Correspondence
to validate the use of clinically Oxford Biomedical Research Centre, University of
driven intervention thresholds. This
approach, which avoids inappropriate
over-treatment of older individuals
and under-treatment of younger
individuals, has been shown to be
cost-effective3 and has been adopted
in many countries.6
Unthinking assimilation of the NICE
multiple technology appraisal risks a
generation of older individuals taking
a bisphosphonate regardless of the
individual benefit-to-risk ratio and an
increased burden of rare long-term
side-effects across the population.
Given recent debates about the role
of pharmaceutical interventions in
the prevention of several chronic non-
communicable diseases, this would
be an unexpected and unwelcome
consequence of national guidance.
NCH has received consultancy fees, lecture fees,
honoraria, and grant funding from Alliance for
Better Bone Health, Amgen, MSD, Eli Lilly, Servier,
Shire, Consilient Healthcare, and Internis Pharma,
and is a member of the (NOGG) Expert Advisory
Group. EM has received consultancy fees, lecture
fees, grant funding, and honoraria from
ActiveSignal, Amgen, Consilient Healthcare,
Gilead, GlaxoSmithKline, Internis, Lilly, Merck,
Radius Pharmaceuticals, Roche, Synexus, UCB, and
I3 Innovus, and is a member of the NOGG Expert
Advisory Group. JAK reports grants from Amgen,
Lilly, and Radius Health, and consulting fees from
Meda; he is a member of NOGG and the architect
of FRAX but has no financial interest. JC has
received advisory and speaking fees from Gilead,
speaking fees from Amgen, and is Chairman of
NOGG. CC has received consultancy fees, lecture
fees, honoraria, and grant funding from Amgen,
GlaxoSmithKline, Alliance for Better Bone Health,
MSD, Eli Lilly, Pfizer, Novartis, Servier, Medtronic,
and Roche, and is a member of the NOGG Expert
Advisory Group.
Nicholas C Harvey, Eugene McCloskey,
John A Kanis, Juliet Compston,
*Cyrus Cooper
cc@mrc.soton.ac.uk
Medical Research Council Lifecourse Epidemiology
Unit, University of Southampton, Southampton,
SO16 6YD, UK (NCH, CC); National Institute for
Health Research (NIHR) Southampton Biomedical
Research Centre, University of Southampton and
University Hospital Southampton National Health
Service Foundation Trust, Southampton, UK (NCH,
CC); Centre for Metabolic Bone Diseases (EM, JAK),
Centre for Integrated Research in Musculoskeletal
Ageing, Mellanby Centre for Bone Research (EM),
University of Sheffield, Sheffield, UK; Institute for
Health and Aging, Catholic University of Australia,
Melbourne, VIC, Australia (JAK); Cambridge
Biomedical Campus, Cambridge, UK (JC); and NIHR
2244 www.thelancet.com Vol 390 November 18, 2017
dominate our aging populations.2
Oxford, Oxford, UK (CC)
1 National Institute for Health and Care
Excellence. Bisphosphonates for treating
osteoporosis. Aug 9, 2017. https://www.nice.
org.uk/guidance/ta464/resources/
bisphosphonates-for-treating-osteoporosis-
pdf-82604905556677 (accessed
Oct 11, 2017).
2 National Institute for Health and Care
Excellence. Osteoporosis: fragility fracture risk.
Short clinical guideline—evidence and
recommendation. London: National Clinical
Guideline Centre, 2012. https://www.nice.org.
uk/guidance/cg146/evidence/full-guideline-
pdf-186818365 (accessed Oct 11, 2017).
3 Kanis JA, McCloskey EV, Johansson H, Strom O,
Borgstrom F, Oden A. Case finding for the
management of osteoporosis with FRAX—
assessment and intervention thresholds for
the UK. Osteoporos Int 2008; 19: 1395–408.
4 Adler RA, El-Hajj Fuleihan G, Bauer DC, et al.
Managing osteoporosis in patients on long-
term bisphosphonate treatment: report of
a Task Force of the American Society for Bone
and Mineral Research. J Bone Miner Res 2016;
31: 16–35.
5 Compston J, Cooper A, Cooper C, et al. UK
clinical guideline for the prevention and
treatment of osteoporosis. Arch Osteoporos
2017; 12: 43.
6 Kanis JA, Harvey NC, Cooper C, Johansson H,
Oden A, McCloskey EV. A systematic review of
intervention thresholds based on FRAX:
a report prepared for the National
Osteoporosis Guideline Group and the
International Osteoporosis Foundation.
