Released by FDA: 6/25/01.  Posted by FDA:  7/26/01

Glynn T. Faircloth, Ph.D. 
Vice President 
PharmaMar, USA, Inc. 
320 Putnam Avenue 
Cambridge, MA 02 139-4616

RE:   [confidential, deleted by FDA] Ecteinasicidin-743 
        MACMIS # 10136

Dear Dr. Faircloth:

This letter notifies PharmaMar. USA, Inc. (PharmaMar) that the Division of Drug Marketing, Advertising, and Communications (DDMAC) has identified promotional materials and activities for Ecteinasicidin-743, an investigational new drug, that are in violation of the Federal Food. Drug. and Cosmetic Act (act) and its implementing regulations.   Specifically, PharmaMar distributed a brochure in the commercial exhibit hall at the 37^th American Society of Clinical Oncology (ASCO) Annual meeting held in San Francisco, California, May 12-15, 2001, that made conclusions about safety and efficacy for the investigational new drug. Our specific objections follow:

Promotion of an Unapproved New Drug

Sponsors may not represent in a promotional context that an investigational new drug is safe or effective for the uses that are under investigation (see 21 CFR 312.7(a)).   Your brochure titled, “The PharmaMar Oncology Pipeline: Meeting Presentations,” however, includes many abstracts that present claims and representations concerning the safety or efficacy of Ecteinasicidin-743, an investigational new drug.   For example, in the abstract by Demetri et al¹, you state that the drug achieved objective responses in 6/34 evaluable patients and that progression-free and overall survival rates at 1 year were 18% and 49% for the first-line study.   Your conclusion was that “ET-743 yields durable disease control and objective responses in a subset of patients with a variety of STS (soft tissue sarcoma) histologies.”

You further claim in the abstract by Cesne et al.² that ET-743 achieved an objective response rate of 11.4% and that its median time to progression of 3 months and the median overall survival of 7 months compare favorably with results obtained with other thugs tested in second-line CT.

Still further, you claim in the abstract by Shtil et al.³ that ET-743 is “extremely potent (at sub-to low nanomolar concentrations) for a panel of neuroblastoma and rhabdomyosarcorna cell lines in vitro.”   Thus you conclude that the “diversity of mechanisms involved in cytotoxicity of ET-743 may broaden the therapeutic potential of this compound for childhood solid malignancies.”

Requested Action

You should immediately discontinue the use of the above brochure, and any other materials that promote the investigational new drug as safe or effective.   You should respond to me regarding this violation by letter no later than July 10, 2001.   In your response, you should state how PharmaMar has addressed this violation.

If you have any questions, please contact me by facsimile at (301) 594-6771, or by written communication at the Division of Drug Marketing, Advertising, and Communications, HFD-42; Room 17B-20; 5600 Fishers Lane, Rockville, MD 20857. DDMAC reminds PhannaMar that only written communications are considered official.

In all future correspondence regarding this matter, please refer to MACMIS # 10136 and IND 50-286.

Sincerely,

Warren F. Rumble 
Regulatory Review Officer 
Division of Drug Marketing, 
       Advertising and Communications

______________________________________

¹ “Ecteinascidin-743 (ET-743) Induces Durable Responses and Promising 1-Year Survival Rates in Soft Tissue Sarcomas (STS): Final Results of Phase 2 and Pharmacokinetic Studies in the USA,” George D. Demetri, Judith Manola, Dana-Farber Cancer Institute, Boston, MA. David Harmon, Massachusetts General Hospital, Boston, MA. Robert G. Maid, Memorial Sloan-Kettering Cancer Center, New York, NY. Michael V. Seiden, Jeffrey G. Supko, David P. Ryan, T.A. Puchlaski, Geraldine Goss, Priscilla Sancho, C. Guzman, Jose Jimcno, PharmaMar, S.A., Madrid, Spain. Rocio Garcia-Carbonero.

² “ET-743 is an Active Drug in Adult Soft-tissue Sarcoma (STS): A STBSG-EORTC Phase 2 Trial,” Axel Le Cesne, lnstitut Gustave Roussy, Villejuif, France. Jean-Yves Blay, Centre Leon Berard, Lyon, France. Ian Judson, Royal Marsden Hospital, London, UK. Alan ‘Van Oosterom, U.Z. Gasthuisberg, Leuven, Belgium. Jaap Verweij, A.Z. Rotterdam, Rotterdam, Netherlands. John Radford, Christie Hospital, Manchester, UK. Paul Lorigan. Weston Park Hospital, Sheffield, UK. Sjoerd Rodenhuis, Antoni Van Leeuwenhoekhuis, Amsterdam, Netherlands. Eugenio Donato Di Paola. Martine Van Glabbeke, EORTC, Bruxelles, Belgium. Jose Jimero, PharmaMar, Madrid, Spain. Ole Nielsen, Aarhus Kommunehospital, Aarhus, Denmark. 

³ “Ecteinascidin-743 (ET-743), A Novel Natural Cytotoxic Compound, Is Potent For Human Neuroblastoma and Rhabdomyosarcoma Cell Lines: Multiple Mechanism of Cell Kill” Alexander A. Shtil, E. Anders Holb. Glynu Faircloth, Michael LaQuaglia, Kathleen Scotto, Memorial Sloan- Kettering Cancer Center. New York, NY; PharmaMar USA, Cambridge, MA.