Medical Researchers’ Ancillary Clinical Care Responsibilities Essay

Healthcare workers using clinical practice guidelines
and other recommendations need to know how much
confidence they can place in the recommendations.
Systematic and explicit methods of making judgments
can reduce errors and improve communication. We
have developed a system for grading the quality of evidence and the strength of recommendations that can
be applied across a wide range of interventions and
contexts. In this article we present a summary of our
approach from the perspective of users of guidelines.
What makes a good guideline?Medical Researchers’ Ancillary Clinical Care Responsibilities Essay

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Judgments about evidence and recommendations are
complex. Consider, for example, the choice between
selective serotonin reuptake inhibitors and tricyclic
antidepressants for the treatment of moderate depression. Clinicians must decide which outcomes to
consider, which evidence to include for each outcome,
how to assess the quality of that evidence, and how to
determine if selective serotonin reuptake inhibitors do
more good than harm compared with tricyclics.
Because resources are always limited and money that is
spent on serotonin reuptake inhibitors cannot be used
elsewhere, they may also need to decide whether any
incremental health benefits are worth the additional
costs.
It is not practical for individual clinicians and
patients to make unaided judgments for each clinical
decision. Clinicians and patients commonly use clinical
practice guidelines as a source of support. Users of
guidelines need to know how much confidence they
can place in the evidence and recommendations. We
describe the factors on which our confidence should
be based and a systematic approach for making the
complex judgments that go into clinical practice
guidelines, either implicitly or explicitly. To achieve
simplicity in our presentation we do not discuss all the
nuances, some of which are discussed in the longer
version of this article on bmj.com.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
The GRADE Working Group began as an informal
collaboration of people with an interest in tackling the
shortcomings of present grading systems. Table 1 summarises these shortcomings and the ways in which we
have overcome them. The GRADE system enables
more consistent judgments, and communication of
such judgments can support better-informed choices
in health care. Box 1 shows the steps in developing and
implementing guidelines from prioritising problems
through evaluating their implementation. We focus
here on grading the quality of evidence and strength of
recommendations.
Definitions
We have used the following definitions: the quality of
evidence indicates the extent to which we can be confident that an estimate of effect is correct; the strength of
a recommendation indicates the extent to which we
can be confident that adherence to the recommendation will do more good than harm.
The steps in our approach are to make sequential
judgments about:
x The quality of evidence across studies for each
important outcome
x Which outcomes are critical to a decision
x The overall quality of evidence across these critical
outcomes
x The balance between benefits and harms
x The strength of recommendations
All of these judgments depend on having a clearly
defined question and considering all of the outcomes
that are likely to be important to those affected. The
question should identify which options are being comThis is an abridged version; the full version is on bmj.com
Correspondence to:Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Andrew D Oxman,
Informed Choice
Research
Department,
Norwegian Health
Services, PO Box
7004, St Olavs plass,
0130 Oslo, Norway
[email protected]
BMJ 2004;328:1490–4
1490 BMJ VOLUME 328 19 JUNE 2004 bmj.com
pared (for example, selective serotonin reuptake
inhibitors and tricyclic antidepressants), for whom
(moderately depressed adult patients), and in what setting (primary care in England).
Quality of evidence
Judgments about quality of evidence should be guided
by a systematic review of available evidence. Reviewers
should consider four key elements: study design, study
quality, consistency, and directness (box 2). Study
design refers to the basic study design, which we have
broadly categorised as observational studies and
randomised trials. Study quality refers to the detailed
study methods and execution. Consistency refers to the
similarity of estimates of effect across studies.
Directness refers to the extent to which the people,
interventions, and outcome measures are similar to
those of interest. Another type of indirect evidence
arises when there are no direct comparisons of
interventions and investigators must make comparisons across studies.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
The quality of evidence for each main outcome can
be determined after considering each of these four elements. Our approach initially categorises evidence
based on study design into randomised trials and
observational studies (box 2). We then suggest considering whether the studies have serious limitations,
important inconsistencies in the results, or whether
uncertainty about the directness of the evidence is warranted.
