Ethics and Evidence-based Medicine (EBM)

Ethics and Ethics and Evidence-based Medicine (EBM)Evidence-based Medicine (EBM)

PHL281Y BioethicsPHL281Y BioethicsSummer 2005 Summer 2005

University of TorontoUniversity of Torontowww.chass.utoronto.ca/~kirstinwww.chass.utoronto.ca/~kirstin

OverviewOverview

1.1. (Olivieri case)(Olivieri case)

2.2. Decision-making in MedicineDecision-making in Medicine

3.3. What is EBM?What is EBM?

4.4. Evaluating the Evidence Evaluating the Evidence HierarchyHierarchy

5.5. Ethics and EBMEthics and EBM

6.6. Ethics and Corporate Influences Ethics and Corporate Influences on Decision-making in Medicineon Decision-making in Medicine

Interim findings of RCTsInterim findings of RCTs Case: Dr. Nancy OlivieriCase: Dr. Nancy Olivieri Mid 1990’sMid 1990’s Hospital for Sick Children (Toronto)Hospital for Sick Children (Toronto) ApotexApotex Thalassemia Thalassemia Hydroxypyridin-4-1 (deferiprone)Hydroxypyridin-4-1 (deferiprone)

Physician/scientist roles (Hellman & Physician/scientist roles (Hellman & Hellman)Hellman)

Individual equipoise vs. clinical equipoiseIndividual equipoise vs. clinical equipoise Academic freedom in clinical researchAcademic freedom in clinical research

Decision-making in MedicineDecision-making in Medicine How do physicians make decisions about treatments How do physicians make decisions about treatments

for particular patients? for particular patients? • Intuition? Experience? Authority? Case studies? RCT Intuition? Experience? Authority? Case studies? RCT

evidence?evidence?

Is it ethical of a physician to make decisions on other Is it ethical of a physician to make decisions on other grounds? Why/Why not?grounds? Why/Why not?• Decision based on ‘gut feeling’?Decision based on ‘gut feeling’?

It matters quite a lot whether these decisions are right It matters quite a lot whether these decisions are right or wrong (life/death)or wrong (life/death)

EBM Version 1.0EBM Version 1.0 Evidence-based Medicine (EBM)Evidence-based Medicine (EBM) MotivationMotivation

• History: textbook information + authority of superiors + History: textbook information + authority of superiors + personal experience as sources of evidencepersonal experience as sources of evidence

• Surveys in the 70’s and 80’s - lack of standardizationSurveys in the 70’s and 80’s - lack of standardization

• Increase in biomedical research - overload of information Increase in biomedical research - overload of information (read 19 articles/day, 365 days/year vs. 1 hour a day to (read 19 articles/day, 365 days/year vs. 1 hour a day to read)read)

Goal: Make the practice of medicine more objective (and Goal: Make the practice of medicine more objective (and hopefully therefore more standardized)hopefully therefore more standardized)

The (In)famous Declaration (1.0)The (In)famous Declaration (1.0)

EBM “de-emphasizes intuition, unsystematic clinical EBM “de-emphasizes intuition, unsystematic clinical experience and pathophysiologic rationale as experience and pathophysiologic rationale as sufficient grounds for clinical decision-making and sufficient grounds for clinical decision-making and stresses the examination of evidence from clinical stresses the examination of evidence from clinical research”research”

- - EBM Working Group 1992 EBM Working Group 1992 JAMAJAMA

The Process (1.0)The Process (1.0)

1.1. Formulate a questionFormulate a question

2.2. Do a literature search (MEDLINE)Do a literature search (MEDLINE)

3.3. Use the evidence hierarchy to ‘critically evaluate’ the Use the evidence hierarchy to ‘critically evaluate’ the quality of evidencequality of evidence

4.4. Apply the recommendations of the ‘best evidence’ Apply the recommendations of the ‘best evidence’ directly to patientsdirectly to patients

*Don’t let intuition or clinical experience interfere*Don’t let intuition or clinical experience interfere

The Reaction to EBM 1.0The Reaction to EBM 1.0

Medical journals flooded with articles, editorialsMedical journals flooded with articles, editorials

