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: Outline. - PowerPoint PPT Presentation
Evidence-based Evidence-based Medicine Medicine Robert A. Harrington, MD, FACC Robert A. Harrington, MD, FACC Professor of Medicine Professor of Medicine Division of Cardiology/Department of Medicine Division of Cardiology/Department of Medicine Director, Cardiovascular Clinical Trials Director, Cardiovascular Clinical Trials Duke Clinical Research Institute Duke Clinical Research Institute Duke University Medical Center Duke University Medical Center
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Evidence-based Evidence-based MedicineMedicine
Robert A. Harrington, MD, FACCRobert A. Harrington, MD, FACCProfessor of MedicineProfessor of MedicineDivision of Cardiology/Department of MedicineDivision of Cardiology/Department of MedicineDirector, Cardiovascular Clinical TrialsDirector, Cardiovascular Clinical TrialsDuke Clinical Research InstituteDuke Clinical Research InstituteDuke University Medical CenterDuke University Medical Center
Evidence-based Medicine Evidence-based Medicine and Drug Development: Outlineand Drug Development: Outline■ Background/philosophyBackground/philosophy
■ What is EBM? What is EBM? ■ Why does it matter?Why does it matter?■ Why is it important to drug development?Why is it important to drug development?
■ Basics of clinical researchBasics of clinical research■ Observational studies versus RCTObservational studies versus RCT■ Types of trialsTypes of trials■ Concepts (randomization, sample sizes, etc.)Concepts (randomization, sample sizes, etc.)
■ Overview of regulatory issuesOverview of regulatory issues
Understanding the Need Understanding the Need for Evidence in Practicefor Evidence in PracticeSystematic Approach to Evaluating New TherapiesSystematic Approach to Evaluating New Therapies
Half of what you learn in Half of what you learn in your medical apprenticeship your medical apprenticeship
(about therapy) will be correct…(about therapy) will be correct…
you just don’t know which half.you just don’t know which half.
Joe Greenfield, MDJoe Greenfield, MDFormer Chair, MedicineFormer Chair, Medicine
Duke University Medical CenterDuke University Medical Center
Health Care Financing AdministrationHealth Care Financing Administration
U.S. Health Care Costs: U.S. Health Care Costs: On The Rise Again!On The Rise Again!
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NIH Office of Extramural Research, NIH Office of Extramural Research, PhRMA Annual Survey, 2001PhRMA Annual Survey, 2001
U.S. Health-related R&D Spending:U.S. Health-related R&D Spending:1986–20011986–2001
Cost of New Drug DevelopmentCost of New Drug Development
5.5. Impact of long Impact of long developmentdevelopment
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http://csdd.tufts.edu/, accessed November 30, 2001http://csdd.tufts.edu/, accessed November 30, 2001
Evidence-based Medicine:Evidence-based Medicine:What’s the Problem?What’s the Problem?
““There is an unsettling, if little known, There is an unsettling, if little known, truth about the practice of medicine… truth about the practice of medicine… Study after study shows that few Study after study shows that few physicians systematically apply to physicians systematically apply to everyday treatment the scientific everyday treatment the scientific evidence about what works best.”evidence about what works best.”
Millenson, ML. Demanding Medical Excellence: Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age, 1997Doctors and Accountability in the Information Age, 1997
Why Do Clinical Trials?:Why Do Clinical Trials?:Lessons from PediatricsLessons from Pediatrics■ Top 10 prescription drugsTop 10 prescription drugs
■ None approved by FDA for childrenNone approved by FDA for children
■ 900,000 children on SSRI antidepressants900,000 children on SSRI antidepressants
Menopause and HRT Use in the U.S.Menopause and HRT Use in the U.S.
■ 50 million post-menopausal women in U.S.50 million post-menopausal women in U.S.
