JAMVIGIG’/‘fie I
`USERS’ GUIDES
`-———--TO THE—--————
` MEDICAL
` LTERATURE
`
`A MANUAL FOR
`
`EVIDENCE—BASED CLINICAL PRACTICE
`
`SECOND EDITION
`
`Gordon Guyatt, MD - Drummond Rennie, MD
`
`Maureen O. Meade, MD - Deborah I. Cook, MD
`
`Mallinckrodt Hosp. Prods. IP Ltd.
`Exhibit 2042
`Praxair Distrib., Inc. et al., v. Mallinckr
`Case lPR2o16-00
`
`Hosp. Prods. IP Ltd.
`
`EX. 2042-0001
`
`Ex. 2042-0001
`
`

`
`JAlylA
`
`KRCHIVES
`lOUFINALS
`1arEcan Medical Association
`
`The M.-:Graw-Hill Companies
`
`ers’ Guides to the Medical Literature: A Manual forEvidence-Based Clinical Practice, Secondfidition
`pyright @ 2008 by the American Medical Association. All rights reserved. Published by The
`‘Grow-Hill Companies, inc. Printed in the United States ofAn'ierica. Except as permitted under the
`ited States Copyright Act of1976, no part of this publication may'be reproduced or distributed in
`7 form or by any means, or stored in a data base or retrieval system, without the prior written
`mission of the publisher.
`
`vious edition copyright © 2002 by the American Medical Association.
`
`34567890 DOCIDOC 098
`
`ISBN 973-0-073159034-1; MHID 0—07—159034-X
`)l(! ISBN 97il—0—07—l59036-5; MHID 0-07-159036-6
`ket Cards: ISBN 978—0—07—l60850A3; MHID 0-07-160850-8
`
`IA and Archives Journals:
`tor in Chief: Catherine D. DeAngelis, MD, MPH
`cutive Deputy Editor: Phil B. Fontanarosa, MD, MBA
`riaging Deputy Editor: Annette 1'-‘lanagin, RN, MA
`1LiSCl.'lpt Editor: Cara Wallace
`
`Sraw-Hill Professional
`3 book was set in Minion and Zurich by Silverchair Science -3- Communications, Inc.
`editors were James F. Shauahan and Robert Pancotti.
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`: book is printed on acidwfree paper.
`
`'ary of Congress Cata.loging—in-Publication Data
`
`:5’ guides to the medical literature : a manual for evidence-based clinical practice} edited by Gordon
`att, Drummond Rennie, Maureen O. Meade, Deborah]. Cook——2ncl ed.
`p. ; cm.
`7'. ed. ofi Users’ guides to the medical literature : a manual for evidence-based clinical practice I
`ad by Gordon Guyatt, Drummond Rennie. C2002.
`zludes bibliographical references and index.
`lN—13:978-0-07-159034-1 (pbk. :all<. paper)
`.
`lN—10: 0-07-E59034-X (pbk. : alk. paper)
`Evidence-based medicine—Handbooks, manuals, etc. 2. Clinical niedicine—1-landbooks, manuals, etc.
`iyatt, Gordon. II. Rennie, Drumrnond. III. Meade, Maureen 0. IV. Cook, Deborah I.
`.‘~iLM: 1. Resource Guides. 2. Evidence-Based Medicine. 3. Decision Making. 4. Review Literature as
`it. WB 39 U845 2.008]
`5.7.U34 2003
`~dc22
`
`2007047773
`
`EX. 2042-0002
`
`Ex. 2042-0002
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`

`
`OF EVIDENCE»
`BASED MEDICINE
`
`Gordon Guyatt, Brian Haynes, Roman Jaeschke,
`
`Maureen O. Meade, Mark Wilson, Victor Montori,
`and Scott Richardson
`
`EN THIS CHAPTER:
`
`Two Fundamental Principles of EBM
`
`A Hierarchy of Evidence
`
`Clinical Decision Making: Evidence Is Never Enough
`
`Clinical Skills, Humanism, and EBM
`
`Additional Challenges for EBM
`
`EX. 2042-0003
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`Ex. 2042-0003
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`
`PART A-. THE Fl‘|L'.\'||.-\TIt1N:€
`
`ill
`
`Evider-ice—brzsed medicine (EBM) is about solving clinical problems.‘ in 1992, we
`described EBM as a shift in medical paradigms.‘ In contrast to the traditional
`paradigm of medical practice, EBM places lower value on unsystematic clinical
`experience and pathophysiologic rationale,.stresses the examination of evzklerice
`from clinical research, suggests that interpreting the results of clinical research
`requires a formal set of rules, and places a lower value on authority than the
`traditional medical paradigm. Although we continue to find this paradigm shift a
`valid way of conceptualizing EBM, the world is often complex enough to invite
`more than I useful way of thinking about an idea or a phenomenon. In this
`chapter, we describe another conceptualization that emphasizes how EBM comple-
`ments and enhances the traditional skills of clinical practice.
