22 Ann Ist Super Sanità 2011 | Vol. 47, No.

1: 22-25
DOI: 10.4415/ANN_11_01_06

Evidence-based medicine:
New Challenges in Translational Medicine

what it can and cannot do

Goffredo Freddi and José Luis Romàn-Pumar
Merck Sharp & Dohme Italia and Schering Plough Italia, Rome, Italy

Summary. Evidence-based medicine (EBM) is not a old hat, a “cookbook” medicine perpetrated by
arrogant to serve cost cutters to suppress clinical freedom, a mandatory, deterministic, totalitarian
practice of medicine, a way to control cost and to ignore patient preferences, a limit to personal/
humanistic/individual medicine. EBM is a reference of excellence to guide clinical decisions, the in-
tegration of own expertise with others’ expertise and patient preferences, a way to improve medical
practice and limit the variability and errors created when there is not evidence to identify the gold
standard and differentiate among alternatives available. But evidences need to be integrated with
a new thinking based on Complexity Science. Health care systems operates as complex adaptative
systems rather than rigid, linear or mechanical organizations and innovation is a critical outcome of
Complexity Science. How does EBM impact drug innovation? New drug approvals are not keeping
pace with rising Research and Development spending, clinical approval success rate for new chemi-
cal entities (NCEs) is progressively dropping and maybe, through these indicators, we are seeing the
worst face of EBM: its limiting, blocking, and controlling side. If that is the case, EBM is the main
ally to keep the economy of health systems under control and the great excuse to block the access of
the innovation to patients. Certainly not the best way to maximize the benefits of EBM.
Key words: evidence-based medicine, complexity science, innovation, clinical practice.

Riassunto (La medicina basata sull’evidenza: cosa può e non può fare). La medicina basata sull’evi-
denza (evidence-based medicine, EBM) non è un vecchio cappello, un ricettario scritto da qualche
“arrogantello” a beneficio di qualche “ragioniere” della Sanità per sopprimere la libertà del medico,
una prassi medica obbligatoria, deterministica e totalitaria, una disciplina per controllare i costi e
ignorare le preferenze dei pazienti, un limite invalicabile alla medicina personalizzata, umanisti-
ca, individuale. L’EBM è, invece, un riferimento di eccellenza per indirizzare le decisioni cliniche,
l’integrazione della propria con le migliori esperienze e con le preferenze dei pazienti, un modo
per migliorare la pratica medica limitando la variabilità e gli errori laddove non esistano evidenze
concrete, per identificare il gold standard e differenziare tra le diverse alternative disponibili. Ma
le evidenze devono essere integrate con un nuovo modo di pensare che si basa sulla Complexity
Science. I sistemi sanitari operano come sistemi adattativi complessi piuttosto che come organizza-
zioni meccaniche, rigide e lineari e l’innovazione è uno dei risultati più importanti della Complexity
Science. Che impatto ha l’EBM sull’innovazione, in particolare su quella farmacologica? Il tasso di
approvazione di nuove molecole non tiene il passo con la crescita degli investimenti in Ricerca &
Sviluppo e, forse, dietro questo indicatore, si nasconde la faccia peggiore dell’EBM: la sua capacità
di limitare, bloccare e controllare. Se questo è vero, l’EBM è il principale alleato di chi vuole tenere
i conti della sanità sotto controllo e la scusa migliore per bloccare l’accesso all’innovazione da parte
dei pazienti. Certamente, non il modo migliore per massimizzare i benefici dell’EBM.
Parole chiave: medicina basata sull’evidenza, scienza della complessità, innovazione, pratica clinica.

INTRODUCTION The practice of EBM therefore means integrat-

Philosophical origins of evidence-based medicine ing individual clinical expertise (i.e., proficiency and
(EBM) extend back to 19th century and earlier but EBM judgment that individual clinicians acquire through
still remains a hot topic for clinicians, public health practi- clinical experience/practice) with the best available
tioners, purchasers, planners, and the public as well. external clinical evidence from systematic research.
According to David Sackett’s definition [1], EBM Good physicians should use both and neither alone
is the “conscientious, explicit, and judicious use of is enough.
current best evidence in making decisions about the Such a needed integration also comes from the
care of individual patients”. multifaceted concept of evidence (proof, causality

Address for correspondence: José Luis Romàn-Pumar, Merck Sharp & Dohme Italia, Via Vitorchiano 151, 00189 Rome,
Italy. E-mail: [email protected].
 Evidence-based medicine 23

but uncertainty as well) where every component has On the other hand, we would apply EBM as:

