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The Importance of Clinical Trials for Natural Products
The Wake Forest and Brigham and Women’s Center for Botanical Lipids
Future of Dietary Supplements
YESTERDAY: TODAY: THE FUTURE:
-High Growth -Growth Slowed -Science-Based, Ethical Products-Cluttered Category -Category Regrouping -Strong IP-Short Life Cycle -Skepticism-HCP/Consumer -Long Life Cycles-Weak Brands -Regulatory Involvement -Strong, Power Brands-Fragmented Category -Untapped Demand -HCP Involvement
-Development-Marketing
- Sophisticated, Ethical Marketing
Mechanistically Based/Clinically Proven Dietary Supplements, Medical Foods and BotanicalRx Products
Unproven Dietary Supplements
Why Do Clinical Trials?
It is the right thing to do. When we provide products to humans, there is a moral and ethical responsibility that they be both safe and effective
Rigorous clinical trials are critical if we are to move this industry to the next level, and enhance our credibility with our patients and their physicians
Clinical trials will dramatically increase the profitability of those companies that are progressive enough to lead (ex. supplementation of infant formula for cognitive development)
How Will It Make You More Profitable?Major Barriers to Entry (your competitive edge)
Intellectual property
Control of the supply chain
Rigorous clinical trials to support the safety and efficacy of the product and it regulatory status
Sophisticated, ethical marketing including physician, naturopaths, pharmacist and consumer detailing.
Physicians Are Overwhelmingly
63.5%
28.5%
8.0%
Recommend as Useful Neither Recommend Nor Discourage Not Recommend
(detailed interviews with 203 MDs)
Positive If Natural Products are Taken Through Reasonable Safety and
Efficacy Trials
What are Clinical Trials? Clinical trials are designed to test safety and effectiveness in humans. They
take place in phases. In each phase, different research questions are answered
Phase I: What is the safe dose? How does the treatment affect the human body? How should the treatment be given?
Phase II: Does the treatment treat the disease or cure the condition?
Phase III: Is the treatment better than, the same as, or worse than the standard (or most widely accepted) treatment? If there is no standard treatment available, is it better than, the same as, or worse than a placebo?
R&D Process Milestones for Drugs
Drug Discovery
Early Development
Early Development
Full Development
Full Development RegistrationRegistration Post-
ApprovalPost-
Approval
INDSubmission
ResearchProgramProposal
NMEProposal
ERTProposal
Phase IIa / IIbFull Development
Decision(NPDC)
License Application Submission
License Application
Approval
Project Launch
Phase III(NPDC)
7.9 Years New Drug
ERT=Experimental Research TargetNME=New Molecular EntityIND= Investigational Drug
The Bad News
Researchers at Tufts University found that new medicines cost an average of $802 million to bring to market.
Tufts Center for the Study of Drug DevelopmentNovember 30, 2001
THE PROBLEM: We have all agreed that we have a moral and ethical responsibility that our products be both safe and effective. I have also shown you that it costs over $800 million over 8 years to develop an ethical drug. You tell me that the margins of natural products simply
will not support that type of development. What are we to do?
Can We Reduce the Cost and Time that It Takes to Develop an
Ethical, Natural Product?
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key surrogate biomarkers for human diseases to test.
For which diseases and conditions does it work? What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Development of a Clinically Proven, Mechanistically Based Medical Food ( A Case Study of a Gammalinolenic
Acid/ Eicosapentaenoic Acid Combination)
Overview of Clinical Trials with Our GLA/EPA Combination
• A proof of principle study in the General Clinical Research Center at Wake Forest University School of Medicine
• An optimization of dose and active ingredients trial in the General Clinical Research Center at Wake Forest University School of Medicine
• A trial to optimize the bioavailability, safety and efficacy of the active ingredients in Airozin™ at the Quintiles Phase I Clinical Trials Center in Lenexa, Kansas
• A Phase II efficacy trial in asthmatics in the General Clinical Research Center at Wake Forest University School of Medicine
• A multi-center pediatric pharmacokinetics trial completed by CompleWareCorporation, Iowa City, Iowa
• Analysis of responders and non-responders
Results have led to seven peer-reviewed journal articles and patents covering this GLA/EPA combination for numerous inflammatory disorders, its formulations, and bioavailability
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key surrogate biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Theoretical: The Arachidonic Acid Pathway: Precedent for Safe and Profitable Intervention
5-lipoxygenase
LEUKOTRIENES
CysLTLTB4
Cox II
PROSTAGLANDINS
Cox I
ARACHIDONICACID
GLA/EPA
CYTOKINES
TNFα IL-1β
Zyflo
SingulairAccolate
CelebrexVioxx
AspirinIbuprofen
Enbrel
InflammationBronchoconstrictionAirway Obstruction
Cell Infiltration
InflammationPain
Swelling
Pivotal, Double Blind, Clinical Trials in Arthritis and ARDS by Zurier and Gadek and colleagues
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key surrogate biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Leukotriene Blockers are Proven for Leukotriene Blockers are Proven for Asthma ManagementAsthma Management
US incidence - 26.7 million in 2002*US incidence has doubled over the last 20 years**Asthma is a profound inflammation of airwaysAnti-inflammatory drugs, steroids and leukotriene blockers, are proven to be the most successful therapyLeukotriene blockers are a rapidly growing class of drugs, exemplified by Merck’s Singulair® with 2003 projected sales of $2.2 billion up from $1.0 billion in 2000***
* Center for Disease Control** American Academy of Allergy and Immunology*** Morgan Stanley research (1/28/03)
Time after administration (minutes)
0 20 40 60 80 100 1200
20
40
60
80
100
120
Adapted from: Israel et al., Annals of Internal Medicine 119:1059Rubin et al., Agents and Actions (Suppl.) 35:103
LTB
4(p
erce
nt o
f con
trol
)C
hang
e in
FEV
1(d
L)
Blood LTB4 Levels on Pulmonary Function
GLA
GLA inhibition of 5-lipoxygenase and reduction
of leukotrienesDGLA
LEUKOTRIENES
AsthmaSymptoms5 - lipoxygenase
ARACHIDONICACID
Effect of GLA supplementation on Leukotriene Generation (J.Nutr.127:1435)
Baseline Week 30.0
0.2
0.4
0.6
0.8
1.0
LE
UK
OT
RIE
NE
B4
(nm
ol/1
0m
illio
nPM
N)
*
T I M E PO I N T S
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Dose-dependence of dietary GLA for the inhibition of leukotriene synthesis in zymosan-stimulated blood leukocytes.