`
`Hid HMEMENFEE. ?hEEEl?iE$
`
`As a distinctive approach to patient care, EBM involves 2 fundamental principles.
`First, EBM posits a liiemrclty of evidence to guide clinical decision making. Second,
`evidence alone is never sufficient to make a clinical decision. Decision makers must
`
`always trade off the benefits and risks, inconvenience, and costs associated with
`alternative management strategies and, in doing so, consider their patients’ values
`and preferences.‘
`
`A Hierarchy of Evidence
`What_is the nature of the evidence in EBM? We suggest a broad definition: any
`empirical observation constitutes potential evidence, whether systematically col-
`lected or not. Thus, the unsysternatic observations of the individual clinician
`constitute one source of evidence; physiologic experiments constitute another
`source. Unsystematic observations can lead to profound insights, and wise clini-
`cians develop a healthy respect for the insights of their senior colleagues in issues of
`clinical observation, diagnosis, and relations with patients and colleagues.
`At the same time, our personal clinical observations are often limited by small
`sample size and by deficiencies in human processes of making inferences.3
`Predictions about
`intervention efife.-:ts on patient-important outcomes based on
`physiologic experirnents usually are right but occasionally are disastrously wrong.
`Numerous factors can lead clinicians astray as they try to interpret the results of
`conventional open trials of therapy. These include rmnrral history, placebo efi‘ects,
`patient and health worker expectations, and the patient’s desire to please. We
`provide a number of examples of j ust how wrong predictions based on physiologic
`rationale can be in Chapter 9.2, Surprising Results of Randomized Trials.
`Given the limitations of unsysternatic clinical observations and physiologic
`rationale, EBM suggests a number of hierarchies of evidence, one of which relates
`to issues ofprevention and treatment (Table 2-1).
`
`EX. 2042-0004
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`Ex. 2042-0004
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`

`
`2: THE PHILOSOPHY OF EVIDENCE-BASED Mnoicnqs
`
`° N-of-1 randomized trial
`
`- Systematic reviews of randomized trials
`° Single randomized trial
`
`'- Systematic review of observational studies addressing patient—important out-
`comes
`
`° Single observational study addressing patient-important outcomes
`
`' Physiologic studies (studies of blood pressure, cardiac output, exercise capac-
`ity, bone density, and so forth)
`
`- Unsysternatic clinical observations
`
`
`Issues of diagnosis or prognosis require different hierarchies. For instance,
`randomization is not.relevant to sorting out how well a test is able to distinguish
`individuals with a target condition or disease from those who are healthy or have a
`competing condition or disease. For diagnosis, the top of the hierarchy would
`include studies that enrolled patients about whom clinicians had diagnostic
`uncertainty and that undertook a blind comparison between the candidate test and
`a criterion standard {see Chapter 16, Diagnostic Tests).
`Clinical research goes beyond unsystematic clinical observation in providing
`strategies that avoid or attenuate spurious results. The same strategies that
`minimize bias in conventional therapeutic trials involving multiple patients can
`guard against misleading results in studies involving single patients/4 In the n-of-1
`randomized controlled trial
`(n—of—1 RC1’), a patient and clinician are blind to
`whether that patient is receiving active or placebo medication. The patient makes
`quantitative ratings of troublesome symptoms during each period, and the n—of—1
`RCT continues until both the patient and the clinician conclude that the patient is
`or is not obtaining benefit from the target intervention. N-of~1 RCTs can provide
`definitive evidence of treatment effectiveness in individual patients5'5 and maylead
`to long—term differences in treatment administration (see Chapter 9.5, N—of—l
`Randomized Controlled Trials).7 Unfortunately,_ n—of—1 RCTs are restricted to
`chronic conditions with treatments that act and cease acting quickly and are subject
`to considerable logistic challenges. We must therefore usually rely on studies of
`other patients to make inferences regarding the patient before us.
