Agency Response Letter - Objection: Biomarine Complex FALN No. 007 (Docket No. 2006FL-0510)
Lotte Damgaard Valencia
Dear Ms. Valencia,
This letter is in response to the notification dated December 4, 2006, that Ferrosan A/S (Ferrosan or notifier) submitted in accordance with section 403(w)(7) of the Federal Food, Drug, and Cosmetic Act (the Act) requesting an exemption from the labeling requirements of section 403(w)(1). The United States (U.S.) Food and Drug Administration (FDA) received the notification on December 7, 2006, and designated it as FALN 007.
The subject of FALN 007 is Ferrosan’s "Biomarine Complex – an extract of Deep Sea Fish" (hereafter referred to as "Biomarine Complex"), which is an ingredient in Imedeen oral beauty products that, according to Ferrosan, are marketed as dietary supplements in the U.S. (Imedeen Time Perfection™ targeted to women 35 to 50 years old and Imedeen Prime Renewal™ targeted to postmenopausal women over 50 years old). Ferrosan states that Imedeen products have been produced and sold since 1993 and that, currently, these products are sold in 52 countries worldwide, including the U.S., through doctors, spas, apothecaries, beauty e-tailers, and Ferrosan’s website, www.Imedeen.us.
As part of its notification, Ferrosan states that the "main ingredient" in the Imedeen products is "Biomarine Complex – an extract of Deep Sea Fish" and that the "extraction includes hydrolysis by protease" with a resultant purified extract containing peptides of 8-23 amino acids. The notification includes a study report titled, "Screening of fish extract materials for Imedeen™ in relation to patients with proven allergy for codfish," prepared by Poulsen et al., which describes a series of experiments conducted using sera from a select group of individuals stated to have been confirmed as allergic to codfish according to the guidelines of the European Academy of Allergology and Clinical Immunology. The study report includes results of Enzyme-Linked Immunosorbent Assay (ELISA) screening for detection of codfish Gad c 1 (a major codfish allergen), Enzyme-Allergosorbent Test (EAST) and EAST-inhibition tests, and histamine release experiments. Three different test materials described as "related to production of Imedeen" (fish extract, fish dry cartilage, and fish frozen meat; hereafter referred to as "Imedeen-related fish materials") along with frozen codfish fillet extract were included in these experiments.
FDA objects to FALN 007. FALN 007 does not contain scientific evidence (including the analytical method used) that demonstrates that Ferrosan’s Biomarine Complex does not contain allergenic protein, as required by section 403(w)(7). FALN 007 neither provides sufficient scientific evidence to determine that Biomarine Complex does not contain allergenic protein nor otherwise meets the requirements of section 403(w)(7).
The identity, composition, and method of derivation of Biomarine Complex are not clear. Ferrosan states that "extraction includes hydrolysis by protease. Result is a purified extract containing peptides of 8-23 amino acids." However, Ferrosan does not explain the origin or type of deep sea fish or provide any information on the type of proteolysis, analytical profile of the resulting peptides, or the composition of Biomarine Complex. Peptides comprising of 8 to 23 amino acids can be potentially allergenic (Ivanciuc et al. 2002; Silvanovich et al. 2006) as they may contain full or partial immunodominant epitopes with IgE-binding ability. Further, the notification provides no description of the manufacturing process or monitoring controls implemented in the preparation or refining of Biomarine Complex that would confirm that the manufacturing process effectively and consistently eliminates all allergenic fish proteins.
It is difficult to assess the scientific evidence on allergenicity of the Imedeen-related fish materials because Ferrosan does not present any data characterizing these materials or explain how they were prepared, or if or how they are used in the manufacture of Biomarine Complex. Without information on how the test materials relate qualitatively or quantitatively to Biomarine Complex, it is not possible to assess the relevance of the test results or to use the test results to determine the presence or absence of allergenic protein in Biomarine Complex.
Ferrosan’s ELISA tests for codfish Gad c1 do not confirm the absence of Gad c 1 fish allergenic protein in Biomarine Complex. Although the study authors conclude that the Imedeen-related fish extract tested has "less than 10-7 times the activity of Gad c 1," this finding does not equate to a lack of allergenic reactivity, as would be expected for an ingredient containing no allergenic protein.
The experiments described in the study report are limited to a sample population of Gad c 1 and codfish allergic individuals. Ferrosan does not provide a rationale for why the Gad c1 or codfish was chosen or should be considered representative of all fish allergens. Ferrosan’s Biomarine Complex is said to be derived from "deep sea fish," which suggests that Biomarine Complex may be derived from various fish species, and not just codfish. Thus, Biomarine Complex may contain allergens other than the predominant allergen in codfish, Gad c 1. Although Gad c 1 is a recognized fish panallergen, individuals allergic to Gad c 1 (and codfish) are not necessarily representative of the entire spectrum of clinically relevant fish allergic individuals. The notification does not address the possibility that the Imedeen-related fish materials may contain other codfish allergens or allergens from other fish species that may not be detected by the codfish Gad c 1 ELISA test. Scientific studies have demonstrated the presence in fish, including cod, of allergens other than Gad c 1 (Galland et al. 1998; Yamada et al. 1999). Without information about the identity of the fish species used either in the Imedeen-related fish materials tested or in the manufacture of Biomarine Complex, FDA could not determine whether Ferrosan’s study targeted the appropriate fish allergen(s) or fish allergic population.
