cv safety in pharmaceutical development – academic perspective rob califf md vice chancellor for...

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


Fleming and Demets

Annals Int Med

InterventionInterventionInterventionIntervention

AA

BB

TimeTime


SurrogateEndpoint

True ClinicalOutcomeFlemming and Demets




SurrogateEndpoint



CC

DD

TimeTime

DiseaseDiseaseDiseaseDiseaseSurrogateEndpoint

SurrogateEndpoint





SurrogateEndpoint




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





Expected Number of ADEs

Smaller safety database

Smaller safety database

Larger safety database

Larger safety database

Less powerLess

power

More powerMore power


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!)

cv safety in pharmaceutical development – academic perspective rob califf md vice chancellor for...

Documents

safety slide

safety effectiveness

interesting slide

preclinical cardiac

balancing safety

rational decisions slide

early clinical cv safety

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