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Evidence-based Medicine


Evidence-based Medicine Robert A. Harrington, MD, FACC Professor of Medicine Division of Cardiology/Department of Medicine Director, Cardiovascular Clinical Trials – PowerPoint PPT presentation

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Title: Evidence-based Medicine

Evidence-based Medicine
  • Robert A. Harrington, MD, FACC Professor of
    Medicine Division of Cardiology/Department of
    Medicine Director, Cardiovascular Clinical
    Trials Duke Clinical Research Institute Duke
    University Medical Center

Evidence-based Medicine and Drug Development
  • Background/philosophy
  • What is EBM?
  • Why does it matter?
  • Why is it important to drug development?
  • Basics of clinical research
  • Observational studies versus RCT
  • Types of trials
  • Concepts (randomization, sample sizes, etc.)
  • Overview of regulatory issues

Understanding the Need for Evidence in
Practice Systematic Approach to Evaluating New
  • Half of what you learn in your medical
    apprenticeship (about therapy) will be correct
  • you just dont know which half.

Joe Greenfield, MD Former Chair, Medicine Duke
University Medical Center
U.S. Health Care Costs On The Rise Again!
Health Care Financing Administration
U.S. Health-related RD Spending 19862001
NIH Office of Extramural Research, PhRMA Annual
Survey, 2001
Cost of New Drug Development
  • Analysis includes
  • 1. Discovery preclinical costs
  • 2. Clinical costs
  • 3. Capital costs
  • 4. Project failures
  • 5. Impact of long development

http//csdd.tufts.edu/, accessed November 30, 2001
Evidence-based Medicine Whats the Problem?
  • There is an unsettling, if little known, truth
    about the practice of medicine Study after study
    shows that few physicians systematically apply to
    everyday treatment the scientific evidence about
    what works best.

Millenson, ML. Demanding Medical Excellence
Doctors and Accountability in the Information
Age, 1997
Why Do Clinical Trials? Lessons from Pediatrics
  • Top 10 prescription drugs
  • None approved by FDA for children
  • 900,000 children on SSRI antidepressants
  • Otitis media
  • Widespread antibiotics (?viral, ?long-term
  • Asthma
  • More drugs, little to no data on long-term safety
  • Increasing mortality

Evidence-based Medicine
  • Why should we rely on evidence for medical
  • Because our intuition might be wrong!

CAST Cardiac Arrhythmia Suppression Trial
Placebo (n 743)
Encainide or Flecainide (n 755)
Patients Without Event ()
P 0.0004
Days After Randomization
Odds of death
-0.5 1 2 3 4 5
Echt, New Engl J Med, 1991
Preventable Deaths Exposed by CAST
  • 7 million pts with active CAD, 2 million with CHF
  • 25 have significant ventricular ectopy
  • 10 with ectopy rx with antiarrhythmics, for 10
  • 5 annual mortality, doubled with antiarrhythmics

25,000 unnecessary deaths
Menopause and HRT Use in the U.S.
  • 50 million post-menopausal women in U.S.
  • 1.8 million reach menopause each year
  • 38 of U.S. menopausal women use HRT
  • In 2000
  • 46 million prescriptions for Premarin
  • 2nd most frequently prescribed drug in US
  • 22 million prescriptions for Prempro
  • 6 million users
  • 900 million in sales

Womens Health Initiative (HRT)
Primary prevention 7 with baseline CAD Primary
endpoint cardiovascular death, nonfatal
MI Co-primary endpoint invasive breast cancer
WHI Investigators, JAMA, 2002
Evidence-based Medicine
  • Combining quantitative evidence about medical
    practice with expert judgment in an effort to
    ensure the provision of medical care with
    reproducible high quality

Adapted from D Sackett
Alternatives to Evidence-based Medicine
  • Basis for Clinical Unit of Decisions Marker M
    easuring Device Measurement
  • Evidence Randomised controlled trial Meta-analysis
    Odds ratio
  • Eminence Radiance of white hair Luminometer Optica
    l density
  • Vehemence Level of stridency Audiometer Decibels
  • Eloquence Smoothness of tongue (or elegance) or
    nap of suit Teflometer Adhesin score
  • Providence Level of religious fervour Sextant to
    measure International angle of
    genuflection units of piety
  • Diffidence Level of gloom Nihilometer Sighs
  • Nervousness Litigation phobia level Every
    conceivable test Bank balance
  • Confidence Bravado Sweat test No sweat

