nutritional Products, Labeling
and Dietary Supplements
Center for Food Safety
and Applied Nutrition
ULLMAN.SHAPIRO&ULLMAN,LLP
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January 9,2002
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Division of Standardsand Labeling Regulations
Office of Nutritional Products, Labeling, and Dietary Supplements(HFS-820)
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5 100 Paint Branch Parkway
College Park, MD 20740-3835
Re:
New Dietary Ingredient Notification
Haematococcus Algae
for Astaxanthin
Extracted from
Dear Sir/Madame:
Pursuantto 2 1 CFR 9 190.6, pleasebe advisedthat Micro Gaia Inc. (“Micro Gaia”) of
Maui, Hawaii’, is hereby providing you with notification of its intent to market a New Dietary
Ingredient, namely astaxanthinextracted from Haematococcusalgae. Micro Gaia will commence
marketing of its astaxanthin extract 75 days after acknowledgmentof your receipt of this
notification, unless otherwise instructed by your agency. Enclosedwith this original document
are two additional copies of Micro Gaia’s submissionand the attachmentsthereto.
Based upon the following, Micro Gaia respectfully submits that there are no safety issues
relating to its intended marketing of astaxanthin extractedfrom Haematococcusalgae:
1.
Micro Gaia produces its astaxanthinextract from Heamatococcusalgae grown at
the company’s facilities in Maui, Hawaii. The algae is cultivated in a proprietary
Bra-Dome technology on Maui, which is constructedin a manner designedto
ensure that the algae is grown under sterile conditions, free from pollutants and
other environmental toxins. The facility has been inspectedby the State of
Hawaii and has been found to be in compliancewith all applicable rules and
regulations.
‘The company’s facilities are located at: Maui Researchand Technology Park, Premier
Place, 535 Lipoa Parkway, Suite 177, Kihei, Maui, Hawaii 96753.
ULLMAN. SHAPIRO & ULLMAN, LLP
Division of Standards and Labeling Regulations
Office of Nutritional Products, Labeling, and Dietary Supplements@IFS-820)
Center for Food Safety and Applied Nutrition
January 9,2002
Page 2
2.
The algae produced at the Maui facility will be extracted at Fuji Chemical
Company, Ltd. (“Fuji”) of Toyama, Japan. Fuji is a pharmaceutical ingredient
supplier that has been in operation since 1946. Fuji is one of the leading custom
manufacturers of bulk pharmaceuticalsand chemicals for utilization in both Japan
and the United States. Fuji’s Toyama facility operatesin compliance with all
Current Good Manufacturing Practices applicable to companies whose
pharmaceutical products are imported into the United States.
3.
The name of the new dietary ingredient is astaxanthin, which will initially be
marketed under the trade name AstaReal”“.
4.
AstaReal” will initially be marketed in tablet form. Each tablet will contain lmg
of astaxanthin extract. The recommended dose of AstaReal will be 1 to 2mg
daily. As noted in the attachedreport of Harry G. Preuss,M.D.2 (“the Preuss
Report”), this is well within the range of astaxanthin ingested in a .25kg serving of
salmon. The PreussReport specifically notes that the expected intake of
astaxanthin from salmon can range from 10.1 mg per .25 kg serving of Sockeye
salmon to a low of 1.325 mg per .25 kg serving of Atlantic salmon.
5.
Haematococcus algae is found worldwide in nature and is believed to be the
organism that can accumulate the highest levels of naturally occurring
astaxanthin. The PreussReport concludes that there are no reports of toxicity
associatedwith Haematococcusalgae in the published literature.
6.
Astaxanthin is approved for use in Salmonid feeds at a maximum level of
8OmgIkg pursuant to 2 1 CFR 0 73.35. The data submitted in support of Color
Additive Petition 7CO211(Roche Vitamins, Fine Chemicals, Hoffman LaRoche,
Inc.) (the “Roche Petition”) includes various toxicity studies involving
astaxanthin, which was reviewed in conjunction with the adoption of 21 CFR 0
73.35. The level required for acute toxicity for astaxanthin in rats over a 10 day
period was at an oral dose in excessof 2000 mg/kg.
