**To: Food & Drug Administration -- Food Advisory Committee**

**From: Nutramax Laboratories, Inc. -- Edgewood, Maryland**

**Date: May 28, 2004**

**Re: Written Comments at Public Meeting -- June 7 & 8, 2004**

**Health Claim Petition: Glucosamine Sulfate & Osteoarthritis filed by
Rotta Pharmaceuticals, Inc. Docket No. 2004P-0060**

We appreciate the opportunity to submit these written comments to the
Food & Drug Administration Food Advisory Committee for the above
referenced public meeting and health claim petition.

There are several issues in this health claim petition regarding assay
methods and claims on effectiveness that should be considered very
thoroughly.

1.  The National Institutes of Health is conducting a large clinical
    study, the Glucosamine/Chondroitin Sulfate Arthritis Intervention
    Trial (GAIT)^1^, using glucosamine hydrochloride and chondroitin
    sulfate, not glucosamine sulfate. The rationale for this approach is
    based on the assumption that glucosamine alone produces the observed
    clinical effects observed in studies of glucosamine. Furthermore,
    recent clinical studies on glucosamine sulfate that lacked active
    industry involvement in analysis and description of data have not
    found the benefit previously observed in studies supported by
    Rotta^2-6^. Further research is clearly needed with better endpoints
    to eliminate bias and resolve these differences.

2.  The petitioner's argument that the sulfate component of glucosamine
    sulfate plays a significant role in its biological effects is at
    best only speculative. Biochemical studies show that glucosamine
    hydrochloride alone produces effects on chondrocytes that may
    underlie the ameliorative effects of this supplement^7-12^. The
    petitioner's distinction between the clinical effects of glucosamine
    hydrochloride and glucosamine sulfate is questionable based on the
    available independent research on bioavailability and effectiveness
    of glucosamine base. Many experts feel that the base is active
    irrespective of salt.

3.  The petitioner claims to have a validated assay for glucosamine
    sulfate that is specific, accurate and precise, and that is based on
    a potentiometric measurement. Examination of the attachment in the
    health claim petition describing this method indicates no data
    showing specificity for glucosamine sulfate. Many organic molecules
    with a primary amine group will give the same result as glucosamine
    when titrated as described, as such it is by definition not
    specific. In fact, the method relies on the use of a factor to
    correct for the endpoint in the titration that is present due to an
    excipient, citric acid. An alternative, specific, commonly used
    assay must be used in analyzing the petitioner's glucosamine sulfate
    to ascertain what is actually present and being studied clinically.

4.  At present there are several methods available that can be used to
    analyze glucosamine and glucosamine sulfate, but many suffer
    limitations. The petitioner criticizes the USP method while at the
    same time offering it as an indicator of the exact composition of
    glucosamine sulfate for which a claim is sought. Part of the
    criticism of the indicated USP method may be justified (use of
    detection wavelength that is relatively nonspecific), but the
    evidence provided regarding chloride detection is questionable. When
    properly run, the HPLC procedure will result in elution of
    glucosamine at a specific retention time that does not coincide with
    chloride. There is a clear need for clarification and uniformity in
    the industry in analysis methodology prior to granting any type of
    health claim for glucosamine sulfate.

5.  The petitioner asks for a health claim on "crystalline glucosamine
    sulfate" with the implicit assumption that the specific glucosamine
    sulfate being considered is the same as the form for which
    petitioner has a patent that relates to its method of preparation.
    The term "crystalline glucosamine sulfate" should be clearly
    defined. Were the studies cited performed on this patented
    formulation and is it strictly this formulation for which the health
    claim is requested? The USP clearly states that "practically all the
    glucosamine products available in the current market is the mixed
    salt or co-crystals of glucosamine hydrochloride with sodium or
    potassium sulfate"^11^. At different times the USP has used two
    different formulas to represent glucosamine sulfate containing
    sodium:

> (C~6~H~13~NO~5~^.^HCl)~2~^.^Na~2~SO~4~ and (C~6~H~14~NO~5~)~2~SO~4~^.^
> 2NaCl
>
> The molar ratio of glucosamine:sulfate:sodium:chloride is 2:1:2:2 for
> both.
>
> These formulas may be intended to reflect the method of production of
> "glucosamine sulfate". While the crystalline products are
> indistinguishable upon dissolution they may differ in their
> stabilities as crystals. In contrast, glucosamine hydrochloride does
> not suffer from this ambiguity and is highly stable.