Isaacs D, BMJ, 1999
Guidelines Weighing the Evidence
  • Weight of evidence grades
  • Data from many randomized clinical trials
  • Data from single randomized trial or
    nonrandomized studies
  • Expert consensus

Guidelines Classes of Recommendation
  • Intervention is useful and effective
  • Evidence conflicts/opinions differ but lean
    towards efficacy
  • Evidence conflicts/opinions differ but lean
    against efficacy
  • Intervention is not useful/effective and may be

The Cycle of Research
Observation and Surrogates
Scientific Discovery
Observation and Outcomes
Evidence-based Medicine Randomized Clinical
  • The true method of knowledge is experiment.

William Blake, 1788
Using Evidence for Clinical Decision-making
Role of the Randomized Clinical Trial
  • Statistical methods may be no substitute for
    common sense but they are often a powerful aid to

D. D. Reid, commenting on the work of Austin
Bradford Hill, father of the randomized clinical
Measurement of Effect in Clinical
Studies Randomized Clinical Trials versus
Observational Studies
  • Efficacy (RCTs)
  • Experimental setting
  • Ideal circumstances
  • Limited population
  • Optimal care
  • Effectiveness (observational)
  • Clinical practice setting
  • Broad range of patients/providers
  • Community standard of care

Ayanian JZ, Eur Heart J, 1999
Randomized Clinical Trials Basic Principles in
Evaluating Therapies
  • Treatment effects usually modest
  • Need large sample sizes
  • Qualitative interactions uncommon
  • Simple studies reasonable
  • Quantitative interactions common
  • Biggest effect in sickest patients
  • Unintended targets common
  • Pathophysiological reasoning unreliable
  • Long-term vs. short-term effects may differ
  • Combinations are unpredictable
  • Class effect may not be valid

Drug Rx in the U.S. Prior to 1938 The Wild, Wild
  • Wild claims made for pills, and drugs sold
    without testing
  • Radams Microbe Killer (99.9 water) advertised
    as cure for measles ? cancer
  • Remedy for teething baby could include opium
  • Manufacturers not required to list secret

Pure Food and Drug Act of 1906
  • Mostly focused on cleaning up interstate commerce
    in food
  • Also required drug labels to be complete and
  • Did not regulate/require
  • False claims of efficacy (snake oil)
  • Testing before marketing
  • Proof of safety

Sulfanilamide Antibiotics The First Modern
Miracle Drug
  • President Calvin Coolidges son dies in 1924 of
    septicemia from a tennis blister
  • Sulfanilamide discovered in 1934 by G Domagk
  • President Franklin Roosevelts son cured of
    serious streptococcal infection
  • Intense competition among pharma companies to
    sell the most sulfa pills

Tragedy Drives U.S. Health Policy The Case of
the SE Massengill Co. of Bristol, TN
  • Market opportunity other companies making sulfa
    pills, lets make liquid sulfa
  • Developed 1 gallon bottles of Elixir
    Sulfanilamide (drug dissolved in diethylene
  • Before shipping, carefully tested for appearance,
    flavor, and fragrance
  • Over 4 wks in 1937, 353 pts (many children) took
    drug. Within 1 wk, 105 were dead
  • FDA confiscated supplies due to labeling
    deficiency fined company 26,000
  • Company denied any responsibility, but
    responsible chemist committed suicide

Food, Drug, and Cosmetic Act (FDCA) of 1938 Key
  • Banned interstate commerce of harmful substances
  • Required new drugs to be approved by FDA via a
    New Drug Application (NDA)
  • Required scientific proof of safety for drug

Tragedy Drives U.S. Health Policy (Again) The
Case of Thalidomide
  • Synthesized in West Germany in 1954 as
    antihistamine for allergy
  • Found to be wonder drug for providing safe,
    sound sleep and for relieving morning sickness
    of pregnancy
  • Introduced to market in West Germany on Oct. 1,
    1957 widely used outside U.S.
  • Animal testing showed it to be extremely safe no
    lethal dose ever found