Concern about a ‘cook-book’ approach to Concern about a ‘cook-book’ approach to medicine (no deviation)medicine (no deviation)

The art vs. science of medicineThe art vs. science of medicine

EBM Version 2.0EBM Version 2.0

““Evidence-based Medicine is the conscientious, Evidence-based Medicine is the conscientious, explicit and judicious use of current best evidence explicit and judicious use of current best evidence in making decisions about the care of individual in making decisions about the care of individual patients” patients”

- Sackett, - Sackett, JAMAJAMA 1996 1996

Integration model – best evidence + individual Integration model – best evidence + individual clinical expertise (‘neither alone is enough’)clinical expertise (‘neither alone is enough’)

Comparing Versions 1 & 2Comparing Versions 1 & 2 EBM 1 “de-emphasizes EBM 1 “de-emphasizes

intuition, unsystematic intuition, unsystematic clinical experience and clinical experience and pathophysiologic rationale pathophysiologic rationale as sufficient grounds for as sufficient grounds for clinical decision-making clinical decision-making and stresses the and stresses the examination of evidence examination of evidence from clinical research” from clinical research” (1992)(1992)

EBM 2 “is the EBM 2 “is the conscientious, explicit and conscientious, explicit and judicious use of current judicious use of current best evidence in making best evidence in making decisions about the care of decisions about the care of individual patients” (1996)individual patients” (1996)

The Process (2.0)The Process (2.0)

1.1. Formulate a questionFormulate a question

2.2. Do a literature search (MEDLINE)Do a literature search (MEDLINE)

3.3. Use the evidence hierarchy to ‘critically evaluate’ the Use the evidence hierarchy to ‘critically evaluate’ the quality of evidencequality of evidence

4.4. Integrate ‘best evidence’ with clinical experience to Integrate ‘best evidence’ with clinical experience to produce a decision regarding treatmentproduce a decision regarding treatment

Simplified Evidence HierarchySimplified Evidence Hierarchy

Meta-analysesMeta-analyses

Randomized Controlled TrialsRandomized Controlled Trials

Non-randomized / Observational ResearchNon-randomized / Observational Research

Case-series, Case Studies, Qualitative Research, Anecdotal EvidenceCase-series, Case Studies, Qualitative Research, Anecdotal Evidence

Assumptions Underlying the HierarchyAssumptions Underlying the Hierarchy

Why is the hierarchy ordered the way it is?Why is the hierarchy ordered the way it is?

Best evidence is identified by 3 characteristics:Best evidence is identified by 3 characteristics:

1.1. SimpleSimple• The simplest explanation is often the best (Ockham’s razor)The simplest explanation is often the best (Ockham’s razor)

2. Generalizable2. Generalizable• The results of research need to be generalizable to as many The results of research need to be generalizable to as many

patients as possiblepatients as possible

3. Objective (free from bias)3. Objective (free from bias)

SuccessSuccess EBM now widely accepted in medical schools and hospitals EBM now widely accepted in medical schools and hospitals

across North America and much of Europeacross North America and much of Europe

Extended to physiotherapy, nursing, public policy, Extended to physiotherapy, nursing, public policy, dentistry… “Evidence-based practice”dentistry… “Evidence-based practice”

Practice GuidelinesPractice Guidelines

““One of the most influential ideas of the year” New York One of the most influential ideas of the year” New York Times Magazine 2001Times Magazine 2001

Funding bodies, journal editors and policy makers continue Funding bodies, journal editors and policy makers continue to rely on strict application of the evidence hierarchy (RCTs to rely on strict application of the evidence hierarchy (RCTs and meta-analyses of RCTs)and meta-analyses of RCTs)

7 Alternatives to EBM (BMJ)7 Alternatives to EBM (BMJ)

1. Eminence-based medicine1. Eminence-based medicine - the more senior the colleague, - the more senior the colleague, the less importance he or she placed on the need for anything as the less importance he or she placed on the need for anything as mundane as evidence. These colleagues have a touching faith in mundane as evidence. These colleagues have a touching faith in clinical experience, which has been defined as “making the same clinical experience, which has been defined as “making the same mistakes with increasing confidence over an impressive number mistakes with increasing confidence over an impressive number of years.”of years.”

