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CV SAFETY IN PHARMACEUTICAL CV SAFETY IN PHARMACEUTICAL DEVELOPMENT – ACADEMIC DEVELOPMENT – ACADEMIC
PERSPECTIVEPERSPECTIVE
Rob Califf MDRob Califf MD
Vice Chancellor for Clinical ResearchVice Chancellor for Clinical Research Director, Duke Translational Director, Duke Translational
Research InstituteResearch Institute
AcademicAcademic
“Of theoretical interest, but of “Of theoretical interest, but of no practical value”no practical value”
Source: PhRMA, 2006 Industry Profile
Compound Compound Success Success RatesRates
3
6
9
12
15
Years
Reproduced from Moses et al., JAMA 2005;294:1333-42Reproduced from Moses et al., JAMA 2005;294:1333-42
Device firmsDevice firms
Biotech firmsBiotech firms
Pharma firmsPharma firms
Federal—Federal—non-NIHnon-NIH
State/localState/local
Source:Source:
PrivatePrivate
NIHNIH
19941994 1995 1995 1996 1996 1997 1997 19981998 19991999 20002000 20012001 20022002 20032003
100 –100 –
80 –80 –
60 –60 –
40 –40 –
20 –20 –
0 –0 –
Fu
nd
ing
($
in b
illio
ns
)F
un
din
g (
$ in
bill
ion
s)
363505
868
424
848
1272
0
500
1000
1500
Preclinical** Clinical Total
Mill
ion
s (2
004$
)
Original** 2004 Time Adjusted***
** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing** 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*** Based on a 5-year shift and prior growth rates for the preclinical and clinical periods
DiMasi et al. 2003DiMasi et al. 2003
Comparative Pre-Approval Capitalized Comparative Pre-Approval Capitalized Costs per Approved New MoleculeCosts per Approved New Molecule
Innovation Gap Getting WiderInnovation Gap Getting Wider
26 2522
28
53
39
30
35
2724
1721
16
11
$39.40
$11.50
0
20
40
60
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
NMEs (New Drug Approvals)
PhRMA Member R&D Spending
Burrill & CompanyBurrill & Company
Pharma Innovation
Gap
Pharma Innovation
Gap
Drug Safety SystemDrug Safety System Requires complex synergy between first rate science and first Requires complex synergy between first rate science and first
rate operational management on many levels in a complex rate operational management on many levels in a complex supply chainsupply chain
ComponentsComponents
Manufacturers/distributors including multiple subcontractorsManufacturers/distributors including multiple subcontractors
Practitioners/hospitals/health systems/insurers/payers/public Practitioners/hospitals/health systems/insurers/payers/public health systemshealth systems
ResearchersResearchers
Patients and consumersPatients and consumers
A regulatory agency dealing with this complexity needs A regulatory agency dealing with this complexity needs adequate staffing for routine function and first rate scientists adequate staffing for routine function and first rate scientists for complex functionsfor complex functions
Globalization, new understanding of clinical effectiveness and Globalization, new understanding of clinical effectiveness and genomic sciences have made this job much more difficult (and genomic sciences have made this job much more difficult (and interesting)interesting)
SafetySafety
the condition of being safe from undergoing or the condition of being safe from undergoing or causing hurt, injury, or losscausing hurt, injury, or loss
Merriam-Webster DictionaryMerriam-Webster Dictionary
The difficulty with safety of medical productsThe difficulty with safety of medical products
Hurt, injury or loss occurs due to use or can occur due Hurt, injury or loss occurs due to use or can occur due to lack of useto lack of use
Often the patient with the most to gain also has a high Often the patient with the most to gain also has a high risk of toxicityrisk of toxicity
AccordinglyAccordingly
Minimizing risk does not maximize safetyMinimizing risk does not maximize safety
Balancing Safety and Effectiveness Balancing Safety and Effectiveness Conceptual Goal: Not a ratio that can be Conceptual Goal: Not a ratio that can be calculated the same way for every person!calculated the same way for every person!