7.
As noted in the PreussReport, Haematococcusalgae meal has been approved in
Japan for use as a natural food color and as a pigment in fish feeds. Moreover, the
PreussReport further notes that the structure of astaxanthin is similar to other
carotenoid pigments such as beta carotene and vitamin E. In light of this, and
other information cited therein, the PreussReport concludes that “astaxanthin is a
Professor of Physiology, Medicine and Pathology, Georgetown University Medical
Center, Washington, D.C.
SHAPIRO 8~ ULLMAN. LLP
ULLNAN.
Division of Standardsand Labeling Regulations
Office of Nutritional Products, Labeling, and Dietary Supplements @IFS-820)
Center for Food Safety and Applied Nutrition
January 9,2002
carotenoid and should be as safe as other carotenoid”.
8.
This conclusion is supported by the PreussReport’s review of the data submitted
in conjunction with the Roche Petition. There, FDA was presented with data
indicating toxicity in rats at extremely high levels, and an absenceof mutagenicy
in salmonella testing. Data also indicated that astaxanthin was well tolerated in
pregnant rabbits who ingested dosesof 100,200 and 400 mg/kg/day over a 12 day
period. Reproductive studies on rats and dogs revealed no perturbations from the
high doses administered. Thirteen week tolerance tests on rats indicated an
absenceof toxic effects.
9.
The PreussReport further cites three toxicity-related studies conducted in
humans. None of the studies, involving 78 subjects, indicated any evidence of
adverseevents from the consumption of astaxanthin.
10.
The PreussReport concludes that there “appears to be no question as to the safety
of Micro Gaia’s astaxanthin product” and that “all evidence points to complete
safety in the use of astaxanthin.”
11.
A report prepared by ISSI Laboratories, Inc., dated October 3 1,2001, concluded
that, following testing for 62 chlorinated hydrocarbon pesticides, 59 organophosphorous/organo-nitrogenpesticides , 11 carbamatepesticides, heavy metals,
toxins, and microorganisms, “AstaReal finished product was found to be free of
all listed potential contaminants.” A copy of this report is attached hereto.
12.
The conclusion to the PreussReport also states that “Micro Gaia and the Food and
Drug Administration can reasonably rely upon the Agency’s prior acceptanceof
safety data submitted by other companies marketing astaxanthin as a ‘new dietary
ingredient’ in the United States.”
13.
In light of the above, Micro Gaia hereby incorporates by reference FDA’s
acceptanceof safety related data in connection with docket number 958-03 16 by
the following companies:
0
0
0
0
Igene Biotechnology, Inc
Cyanotech Corp.
Aquasearch, Inc.
Cyanotech Corp.
May 4,200O
May 25,1999
December 16,1999
March 22,1999
ULLMAN. SHAPIRO
& ULLMAN.
LLP
Division of Standards and Labeling Regulations
Office of Nutritional Products, Labeling, and Dietary Supplements (HFS-820)
Center for Food Safety and Applied Nutrition
January 9,2002
Based on the foregoing, we believe that FDA should accept this filing on behalf of Micro
Gaia as providing sufficient evidence that AstaReal, astaxanthin extracted from Haematococcus
algae, when used under the conditions recommended in the product labeling, can reasonably be
expected to be safe for human consumption. In support of this, we have also included testing
data which reflect the purity of Micro Gaia’s product as manufactured.
If you require any additional information, please direct all correspondence to the
undersigned.
Very truly yours,
ULLMAN,
Encls.
SHAPIRO & ULLMAN,,&P
GEORGETOWN
UNIVERSITYMEDICALCENTER
Department
of Physiology
and Biophysics
School of Medicine
To
Mark Day
Chief Financial Officer
Micro Gaia, Inc.
