Transcript document

CV SAFETY IN PHARMACEUTICAL
DEVELOPMENT – ACADEMIC
PERSPECTIVE
Rob Califf MD
Vice Chancellor for Clinical Research
Director, Duke Translational
Research Institute
Academic
“Of theoretical interest, but of
no practical value”
Years
3
Compound
Success
Rates
6
9
12
15
Source: PhRMA, 2006 Industry Profile
Funding ($ in billions)
100 –
Source:
Device firms
80 –
Biotech firms
60 –
Pharma firms
40 –
Private
State/local
20 –
Federal—
non-NIH
0–
NIH
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Reproduced from Moses et al., JAMA 2005;294:1333-42
Comparative Pre-Approval Capitalized
Costs per Approved New Molecule
Millions (2004$)
1500
Original**
2004 Time Adjusted***
1000
500
848
363
424
1272
868
505
0
Preclinical**
Clinical
Total
** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing
*** Based on a 5-year shift and prior growth rates for the preclinical and clinical periods
DiMasi et al. 2003
Innovation Gap Getting Wider
60
NMEs (New Drug Approvals)
53
PhRMA Member R&D Spending
$39.40
39
40
35
26
28
25
22
20
30
27
24
21
17
Pharma
Innovation
Gap
16
$11.50
11
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
0
Burrill & Company
Drug Safety System
 Requires complex synergy between first rate science and first
rate operational management on many levels in a complex
supply chain
 Components
Manufacturers/distributors including multiple subcontractors
Practitioners/hospitals/health systems/insurers/payers/public
health systems
Researchers
Patients and consumers
 A regulatory agency dealing with this complexity needs
adequate staffing for routine function and first rate scientists
for complex functions
 Globalization, new understanding of clinical effectiveness and
genomic sciences have made this job much more difficult (and
interesting)
Safety
 the condition of being safe from undergoing or
causing hurt, injury, or loss
Merriam-Webster Dictionary
 The difficulty with safety of medical products
Hurt, injury or loss occurs due to use or can occur due
to lack of use
Often the patient with the most to gain also has a high
risk of toxicity
 Accordingly
Minimizing risk does not maximize safety
Balancing Safety and Effectiveness
Conceptual Goal: Not a ratio that can be
calculated the same way for every person!
Safety
Effectiveness
Domains of Cardiovascular Safety Assessment
 Preclinical
 Early clinical observation
 Registration trials
 Comparative Effectiveness
PCTs
Observational data
 Safety surveillance
Active
Passive
Preclinical Cardiac Safety
 Can we develop reproducible models that truly
inform the human condition when exposed to a
drug?
 Human genetic disease models?
 Transgenic models?
 Can we link probabilistic information from
preclinical models to the human condition?
The Real Question: What is the probability of this
in clinical use relative to the probability of benefit?
Take the QT interval and Channel Testing
 If QT is long and biological channel testing
positive there is very likely a risk of torsades
 We currently have no way of translating those
signals into a quantitative risk of
torsades/death
 The epidemiology simply has not been done!
 Without a quantitative estimate
Decision makers tend to revert to “safe mode”
Even the most rational person cannot make rational
decisions
Early Clinical CV Safety
 Can we develop effective biomarker signatures
of cardiac toxicity in humans?
 Can we understand the mechanistic/systems
basis for observations with biomarkers?
Why do we need Systems
Biology to identify and
predict Biomarker Sets?
Disease and drug
action originate at
the level of cellular
components but
physiological
effects (e.g.
symptoms, drug
action) are at the
organismal levels.
Unraveling such
complexity requires
a systems
approaches
Move from “Phase I” to true biological proof
of concept!
Target/Disease
1
2
Intervention
3
4
Data Integration
 Research Tool Box


Move
Patient
Results
discovery
populations
into human
highly testing
characterized

Easy
access
 IT & Bioinformatics deployed to collate


Best
Better
technology
with
understanding
efficient management
Best
ofbiological
its kind
Reclassify
disease
and
organize
the arraycharacteristics
of results so they


