the importance of clinical trials for natural products importance of...the importance of clinical...

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