*significantly different from control
Treatmentcontrol 0.75g GLA 1.5g GLA
Leuk
otrie
ne B
4
(per
c ent
of c
ontr
ol)
0
20
40
60
80
100
*
This GLA/EPA CombinationBlocked Leukotrienes in a Time
Dependent Manner120
Leuk
otrie
ne B
4(ng/
ml p
lasm
a)
*P<0.025*P<0.025
100
80
60
40
20
0Baseline Week 1 Week 2 Week 3 Washout
Treatment
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
GLA
DGLA
GLA as a mono-therapy increased liver arachidonic acid levels because ∆5 desaturase is present
5 - lipoxygenase
ARACHIDONICACID
∆5 desaturase
LEUKOTRIENES
0 2 4 8 10 12 WO0
200
400
600
800
1000FA
TTY
A CID
( um
o l/L
s eru
m) * * * *
arachidonicaciddihomogammalinolenic acidgammalinolenicacid
**
*
*
**
*
*
Effect of GLA Supplementation on Serum Effect of GLA Supplementation on Serum Fatty Acid Concentrations (J.Nutr.127:1435)Fatty Acid Concentrations (J.Nutr.127:1435)
TIME (weeks)
DGLA
Precise concentrations and ratios of GLA and EPA were developed that reduced leukotrienes and avoided arachidonic acid accumulation
∆5 desaturase
5 - lipoxygenase
EPA
GLA
ARACHIDONICACID
LEUKOTRIENES
Effects of a GLA and EPA Combination Effects of a GLA and EPA Combination on Serum Concentrations of Fatty Acidson Serum Concentrations of Fatty Acids
** *
0 1 2 3 WO0
100
200
300
400
500
600
FATT
Y A
CID
(µm
ol/L
ser
um)
Arachidonic AcidGammalinolenic AcidEicosapentaenoic Acid
(n=4)
Time (Weeks)Barham JB, Edens MB, Fonteh AN, Johnson MM, Easter L, Chilton FH. J Nutr 130:1925-1931, 2000.
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Gel Capsules Required to Get the GLA and EPA Doses Needed to Inhibit Leukotrienes
GLAcapsules
EPAcapsules
fatty
aci
ds, u
mol
/L p
lasm
a
0
50
100
150
200
250
300
GLA DGLA EPA
WK-0 Capsules
WK-3 Capsules
WK-0 Emulsion
WK-3Emulsion
Optimizing the Oral Bioavialibilityof Fatty Acids
Key Questions to Ask When Designing Clinical Trials for a Natural Product
Is there a strong theoretical basis and some data to suggest it will work?
Does it work? Are there key biomarkers for human diseases to test.
What is the correct dose of the supplement and how long must it be given to see an effect?
Is it safe? Does it have a long history of use in humans? What are the side effects? Are there situations in which it might be harmful?
How should it be given?
Are their certain sub groups of patients for which it works better?
Can it be used safely with other forms of treatment?
Time (Days)1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Fatty
Ac i
d s ( u
M)
0
50
100
150
200
250
300
350
400
GLA EPA
Trough plasma GLA and EPA concentrations in subjects consuming the 1.8g/day of GLA
and 0.9g/day of EPA
Surette ME, Koumenis I, Edens M, Tramposch KM andChilton FH. Clin. Therapeutics 25: 972-979, 2003.
Pharmacokinetics Pharmacokinetics in Children and Adultsin Children and Adults
Time, hours0 5 10 15 20 25 30
GLA
, um
ol/L
0
20
40
60
80
100
120
140
160
TIME vs GLA 6-11 yrs, 4g doseTIME vs GLA adults >17 yrs, 10g dose
Comparison of Leukotriene Inhibition Observed in Responder and non-Responder Asthmatics with
GLA/EPA
GLA/EPA
Low LTProducers
High LTProducers
0
60
80
100
120
*
( % c
hang
e fr
om p
lace
bo)
Leuk
otrie
ne
Surette ME, Koumenis I, Edens M, Tramposch KM and Chilton FH. Clin. Therapeutics 25: 948-971, 2003
Can We Reduce the Cost and Time that It Takes to Develop an
Ethical, Natural Product? I Believe the Answer is Yes.
Acknowledgments:NIH/NCCAM/Office of Dietary Supplements-Wake Forest and
Brigham and Women’s Center for Botanical Lipids
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