`The requirement that clinicians generalize from results in other people to their
`patients inevitably weakens inferences about treatment impact and introduces
`complex issues of how trial results apply to individual patients. Inferences may
`nevertheless be strong if results come from a systematic review of rnethodologically
`strong RCTs with consistent results. Inferences generally will be somewhat weaker if
`only a single RCT is being considered, unless it is large and has enrolled patients
`much like the patient under consideration (Table 2-1). Because observational studies
`may underestimate or, more typically, overestimate treatment effects in an unpre~
`dictable fashion,3=9 their results are far "less trustworthy than those of RCTS.
`
`EX. 2042-0005
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`Ex. 2042-0005
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`

`
`I2
`
`PART A: THE FOUNDATIONS
`
`Physiologic studies and unsystematic clinical observations provide the weakest
`inferences about treatment effects.
`
`This hierarchy is not absolute. If treatment effects are sufficiently large and
`consistent, carefully conducted observational studies may provide more compel-
`ling evidence than poorly conducted RCTS. For example, observational studies
`have allowed extremely strong inferences about
`the efficacy of penicillin in
`pneumococcal pneumonia or thatof hip replacement in patients with debilitating
`hip osteoarthritis. Defining the extent to which clinicians should temper the
`strength of their inferences when only observational studies are available remains
`one of the important challenges in EBM.
`'
`The hierarchy implies a clear course of action for physicians addressing patient
`problems. They should look for the highest quality available evidence, from the
`hierarchy. The hierarchy makes it clear that any claim that there is no evidence for
`the effect of a particular treatment is a non sequitur. The evidence may be
`extremely weai<—it may be the unsystematic observation of a single clinician or
`physiologic studies that point to mechanisms of action that are only indirectly
`related—but there is always evidence.
`
`Blinical Decision Making: Evidence is Never Enough
`Picture a woman with chronic pain resulting from terminal cancer. She has come
`to terms with her condition, resolved her affairs, and said her good-byes, and she
`wishes to receive only palliative care. She develops severe pneumococcal pneumo-
`nia. Evidence that antibiotic therapy reduces morbidity and mortality from
`pneumococcal pneumonia is strong. Even evidence this convincing does not,
`however, dictate that this particular patient should receive antibiotics. Her values
`are such that she would prefer to forgo treatment.
`Now picture a second patient, an 85-year-old man with severe dementia who is
`mute and incontinent, is without family or friends, and spends his days in apparent
`discomfort. This man develops pneumococcal pneumonia. Although many clinicians
`would argue that those responsible for his care should not administer antibiotic
`therapy, others would suggest
`that they should. Again, evidence of treatment
`effectiveness does not automatically imply that treatment should be administered.
`Finaily, picture a third patient, a healthy 30-year-old mother of 2 children who
`develops pneumococcal pneumonia. No clinician would doubt the wisdom of
`administering antibiotic therapy to this patient. This does not mean, however. that
`an underlying value judgment has been unnecessary. Rather, our values are
`sufficiently concordant, and the benefits so overwhelm the risks of treatment, that
`the underlying value judgment is unapparent.
`By values and preferences, we mean the collection of goals. expectations,
`predispositions, and beliefs that individuals have for certain decisions and their
`potentiai outcomes. The explicit enumeration and balancing of benefits and risks
`that is central to EBM brings the underlying value judgments involved in making
`management decisions into bold relief
`Acknowledging that values play a role in every important patient care decision
`highlights our limited understanding of how to ensure that decisions are consistent
`
`EX. 2042-0006
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`

`
`2: THE PHILOSOPHY or EVIDENCEBASED MEDICINE
`
`with individual and, where appropriate, societal values. Health economists have
`played a major role in developing" the science of measuring patient preference_s.1”~“
`Some decision aids incorporate patient values indirectly. If patients truly under-
`stand the potential risks and benefits, their decisions will reflect their preferences.”
`These developments constitute a promising start. Nevertheless, many unanswered
`questions" remain concerning how to elicit preferences and how to incorporate
`them in clinical encounters already subject to crushing time pressures. We discuss
`these issues in more detail in Part G, Moving From Evidence to Action.
`Next, we briefly comment on additional skills that clinicians must master for
`optimal patient care and the relation of those skills to EBM.
