February 5, 2007
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
5214 Maryland Way, Suite 405
Brentwood, TN 37027
Re: BLA STN #103788
CroFab [Crotalidae Polyvalent Immune Fab (Ovine)]
Dear Mr. Lewis:
This letter notifies Protherics, Inc. (Protherics) that the Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed the "Emergency Treatment of Rattlesnake Bite" Card (card) for CroFab [Crotalidae Polyvalent Immune Fab (Ovine)] (CroFab) submitted under cover of Form FDA 2253. The card is misleading because it fails to reveal certain material facts regarding the risks associated with CroFab, fails to adequately present the approved indication for CroFab, and was apparently disseminated without adequate directions for use. Therefore, the card misbrands CroFab in violation of the Federal Food, Drug, and Cosmetic Act (the Act). See 21 U.S.C. §§352(a) & (f); 321(n); cf. 21 C.F.R. 202.1(e)(3)(iii); 201.100(d)(1). By failing to include sufficient information on risks and the approved indication, you have encouraged the potentially unsafe use of CroFab.
According to the Indications and Usage section of the FDA-approved professional labeling (PI):
CroFab is indicated for the management of patients with minimal or moderate North American crotalid envenomation. Early use of CroFab (within 6 hours of snakebite) is advised to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities.
Specific examples of important risk information contained in the PI for CroFab include, but are not limited to, the following:
CroFab should not be administered to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available.
Coagulopathy is a complication noted in many victims of viper envenomation that arises due to the ability of the snake venom to interfere with the blood coagulation cascade. In clinical trials with CroFab, recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterized by decreased fibrinogen, decreased platelets, and elevated prothrombin time, occurred in approximately half of patients studied.
Recurrent coagulopathy may persist for 1 to 2 weeks or more. Patients who experience coagulopathy due to snakebite during hospitalization for initial treatment should be monitored for signs and symptoms of recurrent coagulopathy for up to 1 week or longer at the physician's discretion. During the period, the physician should carefully assess the need for re-treatment with CroFab and use of any type of anticoagulant or anti-platelet drug.
Papain is used to cleave the whole antibody into Fab and Fc fragments, and trace amounts of papain or inactivated papain residues may be present in CroFab. Patients with allergies to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also be at risk for an allergic reaction to CroFab. In addition, it has been noted in the literature that some dust mite allergens and some latex allergens share antigenic structures with papain and patients with these allergies may be allergic to papain.
Of the 25 patients who experienced adverse reactions, 3 patients experienced severe or serious adverse reactions. The 1 patient who experienced a serious adverse event had a recurrent coagulopathy due to envenomation, which required re-hospitalization and additional antivenin administration.
Failure to Reveal Material Facts
Promotional materials are misleading if they fail to reveal material facts in light of the representations made or with respect to consequences that may result from the use of the product as recommended or suggested by the materials. Cf. 21 C.F.R. 202.1(e)(3)(iii). The card promotes use of CroFab in the emergency treatment of rattlesnake bite. However, this promotional material fails to accurately convey certain important risk information from the Warnings and Adverse Reactions sections of the PI.
Although the card does contain some information concerning recurrent coagulopathy, the card fails to make clear, as stated in the Warnings section of the PI, that this condition occurred in approximately half of patients studied in clinical trials of CroFab. Furthermore, in the section of the card captioned "Adverse Reactions," the card states the following: "The majority of adverse reactions to CroFab were mild to moderate in severity..One patient experienced recurrent coagulopathy due to envenomation." This is itself misleading because, as the PI sets forth in its Adverse Reactions section, the recurrent coagulopathy of this patient was classified as a serious adverse event. Together these statements misleadingly suggest that recurrent coagulopathy may not occur with the frequency or severity noted in the PI.
Finally, it appears that the card was disseminated without a PI. The failure to disseminate the card with the PI would render CroFab misbranded within the meaning of section 502(f) of the Act. See 21 U.S.C. §352 (f); 21 C.F.R. 201.100(d)(1).
Failure to State the Indication
CroFab is approved for patients with minimal or moderate North American crotalid envenomation. The card presents information on rattlesnake bites and treatment with CroFab but fails to indicate that CroFab is not approved for severe North American crotalid envenomation. The omission of the actual approved indication misleadingly suggests that CroFab is indicated for all categories of envenomation (e.g., minimal, moderate, and severe) when this has not been demonstrated by substantial clinical evidence. The misleading nature of this omission is heightened by the following statement on the card: "Note: Significant (even lethal) envenomation may initially appear trivial." Without further explanation, this statement also suggests that CroFab is indicated for the treatment of severe envenomation.
Furthermore, we recommend that you include in your promotional materials the statement from the Indications and Usage section of the PI that "[e]arly use of CroFab (within 6 hours of snakebite) is advised to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities."
Conclusion and Requested Actions
For reasons discussed above, the card is misleading because it fails to reveal certain material facts regarding important risk information and fails to state the approved indication for CroFab. In addition, the card is misleading because it was apparently disseminated without adequate directions for use. Therefore, the card misbrands CroFab in violation of the Act. See 21 U.S.C. §§352(a) & (f); 321(n); cf. 21 C.F.R. 202.1(e)(3)(iii); 201.100(d).
OCBQ requests that Protherics immediately cease the dissemination of violative promotional materials for CroFab such as that described above. Please submit a written response to this letter within ten (10) business days of the date of this letter, stating whether you intend to comply with this request, listing all violative promotional materials for CroFab such as that described above, and explaining your plan for discontinuing use of such materials.
Please direct your response to me at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM-602, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number. We remind you that only written communications are considered official responses.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for CroFab comply with each applicable requirement of the Act and FDA implementing regulations.
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research