SafetSafetyy
EffectivenesEffectivenesss
Domains of Cardiovascular Safety AssessmentDomains of Cardiovascular Safety Assessment Preclinical Preclinical
Early clinical observationEarly clinical observation
Registration trialsRegistration trials
Comparative EffectivenessComparative Effectiveness
PCTsPCTs
Observational dataObservational data
Safety surveillanceSafety surveillance
Active Active
PassivePassive
Preclinical Cardiac SafetyPreclinical Cardiac Safety
Can we develop reproducible models that truly Can we develop reproducible models that truly inform the human condition when exposed to a inform the human condition when exposed to a drug?drug?
Human genetic disease models?Human genetic disease models?
Transgenic models?Transgenic models?
Can we link probabilistic information from Can we link probabilistic information from preclinical models to the human condition?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 TestingTake the QT interval and Channel Testing
If QT is long and biological channel testing If QT is long and biological channel testing positive there is very likely a risk of torsadespositive there is very likely a risk of torsades
We currently have no way of translating those We currently have no way of translating those signals into a quantitative risk of signals into a quantitative risk of torsades/deathtorsades/death
The epidemiology simply has not been done!The epidemiology simply has not been done!
Without a quantitative estimateWithout a quantitative estimate
Decision makers tend to revert to “safe mode”Decision makers tend to revert to “safe mode”
Even the most rational person cannot make rational Even the most rational person cannot make rational decisionsdecisions
Early Clinical CV SafetyEarly Clinical CV Safety
Can we develop effective biomarker signatures Can we develop effective biomarker signatures of cardiac toxicity in humans?of cardiac toxicity in humans?
Can we understand the mechanistic/systems Can we understand the mechanistic/systems basis for observations with biomarkers?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 discovery into human testingMove discovery into human testing Best technology with efficient managementBest technology with efficient management Highly professional, reliable staffHighly professional, reliable staff No “limits” on what can be doneNo “limits” on what can be done Academic designAcademic design
Research Tool BoxResearch Tool Box Easy access Easy access Best of its kindBest of its kind Define biological effects of drug/deviceDefine biological effects of drug/device Early responseEarly response ToxicityToxicity
ResultsResults Better biological understandingBetter biological understanding SignaturesSignatures of response, non response, of response, non response,
toxicity and predictiontoxicity and prediction New Research MethodologiesNew Research Methodologies
Move from “Phase I” to true biological proof Move from “Phase I” to true biological proof of concept!of concept!
Patient populations highly characterizedPatient populations highly characterized
Reclassify disease characteristics Reclassify disease characteristics
Define novel biological targets Define novel biological targets
Target/Disease Intervention Data Integration1 3
2 4
5
IT & BioinformaticsIT & Bioinformatics deployed to collate deployed to collate and organize the array of results so they and organize the array of results so they can be interpreted through statistical can be interpreted through statistical analysisanalysis
Protein Biomarkers and ‘OmicsGoal: Detect molecular events in blood as a
surrogate of local tissue responses
Gene Expression Predicts VTE RiskAntiPhosphoLipid
Syndrome/Antibody• 57 APS pts + VTE
• 32 APS pts - VTE
• 32 aPLA - VTE
• 8 controls
• RNA processing, microarrays informatics
• 100% accuracy VTEBlood 2006 107:1391
““Registration Trials”Registration Trials”