`
`suntan sinus. HEJMANESM. nun EBilli
`
`In summarizing the skills and attributes necessary for evidence—based practice,
`Table 2-2 highlights how EBM complements traditional aspects of clinical exper-
`tise. One of us, a secondary-care internist, developed a lesion on his lip shortly
`before an important presentation. He was concerned and, wondering whether he
`should take acyclovir, proceeded to spend the next 30 minutes searching for and
`evaluating the h.ighest—quality evidence. When he began to discuss his remaining
`uncertainty with his partner, an experienced dentist, she cut short the discussion by
`exclaiming, “But, my dear, that isn’t herpes!”
`This story illustrates the necessity of obtaining the correct diagnosis before
`seeking and applying research evidence regarding optimal treatment. After making
`the diagnosis, the clinician relies on experience and background knowledge to
`define the relevant management options. Having identified those options, the
`clinician can search for, evaluate, and apply the best evidence regarding treatment.
`
`TABLE 2-
`
`- Diagnostic expertise
`
`° In-depth background knowledge
`' Effective searching skills
`
`° Effective criticai appraisal skills
`
`° Ability to define and understand benefits and risks of alternatives
`
`-'
`
`ln—depth physiologic understanding allowing application of evidence to the
`individual
`
`° Sensitivity and communication skills required for full understanding of patient
`context
`
`- Ability to elicit and understand patient values and preferences and apply them
`to management decisions —
`
`EX. 2042-0007
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`Ex. 2042-0007
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`
`PART A: THE FOUNDATIONS
`
`In applying evidence, clinicians rely on their expertise to define features that
`affect the applicability of the results to the individual patient. The clinician must
`judge the extent to which differences in treatment (local surgical expertise or the
`possibility of patient nonadherence, for instance), the availability of monitoring, or
`patient characteristics (such as age, comorbidity, or the patient’s personal circum-
`stances) may affect estimates of benefit and risk that come from the published
`literature.
`
`Understanding the patient’s personal circumstances is of particular irnportance”
`and requires compassion, sensitive listening skills, and broad perspectives from the
`humanities and social sciences. For some patients, incorporation ofpatient values for
`major decisions will mean a full enumeration of the possible benefits, risks, and
`inconvenience associated with alternative management strategies that are relevant to
`the particular patient. For some patients and problems, this discussion should involve
`the patient’s family. For other problemsmthe discussion of screening with prostate
`specific antigen with older male patients, for instance-—attempts to involve other
`family members might violate strong cultural norms.
`Some patients are uncomfortable with an explicit discussion of benefits and
`risks and object to clinicians placing what they perceive as excessive responsibility
`for decision making on their shoulders.” In such cases, it is the physician’s
`responsibility to develop insight to ensure that choices will be consistent with the
`patient’s values and preferences. Understanding and implementing the -sort of
`decision—making process that patients desire and effectively communicating the
`information they need require skills in understanding the patient’s narrative and
`the person behind that narrative.14=15
`
`Annrrlnnmt CHALLENGES ms EBM
`
`Clinicians will find that time limitations present the biggest challenge to evidence-
`based practice. Fortunately, new resources to assist clinicians are available and- the
`pace of innovation is rapid. One can consider a classification of information
`sources that comes with a mnemonic device, 4S: the individual study, the systematic
`review of all the available studies on a given problem, a synopsis of both individual
`studies and summaries, and systems of information.15 By systems, we mean
`summaries that link a number of synopses related to the care of a particular patient
`problem {acute upper gastrointestinal bleeding) or type of patient {the diabetic -
`outpatient) (Table 2-3). Evidence-based selection and sumrnarization is becoming
`increasingly available at each level (see Chapter 4, Finding the Evidence).
`A second enormous challenge for evidence—based practice is ensuringthat man»
`agement strategies are consistent with the patient’s values and preferences. In a time-
`constrained environment, how can we ensure that patients’ involvement in decision
`making has the form and extent that they desire and that the outcome reflects their
`needs and desires? Progress in addressing this daunting question will require a major
`expenditure of time and intellectual energy from clinician researchers.
`
`EX. 2042-0008
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`
`2: THE PHILOSOPHY OF EVIDENCEBASED MEDICINE
`
`I5
`
`Systematic
`reviews
`
`Synopses
`
`Systems
`
`Preprocessing involves selecting only those studies that are both
`highly relevant and characterized by study designs that minimize
`bias and thus permit a high strength of inference
`
`Fleviews involving the identification, selection, appraisal, and
`summary of primary studies addressing a focused clinical ques-
`tion using methods to reduce the likelihood of bias
`
`Brief summaries that encapsulate the key methodologie details
`and results of a single study or systematic review
`
`Practice guidelines, clinical pathways, or evidence-based text-
`book summaries that integrate evidence-based information about
`specific clinical problems and provide regular updates to guide
`.
