Report on New Patented Drugs – Gadovist

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 Price Guidelines, for all new active substances introduced after January 1, 2002.

Brand Name: Gadovist

Generic Name: gadobutrol

DIN: 02241089 604.72 mg/mL injectable solution

Patentee: Berlex Canada Inc.

Indication - as per product monograph: Gadovist is indicated for contrast enhancement during cranial and spinal MRI (Magnetic Resonance Imaging) investigations and for contrast-enhanced magnetic resonance angiography (CE-MRA).

Notice of Compliance: November 8, 1999

Date of First Sale: January 29, 2004

ATC Class: V08CA09
Magnetic Resonance Imaging Contrast Media

Application of the Guidelines

Summary:

The introductory price of Gadovist was found to be within the PMPRB's Guidelines because the cost of therapy did not exceed the cost of therapy of existing drugs in the therapeutic class comparison and the price did not exceed the range of prices in other comparator countries where Gadovist is sold.

Scientific Review:

Gadovist is a new active substance and the PMPRB's Human Drug Advisory Panel (HDAP) recommended that Gadovist be reviewed as a category 3 new medicine (provides moderate, little or no therapeutic advantage over comparable medicines).

The Therapeutic Class Comparison (TCC) test of the Guidelines provides that the price of a category 3 new drug product cannot exceed the prices of other drugs that treat the same disease or condition. Comparators are generally selected from among existing drug products in the same 4th level of the Anatomical, Therapeutic, Chemical (ATC) System that are clinically equivalent in addressing the approved indication. See the PMPRB's Compendium of Guidelines, Policies and Procedures for a more complete description of the Guidelines and the policies on TCCs.

The HDAP recommended four comparators, which are all in the same fourth level ATC class, and are clinically equivalent at addressing the same indication as Gadovist.

The PMPRB's Guidelines provide that the dosage recommended for comparison purposes will normally not be higher than the maximum of the usual recommended dosage. The recommended comparable dosage regimens for Gadovist and the comparators are based on their respective product monographs and supported by clinical literature.

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 price of all of the comparable drug products in the TCC test, or if it exceeds the prices of the same medicine in the seven countries listed in the Patented Medicines Regulations. The price of Gadovist was within the Guidelines as the daily cost of therapy did not exceed the cost of therapy with the comparator medicines.

1 Publicly available price as per the Patented Medicines Regulations
2 PPS Pharma

In 2004, Gadovist was also being sold in Germany, Italy, Sweden, Switzerland and the United Kingdom. In compliance with the Guidelines, the price in Canada did not exceed the range of prices in those countries; the price of Gadovist in Canada was the lowest of those countries, below the median international price.

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 publication 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.

Evidence/References Considered by the HDAP

1. Amersham web site www.amershamhealth-us.com.

2. Benner T, et al, (2000) Cerebral MR perfusion Imaging: First Clinical Application of a 1 M Gadolinium Chelate (Gadovist 1.0) in a Double-Blinded Randomized Dose-Finding Study. J Magnetic Reson Imaging 12:371-380.

3. Carvlin MJ, et al, (1992) Phase II clinical trial of gadoteridol injection, a low-osmolal magnetic resonance imaging contrast agent. Invest Radiol 27, s16-s21.

4. Gadovist, Product Monograph dated January 14, 2004.

5. Goldstein, HA, et al (1990) Safety assessment of gadopentetate dimeglumine in US clinical trials. Radio 174, 17-23.

6. Goyen, M, et al, (2001) 0.5 M Gd Chelate (Magnevist) versus 1.0 M Gd Chelate (Gadovist): Dose-Independent Effect on Image Quality of Pelvic Three-Dimensional MR-Angiography. J Mag Resonance Imaging 14:602-607.

7. Goyen M., Herborn C.U., Vogt F.M. et al. (2003) Using a 1M Gd-Chelate (Gadobutrol) for Total-Body Three-Dimensional MR Angiography Preliminary Experience. J Magnetic Reson Imaging 17:565-571.

8. Grossman, RI, et al, (2000) Magnetic Resonance Imaging in patients with central nervous system pathology: a comparison of OptiMark and Magnevist. Invest Radiol 35:412-419.

9. Hentsh A., Aschauer M. A., Balzer J.O. et al. (2003) Gadobutrol-enhanced moving-table magnetic resonance angiography in patients with peripheral vascular disease: a prospective, multi-centre blinded comparison with digital subtraction angiography. Eur. Radiol 13: 2103-2114.

10. Kirchen, MA, et al, (2003) Contrast Agents for magnetic resonance imaging: safety update. Top Magn Reson Imaging 14:426-435.

11. Niendorf, HP, et al, (1991), Tolerance data of Gd-DTPA: a review. Eur J Radiol 13, 15-20.

12. Niendorf, HP, et al (1988) Serum iron and serum bilirubin after administration of Gd-DTPA-dimeglumine: a pharmacologic study in healthy volunteers. Invest Radiol 23, s275-s280.

13. Product Monographs, Compendium of Pharmaceutical Specialties, 1993.

14. Rocklage SM, et al (1992) Contrast agents in magnetic resonance imaging. Chapter 14, Magnetic Resonance Imaging, 2nd Ed, Stark and Bradley, Mosby Yearbook, 1992.

15. Rubin, DL, et al, (1999) A multicenter, randomized, double-blind study to evaluate the safety, tolerability and efficacy of OptiMark (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a phase III clinical trial.

16. Runge VM, et al (1990) Gd-HP-DO3A in clinical MR imaging of the brain. Radiol 177, 393-400.

17. Runge VM, et al (1991) Clinical safety and efficacy of gadoteridol: a study in 411 patients with suspected intracranial and spinal disease. Radiol 181:701-709.

18. Tombach, B, et al, (2001) Renal tolerance of a neutral gadolinium chelate (gadobutrol) inpatients with chronic renal failure: results of a randomized study. Radiology 218:651-657.

19. Tweedle MF, et al (1988) Comparative chemical structure and pharmacokinetics of MRI contrast agents. Invest Radiol 23(suppl 1), s236-s239.

20. Tweedle MF, et al (1991) Reaction of gadolinium chelates with endogenously available ions. Mag Res Imag 9, 409-415.

21. Tweedle MF, et al (1992) Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Invest Radiol 27, s2-s6.

22. Vogl, TJ, et al. (1993) Skull base tumors:Gadodiamide injection-enhanced MR imaging- dropout effect in the early enhancement pattern of paragangliomas versus different tumors. Radiol 188, 339-346.