Highly
Signatures
professional,
of response,
reliable
non
staff
response,
can
be
interpreted
through
statistical
Define
biological
effects
of
drug/device
 Define
novel
biological targets
toxicity
and
prediction

No
“limits”
on
what can be done
analysis
Early response

New Research Methodologies

Academic
Toxicity design
5
Protein Biomarkers and ‘Omics
Goal: Detect molecular events in blood as a
surrogate of local tissue responses
Gene Expression Predicts VTE Risk
•
•
•
•
•
AntiPhosphoLipid
Syndrome/Antibody
57 APS pts + VTE
32 APS pts - VTE
32 aPLA - VTE
8 controls
RNA processing,
microarrays
informatics
• 100% accuracy VTE
Blood 2006 107:1391
“Registration Trials”
 Can we develop effective publicly transparent
methods of deciding when registration trials
must
Provide threshold data for CV safety
Provide definitive data regarding CV safety
Time
Intervention
Disease
Surrogate
Endpoint
True
Clinical
Outcome
Fleming and Demets
Annals Int Med
Time
A
Disease
Surrogate
Endpoint
True
Clinical
Outcome
Intervention
B
Disease
Surrogate
Endpoint
True
Clinical
Outcome
Flemming and Demets
Time
Intervention
C
Disease
Surrogate
Endpoint
True
Clinical
Outcome
Intervention
D
Disease
Surrogate
Endpoint
True
Clinical
Outcome
Flemming and Demets
Unintended Targets
Vesnarinone
? neurohormones
Calcium Blockers
Systolic Function
? Neurohormones
PD Inhibitors
Arrhythmia
Epoprostenol
Neurohormones
Unintended Targets
TNF- blockers
? neurohormones
Moxonidine
Systolic Function
? Neurohormones
Flosequinon
Neurohormones
Doxazocin
Fluid retention
Pre-Approval Development Program
• Pre-approval trials of sufficient size and
duration to rule out a HR of 2.0 for MACE
(upper 95% confidence interval).
• Required: Pre-specified pooling of CV
outcomes in all trials with adjudication by an
independent clinical endpoints committee.
• Useful: At least one study in patients at high
CV risk, perhaps 1000 patients for 1-2 years
Pre-Approval Cardiovascular Studies
Point
Patient-years
Patient-years
Upper
estimate
(2% annual
(3% annual
Number
95% CI
of events
event rate)
event rate)
of hazard
excluded
ratio
death, MI, stroke
MACE
50
2.5
1.44
2500
1667
87
2.0
1.31
4350
2900
122
1.8
1.26
6100
4067
256
1.5
1.17
12800
8533
MACE = major adverse CV events including death, MI, stroke,
and hospitalization for revascularization
87 Events to Exclude Upper 95% CI of 2.0
Active Control
43
0.98
44
48
39
35
52
53
34
1.23
0.67
1.56
0.4
0.5
0.67
Active better
1.0
1.5
2.0
Control better
Nissen
2.5
Comparative Effectiveness (Pragmatic)
 Can we get rid of the useless regulation and
response to regulation that is stifling our ability
to generate critical RCT data?
 Can we convince policy makers that
randomization is critical to sort out modest, but
important differences in treatment effect?
 Can we convince the US health system to
incorporate evidence generation into practice?
Clinical Trial Cost Estimates
$450
$400
Total
$350
Coordinating Center
$300
Site Payments
$250
Other
$200
$ In US 2007 Millions
$150
$100
$50
$0
Full Cost
Industry
Streamlined
Industry
More
Streamlined
Bureaucracy
 1 a : a body of nonelective government officials b
: an administrative policy-making group
 2 : government characterized by specialization of
functions, adherence to fixed rules, and a
hierarchy of authority
 3 : a system of administration marked by
officialism, red tape, and proliferation
Bureaucrats
 Bureaucrats write memoranda both because they
appear to be busy when they are writing and
because the memos, once written, immediately
become proof that they were busy
Charles Peters
 Hell hath no fury like a bureaucrat scorned
Milton Friedman (1912 - )
Bureaucracy
 The only thing that saves us from the bureaucracy is
inefficiency. An efficient bureaucracy is the greatest threat
to liberty
Eugene McCarthy (1916 - ), Time magazine, Feb.
12, 1979
 Bureaucracy defends the status quo long past the time
when the quo has lost its status
Laurence J. Peter (1919 - 1988)
 Any sufficiently advanced bureaucracy is indistinguishable
from molasses.
— Unknown
Comparative Effectiveness (Observational
Studies)
 Is there really way to make chicken salad out of
chicken $%^@?
 Can we develop a sentinel surveillance system
that provides instantaneous
Validation or refutation of observational comparisons
Public review of whether efforts to “adjust” have
been adequate
Launching of proper RCT if needed
Consider Hemoglobin and Erythrpoieten
 Anemia is bad
The worse the anemia the worse the prognosis
 Erythropoieten is a “natural product”
 When erythropieten is given the higher the
Hgb, the better the outcome
 When people are randomized to higher or lower
Hgb targets, lower does as well or better!
Safety Surveillance (Active)
 Can we develop embedded systems in
electronic health records that will enable rapid
collection of well defined data?
 What will happen with consumer driven
reporting of drug events?
Fundamental Informatics
Infrastucture--Matrix
Organizational Structure
Integrated at
“enterprise
level”
Electronic
Health
Records
Adaptable
to all!
Health
System A
Health
System B
Etc…
Disease Registries—Granular,
Detailed
Primary
Care
Mental
Health
Cancer
Cardiov
ascular
Etc…
Expected Number of ADEs
Target Population
Background
AEs
All AEs
=
+DRUG
=
=
ADEs
Expected Number of ADEs
Smaller safety
database
Less
power
ADEs prevented
ADEs prevented
ADEs prevented
ADEs prevented
Larger safety
database
More
power
ADEs prevented
ADEs prevented
Safety Surveillance (Passive)
 Can we develop more effective methods of
sorting signal from noise?
 How will we deal with the ubiquitous nature of
data warehouses that will be able to link use of
a drug with adverse outcomes?
Risk Communication
 Can we develop more effective methods of
presenting uncertainty (probabilities) to
The public?
Professional audiences?
The press?
Congress?
Therapies Always Cause a Combination of:
  
