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Drug Safety Regulation in the US:Drug Safety Regulation in the US:

YuYu--Xiao Yang, MD, MSCE, FACPXiao Yang, MD, MSCE, FACP

Division of GastroenterologyDivision of GastroenterologyCenter for Clinical Epidemiology and BiostatisticsCenter for Clinical Epidemiology and Biostatistics

University of PennsylvaniaUniversity of Pennsylvania

20112011

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e ere man c oo o e c ne at t e

University of Pennsylvania en or sc o ar a e en er or n ca p em o ogy

and Biostatistics (CCEB)

Clinical Epidemiologist Pharmacoepidemiology

Cancer epidemiology

Editorial roles Pharmacoepidemiology and Drug Safety

Annals of Internal Medicine

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Historical perspectiveHistorical perspective

PrePre--marketingmarketing

ostost-- ar et ngar et ng Current status of the US harmaco oeiaCurrent status of the US harmaco oeia

New initiativesNew initiatives

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The history of drug regulation inThe history of drug regulation in

the US is a histor of oliticalthe US is a histor of oliticalresponses to epidemics of adverseresponses to epidemics of adverse

,,public health importance to lead topublic health importance to lead to

change.change.Brian L. Strom, MD, MPHBrian L. Strom, MD, MPHPharmacoepidemiology, Preface to 1Pharmacoepidemiology, Preface to 1stst Ed.Ed.

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Wiley and the Poison SquadWiley and the Poison Squad

Harvey Washington Wiley (1844 -1930) Chief Chemist in the United States Department of Agriculture

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rs comm ss oner o e oo an rug m n s ra on

Father of the Pure Food and Drug Act of 1906 Known for the Poison Squad studies

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History of Drug Regulation in US

1900s

1906

The Pure Food and Dru Act

Prohibiting interstate commerce of adulterated

Safety after consumption was not addressed

o requ rement or proo o e cacy or sa ety

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Elixir of sulfanilamide - 1937 ew an - n ec ve won er rug

Diethylene glycol used as solvent

1938 , ,

Manufacturer provide safety data

No proof of efficacy required

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1950s1950s 19501950

Chloramphenical and aplastic anemiaChloramphenical and aplastic anemia

DurhamDurham--Humphrey AmendmentHumphrey Amendment

Distinction of rescri tion and OTC dru sDistinction of rescri tion and OTC dru s

19521952

stst publishedpublished

established

later incorporated into the spontaneous reporting

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system of the U.S. FDA

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1960s1960s

Thalidomide disasterThalidomide disaster

19621962

--

Extensive preclinical testing requiredExtensive preclinical testing required

. .,. .,

Mandatory reporting of ADRsMandatory reporting of ADRs

ncrease me an cos o rug approvancrease me an cos o rug approvaprocessprocess

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prepre--1962 drugs1962 drugs

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1980s and 1990s1990s s

AIDS Epidemic ro onge rug approva process

criticized

Prescription Drug User Fee ActPDUFA Drug manufacturers pay fees to allow

the FDA to assign more resources to the

Drug review time cut from ~30 months to~15 months

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x en e y o ern za on

Act

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2000s

Vioxx and increased risk of myocardialinfarction

2006 Institute of Medicine Review of FDA

Major deficiencies revealed Called for an increase in the regulatory powers,

funding, and independence of the FDA

2007

PDUFA 4 Increased policing power for FDA Increase in user fee ($1-1.8 million per NDA in

2012)

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$702,172,000 for FY 2012

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Diabetes Drug Avandia Should Beemove rom t e ar et, u c

Committee

,

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Characteristics of Cases of

Risoglitazone-induced liver failure 13 cases tota regar e as e ng assoc ate w t van a y u c c t zen

Limited information on most

Patient # Duration Max Max Max Alk Max Outcome Liver Path(wks) AST ALT Phos TB

1 NA 65 70 520 4.1 Death NA

., death

inflammation, fibrosis

3 NA 99 78 158 3.1 Death NA

4 58 123 83 296 4.3 Death Massive necrosis withcollapse of architecture,cirrhosis

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5 26 NA NA NA 36 Death NA

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ostost-- ar et ngar et ng Current status of the US harmaco oeiaCurrent status of the US harmaco oeia