Can we develop effective publicly transparent Can we develop effective publicly transparent methods of deciding when registration trials methods of deciding when registration trials must must
Provide threshold data for CV safetyProvide threshold data for CV safety
Provide definitive data regarding CV safetyProvide definitive data regarding CV safety
TimeTime
DiseaseDiseaseDiseaseDisease SurrogateEndpoint
SurrogateEndpoint
True ClinicalOutcome
Fleming and Demets
Annals Int Med
True ClinicalOutcome
Fleming and Demets
Annals Int Med
InterventionInterventionInterventionIntervention
AA
BB
TimeTime
DiseaseDiseaseDiseaseDisease SurrogateEndpoint
SurrogateEndpoint
True ClinicalOutcomeFlemming and Demets
True ClinicalOutcomeFlemming and Demets
InterventionInterventionInterventionIntervention
DiseaseDiseaseDiseaseDisease SurrogateEndpoint
SurrogateEndpoint
True ClinicalOutcome
True ClinicalOutcome
CC
DD
TimeTime
DiseaseDiseaseDiseaseDiseaseSurrogateEndpoint
SurrogateEndpoint
True ClinicalOutcomeFlemming and Demets
True ClinicalOutcomeFlemming and Demets
InterventionInterventionInterventionIntervention
DiseaseDiseaseDiseaseDisease SurrogateEndpoint
SurrogateEndpoint
True ClinicalOutcome
True ClinicalOutcome
InterventionInterventionInterventionIntervention
Unintended TargetsUnintended Targets
VesnarinoneVesnarinone ? neurohormones? neurohormones
Calcium BlockersCalcium BlockersSystolic Function? NeurohormonesSystolic Function? Neurohormones
PD InhibitorsPD Inhibitors ArrhythmiaArrhythmia
EpoprostenolEpoprostenol NeurohormonesNeurohormones
Unintended TargetsUnintended Targets
TNF- blockersTNF- blockers ? neurohormones? neurohormones
MoxonidineMoxonidineSystolic Function? NeurohormonesSystolic Function? Neurohormones
FlosequinonFlosequinon NeurohormonesNeurohormones
DoxazocinDoxazocin Fluid retentionFluid retention
Pre-Approval Development ProgramPre-Approval Development ProgramPre-Approval Development ProgramPre-Approval Development Program
• Pre-approval trials of sufficient size andPre-approval trials of sufficient size andduration to rule out a HR of 2.0 for MACEduration to rule out a HR of 2.0 for MACE(upper 95% confidence interval). (upper 95% confidence interval).
• Required: Pre-specified pooling of CVRequired: Pre-specified pooling of CVoutcomes in all trials with adjudication by anoutcomes in all trials with adjudication by anindependent clinical endpoints committee.independent clinical endpoints committee.
• Useful: At least one study in patients at highUseful: At least one study in patients at highCV risk, perhaps 1000 patients for 1-2 yearsCV risk, perhaps 1000 patients for 1-2 years
Pre-Approval Cardiovascular StudiesPre-Approval Cardiovascular StudiesPre-Approval Cardiovascular StudiesPre-Approval Cardiovascular Studies
Number of events
Upper 95% CI
excluded
Point estimate
of hazard ratio
Patient-years (2% annual event rate)
death, MI, stroke
Patient-years (3% annual event rate)
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 2.087 Events to Exclude Upper 95% CI of 2.087 Events to Exclude Upper 95% CI of 2.087 Events to Exclude Upper 95% CI of 2.0
Active Control
43 44
48 39
35 52
53 34
1.23
0.67
1.56
0.4 0.5 2.01.51.0
Control betterNissen
Active better
2.50.67
0.98
Comparative Effectiveness (Pragmatic)Comparative Effectiveness (Pragmatic)
Can we get rid of the useless regulation and Can we get rid of the useless regulation and response to regulation that is stifling our ability response to regulation that is stifling our ability to generate critical RCT data?to generate critical RCT data?
Can we convince policy makers that Can we convince policy makers that randomization is critical to sort out modest, but randomization is critical to sort out modest, but important differences in treatment effect?important differences in treatment effect?
Can we convince the US health system to Can we convince the US health system to incorporate evidence generation into practice?incorporate evidence generation into practice?
