FDA Sends Warning Letter to Three Rivers Pharmaceuticals Over Infergen STATgram

SILVER SPRING, Md., May 3, 2011 - The FDA posted on its website a warning letter sent to Kadmon Pharmaceuticals regarding a  STATgram for hepatitis C treatment Infergen. The letter is below.

TRANSMITTED BY FACSIMILE
March 21, 2011

Three Rivers Pharmaceuticals, LLC
Attention: Samuel D. Waksal, Ph.D.
Chairman and Chief Executive Officer
Kadmon Pharmaceuticals
Alexandria Center for Life Sciences
450 East 29th Street, 5th Floor
New York, NY 10016

RE: BLA #103663
INFERGEN® (interferon alfacon-1) injection for subcutaneous use
MACMIS #19357

WARNING LETTER

Dear Dr. Waksal:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a STATgram for INFERGEN® (interferon alfacon-1) injection for subcutaneous use (Infergen) by Three Rivers Pharmaceuticals (Three Rivers), a Kadmon company, submitted as a complaint to the DDMAC Bad Ad program and submitted by Three Rivers under cover of Form FDA 2253. The STATgram is false or misleading because it omits and minimizes important risk information for Infergen, broadens and omits material facts about Infergen’s approved indication, overstates its efficacy, and makes an unsubstantiated claim. Thus, the STATgram misbrands Infergen in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n), and FDA implementing regulations. Cf. 21 CFR 202.1 (e)(5); & (e)(6)(i). In addition, it appears that the STATgram was not disseminated with the full FDA-approved product labeling (PI) for Infergen in violation of 21 CFR 201.100(d). These violations are concerning from a public health perspective because they suggest that Infergen is safer and more effective than has been demonstrated.

Background

The INDICATIONS AND USAGE section of the approved product labeling (PI) for Infergen states the following:

INFERGEN® (interferon alfacon-1) is indicated for treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. This indication is based on clinical trials conducted using INFERGEN as monotherapy prior to the time that combination treatment was the standard of care and on a single trial evaluating INFERGEN in combination with ribavirin in patients who failed to respond to previous treatment with a pegylated interferon and ribavirin.

The following points should be considered when initiating treatment with INFERGEN:
 

* Use of monotherapy with an interferon such as INFERGEN for the treatment of hepatitis C is not recommended unless a patient is unable to take ribavirin.
* The safety and efficacy of the combination of INFERGEN/ribavirin in treatment-naïve patients or in patients co-infected with HBV or HIV-1 have not been evaluated.
* Patients with the following characteristics are less likely to benefit from retreatment with combination therapy: response of <1 log10 drop HCV RNA on previous treatment, Genotype 1, high viral load (≥850,000 IU/mL), African American race, and/or presence of cirrhosis.
* No safety and efficacy data are available for treatment of longer than one year.

The CLINICAL STUDIES section of the PI reports that, in the DIRECT trial of patients who were nonresponders to previous pegylated interferon plus ribavirin therapy being retreated with Infergen 15 mcg plus ribavirin, 9% (21/242) achieved a sustained virologic response (SVR). SVR is defined as undetectable HCV RNA 24 weeks after the end of treatment.

Infergen use is also associated with many serious risks. For example, the use of Infergen alone and when combined with ribavirin is associated with the following fatal or life threatening risks as described in the Boxed Warnings section of the PI:

WARNING: FATAL OR LIFE-THREATENING DISORDERS

Alpha interferons, including INFERGEN, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping interferon alfacon-1 therapy.

Use with Ribavirin: Ribavirin may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.

Infergen is contraindicated in patients with hepatic decompensation (Child-Pugh score >6 [class B and C]), autoimmune hepatitis, and known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis to interferon alphas or to any component of the product. Additionally, ribavirin is contraindicated in women who are pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), patients with hypersensitivity to ribavirin or any other component of the product, and patients with creatinine clearance <50 mL/min.

In addition to the Boxed Warning regarding neuropsychiatric disorders, the WARNINGS AND PRECAUTIONS section of the PI expands on this risk, stating the following (in pertinent part):

“Depression, suicidal ideation, suicide attempt, suicide, and homicidal ideation may occur.”

Furthermore, the PI discusses many other warnings and precautions associated with Infergen use, including cardiovascular events, pulmonary disorders, hepatic failure, renal insufficiency, cerebrovascular disorders, bone marrow toxicity, colitis, pancreatitis, hypersensitivity, autoimmune disorders, ophthalmologic disorders, peripheral neuropathy, and endocrine disorders.

The most common adverse reactions associated with Infergen therapy (incidence >40%) are fatigue, fever, rigors, body pain, headache, abdominal pain, nausea, granulocytopenia, arthralgia, myalgia, back pain, neutropenia and influenza-like illness.

Omission and Minimization of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made or with respect to the consequences that may result from the use of the biologic as recommended or suggested in the materials. The STATgram claims, “Providers can obtain additional prescribing information regarding INFERGEN, including the product’s safety profile and the box warning for all interferon alphas regarding neuropsychiatric, autoimmune, ischemic and infectious disorders, and complete product information by visiting our product website at www.infergen.com1.” This statement represents the sole presentation in the piece of the significant and potentially fatal risks associated with Infergen. The other boxed warnings related to combination use with ribavirin, all contraindications to the use of Infergen and ribavirin, most warnings and precautions, and common adverse events are completely absent. Furthermore, although the STATgram mentions one of the boxed warnings associated with use of Infergen, regarding neuropsychiatric, autoimmune, ischemic, and infectious disorders, it seriously minimizes these risks by failing to reveal that these reactions can be fatal or life-threatening. The STATgram also minimizes these risks by failing to reveal that “patients should be monitored closely with periodic clinical and laboratory evaluations” and that “patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy.” In addition, notwithstanding the fact that the boxed warning broadly addresses the warning/precaution regarding neuropsychiatric disorders, the STATgram omits specific information from the WARNINGS AND PRECAUTIONS section of the PI related to the risk of severe psychiatric adverse events, including the risk of suicide attempt, suicidal ideation, depression, and homicidal ideation. Referring readers to the product website for safety information is insufficient to balance the efficacy claims in the piece. As a result, the STATgram misleadingly suggests that Infergen is much safer than has been demonstrated by substantial evidence or substantial clinical experience. Omitting information about serious and potentially fatal risks associated with Infergen’s use in combination with ribavirin raises serious public health and safety concerns.