Good Effects
 
Bad Effects
Adapted from Furberg
Numeracy is the ability to reason with
numbers and other mathematical concepts.
To be numerically literate, a person has to
be comfortable with logic and reasoning.
Some of the areas that are involved in
numeracy include: basic numbers, orders of
magnitude, geometry, algebra, probability
and statistics.
45
Poll: 7/5 of Americans Don't Bother To Do
The Math A new poll shows that seven out
of every five of Americans don't bother to
do the math. "When asked, 53% percent
said that, when reading or hearing anything
that involves two or more numbers, they
don't even rtry to do the math," said lead
pollster Bradley Noel. "Another 49% said
they will often think about doing the math
but ultimately decide against it. Only 19%
said they will actually add things up to see if
the report makes sense.“
Source: innumeracy.com
46
Consequences of Innumeracy
 Inaccurate reporting of news stories and insufficient skepticism
in assessing these stories
 Financial mismanagement and accumulation of consumer debt,
specifically related to misunderstanding of compound interest
 Loss of money on gambling, in particular caused by belief in
the gambler's fallacy
 Belief in pseudoscience. According to Paulos, "Innumeracy
and pseudoscience are often associated, in part because of the
ease with which mathematical certainty can be invoked, to
bludgeon the innumerate into a dumb acquiescence."
 Poor assessment of risk, for example, refusing to fly by
airplane (a relatively safe form of transport) while taking
unnecessary risks in a car (where an accident is more likely)
 Limited job prospects
47
“I skate to where the puck is going to be, not to
where it has been.”
Wayne Gretzky
(the Puck Stops Here!)
48