EBM Practical issues in Pediatric Infect...

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Published on January 12, 2009

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Evidence-based Medicine The Practical Issues in Pediatric Infectious Diseases : Evidence-based Medicine The Practical Issues in Pediatric Infectious Diseases Annual Meeting of Pediatric Infectious Disease Society24 Feb 2006 Warunee Punpanich Queen Sirikit National Institute of Child Health The Great Irony . . . : The Great Irony . . . Why do doctors kill more people than airline pilots do? Pilots are required to have time off to sleep They do everything in duplicate They follow protocols If doctors died with their patients they would take a great deal more care. Evidence-based medicine : Evidence-based medicine "…the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.“ Sackett 1996 "…integration of best research evidence with clinical experience and patient values.“ Sackett et al. 2000 Evidence-based medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision-making, stresses the examination of evidence from clinical research. Evidence Based Medicine (EBM): Definition : Evidence Based Medicine (EBM): Definition The key difference between evidence-based medicine and traditional medicineis not that EBM considers the evidence while that latter does not. EBM demands better evidence than has traditionally been used. Slide 5: Why do we need to talk about EBM in this meeting? Why is EBM becoming more important ? : Why is EBM becoming more important ? quantity of information (increasing!) >2,000,000 biomedical publications per year quality of information (variable!) peer-reviewed publication grey literature internal documents other - lack of quality indication (e.g. internet) Slide 7: Hibble A, Kanka D, Pencheon D, Pooles F. “Guidelines in general practice: the new Tower of Babel?” BMJ 1998;317:862-863. In 22 doctor’s surgeries, were found 855 different guidelines - a pile 68 cm tall weighing 28 kg. Slide 8: Information Mastery: The practical approach to implementing EBM Usefulness of Information : Usefulness of Information Usefulness = Relevance x Validity Work Shaughnessy AF, et al. Becoming an information master: a guidebook to the medical information jungle J Family Practice 1994;39:489-99 Evaluating promotional material from industry: Evidence-based Approach : Evaluating promotional material from industry: Evidence-based Approach Facts about pharmaceutical investments : Facts about pharmaceutical investments Medicines are big business. The NHS currently spends about 10 billion/year on pharmaceuticals, equating 30 million a day. This expenditure in increasing both in the UK and throughout the world. Although a lot resources are invested in R&D, the PI spends far more on marketing and administration (~ 35% on sale) than trying to discover new ones. Devlin J, Hemley P. Management views on industry issue, pressures and consultants. Scrip magazine 1997 Facts about pharmaceutical investments : Facts about pharmaceutical investments In 2000, Merck spent $161 m advertising Vioxx (rofecoxib) this was more than PepsiCo spent advertising Pepsi ($125m) Anheuser-Busch spent advertising Budweiser ($146) in the same period. Devlin J, Hemley P. Management views on industry issue, pressures and consultants. Scrip magazine 1997 www.nofreelunc-uk.org/about.shtml (accessed 9/11/05) Slide 13: The pharmaceutical industry employs various strategies to interact with health professionals The method we most familiar with is face-to-face visits from sales representatives. Although much information is based on good evidence, this is not always the case. “Pharmaceutical reps” : “Pharmaceutical reps” In UK alone, the PI employs over 8,000 pharmaceutical representatives to promoted its products to ~ 60,000 doctors. This equates to a ratio of 1:7.5 full-time pharmaceutical representative: doctors—a “teacher:student” ratio a school could only dream of! Pegler S, the Pharmaceutical J 2005;274:271 “Pharmaceutical reps” : “Pharmaceutical reps” Pharmaceutical representatives are effective at packaging and delivering key messages about their products. Pegler S, the Pharmaceutical J 2005;274:271 Usefulness of Information : Usefulness of Information Usefulness = Relevance x Validity Work Shaughnessy AF, et al. Becoming an information master: a guidebook to the medical information jungle J Family Practice 1994;39:489-99 Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? Statistical vs. clinical significant? Other factors What sort of evidence is available? : What sort of evidence is available? A Medical Paradigm Shift: from DOE to POEM What sort of evidence is