From: Harry G. Preuss MD, MACN, FAAIM, CNS
Professor of Physiology, Medicine, and Pathology
Georgetown University Medical Center
Washington, D.C. 20007
Re:
Astaxanthin Safety
Date: 1 1/20/01,2001
At your request, I have examined the literature pertaining to the safety of
astaxanthin. The report below was derived from the material you fwwarded, and
material obtained over the intemet from PubMed and companies involved in the
manufacture of the antioxidant. From the material presented to me by your company, I
am also aware that prior astaxanthin notifications to other manufacturers of
astaxanthin by the FDA determined that astaxanthin presented essentially no safety
issue.
1.
EVIDENCE FOR SAFETY FROM DIETARY FINDINGS
Astaxanthm is a red pigment that gives color to many living organisms (7).
Natural astaxanthin gives salmon and shrimp their red color. Astaxanthin is prewlent
in human food stuffs, especially salmon and rainbow trout and also occurs in lobsters
and shrimps, in fish eggs, and in other fish species (2). Accordingly, the pigment is
found in many human foods and consumed by many. In commercial fish and
austa~farms,astaxa~iscommon~addedtofeedstomakeupfora~d<of
natural dietary sources (3,4). Indeed, it was found to be necessary for the growth and
survival of many organisms (3).
A reGent S~~WY of salmonid fish found the following concentrations of
astaxanthin ( 5):
1
3900 Reservoir Road NW
202 687-1512
Washington DC 20007-2197
202 687-7407 jti&
SPECIES
Wild sockeye salmon
Wild Coho salmon
Wild pink salmon
Wild chum salmon
Wild Chinook king salmon
Wild Atlantic salmon
ASTAXANTHIN RANGE
3&58 mglkg
9-a
wrg/kg
3-7 Tl&l
+fmm
l-22mgkg
5-7fwkl
.
ASTAXANTHIN AVERAGE
40.4 nlgikg
13.8 n@q
5.4 mg/kg
5.6 mgkg
8.9 mq/kg
5.3 mgikg
average of all species = 13.2 mg/kg
Based on these concentrations, the typical f&h consumption of 0.25 kg would result in
a low intake of 1.325 mg of astaxanthin from the Atlantic salmon to a high intake of
10.1 mg from the sockeye salmon. Based on the all species average concentration,
the intake of astaxanthin from salmon would be 3.3 mg. The recommended dose of
astaxanthin for nutraceutical use would easily fit in this range.
A ubiquitous algae is the most prevalent commercial source. Haematococcus
pluvalis algae occurs worldwide and is believed to be the organism which can
accumulate the highest levels of astaxanthin in nature. Thii organism accumulates
1,000 to 3,000 higher levels than salmon. No toxicity associated with Haematococas
has ever been reported in the literature (6). The general composition of
Haematococcus algae consist of common carotenoids, fatty acids, proteins,
carbohydrates and minerals. Haematococcus algae meal has been approved in
Japan as a natural food color and as a pigment in fish feeds.
The structure of astaxanthin is similar to that of other carotenoid pigments like
beta carotene; however astaxanthin is a more powerful antioxidant than either beta
carotene or vitamin E (7,8). Like other carotenoids, astaxanthin cannot be synthesized
In anlmak and must be provided ln the diet. Because of its strong antloxkkm
capabilities, astaxanthin has been postulated to have some benefit in cardiovascular
diseases like atherosclerosis and strokes, macular degeneration, cancer and various
neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Much
interest has been focused on the latter two diseases, because astaxanthin can pass
the “blood brain banier”, meaning it can deli antioxidant benefit diiectly to the brain
and central nervous system.
SUMMARY
Astaxanthin is a carotenoid and shouM be as safe as other carotenoids. In
addition, astaxanthin has been found safe as an animal supplement and is already in
the human faad chain.
2. ASTAXANTHIN TOXICITY-RELATED STUDIES IN ANIMALS
Astaxanthin has been approved as feed for salmonid fish for a number of years.