■ 1.8 million reach menopause each year1.8 million reach menopause each year
■ ~38% of U.S. menopausal women use HRT~38% of U.S. menopausal women use HRT
■ In 2000:In 2000:
■ 46 million prescriptions for Premarin46 million prescriptions for Premarin— 2nd most frequently prescribed drug in US2nd most frequently prescribed drug in US
■ 22 million prescriptions for Prempro22 million prescriptions for Prempro— 6 million users6 million users— $900 million in sales$900 million in sales
Women’s Health Initiative (HRT)Women’s Health Initiative (HRT)
Primary prevention; 7% with baseline CADPrimary prevention; 7% with baseline CADPrimary endpoint: cardiovascular death, nonfatal MIPrimary endpoint: cardiovascular death, nonfatal MI
Co-primary endpoint: invasive breast cancerCo-primary endpoint: invasive breast cancer
Combining quantitative evidence Combining quantitative evidence about medical practice with expert about medical practice with expert judgment in an effort to ensure the judgment in an effort to ensure the provision of medical care with provision of medical care with reproducible high qualityreproducible high quality
Adapted from D SackettAdapted from D Sackett
Alternatives to Evidence-based MedicineAlternatives to Evidence-based MedicineBasis for Basis for Clinical Clinical Unit of Unit of DecisionsDecisions MarkerMarker Measuring DeviceMeasuring Device MeasurementMeasurement
EvidenceEvidence Randomised controlled trialRandomised controlled trial Meta-analysisMeta-analysis Odds ratioOdds ratio
EminenceEminence Radiance of white hairRadiance of white hair LuminometerLuminometer Optical densityOptical density
VehemenceVehemence Level of stridencyLevel of stridency AudiometerAudiometer DecibelsDecibels
EloquenceEloquence Smoothness of tongue Smoothness of tongue (or elegance)(or elegance) or nap of suitor nap of suit TeflometerTeflometer Adhesin scoreAdhesin score
ProvidenceProvidence Level of religious fervourLevel of religious fervour Sextant to measureSextant to measure InternationalInternationalangle of genuflectionangle of genuflection units of pietyunits of piety
DiffidenceDiffidence Level of gloomLevel of gloom NihilometerNihilometer SighsSighs
NervousnessNervousness Litigation phobia levelLitigation phobia level Every conceivable testEvery conceivable test Bank balanceBank balance
ConfidenceConfidence BravadoBravado Sweat testSweat test No sweatNo sweat
Isaacs D, BMJ, 1999Isaacs D, BMJ, 1999
Guidelines: Weighing the EvidenceGuidelines: Weighing the Evidence
Weight of evidence grades:Weight of evidence grades:
== Data from many randomized clinical trialsData from many randomized clinical trials
== Data from single randomized trial or Data from single randomized trial or nonrandomized studiesnonrandomized studies
== Expert consensusExpert consensus
II IIaIIa IIbIIb IIIIII
Guidelines: Classes of Guidelines: Classes of RecommendationRecommendation
Intervention is useful and effectiveIntervention is useful and effective
Evidence conflicts/opinions differ but lean Evidence conflicts/opinions differ but lean towards efficacytowards efficacy
Evidence conflicts/opinions differ but lean Evidence conflicts/opinions differ but lean against efficacyagainst efficacy
Intervention is not useful/effective and Intervention is not useful/effective and may be harmfulmay be harmful
““The true method of knowledge The true method of knowledge is experiment.”is experiment.”
William Blake, 1788William Blake, 1788
Using Evidence for Clinical Using Evidence for Clinical Decision-making: Decision-making: Role of the Randomized Clinical TrialRole of the Randomized Clinical Trial
““Statistical methods may be no Statistical methods may be no substitute for common sense but substitute for common sense but they are often a powerful aid to it.”they are often a powerful aid to it.”
