Report on New Patented Drugs – Erbitux

Under its transparency initiative, the PMPRB publishes the results of the reviews of new patented drugs by Board Staff, for purposes of applying the PMPRB's Excessive Price Guidelines (Guidelines) for all new active substances introduced after January 1, 2002.

Brand Name: Erbitux

Generic Name: (cetuximab)

DIN: 100 mg/50 mL solution for IV infusion

Patentee: Bristol-Myers Squibb Canada Inc.

Indication - as per product monograph: Used in combination with irinotecan, for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy

Date of issuance of First Patent(s) Pertaining to the Medicine: March 2, 1999

Notice of Compliance: September 9, 2005

Date of First Sale: June 24, 2005 (under Special Access Program)

ATC Class: L01XC06
Antineoplastic and immunodulating agents, antineoplastic agents, other antineoplastic agents, monoclonal antibodies

Application of the Guidelines

Summary

The introductory price of Erbitux under the Special Access Program was found to be within the Guidelines because the price in Canada did not exceed the median of the prices of the same drug in those countries listed in the Patented Medicines Regulations (Regulations) in which Erbitux was sold.

Scientific Review

Erbitux is a new active substance and the PMPRB's Human Drug Advisory Panel (HDAP) recommended that Erbitux be reviewed as a category 3 new medicine as
it provides moderate, little or no improvement over comparable medicines). Although Erbitux is the first agent that treats EGFR-expressing tumours, it did not meet the criteria for a category 2 new medicine (breakthrough or substantial improvement).

The HDAP did not identify any comparators for the conduct of a Therapeutic Class Comparison (TCC) Test since Erbitux is the first agent that treats EGFR-expressing tumours.

Price Review

Under the Guidelines, the introductory price of a new category 3 drug product will be presumed to be excessive if it exceeds the prices of all comparable drug products, based on a TCC test, or if it exceeds the prices of the same medicine in the seven countries listed in the Regulations. The HDAP did not identify any comparators for the conduct of a TCC test. The Guidelines further state that when it is inappropriate or impossible to conduct a TCC test, Board Staff will give primary weight to the median of the international prices identified in an International Price Comparison (IPC) test. See the PMPRB's Compendium of Guidelines, Policies and Procedures for a more complete description of the Guidelines. The price of Erbitux under the Special Access Program was within the Guidelines as the price in Canada did not exceed the median of the international prices identified in an IPC test. The table below does not include a price for Erbitux in Canada as there is no publicly available source for its price.

Introductory Period (July to December 2005)

* Derived based on methodology set out in Verification of Foreign Patented Drug Prices (2000), PMPRB Study Series S-0215.

Sources:

Germany: Rote Liste, July 2005
France: Published in formulary, no price listed, Sempex, August 2005
Italy: L'informatore farmaceutico, December 2005
Sweden: Prislista, November 2005
Switzerland: Medwin Web site, July-December 2005
U.K.: Mims Web site, December 2005
U.S.: Average of Thomson Micromedex Wholesale Acquisition Cost (WAC), October 2005 and Federal Supply Schedule (FSS), July-December 2005.

Where comparators and dosage regimens are referred to in the Summary Reports, they have been selected by the PMPRB Staff and the HDAP for the purpose of carrying out the PMPRB's regulatory mandate, which is to review the prices of patented medicines sold in Canada to ensure that such prices are not excessive. The publicati on of these reports is also part of the PMPRB's commitment to make its price review process more transparent.

The information contained in the PMPRB's Summary Reports should not be relied upon for any purpose other than its stated purpose and is not to be interpreted as an endorsement, recommendation or approval of any drug nor is it intended to be relied upon as a substitute for seeking appropriate advice from a qualified health care practitioner.

References – Erbitux

1. Badarinath S, Mitchell EP, Jennis A, et al. Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): Preliminary safety analysis of a randomized phase III trial. J Clin Oncol 2004;22(14S):3531.