Thalidomide Teaches World a Hard Lesson About
Drug Safety
  • Safety testing did not include pregnant animals
  • Unappreciated that drug crossed placenta and
    caused severe damage to fetus between 3 and 5
    weeks post-conception
  • Caused fetal death or severe malformations of
    limbs (phocomelia) and internal organs

The Thalidomide Tragedy The U.S. Dodges a Bullet
  • Company applied to FDA for approval in 1960
  • FDA administrator (Dr. Frances Kelsey) delayed
    review, asked for more safety tests
  • By 1961, ? reports of thalidomide-related birth
  • Fewer than 2 dozen American children affected
    (mothers overseas)

1962 Kefauver-Harris Amendment to FDCA
  • Required extensive animal, pharmacological, and
    toxicological testing before initial testing in
  • These data must be submitted in form of
    Investigational New Drug (IND) application and
    approved by FDA
  • NDA must show substantial evidence of drugs
    efficacy (effectiveness) as well as safety

Investigational New Drug (IND) Application
  • Summarizes evidence that it is reasonable to move
    from preclinical to RCTs
  • Provides exemption from federal statute that
    prohibits interstate shipping of unapproved drugs
  • Three major components
  • Animal pharmacology and toxicology (safety)
  • Manufacturing
  • Initial clinical protocols

Prescription Drug User Fee Act (PDUFA) of 1992
  • Response by Congress to concerns about length of
    drug approval process in U.S.
  • User fees for NDAs used to hire gt 600 drug
    reviewers and support staff
  • By 1997, added 84 million/year to FDA budget
  • Goal standard application review 12 mos,
    priority application review 6 mos

Food and Drug Administration Modernization Act
(FDAMA) of 1997
  • Reauthorizes Prescription Drug User Fee Act of
    92 for 5 more years
  • Creates fast track review of rxs for
    serious/life threatening disorders
  • Allows drug companies to disseminate info about
    off label use (must file suppl. application)
  • Preserves the general assumption that 2 adequate
    and well-controlled studies are needed to prove
    safety and effectiveness

Safety Evaluation of Marketed Drugs U.S. FDA
  • Clinical testing
  • 1994 drug safety standard 1500 patients exposed,
    with 600 exposed for 6 mos and 300 for 1 yr
  • Adequate to detect 1/300500 AE
  • Recognized limitations
  • Clinical trials are not real life
  • FDA review
  • Toxicology, clinical studies
  • Review of proposed label, promotions
  • Postmarketing surveillance
  • MedWatch system

Friedman MA, JAMA, 1999
RCT Drug Exposure versus Actual Use Recently
Withdrawn Drugs
  • Clinical Trials Prewithdrawal Drug (N) (N)
  • Terfenadine 5000 7,500,000
  • Fenfluramine 340 6,900,000
  • Dexfenfluramine 1200 2,300,000
  • Mibefradil 3400 600,000
  • Bromfenac 2400 2,500,000

Friedman MA, JAMA, 1999
Thalidomide Rises From the Ashes
  • Early use suggested thalidomide had some
    anti-inflammatory properties
  • In 1964, MD in Jerusalem used some remaining
    stock of drug in leprosy pt with severe painful
    skin lesions
  • Within a few days, pts fever ? and skin lesions
  • In 1998, Calgene received FDA approval to market
    thalidomide for leprosy

Recent Major RCTS and Registries in NSTE ACS
Enrolling gt 1000 patients (Total n gt 200,000
Strategies/ Registries TACTICS RITA-3 GUARDIAN NRM
  • Antiplatelets
  • OPUS
  • SYMPHONY 1 2
  • CURE
  • Antithrombins
  • OASIS 2
  • TIMI 11
  • FRIC
  • FRISC 12

Link Between Overall Guidelines Adherence and
Every 10 ? in guidelines adherence results in an
11 ? in mortality (OR 0.89, 95 CI 0.810.98)
Peterson E, ACC, March 2004
Clinical Research Basis of Evidence for Clinical
  • We learn what is effective and safe by evaluating
    therapies in the clinical context
  • Increasingly, this effort will require
    comparisons of active treatments and strategies,
    raising new challenges/complexities
  • Answers to these questions cannot and should not
    come from extrapolations or thought exercises

There are those who wander around on the wards
and those who are doctors. The difference is in
having the data.
  • EA Stead Jr.
  • Former Chair, DOM
  • Founder, Duke CV Databank
  • Founder, PA Profession
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