Additional considerations that can lower the
quality of evidence include imprecise or sparse data
and a high risk of reporting bias. Additional considerations that can raise the quality of evidence include a
very strong association (for example, a 50-fold risk of
poisoning fatalities with tricyclic antidepressants; see
table 2) or strong association (for example, a threefold
increased risk of head injuries among cyclists who do
not use helmets compared with those who do1
) and
evidence of a dose-response gradient. Box 3 gives our
suggested definitions for grading the quality of the evidence.
The same rules should be applied to judgments
about the quality of evidence for harms and benefits.
Important plausible harms can and should be included
in evidence summaries by considering the indirect evidence that makes them plausible. For example, if there
is concern about anxiety in relation to screening for
melanoma and no direct evidence is found, it may be
appropriate to consider evidence from studies of other
types of screening.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Judgments about the quality of evidence for important outcomes across studies can and should be made
in the context of systematic reviews, such as Cochrane
reviews. Judgments about the overall quality of
evidence, trade-offs, and recommendations typically
require information beyond the results of a review.
Other systems have commonly based judgments of
the overall quality of evidence on the quality of
evidence for the benefits of interventions. When the
risk of an adverse effect is critical for a judgment, and
evidence regarding that risk is weaker than evidence of
benefit, ignoring uncertainty about the risk of harm is
problematic. We suggest that the lowest quality of
evidence for any of the outcomes that are critical to
making a decision should provide the basis for rating
overall quality of evidence.
Recommendations
Does the intervention do more good than harm?
Recommendations involve a trade-off between benefits
and harms. Making that trade-off inevitably involves
placing, implicitly or explicitly, a relative value on each
outcome. We suggest making explicit judgments about
the balance between the main health benefits and
harms before considering costs. Does the intervention
do more good than harm?
Recommendations must apply to specific settings
and particular groups of patients whenever the
benefits and harms differ across settings or patient
groups. For instance, consider whether you should recommend that patients with atrial fibrillation receive
warfarin to reduce their risk of stroke, despite the
increase in bleeding risk that will result. Recommendations, or their strength, are likely to differ in settings
where regular monitoring of the intensity of antiBox 1: Sequential process for developing Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
guidelines
First steps
1. Establishing the process—For example, prioritising
problems, selecting a panel, declaring conflicts of
interest, and agreeing on group processes
Preparatory steps
2. Systematic review—The first step is to identify and
critically appraise or prepare systematic reviews of the
best available evidence for all important outcomes
3. Prepare evidence profile for important outcomes—Profiles
are needed for each subpopulation or risk group,
based on the results of systematic review, and should
include a quality assessment and a summary of
findings
Grading quality of evidence and strength of
recommendations
4. Quality of evidence for each outcome—Judged on
information summarised in the evidence profile and
based on the criteria in table 2
5. Relative importance of outcomes—Only important
outcomes should be included in evidence profiles. The
included outcomes should be classified as critical or
important (but not critical) to a decision
6. Overall quality of evidence—The overall quality of
evidence should be judged across outcomes based on
the lowest quality of evidence for any of the critical
outcomes.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
7. Balance of benefits and harms—The balance of benefits
and harms should be classified as net benefits,
trade-offs, uncertain trade-offs, or no net benefits
based on the important health benefits and harms
8. Balance of net benefits and costs—Are incremental
health benefits worth the costs? Because resources are
always limited, it is important to consider costs
(resource utilisation) when making a recommendation
9. Strength of recommendation—Recommendations
should be formulated to reflect their strength—that is,
the extent to which one can be confident that
adherence will do more good than harm
Subsequent steps
10. Implementation and evaluation—For example, using
effective implementation strategies that address
barriers to change, evaluation of implementation, and
keeping up to date
Education and debate
BMJ VOLUME 328 19 JUNE 2004 bmj.com 1491
coagulation is available and settings where it is not.
Furthermore, recommendations (or their strength) are
likely to differ in patients at low risk of stroke (those
under 65 without any comorbidity) and patients at
higher risk (such as older patients with heart failure)
because of differences in the absolute reduction in risk.