New Challenges in Translational Medicine

its own implication in terms of clinical decisions. - a reference of excellence to guide clinical deci-
However, as suggested by the philosopher John sions;
Mackie [2], causality cannot be reduced to single nec- - the integration of own expertise with others’ ex-
essary and sufficient causes; rather it should be de- pertise and patient preferences;
scribed in terms of a complexity of elements he calls - a way to improve medical practice and limit the
INUS (Insufficient Non-redundant component of an variability and errors created when there is not
Unnecessary Sufficient complex). None of them is a evidences;
single sufficient cause but only their conjunction gives - a way to identify the gold standard and differen-
origin to an overall sufficient complex and at least one tiate among different alternatives available;
is necessary (non-redundant), i.e., in its absence the - a valid approach for medical interventions.
complex would be ineffective. Having emphasized the positive aspects of EBM,
we strongly need to stress that evidences alone are
not enough and, to demonstrate that, we will use a
EVIDENCE-BASED MEDICINE parallel between EBM and modern management.
IN THE 21st CENTURY
This said, is evidence, and particularly EBM, the
necessary, non-redundant component for good clin- COMPLEXITY SCIENCE
ical decisions? Paradoxically, in the early 21st cen- As pointed out by Gareth Morgan, “one of the
tury we still need to clarify what EBM is and what most basic problems in modern management is that
is not. the mechanical way of thinking is so grained in our
The reason is that EBM has strong supporters but every day conception of organization that it is often
is not without its critics. As a matter of fact, sup- very difficult to organize in any other way”.
porters have traditionally envisioned EBM as a way Current management thinking largely assumes
to “close the gulf between good clinical research that a well functioning organization is akin to a well
and clinical practice” [3] but critics argue that this oiled machine. This leads to the notion that per-
gulf can never be completely closed because it rep- formance is optimized when work is specified in de-
resents an intrinsic, philosophical gap. tail and shared out to distinct operational units.
Moreover, population-based studies are likely to Conventional models are based on the Newtonian
fulfill the goal of public health, but the application scientific principles which hold that by understand-
of the same knowledge to the individual is problem- ing simple universal rules that control the system
atic. parts, future behaviour of the parts is predictable
In addition, focusing primarily on the results of with linear cause and effects.
clinical trials, minimizes the importance of intangi- The limits of Newtonian reductionism which has
ble physical, emotional, and spiritual aspects of ill- guided scientific thinking for over three centuries
ness. are astonishing if we start to consider management
Furthermore, all evidence is not equally good (e.g., (but healthcare decision-making as well?) in terms
studies’ design, sample sizes, statistical significance) of Complexity Science.
and evidence can be contradictory. Complexity Science is a direct challenge to the
Finally, EBM also has its “internal” enemies: the dominance of the machine metaphor. It is a de-
“enthusiasts”. As pointed out by Dave Holmes, scription of the complex phenomena demonstrated
“The evidence-based movement is outrageously ex- in systems characterized by non linear interactive
clusionary and dangerously normative…and consti- components, emergent phenomena, continuous
tutes a good example of micro-fascism at play in the and discontinuous change and unpredictable out-
contemporary arena”[4]. comes. Complexity, typical of living systems, is
According to our point of view, EBM is not: usually understood in contrast to simple, linear
- a old hat (French Médecine d’Observation in the systems (Table 1).
early 19th Century); We do believe that every stakeholder charged with
- a “cookbook” medicine perpetrated by arrogant making decisions about the care of individual patients
to serve cost cutters to suppress clinical freedom should work with, rather than against, overwhelming
(because it is restricted to randomized trials and complexity. This means making sense of a complex
meta-analyses); world, rather than providing neat answers − when
- a mandatory, deterministic, totalitarian practice not absolutely certain − that promise success.
of medicine; Health care systems operates as complex adapta-
- a block/ban/barrier for not doing something tive systems rather than rigid, linear, or mechanical
when evidences do not exist; organizations. Critical components of the first ones
- a way to control cost and to ignore patient prefer- are creativity and innovation, whereas the second
ences; ones use mainly control and predictability. Perhaps
- a political/economical/commercial/ tool; a good balance between both concepts really ag-
- a limit to personal/humanistic/individual medi- gregates value to the provision of care, as both ap-
cine. proaches are needed to achieve excellence.
 24 Goffredo Freddi and José Luis Romàn-Pumar

to Regina E. Herzlinger [5], there are six forces that

New Challenges in Translational Medicine

Table 1 | Comparison of organizational characteristics:

