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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Octapharma USA, Inc. 31-Aug-05

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

Center for Biologics Evaluation and Research
1401 Rockville Pike
Rockville MD 20852-1448

August 31, 2005

CBER-05-029

VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED

WARNING LETTER

OCTAPHARMA Phatmazeutika Produktionsges, m.b.H.
Flemming Nielsen, U.S. Agent
Octapharma USA, Inc.
5885 Trinity Parkway
Suite 350
Centreville, VA 20120

Re: BLA STN #125062
OCTAGAM® 5% [Immune Globulin Intravenous (Human)]

Dear Mr. Nielsen:

The Office of Compliance and Biologics Quality (OCBQ in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed a file card and dosage guide for OCTAGAM® 5% [Immune Globulin Intravenous (Human)] that were disseminated at the Octapharma booth at the American Academy of Allergy, Asthma and Immunology meeting in San Antonio, Texas on March 18-22, 2005. We have also reviewed the www.octapharma.com website. The file card, dosage guide and website are misleading because they fail to reveal material facts regarding the risks associated with Octagam and, therefore, misbrand Octagam in violation of sections 502(a) and 502(n) of the Federal Food, Drug, and Cosmetic Act (the Act). 21 U.S.C. 352(a), 352(n). In addition, your filc card and website contain unsubstantiated safety, effectiveness, and/or superiority claims in violation of section 502(a) of the Act. 21 U.S.C. 352(a). Lastly, Octaphanna has also failed to submit promotional materials to CBER at the time of initial dissemination, in violation of 21 CFR 601.12(f)(4).

Background

According to the FDA-approved professional labeling (PI), Octagam is a solvent/detergent treated, sterile, 5% liquid preparation of highly purified, immunoglobulin G (IgG) derived from large pools of human plasma. The PI states:

"Octagam is indicated for treatment of primary immune deficient diseases, such as congenital agammaglobulinemia and hypogamma globulinemia common variable immunodeficiency, Wiskott-Aldrich syndrome and severe combined immunodeficiencies ."

"The usual dose of Octagam for replacement therapy in primary irnmunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks."

The PI also includes detailed risk information including contraindications, black box warnings, precautions, and adverse reactions. Octagain is manufactured by OCTAPHARMA Pharrnazeutika Produktionsges m.b.H., Vienna, Austria and distributed by Octapharma USA, Inc ., Herndon, Virginia.

Failure to Reveal Material Facts

The file card and dosage guide fail to provide any risk information and your website fails to provide adequate risk information. This omission of risk information results in your product being misbranded within the meaning of section 502(a) and 502(n) of the Act. 21 U.S.C. 352(a), 352(n). See also section 201(n) of the Act. 21 U.S.C. 321(n). For example, the PI for Octagam includes a black box warning regarding reports of renal dysfunction, acute renal failure, osmotic nephrosis, and death associated with the use of Immune Globulin Intravenous (Human) (IGIV) products and includes a warning regarding products made from human plasma. We note that you do include the statement, "Low adverse events. . .," in the file card, but you provide no additional information on what specific adverse events were observed. We also note that your website mentions adverse drug reactions, but you provide no additional information on contraindications, black box warnings, and other warnings.

In addition, it appears that the file card was disseminated without a PI. The failure to disseminate the file card 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 201.100(d).

Please note that because the Octagam PI contains a black box warning and you included dosage recommendations, your dosage guide does not qualify as reminder labeling. 21 CFR 201.100(f).

Unsubstantiated Safety Claims

The file card contains the text, "Unsurpassed viral safety." We are concerned that this claim could be interpreted to mean that no other immunoglobulin therapy offers better viral safety than Octagam. FDA is unaware of data consisting of substantial evidence or substantial clinical experience supporting this claim. To the extent that you may have such information, we invite you to submit it. In the absence of sufficient substantiation, the claim would be false or misleading, and the file card would misbrand Octagam (21 U.S.C. 352(a); Cf. 21 CFR 202.1(e)(6)(i)).