In addition, some observations of the ELISA, EAST and histamine release experiments raise concerns about the reliability of the test results. For example, in the ELISA test that observed responses to Gad c 1, the fish frozen meat showed a strong positive response to Gad c 1, which was explained as an "interference with the ELISA, when testing under almost undiluted conditions." The possibility that similar interference could affect the other fish materials tested cannot be ruled out, making the reliability of the ELISA assay results uncertain. Moreover, the reliability of the results obtained from the EAST and histamine release assays is also questionable because sera from subjects that are stated to be confirmed as allergic to codfish did not exhibit significant responses to codfish extract. The authors of the study did not explain why a significant portion (about one-third) of sera from individuals stated to be confirmed as allergic to codfish showed little or no response to codfish extract in the EAST experiment, drawing into question the significance of the lack of response to Imedeen-related fish materials. Similarly, the histamine release experiment suffers from this anomaly in that 13 of 28 sera from individuals confirmed as codfish-allergic did not react to codfish extract. As in the case of the EAST assay results, this lack of response to codfish extract calls into question the reliability of the observed lack of response with the Imedeen-related fish materials. Additionally, the significance of the results obtained from these tests cannot be established because of inadequate sampling of the Imedeen-related fish materials that were tested, particularly given that the allergen content of fish materials can be influenced by several factors, including the harvest location, harvest season, storage, and processing of the fish used in preparing the test material.
Ferrosan also states that about 25 adverse events to its Imedeen products have been reported per year from 1993 to 2005 and describes these events as primarily "skin related (red spots and other minor reactions)." Although Ferrosan appears to dismiss the significance of these reports, FDA notes that skin rashes (i.e., red spots) could be a sign of allergic reaction. Ferrosan does not provide data on the specific characteristics of the reactions reported or present any clinical evidence of safe human exposure or challenge to Biomarine Complex in sensitive fish allergic individuals that would lead the agency to discount these reports.
Ferrosan notifies FDA in FALN 007 of its view that its "Biomarine Complex – an extract of Deep Sea Fish" found in Imedeen oral beauty products should be exempt from food allergen labeling requirements. Based on its review, FDA has concluded that FALN 007 fails to provide scientific evidence (including the analytical method used) that demonstrates that Biomarine Complex does not contain allergenic protein, as required by section 403(w)(7). FALN 007 neither provides scientific evidence to determine that Biomarine Complex does not contain allergenic protein nor otherwise meets the requirements of section 403(w)(7). FDA therefore objects to FALN 007.
Michael M. Landa
Deputy Director for Regulatory Affairs
Center for Food Safety and Applied Nutrition
Galland AV, Dory D, Pons L et al. Purification of a 41 kDa cod-allergenic protein. J Chromatogr B Biomed Sci Appl 1998; 706 (1):63-71.
Ivanciuc O, Schein CH, Braun W. Data mining of sequences and 3D structures of allergenic proteins. Bioinformatics 2002; 18 (10):1358-1364.
Silvanovich A, Nemeth MA, Song P et al. The value of short amino acid sequence matches for prediction of protein allergenicity. Toxicol Sci 2006; 90 (1):252-258.
Yamada S, Nolte H, Zychlinsky E. Identification and characterization of allergens in two species of tuna fish. Ann Allergy Asthma Immunol 1999; 82 (4):395-400.
FDA evaluated this notification based on the assumption that the notifier’s request for "Exemptions from Food Allergen Labeling" refers to exemption from the labeling requirements of section 403(w)(1), and that Biomarine Complex is derived only from fish.
Although the notification claims that "people with known food allergy... show no reaction to Imedeen," the notification requests an exemption from allergen labeling requirements for Biomarine Complex. Thus, FDA does not address the question whether one or more of Ferrosan's finished products may be exempt from allergen labeling requirements. FDA notes that section 403(w)(6) provides for the submission of petitions demonstrating that a food ingredient "does not cause an allergic response that poses a risk to human health."
FDA notes that the notifier’s website, www.imedeen.us, advises that "Imedeen’s tablets contain fish proteins and traces of soy proteins and may, like other food products, cause allergic reactions," and that "people allergic to fish or shellfish should therefore not take Imedeen Time Perfection tablets" (Accessed online, January 8, 2007).
This response does not evaluate or otherwise address whether Biomarine Complex meets the regulatory requirements for a dietary ingredient of a dietary supplement product.