Rituxin FDA Warning Letter to Genentech Over Claims about the Effectiveness of Rituxin

Did anyone see this Warning letter on the FDA website that was addressed to Genentech the makers of Rituxin? I am absolutely sick about this.


ROCKVILLE, Md., May 5, 2010 - The FDA today posted on its website a warning letter sent to Genentech regarding table top panels for cancer drug Rituxan. The letter is below.





TRANSMITTED BY FACSIMILE

April 29, 2010
Michelle H. Rohrer, Ph.D.

Vice President, Regulatory Affairs

Genentech, Inc.

1 DNA Way, MS#241B

South San Francisco, CA 94080-4990


RE: BLA # 103705

Rituxan® (Rituximab) Injection for Intravenous Use

MACMIS # 18129

Dear Dr. Rohrer:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed professional table top panels (8271803) for Rituxan® (Rituximab) submitted by Genentech, Inc. (Genentech) under cover of Form FDA 2253. The table top panels are false or misleading because they make unsubstantiated efficacy claims for the drug and omit and minimize important risk information for Rituxan. Therefore, the table top panels misbrand Rituxan in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (x); (e)(7)(viii).

Background

According to the Indications and Usage section of the FDA-approved product labeling (PI)1 for Rituxan (in pertinent part):

Rituxan® (rituximab) is indicated for the treatment of patients with . . . [p]reviously untreated follicular, CD20-positive, B-cell NHL [Non-Hodgkin’s Lymphoma] in combination with CVP chemotherapy . . . [and] [p]reviously untreated diffuse large B-cell, CD20-positive NHL [DLBCL] in combination with CHOP or other anthracycline-based chemotherapy regimens

The PI for Rituxan includes a Boxed Warning for fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML). Additionally, the PI for Rituxan includes several Warnings and Precautions, including Hepatitis B Virus (HBV) Reactivation, Infections, Cardiovascular events, Renal toxicity, and Bowel Obstruction and Perforation.

1 The PI submitted with the table top panels and referred to in this letter is dated September 2008. The most recent PI is dated February 2010. Although not relevant to the issues discussed in this letter, we note that the current PI contains major changes to the Indications and Usage – Limitations of Use section for Infections and the Warnings and Precautions sections for Infections, Renal, and Laboratory Monitoring. Michelle H. Rohrer, Ph.D. Page 2 Genentech, Inc. BLA# 103705/MACMIS# 18129

2 Marcus R, Imrie K, Catalano J, et al. Rituximab plus CVP improves survival in previously untreated patients with advanced follicular non-Hodgkin’s lymphoma. Paper presented at American Society of Hematology 48th Annual Meeting and Exposition; December 9-12, 2006; Orlando, FL. Abstract 481.

3 Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005; 105:1417-1423.

4 Data on File, Genentech, Inc.

Unsubstantiated Efficacy Claims

The table top panels are misleading because they suggest that Rituxan is more effective than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the table top panels include the following claims and presentations for the follicular NHL indication:

“R-CVP more than doubled median PFS at 4.4 years of follow-up”2

“The R-CVP benefit was consistent across patient subgroups, including bulky disease and poor prognosis FLIPI score”3

Bar graph titled, “RITUXAN+CVP as first-line treatment improves median PFS”2 that includes claims “In first-line follicular NHL” – “2.83 years R-CVP vs 1.25 years CVP” – “At 4.4 year follow-up” – “127% improvement in median PFS” – “Marcus (M39021) trial”

Kaplan-Meier curve titled, “Marcus progression-free survival (N=322)”2,4 with cited p-value “p<0.0001”

These claims misleadingly overstate the efficacy of Rituxan in improving progression-free survival (PFS) and providing benefits across all patient subgroups for Rituxan for the follicular NHL indication. We note that the claims of improved results at 4.4 years of follow-up are based on results found within an abstract2 of a study by Marcus et al., that the table top panels cite the Marcus et al. article3 to support the subgroup analysis claim, “The R-CVP benefit was consistent across patient subgroups, including bulky disease and poor prognosis FLIPI score,” and that the table top panels cite the abstract and data on file4 to support the Kaplan-Meier progression-free survival curve. However, these references do not constitute substantial evidence or substantial clinical experience to support these claims and presentations. We note that the Marcus et al. study3 had a median follow-up of 30 months; the study’s original statistical analysis plan did not provide for statistically valid analyses at 4.4 years of follow-up. The reliability of these analyses cannot be substantiated; for example, FDA cannot confirm if there was differential follow-up for PFS following the analysis of the primary endpoint. Additionally, the abstract does not describe whether the PFS findings were based on an independent blinded review. As for the subgroup analyses claim, because the subgroup analyses are exploratory, the accuracy and consistency of PFS results in all subgroups described in the Marcus article cannot be confirmed. Furthermore, the updated p-value in the Kaplan-Meier curve cannot be interpreted based on the Marcus study’s original statistical analysis plan. If you have substantial evidence to support these claims, please submit them to FDA for review. Michelle H. Rohrer, Ph.D. Page 3 Genentech, Inc. BLA# 103705/MACMIS# 18129

5 Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol; 2007; 25; suppl 18S. Abstract 8009 (June 20 Supplement).