Furthermore, your website states, "Over the past ten years, data from more than 6,100 patients and 90,000 treatment episodes has been gathered." Immediately following the paragraph containing this statement, you state, "No viral transmissions have ever been observed. This proves the excellent safety record of Octagam." This statement is misleading. In fact, these data represent a post-marketing study in Europe where questionnaires were sent out and responses were voluntary. Such data do not constitute substantial evidence in support of claims because the monitoring of safety and effectiveness outcomes is not uniform across centers or within centers, the data are subject to observation and reporting bias, and they cannot be verified by independent study monitors. In addition, such statements implicitly overstate the clinical experience which supported Octagam approval in the U.S. and result in a misleading message. In the absence of sufficient substantiation, this statement would misbrand Octagam. (21 U.S.C. 352(a), 352(n); see 21 CFR 202.1(e)(6)(i)).

Unsubstantiated Effectiveness Claims

Your website contains the text, "For patients who undergo bone marrow transplant (BMT), infection with cytomegalovirus (CMV) is one of the major causes of mortality and morbidity. Octagam contains very high titers of CMV antibodies," . . . "In a functionality test performed in an independent laboratory, Octagam demonstrated to be as effective as hyper-CMV immunoglobulin in its ability to neutralize CMV." These statements are misleading because Octagam was not approved in the U.S . for BMT patients with CMV and these statements contain favorable conclusions from nonclinical studies of a drug when in fact no such clinical significance has been demonstrated. Cf. 21 CFR 202.1(e)(6)(vii). FDA is unaware of data consisting of substantial evidence or substantial clinical experience supporting this claim. To the extent that you may have such information, we invite you to submit it. In the absence of sufficient substantiation, this claim is false or misleading, and the website would misbrand Octagam (21 U.S.C. §352(a), 352(n) ; Cf. 21 CFR 202.1(e)(6)(i)).

Unsubstantiated Superiority Claims

The file card contains the text, "Unequalled tolerability." This claim suggests that other immunoglobulins are not as well tolerated and implies that Octagam is superior with regards to tolerability. FDA is unaware of data consisting of substantial evidence or substantial clinical experience to support this superiority claim. Your approved PI states, "In general, reported adverse reactions to Octagam in patients with either congenital or acquired immunodeficiencies are similar in kind and frequency to other IGIV products." In the absence of sufficient substantiation, the claim, "Unequalled tolerability," is false or misleading, and the file card would misbrand Octagam. 21 U.S.C. §352(a); Cf. 21 CFR 202.1(e)(6)(i).

False or Misleading Statements

The website contains false or misleading information regarding the correct storage information for the safe and effective use of this product as approved in the U.S. You claim that Octagam can be stored at room temperature for 24 months; however, FDA is unaware of data supporting this statement, and the approved storage information found in your PI states, "Octagam may be stored for 24 months at +2°C to +g°C (36°F to 46°F) or may be stored at temperatures not to exceed +25°C (77°F) for up to 18 months from the date of manufacture ." Your claim, therefore, results in your product being misbranded within the meaning of section 502(a) and 502(n) of the Act. 21 U.S.C. 352(a), 352(n). Please note that during your initial marketing launch of Octagam, we reminded you, on June 25, 2004, to change your storage information claims to match the approved storage information found in your PI.

Failure to Submit Post-Marketing Reports at the Time of Dissemination

Octapharma USA has failed to submit its promotional material to FDA at the time of initial dissemination of such material, in violation of 21 CFR 601.12(f)(4) . The referenced materials were disseminated at the Octapharma booth at the American Academy of Allergy, Asthma and Immunology meeting in San Antonio, Texas earlier this year and we have no record of these materials being submitted to the FDA. You should immediately revise your procedures to ensure submission of all advertising and promotional material to FDA at the time of initial dissemination.

Conclusion and Requested Actions

Your file card, dosage guide, and website misbrand Octagam within the meaning of section 502(a) and 502(n) of the Act because they fail to reveal material facts regarding the risks associated with the use of this product and are, therefore, misleading. 21 U.S.C. 352(a), 352(n). They also misbrand Octagam within the meaning of section 502(a) and 502(n) of the Act (21 U.S.C. 352(a)) and 352(n)) because they represent that Octagam is safer and more effective than has been demonstrated by substantial evidence or substantial clinical experience and is superior to other drugs when this has not been proven. In addition, the failure to disseminate the file card 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 201 .100(d). Lastly, you have also failed to submit promotional material to FDA at the time of the initial dissemination, in violation of 21 CFR 601.12(f)(4).

OCBQ requests that Octaphanna USA immediately cease the dissemination of violative Promotional material for Octagam such as those 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 Octagam 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-05-029. 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 Octagam comply with each applicable requirement of the Act and FDA implementing regulations. Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,
/s/

G. B. Conley for Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research