`,
`the care of individual patients
`'
`
`This book deals primarily with decision rnaldng at the level of the individual
`patient. Evidence-based approaches can also inform health policy making,” day-
`to—day decisions in public health, and systems—level decisions such as thosefacing
`hospital managers. In each of these areas, EBM can support the appropriate goal of
`gaining the greatest health benefitfrom limited resources.
`In the policy arena, dealing with differing values poses even more challenges
`than in the arena of individual patient care. Should" we restrict ourselves to
`alternative resource allocation within 3. fixed pool of health care resources, or
`shculd we be trading offhealth care services against, for instance, lower tax rates for
`individuals or corporations? How should we deal with the large body of observa-
`tional studies suggesting that social and economic factors may have a larger
`influence on the health of populations than health care delivery? How should we
`deal with the tension between what may be best for a person and what may be
`optimal for the society of which that person is a member? The debate about such
`issues is at the heart of evidence—based health policy making, but, inevitably, it has
`implications for decision making at the individual patient level.
`
`References
`1. Haynes R, Sackett Fl, Gray J, Cook D, Guyatt G. Transferring evidence from
`research into practice, 1: the role of clinicai care research evidence in clinical
`decisions. ACPJ Club. 1996:‘l25l3}:A14-A16.
`. Napcdano Fi. Values in Medical Practice. New York, NY: Hun-Lana Sciences Press;
`1986.
`.'
`
`3. Nisbett H, Ross L. Human Inference. Englewood Cliffs, NJ: Prentice-Hall; 1980.
`4. Guyatt G, Sackett D, Taylor D, Chong J, Roberts Ft, Pugsley.S. Determining optimal
`therapy—ranclomized trials in individual patients. N Eng! J Med. 19B6;314(14l:889-
`892.
`
`%}
`
`.s'
`
`=7?
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`5,-
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`3;
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`2:
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`;.ii
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`EX. 2042-0009
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`Ex. 2042-0009
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`Hi
`
`1",-\ltT A; THE Fol =.-umTitw.-
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`5. Guyatt G, Keller J, Jaeschke R, Rosenbloom D, Adachi J, Newhouse M. The not-
`1 randomized controlled trial: clinical Usefulness: ourthree-year experience. Ann
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`. Larson E. Ellsworth A, Oas J. Randomized clinical trials in single patientsvduring a
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`. Mahon J, Laupacis A, Donner A, Wood T. Randomised study.of n of 1
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`trials
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`. Guvatt G. DiC6'n'-30 A. Farewell V, Willan A, Griffith L. Randomized trials Versus
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`. Kunz R, Oxman A. The unpredictability paradox: review of empirical compari-
`sons of randomised and non-randomised clinical trials. BM./. 1998;317(7167):
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`. Drurnmond M, Richardson W, O'Brien El, Levine M, Heyland D. Users’ Guide to
`the Medical Literature Xlll: how to use an article on economic analysis of clinical
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`. Feeny D, Furlong W, Boyle M, Torrance G. Multi-attribute health status ciassifica—
`tion systems: health utilities index. Pharmacoeconomics. 1995;7i6):49U«502.
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`. O'Connor A, Rostom A, Fiset V, et al. Decision aids for patients facing health
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`.Sutherland H, Llewellyn-Thomas H, Lockwood G, Tritchler D, Till J. Cancer
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`patients: their desire for information and participation in treatment decisions. JR
`Soc Med. 1989,82-(5):25D—263.
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`.Greenhelgh T. Narrative based medicine: narrative based medicine in an
`evidence based World. BMJ. 1999;318(7l7‘9):323-325.
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`. Greenhalgh T, Hurwitz B. Narrative based medicine: why study narrative? BM./.
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`
`. Haynes R. Of studies, syntheses, synopses, and systems: the "48" evolution of
`services for finding current best evidence. ACPJ Club. 2001;‘i34l2):A11-A13.
`
`. Muir Gray F, Haynes R, Sackett D, Cook D, Guyatt G. Transferring evidence from
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`
`EX. 2042-0010
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