2. Vehemence-based medicine2. Vehemence-based medicine - the substitution of volume for - the substitution of volume for evidence.evidence.

3. Eloquence-based medicine3. Eloquence-based medicine - the year-round suntan, - the year-round suntan, carnation in the buttonhole, silk tie, Armani suit, and tongue carnation in the buttonhole, silk tie, Armani suit, and tongue should be equally smooth. Sartorial elegance and verbal should be equally smooth. Sartorial elegance and verbal eloquence are powerful substitutes for evidence.eloquence are powerful substitutes for evidence.

7 Alternatives (continued)7 Alternatives (continued)

4. Providence-based medicine4. Providence-based medicine – decision left in the hands of the – decision left in the hands of the AlmightyAlmighty

5. Diffidence-based medicine - 5. Diffidence-based medicine - do nothing from a sense of do nothing from a sense of despair. (This may still be better than doing something merely despair. (This may still be better than doing something merely because it hurts the doctor’s pride to do nothing)because it hurts the doctor’s pride to do nothing)

6. Nervousness-based medicine - 6. Nervousness-based medicine - fear of litigation is a powerful fear of litigation is a powerful stimulus. In an atmosphere of litigation phobia, the only bad test stimulus. In an atmosphere of litigation phobia, the only bad test is a test you didn’t think of orderingis a test you didn’t think of ordering

7. Confidence-based medicine - 7. Confidence-based medicine - this is restricted to surgeonsthis is restricted to surgeons

Evaluating the HierarchyEvaluating the Hierarchy What is actually being done (almost exclusive focus on What is actually being done (almost exclusive focus on

RCTs and meta-analyses) vs. charitable reading of RCTs and meta-analyses) vs. charitable reading of what is proposedwhat is proposed

• Example: 13 observational studies found same effect, all Example: 13 observational studies found same effect, all trumped by 1 RCT that disagreedtrumped by 1 RCT that disagreed

Evaluating the HierarchyEvaluating the Hierarchy ““Because the randomized trial, and especially the Because the randomized trial, and especially the

systematic review of several randomized trials, is so much systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead more likely to inform us and so much less likely to mislead us, it has become the ‘gold standard’ for judging whether a us, it has become the ‘gold standard’ for judging whether a treatment does more harm than good”treatment does more harm than good”

• Note: the claim that observational research ‘over-Note: the claim that observational research ‘over-estimates’ effects is circularestimates’ effects is circular

Do we have reason to doubt the RCT as the ‘gold standard’?Do we have reason to doubt the RCT as the ‘gold standard’?

Do we have reason to value the lowest levels of evidence Do we have reason to value the lowest levels of evidence more highly?more highly?

Evaluating the HierarchyEvaluating the Hierarchy

A weak claim: “An RCT is not always the best A weak claim: “An RCT is not always the best choice of study design”choice of study design”

A stronger claim: “An RCT, even when possible, A stronger claim: “An RCT, even when possible, often gives markedly worse evidence than an often gives markedly worse evidence than an observational study” observational study” (Grossman & Mackenzie, 2005)(Grossman & Mackenzie, 2005)


1.1. Treating the ‘Average’ Patient (vs. individualized Treating the ‘Average’ Patient (vs. individualized care) care) • The RCT evaluates efficacy rather than effectivenessThe RCT evaluates efficacy rather than effectiveness• Restricted population in trials (inclusion and exclusion criteria)Restricted population in trials (inclusion and exclusion criteria)

• ““Only 10% of patients in primary care have the sort of isolated, Only 10% of patients in primary care have the sort of isolated, uncomplicated form of hypertension that lends itself to uncomplicated form of hypertension that lends itself to management by a standard evidence-based guideline.” management by a standard evidence-based guideline.” (Greenhalgh, 1999)(Greenhalgh, 1999)

