Released by FDA: 5/31/01.  Posted by FDA:  6/11/01

Mr. Charles Davis 
Senior Director, Regulatory Affairs 
Maxim Pharmaceuticals, Inc. 
8899 University Center Lane, Suite 400 
San Diego, CA 92122

RE:   NDA# [confidential, deleted by FDA]
         Ceplene^TM (histamine dihydrochloride) for Injection 
         MACMIS ID# 10042

Dear Mr. Davis:

On December 27, 2000, the Division of Drug Marketing, Advertising, and Communications (DDMAC) sent an untitled letter to Maxim Pharmaceuticals (Maxim) concerning its promotion of histamine dihydrochloride for injection, an investigational drug, as safe and effective.  This was observed by DDMAC at Maxim’s exhibit booth during the 35^th American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting held in Las Vegas on December 4, 2000.   In its January 10, 2001, written response to this untitled letter, Maxim stated that it would cease making claims that promote histamine dihydrochloride as safe or effective prior to approval and cease the distribution or use of any promotional materials for histamine dihydrochloride that contain the same or similar violative statements.   Based on Maxim’s representations, DDMAC considered the matter closed.

Despite Maxim’s assurance that it would not promote histamine dihydrochloride as safe or effective prior to approval, DDMAC has become aware that Maxim is continuing to conduct similar promotional activities for histamine dihydrochloride that are in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. Specifically, DDMAC observed Maxim promoting histamine dihydrochloride as safe and effective at the 37th American Society of Clinical Oncology (ASCO) Annual Meeting held in San Francisco, California.   Similar promotional claims were also found on your website www.maxim.com  (5/21/01).   As stated in our December 27, 2000, letter to you, regulations do not permit a sponsor, investigator, or any person acting on their behalf to represent - in a promotional context - that an investigational drug is safe or effective for the purpose under investigation.

Promotional Activities at the 37^th ASCO Annual Meeting

On May 12, 2301, DDMAC observed one of Maxim’s emnployees at your exhibit booth explaining to visitors the following about histamine dihydrochloride:   

“Phase III studies are showing a doubling of survival.   I would love to tell you more but I can’t in case your with the FDA.”

“You can save on costs by using histamine dihydrochloride in combination with [cytokine interleukin 2] IL-2 because you can send patients home earlier and they can inject thernselves.”

“When histamine dihydrochloride is combined with IL-2 in malignant melanoma less IL-2 needs to be used” 

“You see less side effects of IL-2 when used with histamine dihydrochloride.” 

“Side effects are transient and will pass in an hour or two."

In addition, this verbal promotion was reinforced by convention panels, on display in the exhibit booth, that provided a graphic representation suggesting histamine dihydrochloride “creates a more favorable environment for the survival of activated NK cells and T cells” and made the following claims: 

"in addition to extending survival, the potential to maintain the quality of a patient’s life during drug treatment is an important goal of combining his histamine dihydrochloride with immunotherapy.” 

“The goal of histamine dihydrochoride/IL-2 combination therapy is to enhance the body’s ability to scavenge and attack residual leukemic cells.” 

“Histamine Dihydrochloride: Potentiate immunotherapies by reversing immunosupression caused by the production and release of free radicals.”

Furthermore, two promotional pieces entitled “Creating a Natural Advantage” and “Histamine Dihydrochloride Injection: Mechanism of Action,” that were handed out at the exhibit booth, contained similar claims that provided additional reinforcement to the above promotional activities.   These promotional activities are in violation of the Act and its implementing regulations because they promote an investigational new drug as sate or effective for uses under investigation.

On May 14, 2001, DDMAC contacted Maxim and requested the immediate removal of violative promotional materials from the exhibit area at the 37^th ASCO Annual Meeting.   Maxim agreed to comply with this request and asked for a teleconference for further clarification of DDMAC’s position.   This teleconference took place on May 21, 2001.

Website www.maxim.com

Maxim makes numerous claims regarding the safety and efficacy of histamine dihydrochloride on its website.   These claims are based solely upon preliminary and inconclusive data since the clinical studies of histamine dihydrochioride are in the initial stages of investigation.   In addition, on January 18, 2001, Maxim received a letter from the Food and Drug Administration (FDA) stating that its new drug application for histamine dihydrochloride received on July 19, 2000, was not approvable.   Therefore, the website is in violation of the Act and its implementing regulations because it promotes an investigational new drug as safe or effective for uses under investigation.

Following are selected statements from the website that promote histamine dihydrochloride as safe or effective (emphasis added):

“The Phase 3 trial demonstrated that combination therapy using Ceplene plus the cytokine interleukin-2 (IL-2) showed a significant improvement in the survival of advanced metastatic melanoma patients with liver involvement (p = 0.0040) and did not impair quality of life over treatment with IL-2 alone.” (www.maxim.com/melanoma.html)

“In addition to extending survival, the potential to maintain the quality of a patient’s life during treatment is an important goal of combining Ceplene with immunotherapy.   Many currently available treatments for cancer and some infectious diseases are as harsh as the illnesses themselves, forcing patients to make the difficult choice of whether to continue therapy” (www.maxim.com/ceplene_oview.html)

“Because Ceplene is designed to increase the effectiveness of cytokines, lower doses of cytokines such as IL-2 and IFN- may potentially be used in combination with Ceplene without compromising therapeutic effectiveness, with the goal of reducing side effects and maintaining the patient’s quality of life.” (www.maxim.com/ceplene_works.html)

“Maxim Reports 72-week Results From Completed Phase 2 Hepatitis C Study Demonstrating Benefit Of Treatment With Ceplene.” (www.maxim.com) 

“Maxim Researchers Present Favorable Renal Cell Data And Other Ceplene Research At ASCO Conference.” (www.maxim.com)

Conclusion

In the teleconference of May 21, 2001, DDMAC requested that Maxim and its representatives immediately cease making claims that promote histamine dihydrochloride as safe or effective prior to approval and cease the distribution or use of any promotional materials for histamine dihydrochloride that contain the same or similar violative statements, including its website.   In light of Maxim’s commitment to do so, we consider this matter closed.

Maxim should direct any questions to me by facsimile at (301) 594-6771 or by written communication at the Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857.   In all future correspondence regarding this matter, please refer to MACMIS ID # 10042 in addition to the NDA number.   DDMAC reminds Maxim that only written communications are considered official.

Sincerely,

Joseph A. Grillo, Pharm.D. 
Regulatory Review Officer 
Division of Drug Marketing, 
  Advertising, and Communications