6.  Recent studies of the contents of glucosamine in various commercial
    products, particularly glucosamine sulfate, showed levels
    substantially less than that claimed on the labels^14,15^. This
    situation reinforces the importance of consistent methodology and
    accuracy, or truth, in labeling.

*For questions, please contact: Kristen E. Blanchard, Vice President,
Legal & Government Affairs, Nutramax Laboratories, Inc., 2208 Lakeside
Boulevard, Edgewood, Maryland 21040*

*Phone: 410-776-4000, Fax: 410-776-4053, e-mail:
<kblanchard@nutramaxlabs.com>*

Bibliography

1.  <http://nccam.nih.gov/news/19972000/121100/index.htm>

```{=html}
<!-- -->
```
2.  McAlindon T Why are clinical trials of glucosamine no longer
    uniformly positive? Rheumatology Disease Clinics of North America
    2003; 29:789-801.

```{=html}
<!-- -->
```
3.  Cibere J, Esdaile JM, Thrne A, Singer J, Kopec JA, Canvin J et al.
    Multicenter randomized double-blind placebo-controlled glucosamine
    discontinuation trial in osteoarthritis. Arthritis and Rheumatology
    2002; 46:S15649.

```{=html}
<!-- -->
```
4.  Hughes R and Carr A. A randomized, double-blind, placebo-controlled
    trial of glucosamine sulphate as an analgesic in osteoarthritis of
    the knee. Rheumatology\[Oxford\] 2002; 41:279-284.

```{=html}
<!-- -->
```
5.  Rindone JP, Hiller D, Collacott E, Nordhaugen N, Arriola G.
    Randomized, controlled trial of glucosamine for treating
    osteoarthritis of the knee. Western Journal of Medicine 2000;
    172:91-94.

```{=html}
<!-- -->
```
6.  Thie NMR, Prasad NG, Major PW. Evaluation of glucosamine sulfate
    compared to ibuprofen for the treatment of temporomandibular joint
    osteoarthritis: a randomized double blind controlled 3 month
    clinical trial. Journal of Rheumatology 2001; 28:1347-1355.

7.  Ogema TR, Deloria LB, Sandy JD and Hart DA. Effect of oral
    glucosamine on cartilage and meniscus in normal and
    chymopapain-injected knees of young rabbits. Arthritis 7 Rheumatism
    2002; 46:2495-2503.

8.  Fenton JL, Chlebek-Brown KA, Peters TI, Caron JP and Orth, MW.
    Glucosamine hydrochloride reduces equine articular cartilage
    degradation in explant culture Osteoarthritis and Cartilage 2000;
    8:258-265.

9.  Orth MW, Peters TL and Hawkins JN. Inhibition of articular cartilage
    degradation by glucosamine-HCl and chondroitin sulfate. Equine
    Exercise Physiology 6 Equine Veterinary journal Suppl. 2002;
    34:224-229.

10. Sandy JD, Gamett D, Thompson V, Verscharen C. Chondrocyte-mediated
    catabolism of aggrecan: aggrecanase-dependent cleavage induced by
    interleukin-1 or retinoic acid can be inhibited by glucosamine.
    Biochemical Journal 1998; 335:59-66.

11. Gouze JN, Bordji K, Gulberti S, Terlain B, Netter P, Magdalou J,
    Fournel-Gifleux S and Ouzzine M. Interleukin-1beta down-regulates
    the expression of glucuronosyltransferase I, a key enzyme prining
    glcosaminoglycan biosynthesis: influence of glucosamine on
    interleukin-1beta-mediated effects in rat chondrocytes. Arthritis
    and Rheumatism 2001; 44:351-360.\\

12. Gouze JN, Bianchi A, Becuwe P, Dauca M, Netter P, Magdalou J,
    Terlain B and Bordji K. Glucosamine modulates IL-l-induced
    activation of rat chondrocytes at a receptor level, and by
    inhibiting the NF-kB pathway. Federation of European Biochemical
    Societies 2002; 510:16-170.

13. Briefing: Glucosamine Hydrochloride; Glucosamine Tablets;
    Glucosamine Potassium Sulfate; Glucosamine Sodium Sulfate.
    Pharmacopeial Forum 2000; 26:1449.

14. Russell AS, Aghazadeh-Habashi A and Jamali F. Active ingredient
    consistency of commercially available glucosamine suflate products.
    Journal of Rheumatology 2002; 29:2407-2409.

15. Adebowale A, Liang Z, Eddington N. Nutraceuticals, a call for
    quality control of delivery systems: a case study with chondroitin
    sulfate and glucosamine. *J Nutraceuticals, Functional & Medical
    Foods* 1999;2(2):15-29