Stacey Tosadori
Director, Regulatory Affairs
Amgen, Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799

RE:  BLA # 125147
        Vectibix® (panitumumab) Solution for Intravenous Infusion
        MACMIS # 18227

Dear Ms. Tosadori:

This letter notifies Amgen, Incorporated (Amgen) that, as part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has become aware of oral statements made by an Amgen representative on December 8, 2009, regarding the drug Vectibix® (panitumumab) Solution for Intravenous Infusion (Vectibix) at the 44th American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting and Exhibition held in Las Vegas, Nevada.  The representative’s oral statements are false or misleading because they make misleading comparative claims, promote an unapproved use, minimize serious risks associated with Vectibix, and omit material facts about the use of the drug.  Thus, this promotional activity misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(f)(1) & (n); 321(n), and FDA implementing regulations.  21 CFR 201.100(c)(1); 201.128; 202.1(e)(5)(i) & (iii); (e)(6)(i) & (ii). 

Background

According to the Indications and Usage section of the FDA-approved product labeling (PI) for Vectibix:

Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. 

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival….  Currently no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. 

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13.  Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. 

The PI for Vectibix includes a Boxed Warning for dermatologic toxicity and infusion reactions.  The PI also contains Warnings and Precautions regarding increased toxicity with combination chemotherapy, pulmonary fibrosis, electrolyte depletion/monitoring, and photosensitivity.  The most common adverse reactions are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.  The most serious adverse reactions are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.  Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. 

Misleading Comparative Claims

On Tuesday, December 8, 2009, at approximately 11:35 a.m., during the 44th ASHP Midyear Clinical Meeting and Exhibition, an Amgen representative made the following statements in word or substance to a DDMAC representative:

The PI has been updated with KRAS information, since it is a predictor of response.  It is also for patients who have progressed.  It is a good alternative as a single-agent treatment.  It is the first fully human monoclonal antibody.  That means potentially less infusion reactions.  The liver issues and neuropathies are not as much of an issue with this drug versus FOLFOX or FOLFIRI. 

Amgen’s sales representative’s oral statements misleadingly suggest that Vectibix is safer than other products, when this has not been demonstrated by substantial evidence or substantial clinical experience.  For example, the suggestion that Vectibix may have “less infusion reactions” because it is a human monoclonal antibody misleadingly suggests it is safer than other products that are not fully human monoclonal antibodies, such as cetuximab, a recombinant, human/mouse chimeric EGFR antagonist monoclonal antibody.  We are not aware of substantial evidence or substantial clinical experience demonstrating Vectibix is safer than other therapeutic options that are not fully human monoclonal antibodies.  If you have evidence to support this claim, please submit it to FDA for review. 

Additionally, the Amgen sales representative’s statement that liver issues and neuropathies are not as much of an issue with this drug versus FOLFOX or FOLFIRI suggests that, compared to FOLFOX and FOLFIRI regimens, patients can expect less liver issues and neuropathies while on Vectibix.  FDA is not aware of any adequate and well-controlled head-to-head trials that substantiate this claim. 

Promotion of Unapproved Use

The statements made by the Amgen sales representative also suggest that Vectibix can be used as a first-line agent when the drug is not approved for such use.  Specifically, the sales representative’s statement that Vectibix “is also for patients who have progressed” (emphasis added) implies that Vectibix is intended for use both in patients who have progressed and as a first-line treatment.  This, in combination with the representative’s suggestion that liver issues and neuropathies are not as much of an issue with Vectibix versus FOLFOX or FOLFIRI and that Vectibix is a “good alternative” to these therapies, misleadingly suggests that Vectibix can be used as a first-line treatment instead of a FOLFOX or FOLFIRI regimen to alleviate risk concerns.  However, Vectibix is only approved for use if a patient has disease progression while on or following a FOLFOX or FOLFIRI regimen.  (emphasis added) It is not approved as a single-agent in the first line setting.  Thus, this claim misleadingly promotes a new intended use for Vectibix by suggesting it is approved for use as a first-line alternative to FOLFOX or FOLFIRI regimens, when this is not the case. 

Minimization of Risk Information

The statements made by the Amgen sales representative also minimize the risks associated with Vectibix.  Specifically, the suggestion that Vectibix has less infusion reactions minimizes the important safety information described in the Vectibix Pl.  Vectibix’s PI has a Boxed Warning regarding infusion reactions, and severe infusion reactions, including anaphylactic reactions, bronchospasm, and hypotension, occurred in approximately 1% of patients in clinical trials. 

Omission of Material Facts

We acknowledge that Amgen’s sales representative’s oral statement; “The PI has been updated with KRAS information …” is true on its face.  However, this statement, along with the rest of the statement – “… since it is a predictor of response” – is misleading because it omits material information about the impact of KRAS mutations on the decision to use Vectibix.  Specifically, the PI states, “Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13.  Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.” Through the omission of this material information, the statement made by the representative misleadingly suggests that KRAS mutations are a positive predictor of clinical response to Vectibix, when in fact the information added to the PI regarding KRAS information warns that use of the drug is not recommended in patients with certain KRAS mutations due to a lack of treatment benefit. 

Conclusion and Requested Action

For the reasons discussed above, the oral statements made by Amgen’s representative misbrand Vectibix in violation of the Act, 21 U.S.C. 352(f)(1) & (n); 321(n), and FDA implementing regulations.  21 CFR 201.100(c)(1); 201.128; 202.1(e)(5)(i) & (iii); (e)(6)(i) & (ii). 

DDMAC requests that Amgen immediately cease promotional activities for Vectibix that are the same or similar to those described above.  Please submit a written response to this letter on or before May 26, 2010, stating whether you intend to comply with this request, listing all promotional activities for Vectibix that are the same or similar as those described herein and listing all promotional materials (with the 2253 submission date) for Vectibix that contain violations such as those described above and explaining your plan for discontinuing such promotional activities.  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# 18227 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 Vectibix comply with each applicable requirement of the Act and FDA’s implementing regulations. 

Sincerely,

Carole C. Broadnax, R.Ph., Pharm.D. 
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications