Overview of Scientific Issues

1
Overview of Scientific Issues

• J. Craig Rowlands, Ph.D.
• Nutrition Programs and Labeling Staff
• Center for Food Safety and Applied Nutrition

2
Overview of Scientific Issues

• Background
• Summary of Scientific Evidence Submitted
• Petitioners Conclusions
• FDAs Evaluation of the Evidence
• Questions
• Meeting Objectives

3
Petitioners

• Weider Nutrition International, Inc. (petitioner
  A)
• Rotta Pharmaceutical, Inc. (petitioner B)

4
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

5
Rotta Pharmaceutical, Inc. (petitioner B)

• Crystalline glucosamine sulfate may reduce the
  risk of osteoarthritis

6
Health Claims

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

7
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

8
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

EburnationA change in exposed subchondral bone
in degenerative joint disease in which it is
converted into a dense substance with a smooth
surface like ivory.
9
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)

10
Scientific Evidence

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

11
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

12
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
• Freunds adjuvant in mice
• Surgery in rabbits

13
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

14
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

15
FDAs 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

16
Disease Risk Reduction

• Reduction in incidence of disease
• Intervention and observational studies in healthy
  people demonstrating that a substance reduces the
  incidence of OA

17
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

18
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

Disease or Health Related Condition
Healthy People
Valid Modifiable Risk Factors/ Surr. Endpts
Substance
1
2
Walnuts
LDL-Cholesterol
CHD
20
Valid Modifiable Risk Factors/Surrogate Endpoints
for OA?

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

OA Patients
Healthy People
Valid Modifiable Risk Factors/ Surr. Endpts
1
2
Joint degeneration Cartilage deterioration
21
Valid Modifiable Risk Factors/Surrogate Endpoints
for OA?

• 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

Substance
?
OA Patients
Healthy People
OA Patients
Healthy People
Valid Modifiable Risk Factors/ Surr. Endpts
1
2
22
Valid Modifiable Risk Factors/Surrogate Endpoints
for OA?

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

Substance
?
OA Patients
Healthy People
Valid Modifiable Risk Factors/ Surr. Endpts
1
2
23
Valid Modifiable Risk Factors/Surrogate Endpoints
for OA?

• 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

Substance
?
?
OA Patients
Validated Modifiable Risk Factors
Healthy People
OA Patients
Valid Modifiable Risk Factors/ Surr. Endpts
Healthy People
1
2
24
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 12308-312.
25
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?

26
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?

27
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
  substanceOA relationships