available? : What sort of evidence is available? Many claims made by the PI, particularly for new drugs, are based on the results of trials that use surrogate endpoints and give rise to disease-oriented evidence (DOE). Surrogate endpoint ? variables that are used to predict a rare or distant outcome of an intervention, but not a direct measure of clinical benefit. They are commonly used in trials because the size, duration and, therefore, cost of the trial can be reduced. Slide 23: Claims may be made that an ATB provides ‘better penetration into sputum or ELF”. To base or change clinical practice on the basis of DOE is inappropriate. The WHO Clofibrate Trial (RCT) showed significant reductions in CHD events. Non coronary and total mortality were increased ?NO reduction in overall mortality. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 1978; 40: 1069-118. Slide 24: We should care about are those that measure outcomes that produce tangible benefits to patients “patient-oriented evidence that matters” (POEMs). Consider the marketing of COX-2 inhibitors: much of the early advertising focused on the finding that these drug cost fewer ulcers as detected via an endoscope. This is DOE, since these ulcers do not consistently translate into pain or more serious ulcers, not necessarily indicators of true harm, such as perforation, symptomatic ulcer or bleeding (POEM). Slide 25: Closer scrutiny of the 2 major trials for drugs in this class, rofecoxib (Vioxx) and celecoxib? risk of serious ADR compared with traditional NSAID (ARD= 1.5 and 1%) respectively a factor not always apparent in promotional materials Bombardier C et al. N Engl J Med. 2000 Nov 23;343(21):1520-8 Silverstein FE. JAMA. 2000 Sep 13;284(10):1247-55. POEMs: The “Change” Factor : POEMs: The “Change” Factor Penicillin prevents rheumatic fever Would a study showing this require a change? ALLHAT study Proved other study results: diuretics > effective than other treatments to prevent mortality and morbidity associated with hypertension Would this study require a change in behavior? (ALLHAT Officers and Coordinators.The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97). Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? What is the bottom line: Statistical vs. clinical significant? Other factors Does trial population reflect real life? : Does trial population reflect real life? Patients included in clinical trials are often carefully selected, May not reflect the “typical” patients who will ultimately use the drug in real life. Study form Canada analyzed the characteristics of patients enrolled into trials of NSAIDs only 2.1% aged > 65 years, despite NSAIDs being much more commonly used in the elderly. Another is that of antidepressants, where studies are often performed in highly selected hospital-based populations. The applicability of these data to patients seen in primary care is questionable. Rochon PA. Canadian Medical Association J 1998;159:1373-4 Zimmerman M. AJP 2002;159:469-73 Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? What is the bottom line: Statistical vs. clinical significant? Other factors Choice of comparator drug and dose? : Choice of comparator drug and dose? Researcher may use a comparator drug that is not generally regarded as the standard therapy or choose a suboptimal dose of the comparator drug. Studies comparing (a relatively low dose of) meloxicam with piroxicam (the more GI-toxic NSAIDs). Hawkey C. British J Rheumatology 1998;37: 937-45 DequekerJ, Bristish J Rheumatology 1998;37:946-51 Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? What is the bottom line: Statistical vs. clinical significant? Other factors Hypertension summaries : Hypertension summaries HA: A RCT of over 6,000 men with “mild” hypertension (DBP 90-140) show that the drug treatment regimen used reduced overall mortality from 7.8% in the “usual care” control group to 6.3%, a statistically significant reduction in total mortality of 1.5% over the course of 5 years. HB: When 7850 men were studies in a 5-year RCT, a “special” program of pharmacologic treatment of “mild” hypertension reduced the overall mortality rate by 24.3% compared with in that in the control group of men who received usual medical care. (This difference was statistically significant). Hypercholesterolemia summaries : Hypercholesterolemia summaries CA: When 1900 men given a drug to lower cholesterol level and were compared with 1906 men given a placebo in a carefully conducted RCT, the death rate after 7 years was found to be 2.0% in the group given the placebo and 1.6% in the group given the drug, a reduction in the death rate of 0.4% over those 7 years. (This difference