Recommendations must therefore be specific to a
patient group and a practice setting.
Those making a recommendation should consider
four main factors:Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
x The trade-offs, taking into account the estimated
size of the effect for the main outcomes, the confidence
limits around those estimates, and the relative value
placed on each outcome
x The quality of the evidence
x Translation of the evidence into practice in a specific
setting, taking into consideration important factors
that could be expected to modify the size of the
expected effects, such as proximity to a hospital or
availability of necessary expertise
x Uncertainty about baseline risk for the population
of interest.
If there is uncertainty about translating the
evidence into practice in a specific setting, or
uncertainty about baseline risk, this may lower our
confidence in a recommendation. For example, if an
intervention has serious adverse effects as well as
important benefits, a recommendation is likely to be
much less certain when the baseline risk of the population of interest is uncertain than when it is known.
Table 1 Comparison of GRADE and other systems
Factor Other systems GRADE Advantages of GRADE system*
Definitions Implicit definitions of quality (level) of evidence and
strength of recommendation
Explicit definitions Makes clear what grades indicate and what should
be considered in making these judgments
Judgments Implicit judgments regarding which outcomes are
important, quality of evidence for each important
outcome, overall quality of evidence, balance
between benefits and harms, and value of
incremental benefits
Sequential, explicit judgments Clarifies each of these judgments and reduces risks
of introducing errors or bias that can arise when
they are made implicitly Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Key components of quality of
evidence
Not considered for each important outcome.
Judgments about quality of evidence are often
based on study design alone
Systematic and explicit consideration of study
design, study quality, consistency, and directness
of evidence in judgments about quality of evidence
Ensures these factors are considered appropriately
Other factors that can affect
quality of evidence
Not explicitly taken into account Explicit consideration of imprecise or sparse data,
reporting bias, strength of association, evidence of
a dose-response gradient, and plausible
confounding
Ensures consideration of other factors
Overall quality of evidence Implicitly based on the quality of evidence for
benefits
Based on the lowest quality of evidence for any of
the outcomes that are critical to making a decision
Reduces likelihood of mislabelling overall quality of
evidence when evidence for a critical outcome is
lacking
Relative importance of
outcomes
Considered implicitly Explicit judgments about which outcomes are
critical, which ones are important but not critical,
and which ones are unimportant and can be
ignored
Ensures appropriate consideration of each outcome
when grading overall quality of evidence and
strength of recommendations
Balance between health
benefits and harms
Not explicitly considered Explicit consideration of trade-offs between
important benefits and harms, the quality of
evidence for these, translation of evidence into
specific circumstances, and certainty of baseline
risks Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Clarifies and improves transparency of judgments
on harms and benefits
Whether incremental health
benefits are worth the costs
Not explicitly considered Explicit consideration after first considering whether
there are net health benefits
Ensures that judgments about value of net health
benefits are transparent
Summaries of evidence and
findings
Inconsistent presentation Consistent GRADE evidence profiles, including
quality assessment and summary of findings
Ensures that all panel members base their
judgments on same information and that this
information is available to others
Extent of use Seldom used by more than one organisation and
little, if any empirical evaluation
International collaboration across wide range of
organisations in development and evaluation
Builds on previous experience to achieve a system
that is more sensible, reliable, and widely applicable
*Most other approaches do not include any of these advantages, although some may incorporate some of these advantages.
Box 2: Criteria for assigning grade of evidence
Type of evidence
Randomised trial = high
Observational study = low
Any other evidence = very low
Decrease grade if:
• Serious ( − 1) or very serious ( − 2) limitation to study
quality
• Important inconsistency ( − 1)
• Some ( − 1) or major ( − 2) uncertainty about
directness
• Imprecise or sparse data ( − 1)
• High probability of reporting bias ( − 1)
Increase grade if:
• Strong evidence of association—significant relative
risk of > 2 ( < 0.5) based on consistent evidence from
two or more observational studies, with no plausible
confounders (+1)Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
• Very strong evidence of association—significant
relative risk of > 5 ( < 0.2) based on direct evidence
with no major threats to validity (+2)
• Evidence of a dose response gradient (+1)
• All plausible confounders would have reduced the
effect (+1)
Box 3: Definitions of grades of evidence
High = Further research is unlikely to change our
confidence in the estimate of effect.