• ““Clinical research, as currently envisioned, must inevitably Clinical research, as currently envisioned, must inevitably ignore what may be important, yet non-quantifiable, differences ignore what may be important, yet non-quantifiable, differences between individuals. Defining medical knowledge solely on the between individuals. Defining medical knowledge solely on the basis of such studies, then, would necessarily eliminate the basis of such studies, then, would necessarily eliminate the importance of individual variation from the practice of importance of individual variation from the practice of medicine” (Tonelli, 1998) medicine” (Tonelli, 1998)

Evaluating the HierarchyEvaluating the Hierarchy• ““The empirical observation of populations in randomized trials The empirical observation of populations in randomized trials

and cohort studies cannot be mechanistically applied to and cohort studies cannot be mechanistically applied to individual patients (whose behavior is irremediably contextual individual patients (whose behavior is irremediably contextual and idiosyncratic) or episodes of illness.” (Greenhalgh, 1999)and idiosyncratic) or episodes of illness.” (Greenhalgh, 1999)

• ““When transferred to clinical medicine from an origin in When transferred to clinical medicine from an origin in agricultural research, randomized trials were not intended to agricultural research, randomized trials were not intended to answer questions about the treatment of individual patients” answer questions about the treatment of individual patients” (Feinstein and Horwitz, 1997)(Feinstein and Horwitz, 1997)

• Complexity of human beingsComplexity of human beings Adverse Drug Reactions (rate 4-6Adverse Drug Reactions (rate 4-6thth leading cause of death leading cause of death

in USA)in USA) Support from pharmacogeneticsSupport from pharmacogenetics

• RCT results may be most helpful at policy level RCT results may be most helpful at policy level • Need subgroup analysis (at the very least)Need subgroup analysis (at the very least)


2. False Sense of Objectivity 2. False Sense of Objectivity Some possible sources of bias in research:Some possible sources of bias in research:

Broad social forcesBroad social forces Funding agenciesFunding agencies Publication biasPublication bias

• Suppressing negative results, confidentiality clauses, presenting only Suppressing negative results, confidentiality clauses, presenting only part of the data (ex/ Celebrex – first 6 months of year-long trial, AIDS part of the data (ex/ Celebrex – first 6 months of year-long trial, AIDS vaccine – only presented positive subgroup)vaccine – only presented positive subgroup)

Loopholes in methodologyLoopholes in methodology• Study design bias - testing against placebo rather than current drug, Study design bias - testing against placebo rather than current drug,

testing only young people (less side effects), suboptimal dosing, trials testing only young people (less side effects), suboptimal dosing, trials too brief to be meaningfultoo brief to be meaningful

Backgrounds and goals of researchers (research what you fear)Backgrounds and goals of researchers (research what you fear) Researcher’s values (ex/ interpreting data favourably)Researcher’s values (ex/ interpreting data favourably) Patient’s valuesPatient’s values ……


3. “Lower” Evidence is Often Ignored3. “Lower” Evidence is Often Ignored

• Many research questions cannot be answered with RCTs - think Many research questions cannot be answered with RCTs - think especially of social, psychological and environmental diseases especially of social, psychological and environmental diseases and treatmentsand treatments

• If you treat patients on the EBM model, what happens to If you treat patients on the EBM model, what happens to information from these sources?information from these sources?

• How does this influence treatment?How does this influence treatment? Overmedication (nutrition and exercise vs. drug)?Overmedication (nutrition and exercise vs. drug)?

Evaluating the HierarchyEvaluating the Hierarchy4. The Problem of Moving Away from First Causes4. The Problem of Moving Away from First Causes

• RCTs and symptom alleviationRCTs and symptom alleviation• ““Identify and treat the causes”Identify and treat the causes”• You will need research in basic sciences (biochemistry, etc.) to get at You will need research in basic sciences (biochemistry, etc.) to get at

these first causes these first causes • PathophysiologyPathophysiology

Antibiotics for infection, pacemakers, blood transfusions, fluids for Antibiotics for infection, pacemakers, blood transfusions, fluids for dehydration…dehydration…

Insulin and penicillin!Insulin and penicillin!

