July 6, 2009
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Mary Ann Lamb, Ph.D.
Vice President, Regulatory Affairs
Talecris Biotherapeutics, Inc.
8368 US Highway70W
Clayton, NC 27520
Re: GAMUNEX [Immune Globulin Intravenous (Human), 10%
BLA STN #125046
Dear Ms. Lamb:
Through routine monitoring and surveillance, the Advertising and Promotional Labeling Branch (APLB) of the Food and Drug Administration’s Center for Biologics Evaluation and Research has reviewed an exhibit panel (ID# GX39-0209) for Gamunex [Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified] submitted by Talecris Biotherapeutics, Inc. (Talecris) under cover of Form FDA 2253. The exhibit panel misbrands Gamunex under section 502(a) of the Federal Food, Drug, and Cosmetic Act (Act) (21 U.S.C. §352(a)), because it minimizes risk information and contains misleading safety claims (Cf. 21 CFR 202.1(e)(6)(i), (iv) and (v)).
Gamunex is a sterile solution of human immune globulin protein, indicated for replacement therapy in primary humoral immunodeficiency (PI), for idiopathic thrombocytopenic purpura (ITP), and for treatment and maintenance therapy in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The FDA-approved professional labeling (FPI) for Gamunex has a Boxed Warning regarding its potential to cause acute renal dysfunction and acute renal failure:
“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 concentration available and at the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Gamunex does not contain sucrose, Glycine, a natural amino acid, is used as a stabilizer.”
This risk information is re-iterated in the Warnings and Precautions section of the FPI along with risk information regarding the potential of Gamunex to cause aseptic meningitis and thrombotic events (underlying thrombotic strokes, myocardial infarction (MI), and pulmonary embolism). Cases of aseptic meningitis and thrombotic events have occurred with Gamunex, both in clinical trials and post-marketing (see Adverse Reactions section of the FPI).
Minimization of Risk Information
The exhibit panel prominently highlights Gamunex “results” from the ICE study as
“In the largest-ever IGIV clinical trial program with >600 patients (>4100 infusions) across all indications, results for Gamunex patients demonstrated
ZEROZERO reports of aseptic meningitis
ZEROZERO reports of renal failure
ZEROZERO reports of stroke and MI”
This overall presentation of “ZEROZERO reports” minimizes the serious risks associated with Gamunex and is inconsistent with the FPI for Gamunex. In particular, this presentation minimizes the boxed warning for Gamunex, which highlights its potential to cause renal failure. In addition, the presentation minimizes the aseptic meningitis and the thrombotic events warnings for Gamunex. Finally, the ICE study represents only one study in a program of studies with Gamunex for various indications, which are presented in the FPI for Gamunex. Thus, it is misleading to suggest that the ICE study alone represents the overall safety profile for Gamunex, when such is not the case.
Furthermore, as stated in the FPI for Gamunex, “because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.” In practice, there have been post-marketing reports for aseptic meningitis and thrombotic events. Because post-marketing reporting of adverse reactions is voluntary, it is not possible to reliably estimate the frequency of these reactions; however, these particular reactions are listed in the Warnings and Precautions section of the FPI for Gamunex.
We note that this overall misleading presentation is accompanied by a small footnote stating “Aseptic meningitis has been identified and reported during postmarketing use of Gamunex. Because postmarketing reporting of adverse reaction is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.” This additional information is not sufficient to mitigate the overall misleading impression that the claims of “zero reports” for these serious adverse reactions creates.
