Bayer-magnevist Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committee

U.S. Food and Drug Administration

Notice: Archived Document The content in this document is provided on the FDAs website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

Magnevist(Gadopentetate dimeglumine)

Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committee Gaithersburg, MD, December 8, 2009

Christiane Pering, MD, PhD Vice-PresidentHead of Global Medical Affairs, Diagnostic Imaging, Bayer

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 2

Agenda

Summary of Nonclinical NSF Research Results

Summary

Magnevist & NSF Summary of Clinical Evidence

NSF Risk Mitigation Activities

Magnevist Introduction

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 3

Magnevist: Development and Post-Approval Events in US

10 M

(1993

)

100 M

(2009

)

2006 1st FDA Public

Bayer Nonclinical Research

2006 NSF & GBCAs

(Grobner##)

1989

CN

S in

child

ren

1996

CE

-MRI

of he

ad &

neck

# CE-MRI = contrast-enhanced magnetic resonance imaging

** excluding the heart

## Grobner et al. NDT 2006

Million administrations (cumulative since launch) of Magnevist worldwide: Bayer estimates on basis of sales data and data provided by Arlington Medical Resources (AMR) Inc. (Status Sept 2009)

1993

CE-M

RI of

body

**

1988

CE

-MRI

of C

NS

2000

Bo

dy**/

Head

&

Neck

in ch

ildren

20 M

(1997

)45

M

(2002

)69

M

(2005

)

2007

Bo

xed W

arning

NSF

MRI Study

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 4

Summary of Nonclinical NSF Research Results

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 5

Marketed GBCAs Can be Divided Into Three Categories

MacrocyclicIonic linearNon-ionic linear

OmniscanTM

OptimarkTM

Magnevist

MultiHance

Eovist

AblavarTM

ProHance

(Dotarem)

(Gadovist)

*Frenzel et al. Investigative Radiology Dec 2008

Decreasing Gd Release (in vitro)* Magnevist Gadovist and Eovist is a trademark of Bayer. All other trademarks are the property of their respective owners

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 6

Results of Nonclinical Research

Gd release observed in human serum in vitro was highest from linear non-ionic GBCAs, lower from linear ionic GBCAs, and lowest from macrocyclic GBCAs.

Gd retention observed in rat skin was higher after administration of linear non-ionic GBCAs than after linear ionic GBCAs, and lowest after macrocyclic GBCA administration.

Only non-ionic linear GBCAs induced NSF-like skin lesions in some study rats.

Caution should be exercised when extrapolating results to humans.

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 7

Magnevist & NSF Summary of Clinical Evidence

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 8

Approved* for use in CE-MRI#in a broad range of indications and patients

Studied in > 11,000 subjects in clinical trials worldwide

Cited in > 16,000 scientific publications

Administered an estimated total of > 100 million times worldwide since launch

* US Package Insert (Please note: range of approved indications and dosages may vary across countries.)# CE-MRI = contrast-enhanced magnetic resonance imaging

Magnevist is the Most Widely Used and Studied MRI Contrast Agent

US CE-MRI Administrations and Magnevist share (in thousands)*

* Source: Bayer estimates on basis of sales data and dataprovided by Arlington Medical Resources (AMR) Inc. (Status Sep 2009)

0

1.000

2.000

3.000

4.000

5.000

6.000

7.000

8.000

9.000

1988 1990 1995 2000 2005 2008

Magnevist-enhanced MRICE-MRI in total

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 9

Observational Studies Do Not AllowRobust Conclusions on Differential Risk of GBCAs

* Wertman et al. Radiology 2008 (248) 3:799-806

No adequate observational studies or randomized clinical trials have compared the risk of NSF among available GBCAs.

The only study that compared the risk of NSF among GBCAs reported a significantly higher risk (OR=13.17 [95% CI: 4.6-37.2]) with Omniscan than with Magnevist*.

However, this study did not adjust for many important confounding variables (e.g., dose, indication, number of patients at risk receiving GBCAs, number of procedures per patient).

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 10

Number of NSF Reports Needs to be Consideredin the Context of Overall Usage of GBCAs

* Bayer estimates on basis of sales data and data provided by Arlington Medical Resources (AMR) Inc. (Status Sep 2009)** Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory CommitteeGadolinium-Based Contrast Agents & Nephrogenic Systemic Fibrosis, FDA Briefing Document, p 23

Gd-basedcontrastagent

Categoriesof GBCA

Estimated total administrationssince approval

(in millions,US only)*

Number of US

reportsaccordingto AERS** (all reports)

Omniscan Nonionic > 25.0 929

Optimark Nonionic > 2.5 427

Magnevist Ionic > 50.0 654

MultiHance Ionic > 2.5 335

ProHance Macrocyclic > 7.5 325

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 11

Number of NSF Reports Needs to be Consideredin the Context of Overall Usage of GBCAs

