Evidence-based Medicine

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Evidence-based Medicine

• Robert A. Harrington, MD, FACCProfessor of
  MedicineDivision of Cardiology/Department of
  MedicineDirector, Cardiovascular Clinical
  TrialsDuke Clinical Research InstituteDuke
  University Medical Center

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Evidence-based Medicine and Drug Development
Outline

• 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

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Understanding the Need for Evidence in
PracticeSystematic Approach to Evaluating New
Therapies

• 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
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U.S. Health Care Costs On The Rise Again!
Health Care Financing Administration
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U.S. Health-related RD Spending19862001
NIH Office of Extramural Research, PhRMA Annual
Survey, 2001
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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
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Evidence-based MedicineWhats 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
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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
  effects)
• Asthma
• More drugs, little to no data on long-term safety
• Increasing mortality

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Evidence-based Medicine

• Why should we rely on evidence for medical
  decision-making?
• Because our intuition might be wrong!

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CASTCardiac Arrhythmia Suppression Trial
Placebo (n 743)
Encainideor Flecainide(n 755)
Patients Without Event ()
P 0.0004
Days After Randomization
Odds of death
2.64
1.6
4.4
-0.5 1 2 3 4 5
Echt, New Engl J Med, 1991
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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
  yrs
• 5 annual mortality, doubled with antiarrhythmics

25,000 unnecessary deaths
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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

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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
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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
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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
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Guidelines Weighing the Evidence

• Weight of evidence grades
• Data from many randomized clinical trials
• Data from single randomized trial or
  nonrandomized studies
• Expert consensus

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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
  harmful

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The Cycle of Research
ObservationandSurrogates
ScientificDiscovery
RCT
ObservationandOutcomes
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Evidence-based MedicineRandomized Clinical
Trials

• The true method of knowledge is experiment.

William Blake, 1788
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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
  it.

D. D. Reid, commenting on the work of Austin
Bradford Hill, father of the randomized clinical
trial
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Measurement of Effect in Clinical
StudiesRandomized 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
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Randomized Clinical TrialsBasic 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

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Drug Rx in the U.S. Prior to 1938The Wild, Wild
West

• 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
  ingredients

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Pure Food and Drug Act of 1906

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

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Sulfanilamide AntibioticsThe 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

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Tragedy Drives U.S. Health PolicyThe 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
  glycol)
• 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

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Food, Drug, and Cosmetic Act (FDCA) of 1938 Key
Elements

• 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
  approval

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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

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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

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The Thalidomide TragedyThe 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
  defects
• Fewer than 2 dozen American children affected
  (mothers overseas)

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1962 Kefauver-Harris Amendment to FDCA

• Required extensive animal, pharmacological, and
  toxicological testing before initial testing in
  humans
• 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

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Investigational New Drug (IND) Application
Overview

• 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

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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

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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

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Safety Evaluation of Marketed DrugsU.S. FDA
Perspective

• 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
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RCT Drug Exposure versus Actual Use Recently
Withdrawn Drugs

• Clinical Trials PrewithdrawalDrug (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
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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
  disappeared
• In 1998, Calgene received FDA approval to market
  thalidomide for leprosy

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Recent Major RCTS and Registries in NSTE ACS
Enrolling gt 1000 patients (Total n gt 200,000
patients)
Strategies/Registries TACTICS RITA-3 GUARDIAN NRM
I CRUSADE GRACE

• Antiplatelets
• PRISM/PRISM
• PURSUIT
• PARAGON A B
• GUSTO-IV
• OPUS
• SYMPHONY 1 2
• CURE

• Antithrombins
• GUSTO II
• OASIS 2
• ESSENCE
• TIMI 11
• FRAXIS
• FRIC
• FRISC 12

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Link Between Overall Guidelines Adherence and
Mortality
Every 10 ? in guidelines adherence results in an
11 ? in mortality (OR 0.89, 95 CI 0.810.98)
Peterson E, ACC, March 2004
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Clinical ResearchBasis of Evidence for Clinical
Practice

• 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

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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