D. D. Reid, commenting on the work of D. D. Reid, commenting on the work of Austin Bradford Hill, father of the Austin Bradford Hill, father of the
Measurement of Effect in Clinical Studies:Measurement of Effect in Clinical Studies:Randomized Clinical Trials versus Randomized Clinical Trials versus Observational StudiesObservational Studies■ Efficacy (RCTs)Efficacy (RCTs)
■ Effectiveness (observational)Effectiveness (observational)■ Clinical practice settingClinical practice setting■ Broad range of patients/providersBroad range of patients/providers■ Community standard of careCommunity standard of care
Randomized Clinical Trials:Randomized Clinical Trials:Basic Principles in Evaluating TherapiesBasic Principles in Evaluating Therapies■ Treatment effects usually modestTreatment effects usually modest
■ Long-term vs. short-term effects may differLong-term vs. short-term effects may differ
■ Combinations are unpredictableCombinations are unpredictable
■ Class effect may not be validClass effect may not be valid
Drug Rx in the U.S. Prior to 1938:Drug Rx in the U.S. Prior to 1938:The Wild, Wild WestThe Wild, Wild West
■ Wild claims made for pills, Wild claims made for pills, and drugs sold without and drugs sold without testingtesting
■ Radam’s Microbe Killer Radam’s Microbe Killer (99.9% water) advertised as (99.9% water) advertised as cure for measles cure for measles cancer cancer
■ Remedy for teething baby Remedy for teething baby could include opiumcould include opium
■ Manufacturers not required Manufacturers not required to list “secret ingredients”to list “secret ingredients”
Pure Food and Drug Act of 1906Pure Food and Drug Act of 1906
■ Mostly focused on cleaning up interstate Mostly focused on cleaning up interstate commerce in foodcommerce in food
■ Also required drug labels to be complete and Also required drug labels to be complete and accurateaccurate
■ Did not regulate/require:Did not regulate/require:
■ False claims of efficacy (snake oil)False claims of efficacy (snake oil)
■ Testing before marketingTesting before marketing
■ Proof of safetyProof of safety
Sulfanilamide Antibiotics:Sulfanilamide Antibiotics:The First Modern Miracle Drug The First Modern Miracle Drug ■ President Calvin Coolidge’s son dies in 1924 President Calvin Coolidge’s son dies in 1924
of septicemia from a tennis blister of septicemia from a tennis blister
■ Sulfanilamide discovered in 1934 by G Sulfanilamide discovered in 1934 by G DomagkDomagk
■ President Franklin Roosevelt’s son cured of President Franklin Roosevelt’s son cured of serious streptococcal infectionserious streptococcal infection
■ Intense competition among pharma Intense competition among pharma companies to sell the most sulfa pills companies to sell the most sulfa pills
Tragedy Drives U.S. Health Policy:Tragedy Drives U.S. Health Policy:The Case of the SE Massengill Co. of The Case of the SE Massengill Co. of Bristol, TNBristol, TN ■ Market opportunity: other companies making Market opportunity: other companies making
sulfa pills, let’s make liquid sulfasulfa pills, let’s make liquid sulfa
■ Developed 1 gallon bottles of Elixir Developed 1 gallon bottles of Elixir Sulfanilamide (drug dissolved in diethylene Sulfanilamide (drug dissolved in diethylene glycol)glycol)
■ Before shipping, carefully tested for Before shipping, carefully tested for appearance, flavor, and fragranceappearance, flavor, and fragrance
■ Over 4 wks in 1937, 353 pts (many children) Over 4 wks in 1937, 353 pts (many children) took drug. Within 1 wk, 105 were deadtook drug. Within 1 wk, 105 were dead
■ FDA confiscated supplies due to labeling FDA confiscated supplies due to labeling deficiency; fined company $26,000deficiency; fined company $26,000
■ Company denied any responsibility, but Company denied any responsibility, but responsible chemist committed suicideresponsible chemist committed suicide
Food, Drug, and Cosmetic Act Food, Drug, and Cosmetic Act (FDCA) of 1938: Key Elements(FDCA) of 1938: Key Elements
■ Banned interstate commerce of harmful Banned interstate commerce of harmful substancessubstances
■ Required new drugs to be approved by Required new drugs to be approved by FDA via a New Drug Application (NDA)FDA via a New Drug Application (NDA)
■ Required scientific proof of safety for Required scientific proof of safety for drug approvaldrug approval
Tragedy Drives U.S. Health Policy Tragedy Drives U.S. Health Policy (Again): The Case of Thalidomide(Again): The Case of Thalidomide
■ Synthesized in West Germany in 1954 as Synthesized in West Germany in 1954 as antihistamine for allergyantihistamine for allergy
■ Found to be “wonder drug” for providing “safe, Found to be “wonder drug” for providing “safe, sound sleep” and for relieving morning sickness of sound sleep” and for relieving morning sickness of pregnancypregnancy
■ Introduced to market in West Germany on Oct. 1, Introduced to market in West Germany on Oct. 1, 1957; widely used outside U.S.1957; widely used outside U.S.