Arch Osteoporos 2016; 11: 25.
On evidence-based
medicine
In their Review1 published in The Lancet
(July 22, p 415), Benjamin Djulbegovic
and Gordon H Guyatt provide a
comprehensive overview of the
challenges evidence-based medicine
(EBM) will probably face in the next
25 years. Rightly, they conclude that it
is a triumph that no critic of EBM has
ever suggested that reliable evidence
should not be key to medicine. EBM’s
next challenge will be the continued
development of more efficient and
rapid ways of disseminating evidence
and guidelines.
Although the authors acknowledge
that current EBM guidelines are not
used to inform many clinical decisions,
they almost completely ignore the
biggest challenge clinicians face in
the 21st century: how to apply EBM
to the multimorbidity problems that
For people who are older or dealing
with multiple conditions, or both,
the evidence produced is often
uninformative or its application could
cause harm.2,3
Generalised guidelines are bad for
patients with multiple morbidities
because they often lead to too many
or conflicting therapies that are
not personalised to the patient.3,4
The alternative, which would be
the development of trials for all
potential disease combinations, is
simply unfeasible.4 Moreover, many
complex treatments are influenced
by the patient’s environment, which
makes even cluster randomised trials
impossible. There is no perfect study
design because the research questions
differ too much; before the research
community can find solutions to these
problems, we need to acknowledge
this fundamental mismatch between
the evidence produced and the
evidence that is needed. It is important
to embrace the ambiguity that is
inherent to medicine. Individuals
respond differently to therapy in
clinical care compared with aver­
age responses during trials, and
responses are changed further by
ageing and interactions between
multiple diseases.2–5
Therefore, we plead for disrup­
tive innovation in EBM, including
comple­mentary research paradigms
of complexity science, systems dy­
namics, and narrative, and qualitative
approaches that help clinicians under­
stand the complexities of real life
clinical questions and deliver evidence
that is more meaningful to daily
practice. Once these paradigms are
combined with the virtues of EBM, the
next 25 years will be well spent.
We declare no competing interests.
Marjolein A van der Marck,
René J F Melis, *Marcel G M Olde Rikkert
marcel.olderikkert@radboudumc.nl
Radboud Institute for Health Sciences, Radboud
University Medical Center, Nijmegen, Netherlands
(MAvdM, RJFM); and Department of Geriatrics,
Radboudumc Alzheimer Center, Donders Institute

for Brain, Cognition and Behaviour, Radboud
University Medical Center, 6525 CG Nijmegen,
Netherlands (MGMOR)
1 Djulbegovic B, Guyatt GH. Progress in
evidence-based medicine: a quarter century
on. Lancet 2017; 390: 415–23.
2 Farmer C, Fenu E, O’Flynn N, Guthrie B. Clinical
assessment and management of
multimorbidity: summary of NICE guidance.
BMJ 2016; 354: i4843.
3 Boyd C, Darer J, Boult C, Fried LP, Boult L,
Wu AW. Clinical practice guidelines and quality
of care for older patients with multiple
comorbid diseases. JAMA 2005; 216; 716–24.
4 Upshur R. Looking for rules in a world of
exceptions: reflections on evidence-based
practice. Persp Biol Med 2005; 48: 477–89.
5 Smith GD. Epidemiology, epigenetics and the
‘gloomy prospect’: embracing randomness in
population health research and practice.
Int J Epidemiol 2011; 40: 537–62.
In the Review1 of evidence-based
medicine by Benjamin Djulbegovic
and Gordon H Guyatt, different or con­
flicting interpretation of the literature
was not mentioned. Although such
data selection might not be deliberate,
it can be problematic and could result
in different interpretations of the evi­
dence by guidelines on the same topic.2
For example, the evidence used to
underpin guidelines for the treatment
of pharyngitis differ between North
America and Europe. North American
guidelines cited more North American
references than European guidelines
did (191 [88·4%] of 216 vs 156 [49·5%]
of 309; odds ratios 4·6–12, p<0·0001).2
The result is that the recommendations
of European and American guidelines
for pharyngitis disagree on the use of
a rapid antigen test and throat culture
and the indication for antibiotics.
Notably, the four North American
guidelines state that diagnosis of
group A streptococcus is essential for
antibiotic therapy, and prevention
of acute rheumatic fever remains
an important reason to prescribe
antibiotics. In four of the six European
guidelines, acute sore throat is
considered a self-limiting disease and
antibiotics are not recommended,
except in high-risk patients.2
Although evidence for the treatment
and management of pharyngitis is
easily available, national guidelines
www.thelancet.com Vol 390 November 18, 2017 2245
differ in their use of evidence and the
interpretation for clinical practice.