6 Coiffier B, LePage E, Briere J, et al. CHOP chemotherapy plus Rituximab compared with CHOP alone in Elderly patients with diffuse large B-Cell lymphoma. N Engl J Med. 2002;346:235-42.

Additionally, the table top panels include the following claims and presentations for the DLBCL indication:

“R-CHOP improved 7-year OS by 47% vs CHOP alone (p=0.0004)”5

Bar graph titled, “RITUXAN+CHOP as first-line treatment increases OS in DLBCL”5– “In first-line DLBCL” – “53% R-CHOP vs 36% CHOP” – “At 7 years” – “47% increase in OS” – “GELA LNH 98-5 trial”

Kaplan-Meier curve titled, “GELA overall survival (N=399)”5,6 with cited p-value “p=0.0004” and an x-axis extending out to 8 years

These claims misleadingly overstate the efficacy of Rituxan for the DLBCL indication by suggesting that patients can expect an increase in overall survival beyond the 2-year and 5-year overall survival data presented in the PI. We note that the claims of improved overall survival at 7 years are based on results found within an abstract5 of a study by Coiffier et al, and that the table top panel cites the abstract and the Coiffier et al. article6 to support the “GELA overall survival” Kaplan-Meier curve. However, the abstract and the Coiffier article do not constitute substantial evidence or substantial clinical experience to support claims of improved overall survival at 7 years or the “GELA overall survival” Kaplan-Meier curve. The original statistical analysis plan for this study did not provide for statistically valid analyses at 7 years of follow-up. The reliability of these analyses cannot be substantiated. For example, the abstract does not describe whether the overall survival findings were based on an independent blinded review. Furthermore, the follow-up statistical analyses used in the Coiffier abstract and article do not support these overall survival results. Additionally, the abstract does not describe the p-value and the p-value cannot be interpreted based on the Coiffier study’s original statistical analysis plan. If you have substantial evidence to support these claims, please submit them to FDA for review.

Omission and Minimization of Risk Information

The table top panels are misleading because they omit or minimize important risk information, including information relating to fatalities associated with the use of Rituxan.

The table top panels state, “RITUXAN has also been associated with fatal hepatitis B reactivation with fulminant hepatitis, other serious viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation,” but the panels omit material facts regarding fatalities associated with the use of Rituxan related to some of these risks. For example, according to the Warnings and Precautions sections of the PI (in pertinent part, emphasis added):

Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies.

Abdominal pain, bowel obstruction and perforation, in some cases leading to death, Michelle H. Rohrer, Ph.D. Page 4 Genentech, Inc. BLA# 103705/MACMIS# 18129

can occur in patients receiving Rituxan in combination with chemotherapy.

Furthermore, the table top panels fail to present risk information with a prominence and readability reasonably comparable to the presentation of efficacy information, taking into account all implementing factors such as typography, layout, contrast, headlines, paragraphing, white space, and any other techniques apt to achieve emphasis. Specifically, the table top panels prominently present efficacy claims in bulleted format, with colorful, bolded words, colorful charts, plenty of white space, and large font. However, the risk information that is presented on the first two panels is relegated to the bottom of those panels and is presented in single-spaced block paragraph format in small, black font. Additionally, while these first two table top panels contain a disclosure of adverse reaction information, they fail to present the most significant risk information associated with Rituxan - the Boxed Warning. This is not presented until the third panel.

The overall effect of these misleading presentations undermines the communication of important risk information, thereby misleadingly suggesting that Rituxan is safer than has been demonstrated.

Conclusion and Requested Action

For the reasons discussed above, your professional table top panels misbrand Rituxan in violation of the Act, 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (x); (e)(7)(viii).

DDMAC requests that Genentech immediately cease the dissemination of violative promotional materials for Rituxan such as those described above. Please submit a written response to this letter on or before May 13, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Rituxan that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS# 18129 in addition to the BLA number. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Rituxan comply with each applicable requirement of the Act and FDA’s implementing regulations.

Sincerely,

/S/

Carole C. Broadnax, R.Ph., Pharm.D.

Regulatory Review Officer

Division of Drug Marketing,

Advertising, and Communications