5. Lack of Significant Commitment to Shared Decision-making5. Lack of Significant Commitment to Shared Decision-making

• Even EBM version 2.0 downplays the patient’s role in evidence-based Even EBM version 2.0 downplays the patient’s role in evidence-based decision-making with strict adherence to the evidence hierarchydecision-making with strict adherence to the evidence hierarchy

• If patient’s role is significant, ‘best evidence’ may varyIf patient’s role is significant, ‘best evidence’ may vary


6. Social, Political and Economic Forces Shifting Direction 6. Social, Political and Economic Forces Shifting Direction of Research of Research

• RCTs are expensive and require much infrastructural support RCTs are expensive and require much infrastructural support (gold)(gold)

• Lack of interest in investing/researching un-patentable Lack of interest in investing/researching un-patentable treatments (market demands)treatments (market demands)

• Orphan drugs vs. ‘me-too’ drugsOrphan drugs vs. ‘me-too’ drugs• Some treatments may not be researched because they cannot Some treatments may not be researched because they cannot

be patented and the payoff isn’t high enough – yet they could be patented and the payoff isn’t high enough – yet they could be effective treatmentsbe effective treatments

• This skews the direction/content of ‘good evidence’This skews the direction/content of ‘good evidence’


7.7. New Forms of New Forms of AuthorityAuthority

• The Cochrane Collaboration (based in Oxford) – international The Cochrane Collaboration (based in Oxford) – international consortium of workers who construct, rank, and maintain an ever-consortium of workers who construct, rank, and maintain an ever-enlarging data base of clinical trials (based on the evidence hierarchy enlarging data base of clinical trials (based on the evidence hierarchy of EBM)of EBM)

• Industrial-scale production of meta-analyses?Industrial-scale production of meta-analyses?

8.8. Potential AbusesPotential Abuses

• Cookbook (as much as it is denied)Cookbook (as much as it is denied)• Management by policy-makers and hospitals:Management by policy-makers and hospitals:

““These so-called ‘best practices’ are poised to become coercive mandates These so-called ‘best practices’ are poised to become coercive mandates imposed by government agencies and third-party payers with political and imposed by government agencies and third-party payers with political and financial incentives to ration health care – and the power to do it…The public financial incentives to ration health care – and the power to do it…The public should be alarmed.” (Brase 2005)should be alarmed.” (Brase 2005)

Managed care and EBMManaged care and EBM• Malpractice suits?Malpractice suits?

EBM AssessmentEBM Assessment If physicians uncritically accept the EBM hierarchy, they If physicians uncritically accept the EBM hierarchy, they

may make decisions about patient-care on inappropriate may make decisions about patient-care on inappropriate evidence. Is this acceptable? Is this any different from what evidence. Is this acceptable? Is this any different from what existed before EBM?existed before EBM?

Does the presence of EBM create new moral obligations for Does the presence of EBM create new moral obligations for physicians?physicians?

How do physicians maintain commitment to the ‘central How do physicians maintain commitment to the ‘central aim of medicine’ in light of these developments?aim of medicine’ in light of these developments?

Persistent uncertainty in medicinePersistent uncertainty in medicine

Ethics and UncertaintyEthics and Uncertainty

Uncertainty is unavoidable (though it may be Uncertainty is unavoidable (though it may be reduced through research)reduced through research)

1.1. How should one make a decision under How should one make a decision under uncertainty when an error might harm someone?uncertainty when an error might harm someone?• Moral demand for reasons (vs. hunches, intuitions)Moral demand for reasons (vs. hunches, intuitions)

2.2. How should clinicians communicate this How should clinicians communicate this uncertainty and risk to patients?uncertainty and risk to patients?• Disclosure of relevant uncertaintyDisclosure of relevant uncertainty• Share this management of uncertainty with patients in shared Share this management of uncertainty with patients in shared

decision-makingdecision-making

Ethics and UncertaintyEthics and Uncertainty

3.3. How ought society respond to the problem of scientific or How ought society respond to the problem of scientific or clinical uncertainty, as well as to the tensions raised as clinical uncertainty, as well as to the tensions raised as money and malpractice challenge efforts to incorporate money and malpractice challenge efforts to incorporate more evidence into daily practice?more evidence into daily practice?