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Current Drug Development and

pprova rocess

Preclinical

Testing Phase I Phase II Phase III FDA Phase IV

Years ~3.5 ~1 ~2 ~3 ~2.5~10-12Total

FileIND

FileNDA Additional

TestPopulation

Laboratoryand animal

studies

20 to 80healthy

volunteers

100 to 300patient

volunteers

1000 to 3000patient

volunteersat

FDAat

FDA

marketing

testingrequired

by FDA

Reviewprocess /Approval

Pur ose

Assess

safety andDeterminesafet and

Evaluate

effectiveness

Verifyeffectiveness,

monitoroogcaactivity

dosage, oo or s e

effectsa verse

reactions fromlong-term use

5,000

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Rate

compounds

evaluated

5 enter trials

approved

IND = Investigational New Drug; NDA = New Drug ApplicationIND = Investigational New Drug; NDA = New Drug Application

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m ar n t e an ot er eve ope

countries Preclinical animal testing

A few normal volunteers

To determine drug metabolism and a safe

To exclude common toxic reactions

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Phase II

Small # of atients with the tar et disease

To determine pharmacokinetics

To assess possible efficacy

To determine daily dose and regimen for

phase III

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Phase III

Performed b clinician-investi ators

Involving much larger # of patients (e.g., 500-

At least one of the phase III studies must be

For FDA, at least one of the RCTs must becon ucte n t e

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PremarketingPremarketingUse in General PublicUse in General Public

FDA ApprovalFDA Approval

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- IND Annual progress report to the FDA

Listin all AEs deaths withdrawals due toAEs

the FDA is the norm

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Limitations ofPremarketing Clinical Trials

Too...Too...

fewfew

idealideal

narrownarrow

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briefbriefindirectindirect

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Statistical Power inStatistical Power in

Premarketing Safety StudiesPremarketing Safety Studies

Frequency 500 1500 3000in controls0.1 .99 .99 .99

0.05 .85 .99 .99

0.01 .25 .61 .89

. . . .

0.0001 .05 .06 .06

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Limitations of

Premarketing Clinical Trials oo eaoo ea

Ideal patientsExclude children,

elderly, etc.

Too narrowToo narrow

indication

used off-label

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Limitations of

Premarketing Clinical Trials oo r e

Duration 1-3 years ss s w tlong latency

Indirect (surrogate

Limited by

surrogate

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PremarketingPremarketingUse in General PublicUse in General Public

FDA ApprovalFDA Approval

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Adverse event reporting systems

tomorrow)

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Purpose of Post-Marketing

Surveillance To obtain additional information on

adverse events that ma not have beendetected prior to marketing

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What is an Adverse Drug

Experience? Any adverse event associated with the use

of dru in humans whether or not it isconsidered drug related.

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Serious Adverse Drug

Experience Death

Permanently or significantly disabling

Hospitalization

Important medical events

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Unexpected Adverse Drug

Experience Not listed in current labeling

severity

e.g. rena mpa rmen s e , pa enexperiences renal failure

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Adverse Event Reporting

Requirements

Consumer

Mandatory Reporting of Manufacturers

n ca en ar ays er ous an nexpec e

Quarterly (newly approved) and annual (old drugs)

Serious & Expected ADEs

All Non-serious

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When does the Regulatory

Clock Start? First day a firm or any affiliate receives

event data containin all four elements:An identifiable patient

n ent a e reporter

A suspect drug

An adverse event or fatal outcome

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FDA Adverse Event Reporting System

(AERS) e atc

Voluntary reporting by providers or publicOnly serious AE reports requested

Causality is not a prerequisit for reporting

Convenient and simple A sin le a e www.fda. ov/medwatch FDA form

3500 and 3500a

Fax, mail, phone or web report VAERs (Vaccine Adverse Event Reporting System)

Onl vaccines

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Stren ths ofSpontaneous Reporting

Relativel inex ensive

Large size - detection of rare events

At times sufficient for regulatoryThe plural ofThe plural of

Vital for h othesis enerationis not datais not data

Disproportionality measures

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Si nificant si nalSi nificant si nal

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Limitations ofSpontaneous Reporting

