Drug Safety Regulation in the US:

an Academic Perspective
YuYu-Xiao Yang, MD, MSCE, FACP

Division of Gastroenterology Center for Clinical Epidemiology and Biostatistics University of Pennsylvania 2011

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Who am I?
Th P l The Perelman S h l of M di i at th School f Medicine t the University of Pennsylvania
S i scholar at th C t f Cli i l E id i l Senior h l t the Center for Clinical Epidemiology and Biostatistics (CCEB) Gastroenterologist Clinical Epidemiologist
Pharmacoepidemiology Cancer epidemiology

Editorial roles
Pharmacoepidemiology and Drug Safety Annals of Internal Medicine
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Outline
Historical perspective Drug Safety Regulation and Surveillance
Pre-marketing Pre Post-M k ti Post P t-Marketing

Current status of the US pharmacopoeia p p New initiatives

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A Century of Problems with Drugs

The history of drug regulation in y political the US is a history of p responses to epidemics of adverse drug reactions, each of sufficient reactions public health importance to lead to political pressure for regulatory change.
Brian L. Strom, MD, MPH Pharmacoepidemiology, Preface to 1st Ed.
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History of Drug Regulation in US

Wiley and the Poison Squad

Harvey Washington Wiley (1844 -1930)
Chief Chemist in the United States Department of Agriculture First commissioner of the US Food and Dr g Administration Drug 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 Drug Act g Prohibiting interstate commerce of adulterated and misbranded food and drugs Safety after consumption was not addressed N requirement f proof of efficacy or safety No i t for f f ffi f t

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History of Drug Regulation in US 1930s

1937
Elixir of sulfanilamide - 1937 N New anti-infective wonder d ti i f ti d drug Diethylene glycol used as solvent 107 died

1938
Food Drug, and Cosmetic Act Food, Drug Manufacturer provide safety data FDA to review safety data in 60 days No proof of efficacy required

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 1950 1951

History of Drug Regulation in US 1950s

Chloramphenical and aplastic anemia Durham-Humphrey Amendment Durham Distinction of prescription and OTC drugs

1952
1st textbook of adverse drug reaction published AMA Registry on Blood Dyscrasias established
later incorporated into the spontaneous reporting system of the U.S. FDA
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History of Drug Regulation in US 1960s

1960
Thalidomide disaster
Epidemic of phocomelia in Europe

1962
Kefauver-Harris Amendment to FD&C Act Kefauver Extensive preclinical testing required Proof of efficacy (i.e., RCT) required (i e Mandatory reporting of ADRs I Increased ti d time and cost of drug approval d t fd l process Drug Efficacy Study Implementation for prepre-1962 drugs
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History of Drug Regulation in US 1980s and 1990s

1980 1980s
AIDS Epidemic P l Prolonged d d drug approval process l criticized

1992
Prescription Drug User Fee Act (PDUFA)
Drug manufacturers pay fees to allow the FDA to assign more resources to the drug review and approval process Drug review time cut from ~30 months to ~15 months E t d d b 1997 FDA Modernization Extended by M d i ti Act
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History of Drug Regulation in US 2000s

2004
Vioxx and increased risk of myocardial infarction

2006
Institute of Medicine Review of FDA
Major deficiencies revealed Called for an increase in the regulatory powers, g 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) $ $702,172,000 f FY 2012 for
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Political and Public Influence

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Diabetes Drug Avandia Should Be Removed F R d From th M k t Public the Market, P bli Citizen Tells FDA Advisory Committee July 30 2007 30,

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Characteristics of Cases of Risoglitazone-induced liver failure

13 cases total regarded as b i associated with A l d d being i d i h Avandia b P bli citizen di by Public i i Limited information on most Highly doubtful association in several
Max AST 65 131 99 123 Max ALT 70 111 78 83 Max Alk Max Phos TB 520 168 158 296 4.1 1.3 13 3.1 4.3 Outcome Death Liver Path NA

Patient # Duration (wks) 1 2 3 4 NA 7 NA 58

Transplant Mild chronic portal inflammation, fibrosis , death Death Death NA Massive necrosis with collapse of architecture, cirrhosis NA

5 CCEB

26

NA

NA

NA

36

Death

Outline
Historical perspective Drug Safety Regulation and Surveillance
Pre-marketing Pre Post-M k ti Post P t-Marketing

Current status of the US pharmacopoeia p p New initiatives

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Current Drug Development and Approval P A l Process