Therefore, we need more guarantees
that the available evidence has been
sufficiently appraised to avoid any
inappropriate selection or different
interpretation of the evidence.3–5
I was a co-author of the revised 2017 Belgian
guidelines on acute sore throat.
Jan Matthys
jan.matthys@ugent.be
Department of General Practice and Primary Health
Care, University of Ghent, Ghent 9000, Belgium
1 Djulbegovic B, Guyatt GH. Progress in
evidence-based medicine: a quarter century
on. Lancet 2017; 390: 415–23.
2 Matthys J, De Meyere M, van Driel ML,
De Sutter A. Differences among international
pharyngitis guidelines: not just academic.
Ann Fam Med 2007; 5: 436–43.
3 Créquit P, Trinquart L, Yavchitz A, Ravaud P.
Wasted research when systematic reviews fail
to provide a complete and up-to-date evidence
synthesis: the example of lung cancer. BMC Med
2016; 14: 8.
4 Matthys J, De Meyere M. Antibiotics for acute
sore throat. Lancet Infect Dis 2014; 14: 919–20.
5 Chalmers I, Glasziou P. Systematic reviews and
research waste. Lancet 2016; 387: 122–23.
In their Review, Benjamin Djulbegovic
1
and Gordon H Guyatt do not
adequately address the undue
emphasis placed on randomisation
in clinical research, which is arguably
the main criticism of evidence-based
medicine (EBM).
The calls by EBM pioneers to abandon
evidence from non-randomised
studies2 remain resonant and influen­
tial today, resulting in unwarranted
credibility being given to random­
ised controlled trials that are poorly
designed or conducted.3 This misplaced
authority could potentially mislead
clinicians and policy makers and cause
harm to patients, in addition to the
waste of increasingly scarce research
resources.
For example, several evidence-
based guidelines recommend the use
of cognitive behavioural therapy for
people with schizophrenia. However,
a comprehensive evaluation of all
randomised evidence showed that
such treatment was ineffective when
outcome assessors were blinded.4
Correspondence
Over the next 25 years,1 advances in
precision medicine might challenge
the EBM paradigm, particularly
because—in recent years—there has
been a remarkable increase in the use
of breakthrough therapies that were
approved based on their efficacy in
non-randomised studies.5
I declare no competing interests.
Feras Ali Mustafa
feras.mustafa@nhft.nhs.uk
Northamptonshire Healthcare NHS Foundation
Trust, Northampton NN1 3EB, UK
1 Djulbegovic B, Guyatt GH. Progress in
evidence-based medicine: a quarter century
on. Lancet 2017; 390: 415–23.
2 Sackett DL, Straus SE, Richardson WS,
Rosenberg W, Haynes RB. Evidence-based
medicine: how to practice and teach EBM.
Edinburgh: Churchill Livingston, 2000.
3 McCulloch P, Taylor I, Sasako M, Lovett B,
Griffin D. Randomised trials in surgery:
problems and possible solutions. BMJ 2002;
324: 1448–51.
4 Jauhar S, McKenna PJ, Radua J, Fung E,
Salvador R, Laws KR. Cognitive-behavioural
therapy for the symptoms of schizophrenia:
systematic review and meta-analysis with
examination of potential bias. Br J Psychiatry
2014; 204: 20–29.
5 Darrow JJ, Avorn J, Kesselheim AS. New FDA
breakthrough-drug category—implications
for patients. N Engl J Med 2014;
370: 1252–58.
Authors’ reply
We thank Marjolein A van der Marck
and colleagues, Feras Ali Mustafa,
and Jan Matthys for their interest in
our Review.1 We agree with van der
Marck and colleagues that tackling
multimorbidity is an enormous
challenge for evidence-based prac­tice
AndreaAgrati/iStock
that, so far, has not been met. Authors
within the evidence-based medicine
(EBM) community have, however,
suggested initial strate­gies for those
who write guide­lines2 and for the
broader scientific community,3 and have
emphasised the need for approaches
that are minimally disruptive to
patients’ lives.4 Solutions are likely to
be found through informed decision
making, in innovative research designs
(as van der Marck and colleagues
suggest), and in new approaches to
clinical practice guidelines. Indeed, this
challenge should be a focus of EBM in
the coming decades.