Inspections, Compliance, Enforcement, and Criminal Investigations
Ovation Pharmaceuticals, Inc. 02-Jun-05
Department of Health and Human Services
Public Health Service
Center for Biologics Evaluation and Research
June 2, 2005
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Dr. Timothy Cunniff
Ovation Pharmaceuticals, Inc.
Four Parkway North
Deerfield, IL 60415
Re: BLA STN #101246
PANHEMATIN® (hemin for injection)
Dear Dr. Cunniff
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's (FDA's) Center for Biologics Evaluation and Research (CBER) has reviewed the Dosing, Preparation, and Infusion Instructions brochure (Enclosure A) and a monograph (Enclosure B) for PANHEMATIN® (hemin for injection) submitted under cover of Form FDA 2253. These materials fail to reveal material facts regarding the risks associated with the use of PANHEMATIN, which is a product made from human blood. As a result, the materials violate section 502(a) of the Federal Food, Drug, and Cosmetic Act (the Act). 21 U.S.C. 352(a).Furthermore, the brochure was apparently disseminated without adequate directions for use, in violation of section 502(f) of the Act. 21 U.S.C. 352(f). By failing to include sufficient risk information and adequate directions for use, you encourage the potentially unsafe use of PANHEMATIN.
According to the FDA-approved professional labeling (PI), PANHEMATIN is an enzyme inhibitor derived from processed red blood cells. The PI states
"PANHEMATIN (hemin for injection) is indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women. . . PANHEMATIN is not indicated in porphyria cutanea tarda."
The PI also contains a black box warning which states:
"PANHEMATIN should only be used by physicians experienced in the management of porphyrias in hospitals where the recommended clinical and laboratory diagnostic and monitoring techniques are available. PANHEMATIN therapy should be considered after an appropriate period of alternate therapy . . ."
The PI includes additional detailed risk information including contraindications, warnings, precautions, and adverse reactions.
Failure to Reveal Material Facts
The brochure includes the indication for PANHEMATIN but does not provide any risk information. This omission of risk information results in your product being misbranded within the meaning of section 502(a) of the Act. 21 U.S.C. 352(a). Also see section 201(n) of the Act, 21 U.S.C. 321(n). In addition, it appears that the brochure was disseminated without a PI. The failure to disseminate the brochure with the PI would render your product misbranded within the meaning of section 502(f) of the Act. 21 U.S.C. 352(f). See 21 CFR 210.100(d)(1).
The monograph does not contain complete risk information. The monograph fails to adequately incorporate information contained in the PI's boxed warning. The monograph also contradicts, and therefore weakens, the PI's boxed warning that "PANHEMATIN therapy should be considered after an appropriate period of alternative therapy. . ." For example, the monograph, on p. 14, states that "[c]linical studies and expert opinion now lean toward beginning heme therapy right away, without a trial period of glucose." The monograph also states that "delaying treatment appears to compromise the effectiveness of heme therapy by increasing the likelihood that the attack will progress to irreversible neurologic damage." Monograph, p. 14. Furthermore, the monograph does not contain an adequate warning, as does the PI, concerning the fact that PANHEMATIN is made from human blood. This lack of adequate risk information renders your product misbranded within the meaning of section 502(a) of the Act. 21 U.S.C. 352(a). The fact that the PI accompanies the monograph is not sufficient to rectify this omission of important risk information. Cf. 21 CFR 202.1 (e)(3)(i).
In addition, the brochure and the monograph imply that PANHEMATIN is indicated for the treatment for all porphyrias when, according to the PI, PANHEMATIN is not indicated in porphyria cutanea tarda. The emphasis in the monograph on acute porphyrias and the distinction on p. 5 of the monograph between acute and cutaneous porphyrias does not make the monograph non-misleading. The failure to include adequate information on porphyria cutanea tarda in the brochure and the monograph results in your product being misbranded within the meaning of section 502(a) of the Act. 21 U.S.C. 352(a).
We are also concerned that the monograph fails to represent the established name in letters that are at least half as large as the letters comprising the proprietary name as required by 21 CFR 201.10(g)(2).
Conclusion and Requested Actions
Your brochure and monograph misbrand PANHEMATIN within the meaning of section 502(a) of the Act because they fail to reveal material facts regarding the risks associated with the use of this product and do not make clear that the product is not indicated for porphyria cutanea tarda. In addition, the brochure misbrands PANHEMATIN within the meaning of section 502(f) of the Act if it is disseminated without the PI. (21 U.S.C. 352(a), 352(f) ; see 321(n)).
OCBQ requests that Ovation Pharmaceuticals immediately cease the dissemination of violative promotional materials for PANHEMATIN such as those described above.
Please submit a written response 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 PANHEMATIN such as those described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request, further, that your submission include a plan of action to disseminate truthful, non-misleading, and complete information to the audience(s) that received the violative promotional material . 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-600, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number and to CBER-05-017. 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 PANHEMATIN comply with each applicable requirement of the Act and FDA's implementing regulations. Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research