• Reward quality, not compliance (many cases rather than Reward quality, not compliance (many cases rather than individual cases)individual cases)

• Fix malpractice liability problem (‘catastrophe’ in USA) – don’t Fix malpractice liability problem (‘catastrophe’ in USA) – don’t assume certainty of practice guidelines in lawassume certainty of practice guidelines in law

• Do more, better science (no hidden research) and improve Do more, better science (no hidden research) and improve education (medical students should be taught the education (medical students should be taught the probabilistic and uncertain nature of medicine and the ethical probabilistic and uncertain nature of medicine and the ethical challenges this raises)challenges this raises)

-Goodman (2005)-Goodman (2005)

Influences on Decision-makingInfluences on Decision-making Corporate Influence (Global Corporate Influence (Global

Industry - $400 billion/year):Industry - $400 billion/year):

• Marketing as research Marketing as research (examples earlier)(examples earlier)

““I became increasingly troubled I became increasingly troubled by the possibility that much by the possibility that much published research is seriously published research is seriously flawed, leading doctors to flawed, leading doctors to believe new drugs are generally believe new drugs are generally more effective and safe than more effective and safe than they actually are.” (Angell, they actually are.” (Angell, 2004)2004)

Influences on Decision-makingInfluences on Decision-making• Marketing as education: retreats, Marketing as education: retreats,

conferences, seminars, lunches, conferences, seminars, lunches, information packages information packages

‘‘Thought leaders’ and ‘consultants’Thought leaders’ and ‘consultants’ ‘‘Detailing’ 88,000 sales representatives of Detailing’ 88,000 sales representatives of

pharmaceutical companies employed to pharmaceutical companies employed to promote products in hospitals and doctors promote products in hospitals and doctors offices (USA)offices (USA)

‘‘Preceptorship’ – shadowing doctors as Preceptorship’ – shadowing doctors as they see patientsthey see patients

Marketing off-label use of drugsMarketing off-label use of drugs Educating patients – DTC advertisingEducating patients – DTC advertising

• Should we try to draw a line between Should we try to draw a line between education and marketing (education grants vs. education and marketing (education grants vs. kickbacks) and use restrictions? kickbacks) and use restrictions?

• Angell – it really is Angell – it really is allall marketing. marketing. Pharmaceutical companies are not in the Pharmaceutical companies are not in the education businesseducation business

Influences on Decision-makingInfluences on Decision-making

• ‘‘Free’ samples ($11 billion/year in Free’ samples ($11 billion/year in USA)USA)

• Gifts – books, golf balls, tickets to Gifts – books, golf balls, tickets to sporting events, Christmas trees, sporting events, Christmas trees, champagne, family vacations to champagne, family vacations to HawaiiHawaii

Some new regulations on this recentlySome new regulations on this recently

• Financial incentives for recruiting Financial incentives for recruiting patients into studiespatients into studies

Moral assessment? Moral assessment? Central aim of medicine? Central aim of medicine?

SummarySummary

1.1. (Olivieri case)(Olivieri case)2.2. Decision-making in MedicineDecision-making in Medicine3.3. What is EBM?What is EBM?4.4. Evaluating the Evidence HierarchyEvaluating the Evidence Hierarchy5.5. Ethics and EBMEthics and EBM6.6. Ethics and Corporate Influences on Decision-making Ethics and Corporate Influences on Decision-making

in Medicinein Medicine

Looking AheadLooking Ahead

Next class – last full lectureNext class – last full lecture

Justice and Health CareJustice and Health Care

ContactContactProf. Kirstin BorgersonProf. Kirstin Borgerson

Room Room 359S359S Munk Centre Munk CentreOffice Hours: Tuesday 3-5pm and by appointmentOffice Hours: Tuesday 3-5pm and by appointmentCourse Website: Course Website: www.chass.utoronto.ca/~kirstinwww.chass.utoronto.ca/~kirstin

Email: [email protected]: [email protected]

http://www.chass.utoronto.ca/~kirstin

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Ethics and Evidence-based Medicine (EBM)