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Overview of Scientific Issues

J. Craig Rowlands, Ph.D.Nutrition Programs and Labeling Staff

Center for Food Safety and Applied Nutrition

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Overview of Scientific Issues

Background Summary of Scientific Evidence Submitted Petitioners’ Conclusions FDA’s Evaluation of the Evidence Questions Meeting Objectives

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Petitioners

Weider Nutrition International, Inc. (petitioner A)

Rotta Pharmaceutical, Inc. (petitioner B)

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Weider Nutrition International, Inc. (petitioner A)

Glucosamine may reduce the risk of: Osteoarthritis Joint degeneration Cartilage deterioration

Chondroitin sulfate may reduce the risk of: Osteoarthritis Joint degeneration Cartilage deterioration

Glucosamine and chondroitin sulfate may reduce the risk of:

Osteoarthritis Joint degeneration Cartilage deterioration

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Rotta Pharmaceutical, Inc. (petitioner B)

Crystalline glucosamine sulfate may reduce the risk of osteoarthritis

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Health Claims

Health claims are about a substance –disease relationship Risk reduction in healthy populations, NOT Disease treatment or mitigation (i.e.,

drugs)

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Substance(s)

Glucosamine Glycoprotein, endogenous substance Derived from marine exoskeletons or produced

synthetically Sold as the sulfate sodium chloride (sulfate) salt,

hydrochloride (HCL) salt and N-acetyl-glucosamine

Chondroitin sulfate Glucosaminoglycans (GAGs), large molecule made

of glucuronic acid and galactosamine Manufactured from natural sources, such as shark

and bovine cartilage

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Disease

Osteoarthritis (Stedman's Medical Dictionary 27th Edition) Arthritis characterized by erosion of articular

cartilage, either primary or secondary to trauma or other conditions, which becomes soft, frayed, and thinned with eburnation* of subchondral bone and outgrowths of marginal osteophytes

*Eburnation=A change in exposed subchondral bone in degenerative joint diseasein which it is converted into a dense substance with a smooth surface like ivory.

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Osteoarthritis

Risk Factors Genetic predisposition, trauma,

anatomic/postural abnormalities, obesity

No biomarkers that are valid modifiable risk factors/surrogate endpoints for OA Osteoarthritis Initiative (NIH) Biochemical Markers (e,g., cartilage or bone

metabolism)

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Scientific Evidence

Scientific evidence summarized in petitions included: In vitro mechanistic studies Animal studies Human clinical studies in OA patients

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In Vitro Mechanistic Data

Human and animal primary cell cultures, established cell culture models and tissue/organ cultures

Glucosamine and/or chondroitin sulfate reported to affect Inflammation Cartilage degradation Immune responses Production of proteoglycans

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Animal Studies

Glucosamine Reduce kaolin- and adjuvant-induced tibio-tarsal

arthritis in rats Reduce cartilage degradation in rabbits

(±chondroitin sulfate) Enhance the rate of new articular cartilage

proteoglycan synthesis in mice

Chondroitin sulfate Prevent articular cartilage degradation induced

by: Chymopapain in rabbits Freund’s adjuvant in mice Surgery in rabbits

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Human Clinical Studies

In OA patients, glucosamine and chondroitin sulfate Reported to improve symptoms of pain and

functionality Compared with the non-steroidal anti-inflammatory

drugs (NSAIDs)

Reported to improve joint degeneration and cartilage deterioration

Radiographic evidence: joint space narrowing Biochemical evidence: synovium, serum, urine:

bone/cartilage metabolism

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Petitioners’ Conclusions

Human clinical intervention studies in OA patients support OA risk reduction in healthy populations

Joint degeneration and cartilage deterioration are valid modifiable risk factors/surrogate endpoints for OA

Animal and in vitro models of OA are relevant to OA risk reduction in humans

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FDA’s Evaluation of the Evidence

Several issues identified Relevance of OA treatment studies to OA risk

reduction in healthy populations

Validity of joint degeneration and cartilage deterioration as modifiable risk factors/surrogate endpoints for OA

Relevance of animal and in vitro models of OA to humans

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Disease Risk Reduction

Reduction in incidence of disease Intervention and observational studies

in healthy people demonstrating that a substance reduces the incidence of OA

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Human Studies in Petitions

ALL of the human clinical intervention studies were conducted in OA patients

NO intervention or observational studies in healthy people demonstrating OA risk reduction

