July 1, 2009
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Paul Hartmann, R.Ph.
Senior Director, Regulatory Affairs
CSL Behring LLC
1020 First Avenue
P.O. Box 61501
King of Prussia, PA 19406-0901
Re: Cytogam (Cytomegalovirus Immune Globulin Intravenous, Human)
BLA STN #103189
Dear Mr. Hartmann:
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 Slim Jim sales aid (ID# CTG-032R) for Cytogam (Cytomegalovirus Immune Globulin Intravenous, Human) that was submitted by CSL Behring LLC (CSL) under cover of Form FDA 2253.
This sales aid misbrands Cytogamunder section 502(a) of the Federal Food, Drug, and Cosmetic Act (Act) (21 U.S.C. §352(a)), because it contains misleading safety and efficacy claims (Cf. 21 CFR 202.1(e)(6)(i), (ii), and (v)).
The FDA-approved professional labeling (PI) for Cytogam states that it is indicated for the prophylaxis of cytomegalovirus (CMV) disease associated with transplantation of kidney, lung, liver, pancreas, and heart. In addition, the indication states that in transplantation of lung, liver, pancreas, and heart from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.
Ganciclovir is an antiviral drug that is indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease. The PI for ganciclovir has a boxed warning regarding its potential for causing blood dyscrasias (granulocytopenia, anemia and thrombocytopenia). Valganciclovir, the pro-drug to ganciclovir, has the same boxed warning in its PI and has a more limited indication in that it is not indicated for liver transplant patients and has not been studied in organ transplant patients other than those receiving kidney, heart, or pancreas. Valganciclovir is converted to ganciclovir by intestinal and hepatic esterases.
The Warnings section of the PI addresses the following serious risks associated with Cytogam:
“CMV-IGIV is made from human plasma and, like other plasma products, carries the possibility for transmission of blood-borne viral agents and, theoretically, the Creutzfeldt-Jakob (CJD) agent. The risk of transmission of recognized blood-borne viruses is considered to be low because of the viral inactivation and removal properties in the Cohn-Oncley cold ethanol precipitation procedure used for purification of immune globulin products. Until 1993, cold ethanol manufactured immune globulins licensed in the United States had not been documented to transmit any viral agent. However, during a brief period in late 1993 to early 1994, intravenous immune globulin made by one U.S. manufacturer was associated with transmission of Hepatitis C virus. To further guard against possible transmission of blood-borne viruses, including Hepatitis C, CMV-IGIV is treated with a solvent detergent viral inactivation procedure known to inactivate a wide spectrum of lipid enveloped viruses, including HIV-1, HIV-2, Hepatitis B, and Hepatitis C. However, because new blood-borne viruses may yet emerge, some of which may not be inactivated by the manufacturing process or by solvent detergent treatment, CMV-IGIV, like any other blood product should be given only if a benefit is expected.
Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentrations available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many IGIV products, those containing sucrose as a stabilizer (and given at daily doses of 350 mg/kg or greater) account for a disproportionate share of the total number. Cytogam contains sucrose as a stabilizer.”
In addition, the Precautions section of the PI addresses other potential risks for Cytogam, including hypersensitivity reactions, deterioration of renal function, aseptic meningitis syndrome, hemolysis, transfusion-related acute lung injury, and thrombotic events.
Misleading Safety Claim
“Cytogam … Providing an additional layer of protection without the toxicity – Transplant patients who received a combination of Cytogam and antiviral medication such as ganciclovir or valganciclovir…”
This claim is misleading because it suggests that there is no additional toxicity or other risks associated with the use of Cytogam plus an antiviral versus just the antiviral monotherapy (e.g., ganciclovir or valganciclovir) when used as directed. We are unaware of substantial evidence or substantial clinical experience that supports this claim. Furthermore, as mentioned in the extract from the PI above, the addition of Cytogam may expose the patient to toxicities and other risks associated with intravenous immune globulin therapy.