Clinical Trials
Preclinical Testing Phase I Phase II Phase III FDA Phase IV

Years

~3.5

~1

~2

~3

~2.5

~10-12 Total

Test Population

Laboratory and animal studies

File IND at FDA

20 to 80 healthy volunteers

100 to 300 patient volunteers

1000 to 3000 patient volunteers Verify effectiveness, monitor adverse reactions from long-term use

File NDA at FDA

Purpose p

Assess safety and biological activity

Determine safety and y dosage

Evaluate effectiveness , look for side effects

Review process / Approval

Additional Post marketing testing required by FDA

Success Rate

5,000 compounds evaluated

5 enter trials

1 approved

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IND = Investigational New Drug; NDA = New Drug Application

Current Drug Approval Process

Si il i th US and other d Similar in the d th developed l d countries Preclinical animal testing Phase I
A few normal volunteers Patients are rarely used for highly toxic drugs To determine drug metabolism and a safe dose range To exclude common toxic reactions
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Current Drug Approval Process

Phase II
Small # of patients with the target disease p g To determine pharmacokinetics To determine common toxic reactions To assess possible efficacy To determine daily dose and regimen for phase III

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Current Drug Approval Process

Phase III
Performed by clinician-investigators y g Involving much larger # of patients (e.g., 5003000) At least one of the phase III studies must be an RCT For FDA, at least one of the RCTs must be conducted i th US d t d in the

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How We Assess Drug Safety

Premarketing

Use in General Public

FDA Approval

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Pre-Marketing Pre Marketing Safety Reporting

IND Annual progress report to the FDA
Listing all AEs, deaths, withdrawals due to g , , AEs

Expedited safety reports sent to IRB and the FDA is the norm

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Limitations of Premarketing Clinical Trials

Too...

few ideal narrow brief indirect

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Statistical Power in Premarketing Safety Studies

Exposed Sample Size Frequency q y in controls 0.1 0.05 0.01 0.001 0 001 0.0001
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500 .99 .85 .25 .07 07 .05

1500 .99 .99 .61 .11 11 .06

3000 .99 .99 .89 .17 17 .06

TwoTwo-tailed test, =0.05, 1:1 ratio of exposed to unexposed subjects

Limitations of Premarketing Clinical Trials

T ideal Too id l Ideal patients Exclude children, elderly, etc. Too narrow Focus on specific Focus indication In practice drug In used off-label
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Limitations of Premarketing Clinical Trials

T brief Too b i f
Duration 1-3 years Miss ADR with Mi ADRs ith long latency

Indirect (surrogate endpoints)

Limited by predictive ability of surrogate

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How We Assess Drug Safety

Premarketing

Use in General Public

FDA Approval

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Postmarketing Surveillance
Adverse event reporting systems Formal studies (will discuss tomorrow)

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Purpose of Post-Marketing Surveillance

To obtain additional information on y adverse events that may not have been detected prior to marketing To improve the labeling of drug products

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What is an Adverse Drug Experience?

Any adverse event associated with the use g of drug in humans whether or not it is considered drug related.

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Serious Adverse Drug Experience

Death Life threatening (per initial reporter) Permanently or significantly disabling Hospitalization Congenital anomaly/birth defect Important medical events

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Unexpected Adverse Drug Experience

Not listed in current labeling Listed in labeling but greater specificity or severity
e.g. renal i l impairment li t d patient i t listed, ti t experiences renal failure

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Adverse Event Reporting Requirements

Voluntary reporting
Consumer Healthcare professionals

Mandatory Reporting of Manufacturers

Withi 15 calendar d Within l d days if S i Serious and U d Unexpected t d Quarterly (newly approved) and annual (old drugs) reports
Serious & Expected ADEs All Non-serious Non serious

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When does the Regulatory Clock Start?

First day a firm or any affiliate receives g event data containing all four elements:
An identifiable patient A id tifi bl reporter An identifiable t A suspect drug An adverse event or fatal outcome

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FDA Adverse Event Reporting System (AERS)

M dW t h MedWatch Voluntary reporting by providers or public Only serious AE reports requested Causality is not a prerequisit for reporting y g Convenient and simple
A single p g ( g page (www.fda.gov/medwatch) FDA form g ) 3500 and 3500a

Fax, mail, phone or web report VAERs (Vaccine Adverse Event Reporting System) Only vaccines y
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Strengths of g Spontaneous Reporting

Relatively inexpensive y p Large size - detection of rare events

The plural of At times sufficient for regulatory decisions anecdote is Vital for hypothesis g yp not data generation
Disproportionality measures
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Disproportionality Analysis

Significant signal g g

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Limitations of Spontaneous Reporting