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Disease Risk Reduction

Beneficial changes in valid modifiable risk factor/surrogate endpoint for disease Intervention and observational studies in

healthy humans demonstrating that intake of a substance produces beneficial changes in valid modifiable risk factors/surrogate endpoints for OA

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Valid Modifiable Risk Factors/Surrogate Endpoints

A valid modifiable risk factor/surrogate endpoint for disease meets ALL 3 of the following conditions:

Associated with disease Mediates the relationship between intake in healthy people

and disease Expression is modified by intake of a substance in healthy

people

Diseaseor HealthRelated

Condition

HealthyPeopleSubstance

Walnuts LDL-Cholesterol CHD

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ValidModifiable

Risk Factors/Surr. Endpts

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Valid Modifiable Risk Factors/Surrogate Endpoints for OA?

Are joint degeneration and cartilage deterioration associated with OA? Yes, associated with OA

OAPatients

HealthyPeople

Joint degenerationCartilage deterioration

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ValidModifiable

Risk Factors/Surr. Endpts

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Does joint degeneration and cartilage deterioration mediate the relationship between intake of a substance in healthy people and OA?

Is there evidence that changes in joint degeneration or cartilage deterioration predict clinical outcome for OA?

No intervention studies with ANY substance in healthy individuals that measured BOTH joint degeneration or cartilage deterioration AND OA incidence

OAPatients

HealthyPeople

?OA

PatientsHealthyPeople

Substance

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Valid Modifiable Risk Factors/Surrogate Endpoints for OA?

ValidModifiable

Risk Factors/Surr. Endpts

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Are joint degeneration and cartilage deterioration modified by intake of a substance in healthy people? ALL of the evidence provided was in OA patients

OAPatients

HealthyPeople

Substance

?12

Valid Modifiable Risk Factors/Surrogate Endpoints for OA?

ValidModifiable

Risk Factors/Surr. Endpts

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Are joint degeneration and cartilage deterioration valid modifiable risk factors/surrogate endpoints for OA ?

Associated with OA = Yes Mediates the relationship between intake in healthy

people and OA = Not Known Expression is modified by intake of a substance in

healthy people = Not known

OAPatients

ValidatedModifiable

Risk Factors

HealthyPeople

?OA

Patients

ValidModifiable

Risk Factors/Surr. Endpts

HealthyPeople

?

Substance

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Valid Modifiable Risk Factors/Surrogate Endpoints for OA?

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Animal and in vitro models of OA

Do animal and in vitro models of OA mimic human OA? Animals have a different physiology In vitro models are conducted in an artificial

environment Etiology of OA in humans is poorly understood

Example: non-steroidal anti-inflammatory drugs (NSAIDs) inhibit OA in rodents but not humans*

*Otterness, I.G., Larsen, D., and Lombardino, J.G. An analysis of piroxicam in rodent models of arthritis. Agents Actions 1982; 12:308-312.

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Questions

Is: (1a) joint degeneration; (1b) cartilage deterioration, a state of health leading to disease, i.e., a modifiable risk factor/surrogate endpoint for OA risk reduction? What are the strengths and limitations of the scientific evidence on this issue ?

Are joint degeneration and cartilage deterioration valid modifiable risk factors/ surrogate endpoints for OA?

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Questions

If we assume that: (2a) joint degeneration; (2b) cartilage deterioration, is a modifiable risk factor/surrogate endpoint for OA risk reduction and we assume that research demonstrates that a dietary substance treats, mitigates or slows joint degeneration in patients diagnosed with OA, is it scientifically valid to use such research to suggest a reduced risk of OA in the general healthy population (i.e., individuals without OA) from consumption of the dietary substance ?

Is it scientifically valid to use human OA treatment studies to suggest a reduced risk of OA in the general healthy population?

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Questions

(3) If human data are absent, can the results from animal and in vitro models of OA demonstrate risk reduction of OA in humans?

(a) To the extent that animal or in vitro models of OA may be useful, what animal models, types of evidence, and endpoints should be used to assess risk reduction of OA in humans?

(b) If limited human data are available, what data should be based on human studies and what data could be based on animal and in vitro studies to determine whether the overall data are useful in assessing a reduced risk of OA in humans?

Are the results from animal and in vitro models of OA relevant for demonstrating OA risk reduction in humans?

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Meeting Objectives

About the science needed to demonstrate risk reduction NOT disease treatment or mitigation

About osteoarthritis NOT glucosamine and chondroitin sulfate

Etiology of OA Valid modifiable risk factors/surrogate endpoints for OA Relevant models of OA

Recommendation of FAC can apply to other substance–OA relationships