April 9, 2012
Director, Regulatory Affairs
Merck Animal Health
556 Morris Ave.
Summit, New Jersey 07901
RE: NADA 141-299, Resflor Gold® (florfenicol and flunixin meglumine) promotional labeling and advertisements
- RESFLOR GOLD® Ad (RES 41A)
- RESFLOR GOLD® Sales Aid for Cow Calf (SPAH-RES-43A-R)
- RESFLOR GOLD® Sales Aid for Dairy (SPAH-RES-43C-R)
- RESFLOR GOLD® Sales Aid for Feedyard (SPAH-RES-43D)
- RESFLOR GOLD® Fast Facts (SPAH-RES-51-R)
- About Resflor webpage, http://www.resflorgold.com/about-resflor/default.aspx
Dear Mr. Whaley:
The U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM), Division of Surveillance reviewed your June 16, 2010, Drug Experience Report (DER) concerning Resflor Gold® (florfenicol and flunixin meglumine) injection for cattle, NADA 141-299. This submission includes Resflor Gold® Ad (RES 41A), a one-page promotional piece. In addition, we reviewed your June 21, 2010, DER submissions that include RESFLOR GOLD® Fast Facts (SPAH-RES-51-R), a one-page product detailing piece; RESFLOR GOLD® Sales Aid for Cow Calf (SPAH-RES-43A-R), RESFLOR GOLD® Sales Aid for Dairy (SPAH-RES-43C-R) and RESFLOR GOLD® Sales Aid for Feedyard (SPAH-RES-43D), three similar four-page detailing pieces.
We also reviewed promotional materials on the website for Resflor Gold® www.resflorgold.com. We note that the promotional materials mentioned above are identical to promotional materials currently available on this website.
As explained in more detail below, these materials are false or misleading because they make unsubstantiated effectiveness claims and minimize the risks associated with Resflor Gold®. These materials cause Resflor Gold® to be misbranded within the meaning of sections 502(a) and 502(n) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 352(a) and (n)].
Resflor Gold® is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis, and control of BRD-associated pyrexia in beef and non-lactating dairy cattle. The complete prescribing information for Resflor Gold® contains risk information including Residue Warning statements that specify, “Animals intended for human consumption must not be slaughtered within 38 days of treatment…Do not use in female dairy cattle 20 months of age or older…Do not use in calves to be processed for veal.”
Minimization of Risk Information/Omission of Human Food Safety Information
In the approved package insert for Resflor Gold®, the Residue Warning statement is presented with increased prominence by using bold arrows and offset formatting. These residue warnings are included to address human health concerns related to violative levels of drug residue in milk or meat from treated animals. See 21 CFR 201.105(d)(1). Pursuant to 21 CFR 202.1(e)(1), side effects or contraindications include “side effects, warnings, precautions and contraindications and include such information under such headings as cautions, special considerations, important notes, etc.” (emphasis added) The Residue Warning statement is included under the “Precautions” section of the product information for Resflor Gold® and is titled “Residue Warning.” Thus, this information meets the description of side effect or contraindication as set forth in 21 CFR 202.1(e)(1) and must be included in the true statement of information in brief summary.
CVM has reviewed SPAH-RES-41A, SPAH-RES-43A-R, SPAH-RES-43C-R, SPAH-RES-43D, SPAH-RES-51A and the “About Resflor” webpage. For SPAH-RES-43A-R, SPAH-RES-43C-R, SPAH-RES-43D and the “About Resflor” webpage, we note that there is no residue warning information or risk information presented until the last page of these pieces. This risk information follows 4 pages of benefit information. For SPAH-RES-41A we note the risk information is found at the bottom of the one-page piece in very small font.
We note that risk and residue warning information statements included in these materials do not include the drug withdrawal time information, as stated in the Residue Warnings. In addition, these statements are found only at the bottom of the page (for single-page pieces) or on the last page (for multi-page pieces) and are printed in small font.
In summary, these materials are misleading because they omit pertinent information relating to side effects and contraindications. See 21 CFR 202.1(e)(1).
Unsubstantiated Effectiveness Claims
All of the above-mentioned materials contain the statement: “A fever-reducing, bacteria-killing1, fast-acting2, one-dose treatment for bovine respiratory disease (BRD).”
The Sales Aids SPAH-RES-43A-R, SPAH-RES-43C-R, and SPAH-RES-43D state that Resflor Gold® provides: “… long-lasting BRD therapy”.
The webpage, “About Resflor”, http://www.resflorgold.com/about-resflor/default.aspx, contains the following:
The Future of BRD Therapy in a Single SQ Dose
- Fast acting
- Long acting
- Kills bacteria
As stated in the Freedom of Information (FOI) Summary for Resflor Gold®, the demonstrated treatment success for this product was 68.4% improvement in the treated group compared to 42% improvement in the untreated (saline control) group. Although Resflor Gold® was shown to be effective for treatment of BRD, it was not effective in all cases and should not be expected to successfully treat all cases of BRD. In addition, 42% of the untreated animals (saline control) in the approval studies improved without any treatment. Broad effectiveness claims for Resflor Gold® such as those seen in these promotional materials, without qualification or clarification regarding the limitations of these claims, creates a false or misleading impression of greater effectiveness than has actually been demonstrated by substantial evidence or clinical experience.