2
The original petition for use as a feed was filed by Roche Vitamins and is in seven
volumes (9). Acute toxicii studies in animals were carried out in rats and mice over a
tenrlayperiodanddosesupto8000mg/kgbodyweigtrtshowednomortalityor
toxidty When mut agenlcity -wasrested, no miitatioii were induced in Salmonella
typhimurium strain using concentrations of 0.03-0.05 n-g/plate in the Ames test
whether rat iii homogenates were a-ted
or not. In another test of mutagenic&y
using the Micronucleustest, no chromosamal breaks nor mitotic dysjunction were
found in tiw with doses of 500, 1,000, and 2,000 mg/kg of body weight. concerning
teratology and embryotoxicity studies, doses of 100, ZOO,and 400 mg/kg/day were
given to pregnant rabbits for a 12 day period. At 30 days of gestation, the examination
of fetuses showed no malformations. The mothers all tolerated the astaxanthin well.
In rats given astaxanthin, no embryotoxic or teratogenic effects of astaxanthin were
observed. Reproductive studies on rats and dogs revealed no perturbations from the
high doses used. Thirteen week tderance tests on rats and dogs revealed no toxic
efkts
Three different lots of Haematococcus algae were administered by gavage to
Charles River CD rats (9). 5,000 mg/kg were administered in a 0.5% aqueous
methycellulose solution. In a thirteen day study on both male and female rats, no
visible abnormalities were noted and the rats continued to gain weight during the
entire study. In antoher study, doses of lo,41 7-18,000 mg/Kg given by oral gavage did
not reveal any toxicity, even when organs were examined postmortem. Therefore, the
LD SO was judged to exceed 18,000 mg/kg.
A 13-week oral, repeated-dose toxicity study of haematococcus color, a food
additive mainly composed of astaxanthin, was conducted in male and female F344
rats (10). Rats were randomly divided into ti groups each consisting of 10 males
and 10 females and given a powder diet containing 0,0.025,0.075, and 0.2S”/6
haematococcus, i.e., 0, 0.5, 1.5, and 5% as the pro&t. None of the animals died
during the administration period. There were no exposure-related changes in body
weight gain or food consumption. Serum biochemical examinations showed a doserelated increase in cholesterol, but the differences were slight and not defined as an
adwseefkct
Noeffectsrelatedto tmatmemwerenotedinthehematologii
examinations and organ weights, and no abnormalities that could be ascribed to
exposure to haematococcus color were observed in histopathdogical examinations.
The authors concluded that ingestion of haematococcus colorinthedietfor13weeks
did not cause any toxicdoglcal changes in F344 rats.
ThreegroupsofmaleWbtarrats(13~1~)werefed3Odayswithsynthetic
diets containing 0.1% of beta carotene, canthaxanthin, and astaxanthin (11). Another
gmupwasfedwithaqntheticcftetwithoutcarotenoids.
Theresultsshowedthatthe
beta carotene did not induce change in plasma cholesterol, but cathxanthin and
astaxanthin induced a significant increase in cholesterol concentration. However, the
increase was due mainly to HDL, the good cholesterol.
3
Fii tissues from a Haematococcus algae feeding to rainbow trout were
analyzed for toxic effects and neoplasia (1). All &sues examined were normal in
appearance with no indication of disease, toxicity, or neoplasia. All fish examined
were in excellent nlittitioi~l stti~is iiv’rthabundant body W. Gross findings indicate that
no adverse effects on health were observed from Haematococcus algae meal as the
dietary source of astaxanthin.
SUMMARY
Animal studies, where extremely high doses of astaxanthin were used, show a
wide range of safety in the use of thii antioxidant.
3. ASTAXANTHIN TOXICITY-RELATED STUDIES IN HUMANS
Astaxanthin was administered daily over two weeks to five subjects at 3.6
mg/day,to~subjeccsat7.2mg/day~tothreesubjectsat14.4~~
A
physiological efkcts on oxidized LDL was noted, but no adverse effkts were reported
atanydose(12).