Report quality

en mpor an a a m ss ng

Bias

Reported cases differ from unreported L k f n r l r

Event rate in unexposed rarely known

a o ca cu a e ue c e ce

Not good for common events

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ostost-- ar et ngar et ng

Current status of the US harmaco oeiaCurrent status of the US harmaco oeia


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Rapidly expanding pharmacopoeia

Where we can monitor, the rates of

a verse events appear to e g

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R idl E di Ph iR idl E di Ph i

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Rapidly Expanding PharmacopoeiaRapidly Expanding Pharmacopoeia

140

160

120

80

100

40

60

20

0

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

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P i ti M di ti U D i th

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Prescription Medication Use During the

Previous Week in Ambulatory Patients

CCEBCCEBKaufman et al. JAMA 2002;287:337Kaufman et al. JAMA 2002;287:337--4444

Th P bl

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The Problem:

Too Many Unexpected Outcomes

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This figure illustrates the number of reports receivedThis figure illustrates the number of reports received

(solid bars) and entered (checkered bars) into AERS by(solid bars) and entered (checkered bars) into AERS bytype of report since the year 2000 until the end of 2010.type of report since the year 2000 until the end of 2010.

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1975-99 548 new chemical

entities a roved 56 (10.2%) acquired new

16 (2.9%) were withdrawn

Lasser et al. JAMA2002;287:2215-20

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19991999 -- troglitazonetroglitazone

-- c sapr ec sapr e

20052005 natalizumabnatalizumab20072007 tegaserodtegaserod

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Admit hospital for ADR 63,000

, Total 106,000

th

Lazarou et al. JAMA 1998;279:1200Lazarou et al. JAMA 1998;279:1200

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ostost-- ar et ngar et ng

Current status of the US harmaco oeiaCurrent status of the US harmaco oeia


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Post Marketing Safety Research

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Post-Marketing Safety Research

Efforts s ect ve ea t are rogram

DEcIDE Networks

en ers or uca on an esearc on erapeu cs(CERTs)

Drug Safety collaboration -,

Multiple stakeholders

Testin usin a combination of electronic healthrecords and administrative claims data to detect drugsafety signals

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Increase awareness of the benefits and harms of drugs, medical,

14 Collaborating Centers

Center EmphasisBrigham Health information technology

Duke Therapies for CV disorders

HMO Research Network Population-based delivery system

Rutgers Mental health therapeutics

UAB MS disorders

U Iowa Thera eutics for the elderl

Cincinnati Childrens Pediatric therapeutics

U Penn Anti-infective therapeutics

Cornell Therapeutic medical devices

U of Chicago Clinical and economic issues

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U of Illinois Tools for optimizing prescribing

Vanderbilt Therapeutics for vulnerable populationsU Arizona Drug interactions

The DEcIDE (Developing Evidence to Inform

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The DEcIDE (Developing Evidence to Inform

Decisions about Effectiveness) Network Conducts studies on the outcomes, effectiveness, safety, and

usefulness of medical treatments

Brigham and Womens Hospital Duke

Johns Hopkins UPenn UNC U of Illinois

U Minnesota Vanderbilt

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The Sentinel System under development

Improving FDAs capability to identify and evaluatesafety issues in near real time (active surveillance)

Will use existing electronic health care data to more quickly

events Involves close partnership with academia

Specific examples

Mini-Sentinel

Federal Partners Collaboration between FDA, CMS, DoD,and VA

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Mini-Sentinel (www.minisentinel.org)

Five year contract between FDA and Harvard PilgrimHealth Care Institute, launched in 2009

Over 200 co-investigators from 27 institutions

Create a coordinating center with continuous accessto automated healthcare data systems

eve ops an eva ua es sc en c me o s or e u y-operational Sentinel System

Affords the o ortunity to evaluate safety issues usingexisting electronic healthcare data systems

Allows the FDA to learn more about the barriers and

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surveillance

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Observational Medical Outcomes Partnership

(http://omop.fnih.org/) Public-private partnership led by FDA, PhRMA, andFNIH with participation of academic and privatesec or nves ga ors,

To inform the appropriate use of observational health

Develop methodology for observational studies

Establish a shared resource mer in dis arate health datasource

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Documents

06 dia 01