■ Animal testing showed it to be extremely safe; no Animal testing showed it to be extremely safe; no lethal dose ever foundlethal dose ever found
Thalidomide Teaches World a Hard Thalidomide Teaches World a Hard Lesson About Drug SafetyLesson About Drug Safety■ Safety testing did not include pregnant Safety testing did not include pregnant
animalsanimals
■ Unappreciated that drug crossed placenta and Unappreciated that drug crossed placenta and caused severe damage to fetus between 3 and caused severe damage to fetus between 3 and 5 weeks post-conception5 weeks post-conception
■ Caused fetal death or severe malformations of Caused fetal death or severe malformations of limbs (phocomelia) and internal organslimbs (phocomelia) and internal organs
The Thalidomide Tragedy:The Thalidomide Tragedy:The U.S. Dodges a BulletThe U.S. Dodges a Bullet
■ Company applied to FDA for approval in 1960Company applied to FDA for approval in 1960
■ FDA administrator (Dr. Frances Kelsey) FDA administrator (Dr. Frances Kelsey) delayed review, asked for more safety testsdelayed review, asked for more safety tests
■ By 1961, By 1961, reports of thalidomide-related birth reports of thalidomide-related birth defectsdefects
■ Fewer than 2 dozen American children Fewer than 2 dozen American children affected (mothers overseas)affected (mothers overseas)
1962 Kefauver-Harris 1962 Kefauver-Harris Amendment to FDCAAmendment to FDCA■ Required extensive animal, Required extensive animal,
pharmacological, and toxicological pharmacological, and toxicological testing before initial testing in humanstesting before initial testing in humans
■ These data must be submitted in form of These data must be submitted in form of Investigational New Drug (IND) Investigational New Drug (IND) application and approved by FDAapplication and approved by FDA
■ NDA must show “substantial evidence” NDA must show “substantial evidence” of drug’s efficacy (effectiveness) as well of drug’s efficacy (effectiveness) as well as safetyas safety
Investigational New Drug (IND) Investigational New Drug (IND) Application: OverviewApplication: Overview
■ Summarizes evidence that it is reasonable to Summarizes evidence that it is reasonable to move from preclinical to RCTsmove from preclinical to RCTs
■ Provides exemption from federal statute that Provides exemption from federal statute that prohibits interstate shipping of unapproved drugsprohibits interstate shipping of unapproved drugs
■ Three major componentsThree major components
■ Animal pharmacology and toxicology (safety)Animal pharmacology and toxicology (safety)
Prescription Drug User Fee Act Prescription Drug User Fee Act (PDUFA) of 1992(PDUFA) of 1992■ Response by Congress to concerns about Response by Congress to concerns about
length of drug approval process in U.S.length of drug approval process in U.S.