Lignell(13) followed 40 healthy volunteers over six months: one half received
one capsule containing four mg astaxanthin (algae meal) and the other one half
received a placebo. No signifitint differen&% W&e ob%Wd bmeetl the two group
with the exception of the strength endurance tests. These improved on the antioxidant.
Thirty-three healthy adult volunteers were given astaxanthin obtained from
Haematococcus pluvialis dry algae meal. Each subject consumed daily over 29 days
either a low dose (3.85 mg) or a high dose (19.25 mg) astaxanthii. No adverse
reactions were found after examining -weight, skin coloration, general appearance,
blood pressure, near and distant vision, color vision, depth perception, general eye
condition, ears and nose, mouth, throat and teeth, chest and lungs, reflexes, blood
analyses and urinalyses.
SUMMARY
Although the studies arc iiiited, human trial to date show no adverse e!vents
fiomconsumptionofthenutmceutical.
CONCLUSIONS
Inlightofthisinformation,thereappearstobeM>questionastothesafetyof
Micro Gaia’s astaxanthin product. In addition, I believe that Micro Gaia and the
Federal Food and Drug Administration can reasonably rely upon the Agency’s prior
acceptance of safety data submitted by other companies marketing asta xanthin as a
%ew dietary ingredient” in the United States. All evidence points to complete safkty in
the use of astaxanthin. Astaxanthin deserves no more concern when used in proper
dosing than the use of other carotenoids such as beta carotene.
4
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Torrissen OJ, Hardy RW, Shearer KD: Pigementation of salmonids - carotenoid
l.,
deposition and metabolism. CRCCrit Rev Aquat Sci 1:209-2X, 2000.
Aquasearch, Inc: Technicalreport TR2102.001,1999.
2.
Ton&en OJ, Christianson R: Requirement for carotenoids in fish diets. J Appl
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Ichthyd 11:225-230,1995.
Roche Laboratories: Carophyii Pink http://www.roche.com.
4.
Turujman SA, Warner WG, Wei RR,Albert RH: Rapid liquid Chromatographic
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method to diitinguish wild salmon from aquacultured salmon fed synthetic
astaxanthin.J AOAC int. 80:62X32,1997.
Technical Bulletin ##060, Cyanotech Corporation: A technical review of
6.
Haematococcus A&i& 1999.
Temo J: Antioxidant activity of betxarotene-related carotenoids in solution.
7.
i&ids 24:659-661,1989.
Miki W: Biological functions and activities of animal carotenoids Pure Appl
8,
them 63:141-l 46,199l.
Roche Vitamins and Fine Chemicals: Hoffman La Roche, inc. Astaxanthin as a
9.
pigmenter in salmon feed. CAP 7CO211.
10. Ono A, Sekita K, Saitoh M, Umenmukra T, Ogawa V, Furuya T, Kaneko T, inoue
T:A13weeksubchronicorsdto>dcitystudyofhaemgtococcus
cokxinF344rats.
11. Kokuritsu iyakuhin Shokuhin Eisei Kenkyusho Hokoku 11Z91-98,1999.
Muriiio E: Hypercholesterdemic effect of canthaxanthin and astaxanthin in rats. Arch
Latinoam Nutr 42: 409413,1992.
12. Miki WW, Hosoda K, Kondo K, itakura H: Astaxanthin-containing drink. Patent
application number 10155459. Japanese Patent Office. Publication date 16 June
1998.
13. LigneilA: Medicament for improvement of duration of musde function or
treatment of muscle disorder or diseases. Patent Cooperation Treaty appiiition
#991125 1. AstaCarotene AB, Sweden.
14. Aquasearch, inc.: Technical Repan TR.3005.00 1,1999.
Harry G. Preuss MD, MACN, FAAIM, CNS
P&essw of *ysWgy, bdidne, and Pathology
Georgetown University Medical Center
5