Gd-basedcontrastagent

Date of US

approval

Estimated total administrationssince approval

(in millions,US only)*

Number of US

reportsaccordingto AERS** (all reports)

Number of US reports

accordingto AERS (only one

GBCA administered)

Omniscan 1993 > 25.0 929 382

Optimark 1999 > 2.5 427 35

Magnevist 1988 > 50.0 654 195

MultiHance 2004 > 2.5 335 1

ProHance 1992 > 7.5 325 0* Bayer estimates on basis of sales data and data provided by Arlington Medical Resources (AMR) Inc. (Status Sep 2009)** Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory CommitteeGadolinium-Based Contrast Agents & Nephrogenic Systemic Fibrosis, FDA Briefing Document, p 23

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 12

1. GBCAs with recent-market entry are likely to be used in patients exposed to older GBCAs, especially those with dominant market share.

2. Analyses that focus on unconfounded cases and exclude cases involving multiple GBCAs are likely to yield a biased underestimate of NSF risk among recent-entry agents.

3. Analyses that focus on unconfounded cases ignore available information regarding the temporal proximity of a recently-used GBCA and the development of NSF.

4. Recently-approved GBCAs have been used in an environ-ment of heightened awareness of NSF risk, and thus, their use is likely to have been directed towards low-risk patients.

Comparisons of NSF Risk Among Early-Entry andRecent-Entry GBCAs May be Difficult to Interpret

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 13

AERS Data Mining Analysis: Non-ionic Linear GBCAs Have the Highest Reporting Ratios

GBCADate of US

approval

Estimated total administrations

to date (in millions,US only)

Proportionalreporting

ratio

Relativereporting

ratio

Magnevist 1988 > 50.0 0.780 0.888

ProHance 1992 > 7.5 0.021 0.027

Omniscan 1993 > 25.0 7.192 4.537

Optimark 1999 > 2.5 5.406 5.109

MultiHance 2004 > 2.5 0.064 0.071

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 14

NSF Risk Mitigation Activities

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 15

Current Risk Mitigation Activities Have Been Effectivein Markedly Reducing Reports of NSF

Occurrence of NSF has decreased over the last three years:Date of Onset of Symptoms Suggestive of NSF in Reports with

Documented Magnevist Administration and Known Onset Date (Status Sep 30, 2009)

0

10

20

30

40

50

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Year of Onset

N

u

m

b

e

r

o

f

R

e

p

o

r

t

s

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 16

MRI Study (Magnevist in Renally Impaired Patients)

Study objective

Prospective observational study to assess the magnitude of risk with the administration ofMagnevist for the development of nephrogenic systemic fibrosis (NSF) based on diagnostically specific clinical and histopathologic information

Patient population 1000 patients with moderate (approx. 600) to severe (approx. 400) renal impairment

Participating country US

Number of active sites 18

First patient/First visit November 2008

Enrollment status(Sep 2009)

57 patients; 42 in follow-up (39 moderate,3 severe renal impairment)

MAGNEVIST FDA Advisory Committee Meeting; Gaithersburg, MD; December 8, 2009 Page # 17

Magnevist - Summary

Nonclinical studies suggest a lower NSF risk for ionic linear GBCAs (e.g. Magnevist) and macrocyclic GBCAs as compared with non-ionic linear GBCAs (e.g. Omniscan, Optimark).

Clinical data (from spontaneous reporting and observationalstudies) indicate a lower NSF risk for Magnevist as comparedwith non-ionic agents, such as Omniscan and Optimark.

No data from clinical studies has yielded evidence for reliabledifferences in NSF risk between Magnevist and other ioniclinear (e.g. MultiHance) or macrocyclic GBCAs.

Focusing risk assessment on the frequency of spontaneous unconfounded (single agent) reports is likely to yield biased risk estimates among recently-approved GBCAs.

Current class labeling and awareness of NSF risk factors appear to have nearly eliminated occurrence of new cases of NSF.

Magnevist(Gadopentetate dimeglumine)AgendaMagnevist: Development and Post-Approval Events in USMarketed GBCAs Can be Divided Into Three CategoriesMagnevist is the Most Widely Used and Studied MRI Contrast AgentObservational Studies Do Not Allow Robust Conclusions on Differential Risk of GBCAsNumber of NSF Reports Needs to be Consideredin the Context of Overall Usage of GBCAsNumber of NSF Reports Needs to be Consideredin the Context of Overall Usage of GBCAsAERS Data Mining Analysis: Non-ionic Linear GBCAs Have the Highest Reporting RatiosCurrent Risk Mitigation Activities Have Been Effective in Markedly Reducing Reports of NSFMRI Study (Magnevist in Renally Impaired Patients)Magnevist - Summaryarchive_cover.pdfNotice: Archived Document