The materials claim that the product is “bacteria killing” or “kills bacteria.”
This statement is accompanied by a disclaimer, in fine print, indicating that Resflor Gold® exhibits bactericidal activity against some strains of Mannheimia haemolytica and Histophilus somni. The product information for Resflor Gold® contains a Microbiology section which makes clear that florfenicol exhibits bactericidal activity against strains of M. haemolytica and H. somni in in vitro studies. The disclaimer is misleading because it fails to explain that this information is based on in vitro studies and that the clinical significance of these data is unknown. See 21 CFR 202.1(e)(6)(vii). In addition, we note that the disclaimer is presented in small font and at the end of each promotional piece which, for SPAH-RES-43A-R, SPAH-RES-43C-R and SPAH-RES-43D, is several pages after the claim “bacteria-killing” is first stated.
The materials claim that the product is “fast-acting.” This claim suggests that Resflor Gold® works quickly, or begins to work quickly against BRD in a clinical setting.
Substantiation for this claim is based on achievement of maximal mean plasma (Tmax) concentrations within 30 minutes of administration. The materials conclude that “The result is a fast and powerful bacteria-killing response from florfenicol treatment.” However, a correlation between speed of absorption of florfenicol and clinical effectiveness has not been demonstrated. This statement is accompanied by a disclaimer, in fine print, stating that: “The correlation between in vitro susceptibility data and clinical effectiveness is unknown.” The use of the word “susceptibility” in this footnote appears to pertain to the susceptibility of bacteria to the bactericidal activity of florfenicol rather than the speed of action or absorption. Therefore, this disclaimer is not relevant to the claim of “fast-acting”.
In addition, the study data describing rapid reduction in fever over the 48 hour period post treatment does not support the claim of “fast-acting BRD treatment” found in these materials. Reduction in the body temperature of febrile calves within hours following administration of Resflor Gold® is due to the anti-pyretic effect of the flunixin component of Resflor Gold®. However, while reduction of fever within this time period is related to the treatment of a general clinical sign (in this case, fever), it is not equivalent to successful treatment of BRD. In field studies conducted to demonstrate effectiveness to support the approval of Resflor Gold®, successful treatment of BRD was defined as a calf with normal respiration to mild respiratory distress, normal attitude to mildly depressed, and a rectal temperature < 104.0° F on Day 11.
The claim of “fast-acting” is therefore misleading because it contains a representation or suggestion, not approved or permitted for use in the labeling, that Resflor Gold® is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. See 21 CFR 202.1(e)(6)(i).
3. “Long-acting” and “Long-lasting”
The Sales Aids SPAH-RES-43A-R, SPAH-RES-43C-R, and SPAH-RES-43D and the “About Resflor” website claim that the product is “long-acting” or “long-lasting.”
The claims “long-acting” and “long-lasting” appear to be based on pharmacokinetic data. However, their appearance in promotional materials gives the impression that these claims have clinical relevance related to treatment of bovine respiratory disease. Clinical studies have not been submitted to support the clinical relevance of these claims. In addition, claims related to duration of effect are meaningful only in the context of comparison to another treatment. Thus, these claims suggest that Resflor Gold® is superior to other products approved for the treatment of BRD. This claim has not been demonstrated.
Thus, the claim of “long-lasting” or “long-acting” is misleading because it contains a representation or suggestion, not approved or permitted for use in the labeling, that Resflor Gold® is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. See 21 CFR 202.1(e)(6)(i).
4. Incorrect footnotes
We note that for Resflor Gold® Ad – RES 41A, the footnotes (1&2) are presented in reverse order.
Conclusion and Requested Action
The misleading statements in your materials and website cause Resflor Gold® to be misbranded within the meaning of sections 502(a) and 502(n) of the FD&C Act [21 U.S.C. 352(a) and (n)].
CVM requests that Merck Animal Health, Inc. immediately cease the dissemination of the Resflor Gold® promotional items described above, and any other materials that may contain similar unsubstantiated claims.
Please submit a written response within thirty calendar days of receipt of this letter describing whether you intend to comply with this request. Please direct your response to Dr. Neal Bataller at the Food and Drug Administration, Center for Veterinary Medicine, Division of Surveillance, HFV-216, 7519 Standish Place, Rockville, Maryland 20855.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that the promotional materials for Resflor Gold®, as well as other Merck Animal Health products, comply with the requirements of the FD&C Act and applicable FDA regulations.
If you have any questions, please contact Dr. Dorothy McAdams at the address above, or by phone at (240) 453-6802.
Neal Bataller, ME, DVM
Director, Division of Surveillance
Office of Surveillance & Compliance
Center for Veterinary Medicine
Mr. Raul Kohan
Merck Animal Health
Wim de Körverstraat 35
5831 AN Boxmeer
0485 587 600