Moderate = Further research is likely to have an
important impact on our confidence in the estimate of
effect and may change the estimate.
Low = Further research is very likely to have an
important impact on our confidence in the estimate of
effect and is likely to change the estimate.
Very low = Any estimate of effect is very uncertain.
Education and debate
1492 BMJ VOLUME 328 19 JUNE 2004 bmj.com
We suggest using the following categories for
recommendations:
“Do it” or “don’t do it”—indicating a judgment that
most well informed people would make;
“Probably do it” or “probably don’t do it”—indicating a
judgment that a majority of well informed people
would make but a substantial minority would not.
A recommendation to use or withhold an intervention does not mean that all patients should be treated
identically. Nor does it mean that clinicians should not
involve patients in the decision, or explain the merits of
the alternatives. However, because most well informed
patients will make the same choice, the explanation of
the relative merits of the alternatives may be relatively
brief. A recommendation is intended to facilitate an
appropriate decision for an individual patient or a
population. It should therefore reflect what people
would likely choose, based on the evidence and their
own values or preferences in relation to the expected
outcomes. A recommendation to probably do something indicates a need for clinicians to consider
patients’ values and preferences more carefully when
offering them the intervention.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
In some instances it may not be appropriate to
make a recommendation because of unclear trade-offs
or lack of agreement. When this is due to a lack of good
quality evidence, specific research should be recommended that would provide the evidence that is
needed to inform a recommendation.
Are the incremental health benefits worth the
costs?
Because spending money on one intervention means
less money to spend on another, recommendations
implicitly (if not explicitly) rely on judgments about the
value of the incremental health benefits in relation to
the incremental costs. Costs—the monetary value of
resources used—are important considerations in making recommendations, but they are context specific,
change over time, and their magnitude may be difficult
to estimate. While recognising the difficulty of accurate
estimating costs, we suggest that the incremental costs
of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms.
When relevant and available, disaggregated costs
(differences in use of resources) should be presented in
evidence profiles along with important outcomes. The
Table 2 Quality assessment of trials comparing selective serotonin reuptake inhibitors (SSRIs) with tricyclic antidepressants for treatment of moderate
depression in primary care2
No of studies
Quality assessment Summary of findings
Design Quality Consistency Directness Medical Researchers’ Ancillary Clinical Care Responsibilities Essay

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Other
modifying
factors*
No of patients Effect
SSRIs Tricyclics
Relative
(95% CI) Absolute Quality Importance
Depression severity (measured with Hamilton depression rating scale after 4 to 12 weeks)
Citalopram (8) Randomised
controlled trials
No serious
limitations
No important
inconsistency
Some
uncertainty
about
directness
(outcome
measure)†
None 5044 4510 WMD
0.034
(−0.007 to
0.075)
No
difference
Moderate
Critical
Fluoxetine (38)
Fluvoxamine (25)
Nefazodone (2)
Paroxetine (18)
Sertraline (4)
Venlafaxine (4)
Transient side effects resulting in discontinuation of treatment
Citalopram (8) Randomised
controlled trials Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
No serious
limitations
No important
inconsistency
Direct None 1948/703
2 (28%)
2072/6334
(33%)
RRR 13%
(5% to
20%)
5/100 High
Critical
Fluoxetine (50)
Fluvoxamine (27)
Nefazodone (4)
Paroxetine (23)
Sertraline (6)
Venlafaxine (5)
Poisoning fatalities§
UK Office for
National
Statistics (1)
Observational
data
Serious
limitation‡
Only one study Direct Very strong
association
1/100 000/
year of
treatment
58/100 000/
year of
treatment
RRR 98%
(97% to
99%)§
6/10 000 Moderate Critical
WMD = weighted mean difference, RRR = relative risk reduction.