Clinical Trial Cost EstimatesClinical Trial Cost Estimates
$0
$50
$100
$150
$200
$250
$300
$350
$400
$450
T o tal
Co o rd in atin g Cen ter
S ite Paym en ts
Oth er
Full Cost Industry
Streamlined Industry
More Streamlined
$ In US 2007 Millions
Bureaucracy Bureaucracy
1 a : a body of nonelective government officials b 1 a : a body of nonelective government officials b : an administrative policy-making group: an administrative policy-making group
2 : government characterized by specialization of 2 : government characterized by specialization of functions, adherence to fixed rules, and a functions, adherence to fixed rules, and a hierarchy of authorityhierarchy of authority
3 : a system of administration marked by 3 : a system of administration marked by officialism, red tape, and proliferation officialism, red tape, and proliferation
BureaucratsBureaucrats
Bureaucrats write memoranda both because they Bureaucrats write memoranda both because they appear to be busy when they are writing and appear to be busy when they are writing and because the memos, once written, immediately because the memos, once written, immediately become proof that they were busybecome proof that they were busy
Charles Peters Charles Peters
Hell hath no fury like a bureaucrat scornedHell hath no fury like a bureaucrat scorned
Milton Friedman (1912 - )Milton Friedman (1912 - )
BureaucracyBureaucracy
The only thing that saves us from the bureaucracy is The only thing that saves us from the bureaucracy is inefficiency. An efficient bureaucracy is the greatest threat inefficiency. An efficient bureaucracy is the greatest threat to liberty to liberty
Eugene McCarthy (1916 - ), Eugene McCarthy (1916 - ), Time magazine, Feb. Time magazine, Feb. 12, 197912, 1979
Bureaucracy defends the status quo long past the time Bureaucracy defends the status quo long past the time when the quo has lost its statuswhen the quo has lost its status
Laurence J. Peter (1919 - 1988) Laurence J. Peter (1919 - 1988)
Any sufficiently advanced bureaucracy is indistinguishable Any sufficiently advanced bureaucracy is indistinguishable from molasses. from molasses.
— UnknownUnknown
Comparative Effectiveness (Observational Comparative Effectiveness (Observational Studies)Studies)
Is there really way to make chicken salad out of Is there really way to make chicken salad out of chicken $%^@?chicken $%^@?
Can we develop a sentinel surveillance system Can we develop a sentinel surveillance system that provides instantaneousthat provides instantaneous
Validation or refutation of observational comparisonsValidation or refutation of observational comparisons
Public review of whether efforts to “adjust” have Public review of whether efforts to “adjust” have been adequatebeen adequate
Launching of proper RCT if neededLaunching of proper RCT if needed
Consider Hemoglobin and ErythrpoietenConsider Hemoglobin and Erythrpoieten
Anemia is badAnemia is bad
The worse the anemia the worse the prognosisThe worse the anemia the worse the prognosis
Erythropoieten is a “natural product”Erythropoieten is a “natural product”
When erythropieten is given the higher the When erythropieten is given the higher the Hgb, the better the outcomeHgb, the better the outcome
When people are randomized to higher or lower When people are randomized to higher or lower Hgb targets, lower does as well or better!Hgb targets, lower does as well or better!
Safety Surveillance (Active)Safety Surveillance (Active)
Can we develop embedded systems in Can we develop embedded systems in electronic health records that will enable rapid electronic health records that will enable rapid collection of well defined data?collection of well defined data?
What will happen with consumer driven What will happen with consumer driven reporting of drug events?reporting of drug events?
Integrated at “enterprise level”
Disease Registries—Granular, DetailedPrimary
CareCancer
Mental Health
Cardiovascular Etc…
Health System A
Health System B
Etc…
ElectronicHealth Records
Adaptable to all!
Fundamental Informatics Fundamental Informatics Infrastucture--Matrix Infrastucture--Matrix Organizational Structure Organizational Structure
Expected Number of ADEs
Target PopulationTarget Population ADEsADEsBackground
AEsBackground
AEsAll AEsAll AEs
+DRUG+DRUG
==
==
==
ADEs preventedADEs prevented
ADEs preventedADEs prevented
ADEs preventedADEs prevented
ADEs preventedADEs prevented
ADEs preventedADEs prevented
Expected Number of ADEs
Smaller safety database
Smaller safety database
Larger safety database
Larger safety database
Less powerLess
power
More powerMore power
ADEs preventedADEs prevented
Safety Surveillance (Passive)Safety Surveillance (Passive)
Can we develop more effective methods of Can we develop more effective methods of sorting signal from noise?sorting signal from noise?
