RCxxxxx

1
The Politics of Drug Approval Impact of the
ODAC recommendations for Avastin in metastatic
breast cancer
Prepared by P\S\L Research International May
2008 PBIRG AGM 2008 Washington, DC
RCxxxxx
RA13591COR
2
Background

• FDA mission
• The FDA is responsible for protecting the public
  health by assuring the safety, efficacy, and
  security of human and veterinary drugs,
  biological products, medical devices, our
  nations food supply, cosmetics, and products
  that emit radiation. The FDA is also responsible
  for advancing the public health by helping to
  speed innovations that make medicines and foods
  more effective, safer, and more affordable and
  helping the public get the accurate,
  science-based information they need to use
  medicines and foods to improve their health.
• Oncology Drug Advisory Committee (ODAC) Function
• The Committee reviews and evaluates data
  concerning the safety and effectiveness of
  marketed and investigational human drug products
  for use in the treatment of cancer and makes
  appropriate recommendations to the FDA
  Commissioner.
• Voting members (9) 6 oncologists, 1
  statistician, 1 RN, 1 patient representative

3
Background

• On Dec 5, 07 the ODAC voted 5-4 against approval
  of Avastin in MBC, citing that Avastin's benefits
  in MBC were not outweighed by its toxicities
• 4 oncs (including breast specialist) voted FOR
• 2 oncs the statistician, RN, and patient rep
  voted AGAINST
• Within days, rumors of 2 members wanting to
  switch no vote to yes
• Key issue Is Progression Free Survival (PFS)
  Time to Progression (TTP) suitable analogs to
  Overall Survival (OS), which is difficult to
  demonstrate for a number of reasons? Are the
  known toxicities acceptable?
• Politics at hand would US authorities be less
  willing to accept data that European regulators
  had previously approved Avastin with? And that
  clinicians took for granted?

Almost unbelievably, the federal government may
block of the diseases more promising therapies
for no other reason than the FDAs obsolete, even
anti-modern, regulations and approval models.
Wall Street Journal, Feb 21, 2008 Op-Ed
4
Background

• Debate erupted immediately - some supporting,
  some condemning the recommendation
• KOLs
• Clinicians
• Patient Advocacy Groups
• Very heated opinions on both sides

Since the lives of terminally ill patients are
in the balance, this is fundamentally a moral
test for the FDA -- and one, true to type, that
the FDA may flunk.
Wall Street Journal, Feb 21, 2008 Op-Ed
it would be not only unscientific, but
unethical to deny approval.

• The FDA ultimately approved Avastin for MBC in
  Feb 08 despite the ODAC recommendations
• This resulting confusion with these conflicting
  events is the story today.

5
Avastin Primer

• Avastin is a therapeutic antibody designed to
  specifically inhibit the vascular endothelial
  growth factor (VEGF) protein, a potent source of
  angiogenesis.
• Angiogenesis is a process that connects tumors to
  the blood supply. By inhibiting VEGF, interferes
  with the blood supply to a tumor, which is
  thought to be critical to a tumor's ability to
  grow.
• Avastin was the first anti-VEGF /
  anti-angiogenesis therapy approved by the FDA and
  EMEA
• initially for colorectal cancer (CRC)
• lung (NSCLC) followed in US and EU
• EU approved it additionally for breast (MBC) and
  renal cell carcinoma (RCC)
• Marketed by Genentech in the US and Roche ex-US,
  it reported 2007 sales of 3.5B (2.3B
  in US alone).

6
Timeline of Events
FDA approvals
Oct 06 NSCLC
Dec 07 ODAC recommends AGAINST approval for MBC
Feb 08 FDA APPROVES Avastin for MBC
Feb 04 m-CRC
2006
2007
2008
2005
2004
Mar 05 m-CRC
Aug 07 NSCLC
Mar 07 MBC
Dec 07 RCC
EMEA approvals
7
Research Objectives
EVALUATE Short and longer term impact on Avastin
use of the ODAC recommendations (Dec 07) and FDA
decisions (Feb 08)

• This would serve to
• Update forecasts for MBC agents
• Uncover opportunities for competing MBC agents
• Modify financial analysts outlook of Genentech,
  Roche, and other breast cancer agent
  manufacturers

8
Critical questions to be answered
What was the impact of the news event on
US and EU usage of Avastin in MBC?

• What were oncologists reactions to both the ODAC
  and FDA decisions? Who did they think was right?
• How did the initial ODAC recommendation impact US
  off-label usage in MBC? How, if at all, did it
  impact European usage?
• How will FDA approval influence future usage?

9
The process


50 US oncologists - Current Avastin (MBC) users
Negative ODAC (Dec 5 2007)
Results week of Dec 10


First ImpactSM study (syndicated) fielded
immediately after with key physician
group(s) Fieldwork 24 48 hours
News event
Results within days

75 US 200 EU (50 x FR, DE, IT, ES)
Oncologists - all MBC treaters
FDA Approval (Feb 22 2008)
Results Feb 29
10
some key results
11
ODAC Recommendation (December 2007)
Dec 07 ODAC recommends AGAINST approval for MBC