*Imprecise or sparse data, a strong or very strong association, high risk of reporting bias, evidence of a dose-response gradient, effect of plausible residual confounding.
†There was uncertainty about the directness of the outcome measure because of the short duration of the trials.
‡It is possible that people at lower risk were more likely to have been given SSRIs and it is uncertain if changing antidepressant would have deterred suicide attempts.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
§There is uncertainty about the baseline risk for poisoning fatalities.
Summary points
Organisations have used various systems to grade
the quality of evidence and strength of
recommendations
Differences and shortcomings in these grading
systems can be confusing and impede effective
communication
A systematic and explicit approach to making
judgments about the quality of evidence and the
strength of recommendations is presented
The approach takes into account study design,
study quality, consistency, and directness in
judging the quality of evidence for each
important outcome
The balance between benefits and harms, quality
of evidence, applicability, and the certainty of the
baseline risk are all considered in judgments
about the strength of recommendations
Education and debate
BMJ VOLUME 328 19 JUNE 2004 bmj.com 1493
quality of the evidence for differences in use of
resources should be graded by using the approach
outlined above for other important outcomes.
How it works in practice
Table 2 shows an example of the system applied to evidence from a systematic review comparing selective
serotonin reuptake inhibitors with tricyclic antidepressants conducted in 1997.2 After discussion, we agreed
that there was moderate quality evidence for the
relative effects of both types of drugs on severity of
depression and poisoning fatalities and high quality
evidence for transient side effects. We then reached
agreement that the overall quality of evidence was
moderate and that there were net benefits in favour of
serotonin reuptake inhibitors (no difference in severity
of depression, fewer transient side effects, and fewer
poisoning fatalities).Medical Researchers’ Ancillary Clinical Care Responsibilities Essay Although we agreed that there
seemed to be net benefits, we concluded with a recommendation to “probably” use serotonin reuptake
inhibitors because of uncertainty about the quality of
the evidence. We had no evidence on relative costs in
this exercise. Had we considered costs, this recommendation might have changed.
Conclusions
We have attempted to find a balance between simplicity and clarity in our system for grading the quality of
evidence and strength of recommendations. Regardless of how simple or complex a system is, judgments
are always required. Our system provides a framework
for structured reflection and can help to ensure that
appropriate judgments are made, but it does not
remove the need for judgment.
Contributors and sources: see bmj.com
Competing interests: Most of the members of the GRADE
Working Group have a vested interest in another system of
grading the quality of evidence and the strength of recommendations.
1 Thompson DC, Rivara FP, Thompson R. Helmets for preventing head
and facial injuries in bicyclists. Cochrane Database Syst Rev
2000;(2):CD001855.
2 North of England Evidence Based Guideline Development Project.
Evidence based clinical practice guideline: the choice of antidepressants for
depression in primary care. Newcastle upon Tyne: Centre for Health Services Research, 1997.
(Accepted 5 March 2004)
Medical researchers’ ancillary clinical care responsibilities
Leah Belsky, Henry S Richardson
Investigation of participants in clinical trials may identify conditions unrelated to the study.
Researchers need guidance on whether they have a duty to treat such conditions Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Researchers testing a new treatment for tuberculosis
in a developing country discover some patients have
HIV infection. Do they have a responsibility to provide
antiretroviral drugs? In general, when do researchers
have a responsibility to provide clinical care to participants that is not stipulated in the trial’s protocol? This
question arises regularly, especially in developing
countries, yet (with rare exceptions1
) existing literature
and guidelines on research ethics do not consider
ancillary clinical care. We propose an ethical
framework that will help delineate researchers’
responsibilities.
What is ancillary care?
Ancillary care is that which is not required to make a
study scientifically valid, to ensure a trial’s safety, or to
redress research injuries. Thus, stabilising patients to
enrol them in a research protocol, monitoring drug
interactions, or treating adverse reactions to experimental drugs are not ancillary care. By contrast, following up on diagnoses found by protocol tests or treating
ailments that are unrelated to the study’s aims would be
ancillary care.