How will we deal with the ubiquitous nature of How will we deal with the ubiquitous nature of data warehouses that will be able to link use of data warehouses that will be able to link use of a drug with adverse outcomes?a drug with adverse outcomes?
Risk CommunicationRisk Communication
Can we develop more effective methods of Can we develop more effective methods of presenting uncertainty (probabilities) to presenting uncertainty (probabilities) to
The public?The public?
Professional audiences?Professional audiences?
The press?The press?
Congress?Congress?
Good EffectsGood EffectsGood EffectsGood Effects Bad EffectsBad EffectsBad EffectsBad Effects
Adapted from FurbergAdapted from Furberg
Therapies Always Cause a Combination of:Therapies Always Cause a Combination of:
45
Numeracy is the ability to reason with Numeracy is the ability to reason with numbers and other mathematical concepts. numbers and other mathematical concepts. To be numerically literate, a person has to To be numerically literate, a person has to be comfortable with logic and reasoning. be comfortable with logic and reasoning. Some of the areas that are involved in Some of the areas that are involved in numeracy include: basic numbers, orders of numeracy include: basic numbers, orders of magnitude, geometry, algebra, probability magnitude, geometry, algebra, probability and statistics. and statistics.
46
Poll: 7/5 of Americans Don't Bother To Do Poll: 7/5 of Americans Don't Bother To Do The Math A new poll shows that seven out The Math A new poll shows that seven out of every five of Americans don't bother to of every five of Americans don't bother to do the math. "When asked, 53% percent do the math. "When asked, 53% percent said that, when reading or hearing anything said that, when reading or hearing anything that involves two or more numbers, they that involves two or more numbers, they don't even rtry to do the math," said lead don't even rtry to do the math," said lead pollster Bradley Noel. "Another 49% said pollster Bradley Noel. "Another 49% said they will often think about doing the math they will often think about doing the math but ultimately decide against it. Only 19% but ultimately decide against it. Only 19% said they will actually add things up to see if said they will actually add things up to see if the report makes sense.“the report makes sense.“
Source: innumeracy.comSource: innumeracy.com
47
Consequences of InnumeracyConsequences of Innumeracy Inaccurate reporting of news stories and insufficient skepticism Inaccurate reporting of news stories and insufficient skepticism
in assessing these stories in assessing these stories
Financial mismanagement and accumulation of consumer debt, Financial mismanagement and accumulation of consumer debt, specifically related to misunderstanding of compound interest specifically related to misunderstanding of compound interest
Loss of money on gambling, in particular caused by belief in Loss of money on gambling, in particular caused by belief in the gambler's fallacy the gambler's fallacy
Belief in pseudoscience. According to Paulos, Belief in pseudoscience. According to Paulos, "Innumeracy and "Innumeracy and pseudoscience are often associated, in part because of the pseudoscience are often associated, in part because of the ease with which mathematical certainty can be invoked, to ease with which mathematical certainty can be invoked, to bludgeon the innumerate into a dumb acquiescence."bludgeon the innumerate into a dumb acquiescence."
Poor assessment of risk, for example, refusing to fly by Poor assessment of risk, for example, refusing to fly by airplane (a relatively safe form of transport) while taking airplane (a relatively safe form of transport) while taking unnecessary risks in a car (where an accident is more likely) unnecessary risks in a car (where an accident is more likely)
Limited job prospects Limited job prospects
48
“I skate to where the puck is going to be, not to where it has been.”
Wayne Gretzky(the Puck Stops Here!)
“I skate to where the puck is going to be, not to where it has been.”
Wayne Gretzky(the Puck Stops Here!)