Feb 08
Dec 07
After the negative ODAC recommendations,
Genentech lost 13B in market capitalization (and
20M shares were traded, vs. an average of 3M
daily). Roches shares were down 5.5.
12
Initial Reactions to ODAC recommendations
It is the typical bureaucratic decision from MDs
who do not practice day-to-day medicine.
Reasonable decision but disappointing.
Idiotic! How do these toxicities outweigh the
DOUBLING of TTP?
The FDA panel made the appropriate recommendation
The FDA panel is being overly cautious
of oncologists/hematologists
13
Intended Actions for current Avastin patients
Intended action for patients currently on an
Avastin-containing regimen
Maintain Avastin regimen
Remove Avastin
Dec 6 Feb 22 5 cycles
Reality Jan 08 Intrinsiq data showed a decrease
of 13 in total MBC Avastin patients
Mean of MBC patients currently treated with
Avastin-containing regimen
14
Impact of ODAC on new patient-starts in MBC
Anticipated impact on share of Avastin new
patient-starts for MBC
- 6
(15 to 9)
Post-ODAC (Dec 07)
The reality
Intrinsiq data an erosion of 5.7 share of new
starts from Nov to Feb 08!
Avastins Q1 2008 still sales grew, but at slower
rate than expectations Actual Q1 600
million Expectations 622 million
15
FDA Approval (February 22, 2008)
Dec 5 07 ODAC recommends AGAINST approval for
MBC
Feb 22 08 FDA APPROVES Avastin for MBC

Feb 08
Dec 07
The approval news pushed Roche stock up nearly 4
percent in early trade, following 9 percent
gains for its U.S. partner Genentech late on
Friday.
After the FDA approval, Genentech regained 15B
in market cap!
The potential sales of 1 billion Swiss francs in
2008 had been taken out of our model. Now we are
adding 5 percent to Avastin sales in 2008 and
2009. Zuercher Kantonalbank analyst Michael
Nawrath
16
Initial Reactions to FDAs approval of Avastin
Reactions to the FDAs approval of Avastin in MBC
Reasons

50 physicians Avastin
is effective 30 Data
supports decision 28
Benefits outweigh risks 20

15 physicians? Benefits
do not outweigh the risks 67?
Data does not support approval
33

10 physicians? Need to
review data / need more data 40
(4m)? Wondering why opposing opinions exist
40 (4m)? Due to the recommendation of
the committee 20 (2m)
Please note small base size
Q.13 Avastin has been approved since last year
for the treatment of metastatic breast cancer in
certain European countries. Please select the
statement below which most reflects your opinion
of this decision.
17
EU oncologists awareness of news events
EU awareness of ODAC recommendation final FDA
decision
6

• Why?
• CNN en español
• Oncolink en español

Base All physicians
18
EU Initial Reactions to FDA approval
EU oncs reactions to the FDAs approval of
Avastin in MBC
Reasons


115 physicians Avastin is effective / Avastin
is effective with other types of cancer
26 Data supports decision 22
Facilitates use of Avastin in appropriate patient
groups 20 Benefits outweigh risks
16
67

28
physicians Data does not support approval
50 Benefits do not outweigh the risks
32 Cost is too high 14
24
20


55 physicians Need to review data / need more
data 38 Wondering why opposing
opinions exist 25
Do not know enough of situation to make decision
11
13
Base All physicians (198)
Q.13 Avastin has been approved since last year
for the treatment of metastatic breast cancer in
certain European countries. Please select the
statement below which most reflects your opinion
of this decision. Q.14 Why do you say that?
19
Retrospective impact of ODAC on EU usage
Impact of negative ODAC recommendation on EU
usage of Avastin in MBC (Dec 07 February 08)
Reasons
9 physicians Avastin is effective
56 (5m) Always good to
use/try new regimens 22 (2m)
14 physicians Question efficacy / risk-benefit
ratio 36 (5m) Was waiting for FDA
approval 29 (4m) Data did not
support use 21 (3m)
90 physicians Use Avastin based on patient
situation 23 Was not using / limited use of
Avastin for MBC 21 Had already been using
Avastin 14 Because follow EMEA
guidelines/approval 13
Base All physicians who had heard of the
committee recommendation (113)Please note small
base size
Q.6 What impact did the initial FDA advisory
committee recommendation in December have on your
usage of Avastin in MBC between December 5 and
February 22?Q.7 Why did your use of Avastin in
MBC increase/decrease/stay the same following the
FDA panels recommendation?
20
Impact of FDA on new patient-starts in MBC
Anticipated impact on share of Avastin new
patient-starts for MBC
Reality Intrinsiq data shows that new starts are
up 10 (vs. previous month) in March alone!
28
- 6
8
Feb 08
Post-ODAC (Dec 07)
Post-Approval (Feb 08)
Base All physicians
21
Critical questions revisited
What were oncologists reactions to both the ODAC
and FDA decisions? Who did they think was
right? For the most part, they disagreed with
the ODAC recommendations and applauded the FDA
decision. How did the initial negative ODAC
recommendation impact US off-label usage in MBC?
How did it impact European usage? Some US oncs
decreased their use but reimbursement / access
reasons being as important as negative ODAC.
Some patients missed out on as many as 5
cycles. Impact on EU usage was negligible. How
will FDA approval influence future usage? With
the relief of approval, an explosion in usage is
expected in the US and has been verified by
secondary data source. However, some oncs
remain somewhat confused about the divergent
opinions.

22
Thank you!
Eric Blouin President, P\S\L Research
International Office [phone] Mobile
[phone] eric.blouin_at_pslresearch.com
www.pslresearch.com