where does healthcare stands can drive innovation or kill it:
- players: the friends and foes lurking in the health
Complex adaptative systems Traditional system care system that can destroy or bolster an inno-
Are living organisms Are machines
vation’s chance of success;
- funding: the processes for generating revenue and
Are unpredictable Are controlling and predictable
acquiring capital, both of which differ from those
Are adaptable, flexible, creative Are rigid, self-preserving in most other industries;
Tap creativity Control behaviour - policy: the regulations that pervade the industry,
Embace complexity Find comfort in control because incompetent or fraudulent suppliers can
Evolve continuously Recycle do irreversible human damage;
- technology: the foundation for advances in treat-
ment and for innovations that can make health
care delivery more efficient and convenient;
Complexity Science encourages healthcare lead- - customers: the increasingly engaged consumers
ers to work with, rather than against, overwhelm- of health care, for whom the passive term “pa-
ing complexity by focusing on relationship building, tient” seems outdated;
organizational values and culture, and widespread - accountability: the demand from vigilant consum-
participation, rather than tight integration, formali- ers and cost-pressured payers that innovative health
zation, and centralized decision-making. The health- care products be not only safe and effective but also
care leaders must serve the organization by making cost-effective relative to competing products.
sense of a complex world, rather than providing neat Apparently, none of them is strictly linked to EBM
answers that promise success. but the concept of accountability calls for a more in-
Innovation and creation of new solutions are criti- depth analysis. To this purpose, let’s consider how
cal outcomes of Complexity Science, whereas EBM EBM specifically impacts on drug innovation.
will help to apply innovation into clinical practice in New drug approvals are not keeping pace with ris-
a systematic way and improve therefore the provision ing R&D spending, overall clinical approval success
of care. rate for NCEs is progressively dropping and tailored,
Why should healthcare executives be interested in personalized medicine seems to be the right direction
Complexity Science? For two inter-related reasons: for the future: how EBM rigorousness can combine
the frustration with some of the traditional clinical with progressive uncertainties of R&D outcomes?
and organizational interventions in healthcare and What is the right balance between the lengthy search
because Complexity Science resonates with or ar- for “conscientious, explicit, and judicious use of cur-
ticulates what they were already doing. It provides rent best evidence in making healthcare decisions”
the language and models to explain their intuitive and the urgency of individual/collective patients’ de-
actions. mand for unmet medical needs which could be prop-
erly addressed by innovative treatment?
Last drops in terms of new drugs applications and
IMPACT OF EBM ON INNOVATION approvals are sending us dramatic signals.
A final, open question on possible limits of EBM Perhaps there are physiological reasons for such a de-
refers to how EBM impact on innovation. According crease in R&D productivity: genomics and other new

The ecosystem of innovation

Policies
education, intellectual property, regulation

Supply Demand
Talent skills, knowledge Quality
Investments Safety
Entrepreneurship Convenience
Risk capital Efficiency
Governance Innovation Planning

Infrastructure
Technology; Research; Transportation; Energy
Network of information; Liaison Agencies

Fig. 1 | The ecosystem of innovation.

 Evidence-based medicine 25

sciences did not reach full potential yet, mergers and growing unbalance between those with the respon-

New Challenges in Translational Medicine

other business arrangements have decreased candidates sibility of creating innovation and provide care, vs.
taken forward, costs are rapidly escalating (the aver- those with the responsibility of sustain economically
age cost of bringing a new product to the market now the Health Care System. If that is the case, EBM is
exceeds 1 billion Euro), attrition rates are increasing the main ally to keep the economy of health systems
(higher percentage in clinical development), investments under control and the great excuse to block the ac-
in basic biomedical science has far surpassed investment cess of the innovation to patients. Certainly not the
and progress in the medical product development proc- best way to maximize the benefits of EBM.
ess (a serious bottleneck to delivery of new products). In other words, could EBM hamper rather than
Furthermore, the disappointing performance of the foster pharmaceutical innovation?
R&D productivity cannot be fully explained by sector- It’s not easy to give an answer to this final question
specific factors. It seems to be also the consequence of but we do certainly agree with Stuart Kauffman from
a lack of dynamism in introducing horizontal reforms Santa Fe Institute when he puts the finger on the right
aimed at improving the overall business environment balance and says that “to survive in a variable envi-
as well as reforming its labour and capital markets, ed- ronment, a living system must be stable to be sure, but
ucation systems, public spending and regime of mar- not so stable that it remains for ever static” [6].
ket regulation.
This holistic vision seems to be linked to the theory Conflict of interest statement
of the so-called ecosystem of innovation, that is to
There are no potential conflicts of interest or any financial or per-
say that innovation is often the result of the interac-
sonal relationships with other people or organization that could
tion among an ecology of actors (Figure 1). inappropriately bias this contribution.
But maybe, through these indicators, we are see-
ing the worst face of EBM: its limiting, blocking, Submitted on invitation.
and controlling side. Perhaps also we are seeing a Accepted on 20 September 2010.

References
1. Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, evidence-based discourse in health sciences: truth, power and
Richardson WS. Evidence based medicine: what it is and fascism. Int J Evid Based Health 2006;4:180-6.
what it isn’t. BMJ 1996;312:71.
5. Herzlinger RE. Why innovation in health care is so hard.
2. Mackie JL. Logic and knowledge: selected papers. Vol. 1. Harv Bus Rev 2006;84(5):58-66. Available from: http://hbr.
Oxford: Oxford University Press; 1985. org/hbr-main/resources/pdfs/comm/philips/innovation-
3. Rosenberg W, Donald A. Evidence based medicine: health-care-hard.pdf.
an approach to clinical problem-solving. BMJ 1995; 6. S. Kauffman. At home in the universe: the search for the laws
310(6987):1122-6. of self-organization and complexity. New York, Oxford:
4. Holmes D, Murray SJ, Perron A, Rail G. Deconstructing the Oxford University Press; 1995.