Broadening of Indication/Omission of Material Facts

Promotional materials are misleading if they contain representations or suggestions that a biologic is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. As discussed above, promotional materials are also misleading if they fail to reveal facts that are material in light of the representations made or with respect to the consequences that may result from the use of the biologic in the materials.

The STATgram claims that “INFERGEN® is now approved for daily dosing with ribavirin for retreatment of HCV patients.” This claim broadens the indication for Infergen because it implies that Infergen plus ribavirin is approved for retreating all patients infected with the hepatitis C virus (HCV), when this is not the case. Infergen is only approved for re-treating patients with chronic hepatitis C who are 18 years of age or older with compensated liver disease, an important limitation to the product’s indication that is omitted from the STATgram. Additionally, the STATgram omits the material fact from the approved indication that the safety and efficacy of Infergen in combination with ribavirin have not been evaluated in treatment-naive patients or patients who are co-infected with hepatitis B virus (HBV) or human immunodeficiency virus type 1 (HIV-1).

The STATgram also omits material information concerning important limitations to Infergen’s indication related to efficacy. Specifically, the STATgram omits that patients with the following characteristics are less likely to benefit from retreatment with combination therapy: response of <1 log10 drop HCV RNA on previous treatment, Genotype 1, high viral load (≥850,000 IU/mL), African American race, and/or presence of cirrhosis. Moreover, the STATgram also omits the material fact that no safety and efficacy data are available for treatment with Infergen of longer than one year. The omission of these material facts about the limitations to Infergen’s indication strongly suggests that Infergen is safe and effective in a broader range of patients than has been demonstrated by substantial evidence, such as patients with decompensated liver disease or patients under the age of 18. The STATgram also strongly suggests greater usefulness in patients less likely to benefit from Infergen, such as genotype 1 patients, than has been demonstrated by substantial evidence. This is even more problematic given the serious safety risks associated with the product and the serious deficiencies in the safety information presented in the STATgram.

Overstatement of Efficacy

Promotional materials are misleading if they contain representations or suggestions that a biologic is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience.

The STATgram claims:

- “Patients demonstrating partial response (>2-log10 drop in HCV RNA) with previous treatment and low fibrosis scores F0-F3 had SVRs of 31.6%”
- “In patients achieving viral negativity by Week 12 while on INFERGEN/RBV, SVRs were 63.6%”

These claims are based on open label studies that were not adequately powered to draw valid statistical conclusions about the efficacy of Infergen/ribavirin in the particular sub-groups of the overall study population, and are thus not supported by substantial evidence. The primary endpoint of the DIRECT trial was SVR in the overall study population (242 patients in the Infergen 15 mcg/ribavirin group). The claim, “Patients demonstrating partial response (>2-log10 drop in HCV RNA) with previous treatment and low fibrosis scores F0-F3 had SVRs of 31.6%” is based on only 19 patients. The claim, “In patients achieving viral negativity by Week 12 while on INFERGEN/RBV, SVRs were 63.6%” is based on only 11 patients (7/11). In contrast to the efficacy reported in these claims, the PI reports that overall SVR was seen in only 9% (21/242) of patients receiving Infergen 15mcg plus ribavirin. Therefore, these highly selective claims and presentations that are based on small subgroups of patients in the DIRECT trial are misleading because they suggest that Infergen is more effective than has been demonstrated.

Unsubstantiated Claim

The STATgram claims, “In patients maintaining full dose of INFERGEN/RBV therapy, SVRs were 17%.” However, we are not aware of any substantial evidence or substantial clinical experience to support this claim. Data to support this claim have not been submitted to the FDA. In contrast to the efficacy reported in this claim, and as noted above, the PI reports that overall SVR was seen in only 9% (21/242) of patients receiving Infergen 15mcg plus ribavirin. If you have evidence to support this claim, please submit it to FDA for review.

Failure to Provide Adequate Directions for Use

We note that the STATgram does not appear to have been disseminated with the full FDA-approved product labeling (PI) for Infergen, in violation of 21 CFR 201.100(d). Although the STATgram was disseminated with the HIGHLIGHTS section of the PI, this is not sufficient to satisfy the requirement that promotional labeling be disseminated with the full PI.

Conclusion and Requested Action
For the reasons discussed above, the STATgram misbrands Infergen in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n), and FDA implementing regulations. 21 CFR 201.100(d); Cf. 21 CFR 202.1 (e)(5); & (e)(6)(i).

DDMAC requests that Three Rivers immediately cease the dissemination of violative promotional materials for Infergen such as those described above. Please submit a written response to this letter on or before April 4, 2011, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Infergen that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional 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, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #19357 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 Infergen 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/
Thomas W. Abrams, RPh, MBA
Director, Division of Drug Marketing,
Advertising, and Communications


Promotional Material

Posted: May 2011


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