Evidence-based Medicine

1. Evidence-based Medicine Robert A. Harrington, MD, FACCProfessor of MedicineDivision of Cardiology/Department of MedicineDirector, Cardiovascular Clinical TrialsDuke Clinical Research InstituteDuke University Medical Center

2. 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

3. 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 don’t know which half. Joe Greenfield, MD Former Chair, Medicine Duke University Medical Center

4. U.S. Health Care Costs: On The Rise Again! Health Care Financing Administration

5. U.S. Health-related R&D Spending:1986–2001 NIH Office of Extramural Research, PhRMA Annual Survey, 2001

6. 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

7. Evidence-based Medicine:What’s 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

8. 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

9. Evidence-based Medicine Why should we rely on evidence for medical decision-making? Because our intuition might be wrong!

10. 100 95 90 85 80 0 91 182 273 364 455 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

11. 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

12. 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

13. Post-menopausal Women n = 27,347 With Uterus n = 16,608 No Uterus n = 10,739 CEE 0.625 mg/day CEE + MPA 0.625 mg/day + 2.5 mg/day Placebo Women’s 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

14. 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

15. Alternatives to Evidence-based Medicine Basis for Clinical Unit of Decisions Marker Measuring Device Measurement Evidence Randomised controlled trial Meta-analysis Odds ratio Eminence Radiance of white hair Luminometer Optical 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

16. Guidelines: Weighing the Evidence Weight of evidence grades: = Data from many randomized clinical trials = Data from single randomized trial or nonrandomized studies = Expert consensus

17. I IIa IIb III 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

18. The Cycle of Research ObservationandSurrogates ScientificDiscovery RCT ObservationandOutcomes

19. Evidence-based Medicine:Randomized Clinical Trials “The true method of knowledge is experiment.” William Blake, 1788

20. 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

21. 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

22. 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

23. Drug Rx in the U.S. Prior to 1938:The Wild, Wild West • Wild claims made for pills, and drugs sold without testing • Radam’s 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”

24. 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

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

26. Tragedy Drives U.S. Health Policy:The Case of the SE Massengill Co. of Bristol, TN • Market opportunity: other companies making sulfa pills, let’s 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

27. 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

28. 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

29. 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

30. 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 defects • Fewer than 2 dozen American children affected (mothers overseas)

31. 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 drug’s efficacy (effectiveness) as well as safety

32. 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

33. 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 > 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

34. 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

35. Safety Evaluation of Marketed Drugs:U.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 1/300–500 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

36. 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

37. 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, pt’s fever  and skin lesions disappeared • In 1998, Calgene received FDA approval to market thalidomide for leprosy

38. Antiplatelets PRISM/PRISM + PURSUIT PARAGON A & B GUSTO-IV OPUS SYMPHONY 1 & 2 CURE Recent Major RCTS and Registries in NSTE ACS: Enrolling > 1000 patients (Total n > 200,000 patients) Antithrombins GUSTO II OASIS 2 ESSENCE TIMI 11 FRAXIS FRIC FRISC 1&2 Strategies/Registries TACTICS RITA-3 GUARDIAN NRMI CRUSADE GRACE

39. Link Between Overall Guidelines Adherence and Mortality Every 10%  in guidelines adherence results in an 11%  in mortality (OR = 0.89, 95% CI: 0.81–0.98) Peterson E, ACC, March 2004

40. Clinical Research:Basis 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

41. “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