Report quality Often important data missing Oft i t td t i i Bias Reported cases differ from unreported Lack of a control group Event rate in unexposed rarely known Cannot calculate true incidence Not good for common events
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Outline
Historical perspective Drug Safety Regulation and Surveillance
Pre-marketing Pre Post-M k ti Post P t-Marketing

Current status of the US pharmacopoeia p p New initiatives

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Current Status
Rapidly expanding pharmacopoeia Medications widely used Where we can monitor, the rates of adverse events appear t be hi h d t to b high

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Rapidly Expanding Pharmacopoeia

160 140 120 100 80 60 40 0 20 0
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 20 03 20 04 20 05 20 06

NDAs
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Approvals

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Prescription Medication Use During the Previous Week in Ambulatory Patients

Kaufman et al. JAMA 2002;287:337-44 2002;287:337CCEB

The Problem: Too Many Unexpected Outcomes

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This figure illustrates the number of reports received (solid bars) and entered (checkered bars) into AERS by type of report since the year 2000 until the end of 2010.

Black Box Warnings

1975-99 548 new chemical pp entities approved 56 (10.2%) acquired new black box warnings 16 (2.9%) were withdrawn
Lasser et al. JAMA 2002;287:2215-20

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Recent Withdrawals
1999 - troglitazone 2000 - cisapride i id 2001 alosetron 2005 rofecoxib and valdecoxib 2005 natalizumab 2007 tegaserod
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Estimated Fatal ADRs 1994

Admit hospital for ADR 63,000 ADR during hospitalization 43 000 43,000 Total 106,000 4th leading cause of death
Lazarou et al. JAMA 1998;279:1200

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Outline
Historical perspective Drug Safety Regulation and Surveillance
Pre-marketing Pre Post-M k ti Post P t-Marketing

Current status of the US pharmacopoeia p p New initiatives

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Post-Marketing Safety Research Efforts

AHRQ Effective Health Care Program AHRQs Eff ti H lth C P
DEcIDE Networks C t Centers f Education and R for Ed ti d Research on Th h Therapeutics ti (CERTs)

eHealth Initiatives Connecting Communities for Initiative s Drug Safety collaboration

Independent non-profit national organization Independent, non profit Multiple stakeholders Testing using a combination of electronic health records and administrative claims data to detect drug safety signals
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CERTs
Increase awareness of the benefits and harms of drugs, medical devices, devices and biological products through education and research 14 Collaborating Centers
Emphasis Health information technology Therapies for CV disorders Population-based delivery system Mental health therapeutics MS disorders Therapeutics for the elderly Pediatric therapeutics Anti-infective therapeutics Consumer education Therapeutic medical devices Clinical and economic issues Tools f optimizing prescribing for Therapeutics for vulnerable populations Drug interactions Center Brigham Duke HMO Research Network Rutgers UAB U Iowa Cincinnati Childrens U Penn U of Texas Cornell U of Chicago U of Illinois f Vanderbilt U Arizona CCEB

The DEcIDE (Developing Evidence to Inform Decisions about Effectiveness) Network

Established in 2005 Conducts studies on the outcomes, effectiveness, safety, and usefulness of medical treatments PIs
Brigham and Womens Hospital Duke Havard Medical School Johns Hopkins UPenn Rutger s Rutgers UNC U of Illinois U Iowa U Minnesota Vanderbilt

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New Drug Safety Initiatives

The Sentinel System under development
Improving FDAs capability to identify and evaluate safety issues in near real time (active surveillance)
Will use existing electronic health care data to more quickly identify relationships between medical products and adverse events

Involves close partnership with academia Specific examples

Mini-Sentinel Federal Partners Collaboration between FDA, CMS, DoD, and VA Observational Medical Outcomes Partnership (OMOP)
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FDA New Initiatives

Mini-Sentinel (www.minisentinel.org)
Five year contract between FDA and Harvard Pilgrim Health Care Institute, launched in 2009 Over 200 co-investigators from 27 institutions Create a coordinating center with continuous access to automated healthcare data systems
D Develops and evaluates scientific methods f th f ll l d l t i tifi th d for the fullyoperational Sentinel System Affords the opportunity to evaluate safety issues using pp y y g existing electronic healthcare data systems Allows the FDA to learn more about the barriers and challenges to building a viable and accurate system of safety surveillance
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FDA New Initiatives

Observational Medical Outcomes Partnership (http://omop.fnih.org/)
Public-private partnership led by FDA, PhRMA, and FNIH with participation of academic and private sector investigators, t i ti t To inform the appropriate use of observational health databases for drug safety studies
Develop methodology for observational studies Establish a shared resource merging disparate health data source

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Thank you!

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