2. British Columbia Cancer Agency. Chemotherapy Protocols. Gastrointestinal. Available at: http://www.bccancer.bc.ca/HPI/ChemotherapyProtocols/Gastrointestinal /default.htm

3. Cancer Care Ontario. Chemotherapy Regimens. Gastrointestinal. Colorectal. Available at: http://www.cancercare.on.ca/access_152.htm#colorectal

4. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45

5. European Medicines Agency. Erbitux. Clinical efficacy. November 19, 2004. Available at: http://www.emea.eu.int/humandocs/Humans/EPAR/erbitux/erbitux.htm

6. Hoff PM. Future directions in the use of antiangiogenic agents in patients with colorectal cancer. Semin Oncol 31(suppl 17):17-21.

7. Lenz HJ, Mayer RJ, Gold PJ, et al. Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. J Clin Oncol 2004;22(14S):3510.

8. Maroun J, Ng E, Berthelot JM, et al. Lifetime costs of colon and rectal cancer management in Canada. Chronic Dis Can 2003;24:91-101. http://www.phac-aspc.gc.ca/publicat/cdic-mcc/24-4/c_e.html (accessed March 11, 2005).

9. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005;352:476-87.

10. Mirtsching B, Headlee C, Beasley S, et al. Cetuximab single-agent activity in refractory metastatic colorectal cancer: Single-center experience. J Clin Oncol 2004;22(14S):3703.

11. National Cancer Institute of Canada. Canadian Cancer Statistics 2004. Toronto: NCIC, 2004. http://www.ncic.cancer.ca/vgn/images/portal/cit_86751114/14/35/195991821 ncic_stats2004_en.pdf (accessed March 14, 2005)

12. National Comprehensive Cancer Network Colon Cancer Panel. Colon Cancer. Version 2.2005. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf (accessed March 14, 2005)

13. National Comprehensive Cancer Network Rectal Cancer Panel. Rectal Cancer. Version 2.2005. http://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf (accessed March 14, 2005)

14. Product monograph of Erbitux (cetuximab). Bristol-Myers Squibb, Princeton NJ. February 2004 and December 21, 2004.

15. Reynolds NA, Wagstaff AJ. Cetuximab in the treatment of metastatic colorectal cancer. Drugs 2004;64:109-18.

16. Rosenberg AH, Loehrer PJ, Needle MN, et al. Erbitux (IMC -C225) plus weekly irinotecan (CPT-11), fluorouracil (5FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFr). American Society of Clinical Oncology Annual Meeting 2002. (abstract 536). http://www.asco.org/ac/1,1003,_12-002636-00_18-0016-00_19-00536,00.asp (accessed March 31, 2005)

17. Rougier P, Raoul JL, Van Laethem JL, et al. Cetuximab + FOLFIRI as first-line treatment for metastatic colorectal CA. J Clin Oncol 2004;22(14S):3513.

18. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-8.

19. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC -C225) plus irinotecan (CPT- 11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). American Society of Clinical Oncology Annual Meeting 2001 (abstract 7). http://www.asco.org/ac/1,1003,_12-002636-00_18-0010-00_19-007,00.asp (accessed March 30, 2005)

20. Schöffski P, Lutz CH, Folprecht G, et al. Cetuximab (C225, Erbitux) in combination with irinotecan, infusional 5-fluorouracil (5-FU) and folinic acid (FA) is safe and active in patients (pts) with metastatic colorectal cancer (CRC) expressing epidermal growth factor-receptor (EGFR). Results of a phase I study. Eur J Cancer 2002;38(suppl 7):S148-9. (abstract 495).

21. Tabernero JM, Van Cutsem E, Sastre J, et al. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Preliminary results. J Clin Oncol 2004;22(14S):3512.

22. US National Comprehensive Cancer Network (NCCN) Guidelines for Colon Cancer. V.2.2005.

23. Zehngebot L, Zackon I, Henderson CA, et al. Anti-epidermal growth factor (EGFR) antibody cetuximab in patients with stage IV colorectal carcinoma who failed all standard therapy: An access protocol. J Clin Oncol 2004;22(14S):3753.