Misleading Safety Claims
The safety claims presented on the exhibit panel under the subheading “Proven tolerability across all indications” are misleading because they are inconsistent with the risk information described in the FPI for Gamunex. For example,
- “96% of Gamunex infusions in CIDP patients and >99% in PI patients were free of drug-related headache”
The claim that “96% of Gamunex infusions in CIDP patients were free of drug-related headache” misleadingly implies that only 4% of CIDP patients suffered from headache. The FPI states that 32% of patients receiving Gamunex for CIDP reported headache (compared with 8% of patients receiving placebo). Headache was considered the most common drug-related adverse reaction in the ICE study. Furthermore, counting infusions, rather than patients, does not account for the number of patients that actually had the adverse reaction. Also, this claim is misleading when accounting for the total number of adverse reaction events per infusion (called the “incidence density”). Specifically, the incidence density of headache in patients receiving Gamunex for CIDP was twice that of patients who received placebo (0.052 vs. 0.026).
Similarly, the claim that “>99% in PI patients were free of drug-related headache” is misleading. In the PI studies (comparing Gamunex with Gamimune N), the FPI states that 25% of PI patients reported headache with Gamunex. No incidence density is shown for headaches in the PI patients. However, as discussed in the preceding paragraph, the incidence density is not relevant to the number of patients who reported a headache experience with Gamunex.
- “In CIDP, the incidence of serious adverse events per infusion was 0.8% with Gamunex vs 1.9% with placebo”
The claim that the “Incidence of serious adverse events per infusion was 0.8% with Gamunex vs 1.9% with placebo” is misleading because it minimizes the overall serious adverse events associated with Gamunex and is not supported by substantial evidence or substantial clinical experience. Specifically, the safety claim is based on one small study, and the study was not designed to examine safety. By emphasizing the small incidence rate of serious adverse events per infusion, the claim minimizes the fact that there are serious adverse reactions associated with Gamunex (See the Warnings and Precautions section and the Adverse Reactions section of the FPI), including the case of pulmonary embolism reported in a CIDP clinical study subject described in the FPI.
- “In an ITP study, 98% of patients receiving Gamunex required no rate reduction due to adverse events”
This claim is misleading because it selectively presents favorable data from one population and ignores the overall existing evidence comprised of other Gamunex studies with the same or similar infusion rates that had patients who required infusion rate reductions due to adverse reactions. Additionally, the ITP studies alone represent a small population of patients treated with Gamunex (n=28 and n=48), and highlighting 98% of patients in one of these studies (n=1/48) underestimates the number of patients that would require infusion rate reductions overall.
- “Demonstrated tolerability with Gamunex even at high dosages and fast infusion rates”
The claim that Gamunex has demonstrated tolerability “even at high dosages and fast infusion rates” misleadingly implies that doses for Gamunex routinely may be higher and infusion rates routinely may be faster than recommended or in comparison with other intravenous immune globulins. However, the tolerability of Gamunex doses is based on the recommended dosing as described in the FPI and infusion rates are similar to other marketed sucrose-free intravenous immune globulins. In addition, the maximum infusion rate tolerated by an individual is variable. The Dosage and Administration section of the FPI for Gamunex states that Gamunex
“should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg/min) for the first 30 minutes. If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg/min). Certain severe drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.”
Infusing Gamunex above the recommended dose and beyond the maximum infusion rate of 8 mg/kg/min has the potential to cause serious adverse reactions. By stressing “high dosages” and “fast infusion rates,” this presentation misleadingly implies that gradual, watchful, and individualized attention to infusion with Gamunex is not necessary for safety and tolerability. The very tiny footnote with the maximum infusion rate is not adequate to counter this misimpression.
Conclusion and Recommendations
For the reasons discussed above, your exhibit panel misbrands Gamunex under section 502(a) of the Federal Food, Drug, and Cosmetic Act (Act) (21 U.S.C. §352(a)), because it contains misleading safety claims (Cf. 21 CFR 202.1(e)(6)(i), (iv) and (v)).
We request that Talecris immediately cease the dissemination of this violative promotional material for Gamunex, 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 Gamunex 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 Gamunex 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.
--- signature ---
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
 Hughes, RAC et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE Study): a randomised placebo-controlled trial. Lancet Neurol 7: 136-144, 2008.