■ ““User fees” for NDAs used to hire > 600 User fees” for NDAs used to hire > 600 drug reviewers and support staffdrug reviewers and support staff
■ By 1997, added $84 million/year to FDA By 1997, added $84 million/year to FDA budgetbudget
■ Goal: standard application review 12 mos, Goal: standard application review 12 mos, priority application review 6 mospriority application review 6 mos
Food and Drug Administration Food and Drug Administration Modernization Act (FDAMA) of 1997Modernization Act (FDAMA) of 1997
■ Reauthorizes Prescription Drug User Fee Act of ‘92 Reauthorizes Prescription Drug User Fee Act of ‘92 for 5 more yearsfor 5 more years
■ Creates “fast track” review of rxs for serious/life Creates “fast track” review of rxs for serious/life threatening disordersthreatening disorders
■ Allows drug companies to disseminate info about Allows drug companies to disseminate info about off label use (must file suppl. application)off label use (must file suppl. application)
■ Preserves the general assumption that 2 adequate Preserves the general assumption that 2 adequate and well-controlled studies are needed to prove and well-controlled studies are needed to prove safety and effectivenesssafety and effectiveness
Safety Evaluation of Marketed Drugs:Safety Evaluation of Marketed Drugs:U.S. FDA PerspectiveU.S. FDA Perspective■ Clinical testingClinical testing
■ 1994 drug safety standard: 1500 patients exposed, 1994 drug safety standard: 1500 patients exposed, with 600 exposed for 6 mos and 300 for 1 yrwith 600 exposed for 6 mos and 300 for 1 yr
■ Adequate to detect 1/300–500 AEAdequate to detect 1/300–500 AE
■ Recognized limitationsRecognized limitations— ““Clinical trials are not real life”Clinical trials are not real life”
Thalidomide Rises From the AshesThalidomide Rises From the Ashes
■ Early use suggested thalidomide had some Early use suggested thalidomide had some anti-inflammatory propertiesanti-inflammatory properties
■ In 1964, MD in Jerusalem used some In 1964, MD in Jerusalem used some remaining stock of drug in leprosy pt with remaining stock of drug in leprosy pt with severe painful skin lesionssevere painful skin lesions
■ Within a few days, pt’s fever Within a few days, pt’s fever and skin lesions and skin lesions disappeareddisappeared
■ In 1998, Calgene received FDA approval to In 1998, Calgene received FDA approval to market thalidomide for leprosymarket thalidomide for leprosy
Recent Major RCTS and Registries in Recent Major RCTS and Registries in NSTE ACS: Enrolling > 1000 patients NSTE ACS: Enrolling > 1000 patients (Total n > 200,000 patients)(Total n > 200,000 patients)
AntiplateletsAntiplatelets
PRISM/PRISM +PRISM/PRISM +
PURSUITPURSUIT
PARAGON A & BPARAGON A & B
GUSTO-IVGUSTO-IV
OPUSOPUS
SYMPHONY 1 & 2SYMPHONY 1 & 2
CURECURE
Strategies/Strategies/RegistriesRegistries
TACTICSTACTICS
RITA-3RITA-3
GUARDIANGUARDIAN
NRMINRMI
CRUSADECRUSADE
GRACEGRACE
AntithrombinsAntithrombins
GUSTO IIGUSTO II
OASIS 2OASIS 2
ESSENCEESSENCE
TIMI 11TIMI 11
FRAXISFRAXIS
FRICFRIC
FRISC 1&2FRISC 1&2
5.95
5.16 4.97
4.16
6.33
5.074.63
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Adjusted Unadjusted
5.95
5.16 4.97
4.16
6.33
5.074.63
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Adjusted Unadjusted
Peterson E, ACC, March 2004Peterson E, ACC, March 2004
Link Between Overall Guidelines Link Between Overall Guidelines Adherence and MortalityAdherence and Mortality
Every 10% in guidelines adherence results in an 11% in mortality (OR = 0.89, 95% CI: 0.81–0.98)
Amanda McMillan
I suggest fixing the numbers on the horizontal axis to have en-dashes and underlined > and < signs.
Clinical Research:Clinical Research:Basis of Evidence for Clinical Basis of Evidence for Clinical PracticePractice■ We learn what is effective and safe by evaluating We learn what is effective and safe by evaluating
therapies in the clinical contexttherapies in the clinical context
■ Increasingly, this effort will require comparisons Increasingly, this effort will require comparisons of active treatments and strategies, raising new of active treatments and strategies, raising new challenges/complexities challenges/complexities
■ Answers to these questions cannot and should Answers to these questions cannot and should not come from extrapolations or thought not come from extrapolations or thought exercisesexercises
““There are those who wander There are those who wander around on the wards and those around on the wards and those
who are doctors. The difference is who are doctors. The difference is in having the data.”in having the data.”
EA Stead Jr. EA Stead Jr. Former Chair, DOMFormer Chair, DOM
Founder, Duke CV DatabankFounder, Duke CV DatabankFounder, PA ProfessionFounder, PA Profession
