In the two previous editions of the Burdock Group Advisor, the authors described the differences in dietary supplement claim regulation between the United States and Europe. This third article of the series focuses on the similarities. Regulators in both regions evaluate claims (health, qualified health and structure/function claims in the United States or Article 13 and 14 health claims in Europe) based on the entire body of evidence that is submitted, but primarily consider data from human interventional clinical studies. Regardless of the type of claim, human clinical studies must provide convincing evidence that intake of the substance has a beneficial effect on a variable(s) involved in the development of a health-related condition or disease, or maintenance of healthy function. Studies that are performed with subjects having a pre-existing condition cannot meet this standard, for the condition has already developed, and improvement in symptoms would force a reclassification of the substance as a drug. A beneficial effect is particularly difficult to demonstrate in studies evaluating health or function of joints; to date, all joint-based health claims (U.S.) or joint-based function claims (Europe) for glucosamine/ chondroitin have been rejected based on the lack of evidence of a beneficial effect on normal joints. None of the intervention studies submitted to the FDA (N= 47) or EFSA (N = 11) to support the claims shown in Table 1 were performed in humans that did not already have osteoarthritis (OA) or joint degeneration.
The fact that glucosamine/chondroitin health claims have been rejected in the U.S. and Europe may be old news to some, but this topic deserves revisiting as joint-related health claims for glucosamine/chondroitin are permitted in some countries (e.g. Canada) and last month an Article 13.5 “emerging science” claim for glucosamine was submitted to the European Food Safety Authority (EFSA) (Table 1). Due to the fact that EFSA rejected similar claims in 2009 based on lack of evidence in subjects with normal joints, it is presumed that the Article 13.5 claim includes clinical evidence of a beneficial effect on normal joints. In the 2009 glucosamine/chondroitin opinion letter[1], EFSA stated that the wording of a health claim is very important:
Health claims such as “Substance X supports the function of the joints” may not sufficiently do so, whereas a claim such as “Substance X helps maintain the flexibility of the joints” would. In the first example of a claim, it is unclear which of the various functions of the joints is described or referred to contrary to the latter example which specifies this by using the word “flexibility”.
In recent draft guidance for health claims on bone, joint and oral health, EFSA mentioned that because slowing cartilage degeneration in individuals without OA may reduce the risk of development of the disease, studies measuring the rate of cartilage degeneration (e.g. changes in joint space width) in individuals without OA could be used for the scientific substantiation of disease risk reduction claims.[2] Therefore, it appears that EFSA is willing to accept joint or cartilage-related claims provided they are based on evidence of a beneficial effect on a specific function of the joints or on cartilage degeneration in humans without underlying joint disease. The progress of the Article 13.5 claim should be monitored by anyone who is interested in making joint-related claims in Europe, for it may provide some guidance on study populations and outcome measures that should be used to support properly-targeted health claims.
In 2004, the FDA opined that although cartilage degeneration was a modifiable risk factor for OA, an individual can have cartilage degeneration without developing OA. Therefore, unlike EFSA, the FDA does not consider cartilage degeneration a risk factor for development of OA. Furthermore, the FDA regards joint pain as symptom of joint disease and will not permit such claims for dietary supplements.[3] To date, the FDA has not provided any definitive statements about the appropriate endpoints to be evaluated for joint-related claims, other than that the claim “helps support cartilage and joint function,” would be a permissible structure/function claim because it relates to maintaining normal function, rather than treatment. However, similar claims will not be permitted in Europe, because the claims must be related to a specific function of the joints (see above).
What should a producer of a promising ingredient for joint health do? For joint-related claims, it is clear that one clinical trial or one claim will not “fit” every regulatory body. The clinical trial must be designed to assess endpoints that are consistent with the thought process of the regulatory body that will be evaluating the claim. Although different endpoints may have to be measured to satisfy regulators in different venues, it is clear that a uniform stance has been taken to exclude use of subjects in clinical studies with pre-existing joint disease. To increase the probability of success worldwide, product developers must focus on obtaining evidence that their substance modifies factors involved in reducing the risk of disease development – not factors present as a result of disease. Proper planning and execution of clinical studies is crucial. Subjects and outcome measures should be carefully selected based on the desired claim and the regulatory body that will be evaluating the claim.
Table 1. Rejected, accepted and proposed health claims for glucosamine, chondroitin sulfate or combinations thereof a in the United States, Europe and Canada
References
[1] EFSA (2009). Scientific opinion on the substantiation of health claims related to glucosamine alone or in combination with chondroitin sulphate and maintenance of joints (ID 1561, 1562, 1563, 1564, 1565) and reduction of inflammation (ID 1869) pursuant to Article 13(1) of Regulation (EC) No 1924/20061. http://www.efsa.europa.eu/en/scdocs/doc/1264.pdf.
[2] EFSA (20xx). Draft guidance on the scientific requirements for health claims related to bone, joints, and oral health. http://www.efsa.europa.eu/en/consultations/call/nda110426b.pdf
[3] FDA (2000). Regulations on statements made for dietary supplements concerning the
effect of the product on the structure or function of the body. 65 FR 1000. http://www.gpo.gov/fdsys/pkg/FR-2000-01-06/pdf/00-53.pdf.
[1] EFSA (2009). Scientific opinion on the substantiation of health claims related to glucosamine alone or in combination with chondroitin sulphate and maintenance of joints (ID 1561, 1562, 1563, 1564, 1565) and reduction of inflammation (ID 1869) pursuant to Article 13(1) of Regulation (EC) No 1924/20061. http://www.efsa.europa.eu/en/scdocs/doc/1264.pdf.
[2] EFSA (20xx). Draft guidance on the scientific requirements for health claims related to bone, joints, and oral health. http://www.efsa.europa.eu/en/consultations/call/nda110426b.pdf
[3] FDA (2000). Regulations on statements made for dietary supplements concerning the
effect of the product on the structure or function of the body. 65 FR 1000. http://www.gpo.gov/fdsys/pkg/FR-2000-01-06/pdf/00-53.pdf.