Two extreme views
When asked how much ancillary care they should provide to participants, the first reaction of many clinical
researchers, especially those working in developing
countries, is that they must provide whatever ancillary
care their participants need. From an ethical
perspective, this response makes sense. Research
participants in trials in the developing world are
typically desperately poor and ill, and everyone
arguably has a duty to rescue those in need, at least
when they can do so at minimal cost to themselves.2 3
Yet this response fails to acknowledge that the goal of
research is to generate knowledge not care for
patients.4 5 When researchers consider that offering
ancillary care this broadly may drain limited human
and financial resources and confound study results,
they tend to retreat from this position.Medical Researchers’ Ancillary Clinical Care Responsibilities Essay
Some researchers veer to the opposite extreme.
“We may be doctors,” they note, “but these are our
research participants, not our patients, so we owe
them nothing beyond what is needed to complete the
study safely and successfully—that is, we owe them no
ancillary care.” But this extreme position is ethically
questionable. Consider the case of researchers
studying a rare disease. It is ethically unacceptable to
say to a participant, “We are going to monitor the toxicity and effectiveness of this experimental drug, and
we will make sure it does not kill you, but we are not
going to provide any palliative care for your
condition.” Closely monitoring a participant’s disease
without being willing to treat it in any way amounts to
treating him or her as a mere means to the end of
research.

“Henry Richardson has the rare talent of digging deep theoretically, while being attentive to contextual complexities and constraints of practice. For a decade he has been exploring the moral landscape of medical researchers’ ancillary care responsibilities. This inquiry has yielded a carefully crafted and rigorously argued book. Through comprehensively examining ancillary care obligations, Richardson illuminates the neglected phenomenon of moral entanglements that arise in professional encounters, and in ordinary life, when privacy rights are waived. Reading his book will reward all those interested in the ethics of clinical research, professional ethics, and moral philosophy.” -Franklin G. Miller, Ph.D., Department of Bioethics, National Institutes of Health Medical Researchers’ Ancillary Clinical Care Responsibilities Essay

“In this wonderful book-distinguished by very careful philosophical analysis and real-world examples-Henry Richardson elaborates the “partial-entrustment” model he and Leah Belsky first advanced a decade ago regarding researchers’ obligations to provide care that is ancillary to the purposes of their research projects. He situates this model in a broader set of “entanglements” that will feel very familiar to any person who has engaged not only in medical research but in any complex inter-personal interaction that isn’t cabined by the four corners of an explicit contract. Everyone with an interest in biomedical research and research ethics should read this book: they will profit both from recognizing the pervasive issues on which it shines a bright light and from its thoughtful and nuanced responses.” – Alexander M. Capron, University Professor, University of Southern California & Former Director, Ethics, Trade, Human Rights and Health Law, WHO

“This book sets out the most comprehensive framework to date for delineating the special responsibilities of researchers to address healthcare needs encountered in research in low-resource settings. By asserting that when particular moral conditions can be met, researchers have obligations to take demanding steps to address entrusted conditions, the account in this book provides decision-makers at the coalface with a clear focus. The author also clearly sets out how this framework relates to previous conceptual contributions to the contested area of ‘ancillary care’ obligations in research.” – Catherine Slack, HIV AIDS Vaccines Ethics Group, South African AIDS Vaccines Initiative, South Africa Medical Researchers’ Ancillary Clinical Care Responsibilities Essay

“As the author notes in his conclusion, the ‘practical neglect of the issue of ancillary care seems to have been accompanied by a widely shared theoretical blind spot.’ But Richardson has remedied that error of omission and left us with a fine volume that will be a touchstone for future scholarship and regulation. It is an inspired and highly readable analysis.” — Notre Dame Philosophical Reviews

“Moral Entanglements repays close study and sets a fine example of the kind of work to which normative ethics should aspire: engaged, relevant, philosophically rich, and insightful.” — Ethics Medical Researchers’ Ancillary Clinical Care Responsibilities Essay