was statistically significant). CB: A carefully conducted RCT comparing a drug with placebo among almost 4000 middle-aged hypercholesterolemic men achieved a statistically significant 20% relative reduction in the rate of death from coronary heart disease over 7 years. Slide 34: Forrow L, et al: AJM 1992:92;121-4 Relative risk vs absolute risk reduction : Relative risk vs absolute risk reduction Relative risk (RR) always sound more impressive than absolute risk reductions ?tend to be used in advertising material, particularly when describing the benefit of a product. The chance (absolute risk) of winning the lottery jackpot by buying one ticket is about 1 in 1 million. Buying 2 tickets, the chance (RR) of winning the jackpot are doubled (i.e., increased by 100%), but the absolute risk is still extremely small for rare events. 4 ways to present the benefit : 4 ways to present the benefit Absolute risk reduction (ARR) Proportion of those w/o Tx who die – proportion of those w/ Tx who die = 7.8% – 6.3% = 1.5% Relative risk reduction (RRR): ARR/Proportion of those who die w/o Tx 1.5%/7.8% = 24% Number needed to treat: No. of people who must participate in the treatment to save one life 1/0.015 = 66 [Increase in life expectancy Persons who receive the treatment for 5 year increase their life expectancy by the average of 30 days. ] Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? What is the bottom line: Statistical vs. clinical significant? Other factors Statistical vs. clinical significant? : Statistical vs. clinical significant? Caution is required when promotional material states the results of a study are “significant”. Statistical significance simply means that (given no bias) the results were unlikely to have occurred by chance. Whether a statistically significant will be clinically significant depend on the size (magnitude) of effect AND whether it provides any meaningful benefit to the patients. Slide 39: A Cochrane review into the use of ATB to treat sore throat found that: those taking ATB endured symptoms (headache, throat soreness and fever) for one day less time than those taking placebo. 90% of both treated and untreated patients became symptom-free by one week. Although this was statistically significant, the clinical significance of such an intervention is questionable. Del Mar CB, The Cochrane Database of systematic reviews 2004, Issue 2 Slide 40: Chloramphenicol treatment for acute infective conjunctivitis in children in primary care: a randomized double-blind placebo-controlled trial The mean difference in the time to cure was 0·3 days (log-rank test p=0.025). Clinical cure by day 7 occurred in 83% of children with placebo compared with 86% of those with chloramphenicol (risk difference 3·8%, 95% CI –4·1% to 11·8%). www.thelancet.com Vol 366 July 2, 2005 Slide 41: A double-blind, RCT of 3 fluids (RLS, Dextran, Starch) for initial resuscitation of dengue shock syndrome. The primary outcome measure was requirement for rescue colloid at any time after administration of the study fluid. Results: The primary outcome measure — requirement for rescue colloid — was similar for the different fluids in the two severity groups. NEJM Volume 353:877-889 September 1, 2005 Number 9. Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? What is the bottom line: Statistical vs. clinical significant? Other factors Other factors to consider : Other factors to consider Publication bias Studies showing significant differences are more likely to be published. Studies with significant findings can sometimes lead to multiple publications, particularly in multicenter trials Lead to problem when a meta-analysis is performed Where positive publication bias exists, results are more likely to be included ? overestimation of effect. Steps in evaluating promotional material from industry. : Steps in evaluating promotional material from industry. What sort of evidence is available? Does trial population reflect real life? Choice of comparator drug and dose? How the findings are presented? Statistical vs. clinical significant? Other factors Finding Answers in the Real World : Finding Answers in the Real World Use summary sources that filter for relevance & validity: Best Evidence Clinical Evidence The Cochrane Library InfoRetriever The Clinician of the Future : The Clinician of the Future “I know a lot, therefore I am” Replaceable by a computer “I think, therefore I am” Never replaceable by computer Hand held computer = “stethoscope of the future” Slide 50: We are made wise not by the recollection of the past; but by the responsibility for the future George Bernard Shaw

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