Transcript Risk Management

The Risk Management
Initiatives and Drug
Development
Felix M Arellano, MD, Dip Pharm
Med, FISPE
Princeton, June 2004
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Definitions. Pharmacovigilance
Plan (PVP)
All products launched with PVP
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Data from pre-clinical development
Data from clinical development
Class or “family” safety “issues”
Data from population intended to receive the agent
Steps needed to gain further knowledge
PVP (ICH) = PV Specification + Action Plan
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Risk Minimization Action Plan
(formerly Risk Management Plan)
RMP. Similar to PVP +
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Risk assessment/measurement
Risk confrontation
Risk intervention (minimization or tools)
Risk management evaluation
Risk communication
RM (FDA) = Risk assessment + risk
minimization
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Risk Management
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Where we are
FDA PDUFA III.
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Pre NDA meeting packages should include
safety information and proposal for Risk
Management Plans (RMP)
NDA Review. RMP must be submitted no later
than one month prior to official action date
Guidance Papers. 2nd draft released on May
5th and is open for comments
Implementation expected in 2004
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Where we are (cont.)
EMEA. EU Heads of Agencies developed
a “EU Risk Management Strategy” in
January 2003
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Guidance on Risk Management can be
obtained during “scientific advice”
By the time of approval all products are
expected to have a RMP or a statement that
no specific “safety measure” is needed
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Where we are (cont.)
ICH Guideline (E2E) has been adopted by
FDA
FDA will issue its guidelines in 2004
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Where we are (cont.)
RM concept has shifted
RMP were originally designed to manage
KNOWN risks (terfenadine, mebefranil,
astemizole, bromfenac)
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Where we are (cont.)
RM concept now involves pre-marketing risk
assessment during which, by definition,
post-marketing risks are not known
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Why is RM here?
Perception vs. Reality
General perception of an “increased
regulatory pressure”:
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There are less regulatory approvals
More drugs are withdrawn
Agencies are more cautious in granting
approvals
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Average Number of Drugs Approved per
Year. FDA 1939-2000
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Decade
No. Drugs
1940s
3
1950s
10
1960s
11
1970s
17
1980s
28
1990s
41
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Last 5 years of the 20th Century
(FDA)
Almost a drug per week!!!
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200
180
160
140
120
100
80
60
40
20
0
NDA
Expedited NME
Standard NME
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
Number NME/NDA
Number of NME/NDA Approved per
Calendar Year 1990-2002
Years
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Number of NMEs Withdrawn as a
Percentage of NME Approved
1990-2002
5
16
Proportion
4
12
Number NMEs
Number
10
3
8
2
6
4
1
Proportion NME withdrawn vs. approved
14
2
0
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Years 1990 - 2002
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Proportion of Standard NDA
Approved 1993-2002
100
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
90
80
70
60
50
40
30
20
10
0
6
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Proportion NDA approved
Proportion of Standard NDA
Approved 1993-2002
100
90
80
70
60
50
40
30
20
10
0
1993-1997
1998-2002
6
12
18
24
30
36
Months since NDA receipt
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Number of Drug Safety Alerts
(1996-2001)
clinical alert of SAEs,
black box warnings,
voluntary recalls,
counterfeits and
market withdrawals
CAGR 18%
37
28
25
25
16
1996
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Number of Safety – Related Label
Changes (1997-2001)
CAGR 21%
Flat after 1997 – 1998
Skepticism over
effectiveness of label
changes as RM tool
653
641
639
589
295
1997
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Why is RM here?
Perception vs. Reality
General Perception of an increased
regulatory pressure:
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There are less regulatory approvals +/More drugs are withdrawn +
Agencies are more cautious in granting
approvals +
Overall increase in regulatory pressure over
label changes ++
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Why do companies need RM?
It is the right thing to do
It is here, whether you like it or not
R & D reasons:
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Leaner Pipelines
Less “unmet medical needs”
Narrower indications
Higher R & D Costs
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Why do companies need RM?
(cont)
Regulatory Reasons
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Agencies (and society) are becoming
increasingly risk-averse
Smaller benefits; make benefit: risk analysis
challenging
“Err on caution” translates in restrictions,
delays, withdrawals (or all the above) = lower
revenues
Opportunity is to translate challenge to
advantage
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What to Expect
Compliance must be a given
Focus on life cycle management
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Peri-launch and post-marketing periods are
simply part of a continuum
Sponsors cannot be expected to predict
completely the safety profile…
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But they will be expected to follow up on the
identified ones, and…
Actively look for new ones
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PVP/RMP in Development
Pharmacovigilance Plans (PVP) starting in
exploratory development and being followed
through development
Discovery
Research
Target
Candidate
Profile
(TCP)
Exploratory
Development
Exploratory
Development
Plan
Full
Development
Project
Development
Plan
Plan
Filing
Launch
Growth &
Maintenance
Clinical
Development Plan
Plan
Risk Management Plan
Risk assessment, confrontation, intervention, management, evaluation
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Risk Communication
Of all the components of the RMP this is
the most complex, multidisciplinary and
challenging
Balance between adequate, and
exaggerated
Communication of risk falls on underlying
perceptions of the receiver
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Risk Communication
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Issues
Monumental task impossible to tackle
pleasing everyone
Categorization of drugs was removed from
new version
Risk minimization, not avoidance. Risk
reduction better
Endorses RM as part of life-cycle
Endorsees and guides on RM in pre and
post-marketing
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Issues. Cons
Lack of precision regarding when to prepare
PVP and RMAP as well as “routine PV”
Confusion around whether RM will narrow
exposure to drugs
Older drug issue not tackled
Avoiding need for PVP
Contradiction with ICH E2E (endorsed by FDA)
Label as risk communication tool and
cornerstone
Exclusion of industry from certain forums
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Issues
Will companies take
RM seriously without
clear guidelines?
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Precedents are not
reassuring
Traditionally,
pharmacovigilance is
considered an
expense, not an
investment
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Issues
Distribution of burden
among society
members
Including patients,
and its “informed”
consent
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Issues (cont)
Implementation of RM concept cannot be
harmonized
Information overload
Not a panacea. E.g. toxicity in elderly due
to misadministration
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THANK YOU
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