Misleading Claims that Broaden Indication
- “Heart-lung recipients: Fewer deaths from obliterative bronchiolitis”
- “Defining High-Risk
- Commonly described as D+R- (a seronegative recipient of organ(s) from a seropositive donor)
- Given the arduous procedure involved, all heart-lung transplant patients are considered high-risk
- Heightened immunosupression may place all transplant patients in the high-risk category
No matter how you define high-risk consider Cytogam”
- “Cytogam offers extra protection and proven safety to high-risk kidney transplant recipients”
- “Treatment-resistant CMV presents an extra challenge”
The above-captioned claims are misleading because they broaden the indication for Cytogam by suggesting that: (1) Cytogam has an effect on outcomes not well-defined as having an association with CMV infection (e.g., obliterative bronchiolitis) and that (2) Cytogam is efficacious for treatment-resistant (ganciclovir-resistant) CMV disease. We are unaware of substantial evidence or substantial clinical experience that supports these claims. Moreover, Cytogam’s indication is limited to the prophylaxis of CMV disease associated with transplantation of kidney, lung, liver, pancreas, and heart. In addition, the indication states that in transplantation of lung, liver, pancreas, and heart from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.
Misleading Efficacy Claims
- “Demonstrated survival benefit”
- “Heart recipients: Significantly greater 3-year survival and 3-year freedom from rejection”
- “Significantly longer survival (79% survival at 3 years vs. 55% of those treated with ganciclovir alone”
- “Hopes for a Long-Term Liver – Cytogam was associated with increased 1-year and long-term survival of liver transplant recipients”
Recognizing that the PI discusses limited survival data for Cytogam, we believe that the above-cited claims are misleading because the statements imply greater (or longer) survival benefit for patients than is suggested by the PI or by substantial evidence or substantial clinical experience.
Specifically, there is a lack of substantial evidence or substantial clinical experience for survival claims beyond one year in liver transplant patients given Cytogam, a cytomegalovirus immune globulin (CMVIG) and beyond three months in heart, heart-lung, and lung transplant patients receiving CMVIG plus ganciclovir compared with those patients receiving ganciclovir alone. Moreover, there are no data demonstrating survival benefits for kidney or pancreas transplant patients given Cytogam.
The Clinical Studies section of the PI for Cytogam refers to Falagas et al.(1997), a study that demonstrated increased one-year survival (median follow-up 5-6 years) in liver transplant patients given CMVIG. Although the data in this study showed that there was a trend toward long term survival, the data for survival were not statistically significant beyond one year.
In addition, the Clinical Studies section of the PI for Cytogam refers to a study by Valantine et al. (2001) that found increased survival for a three-month period in heart, heart-lung, and lung transplant patients receiving CMVIG plus ganciclovir compared to patients receiving ganciclovir alone. The investigators of this study detailed its limitations in the publication of their results. In summary, the study was a preliminary cohort study using historical (actuarial) controls and multiple unadjusted endpoints. The investigators recognized these data as preliminary and deserving of a “follow-up prospective, randomized, double-blind study to determine the efficacy of CMVIG plus ganciclovir for preventing the acute and long term-sequelae after heart and lung transplantation.”
Other misleading claims in the promotional material that reference the preliminary findings from Valantine et al. (2001) include
- “Reduced coronary intimal thickening (overall and >0.3 mm; P=0.01)”
- “Significantly higher rejection-free rates 3 years post-transplant (P<0.05)”
- “Significantly higher rejection-free rates and CMV disease-free status over 3 years post-transplant”
- “Outcome of heart-lung and lung transplant patients at 3 years after transplant”
Conclusion and Recommendations
For the reasons discussed above, your Slim Jim sales aid misbrands Cytogam within the meaning of section 502(a) of the Act (21 U.S.C. §352(a); Cf. 21 CFR 202.1(e)(6)(i), (ii) and (v), because it makes misleading efficacy and safety claims.
We request that CSL immediately cease the dissemination of this violative promotional material for Cytogam, as well as promotional materials with the same or similar claims and representations. 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 Cytogam, and explaining your plan for discontinuing use of such materials. Please direct your response to Ms. Ele Ibarra-Pratt, RN, MPH, Branch Chief at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, Division of Case Management, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 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 Cytogam comply with each applicable requirement of the Act and FDA implementing regulations.
If you choose to revise your promotional materials, APLB is willing to assist you in assuring that your revised materials comply with applicable provisions of the Act by reviewing your revisions before you use them in promotion.
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research