Evidence-Based Medicine; what is it, how does it work and what does it tell us about our medicine?

Professor Daniel Weber, PhD; MSc

To speak of “alternative” medicine is, as Pietroni (1992) has pointed out, like talking about foreigners-both terms are vaguely pejorative and refer to large, heterogeneous categories defined by what they are not rather than by what they are. The analogy is apt: the current worldwide trend away from suspicion and hostility between “orthodox” and “alternative” medicine towards investigation, understanding, and consumer protection benefits the larger community (Fisher & Ward, 1994).

Evidence-Based Medicine (EBM)
Evidence-based medicine (EBM) aims to apply evidence gained from the scientific method to certain parts of medical practice. It seeks to assess the quality of evidence (Elstein, 2004) relevant to the risks and benefits of treatments (including lack of treatment).
Evidence based medicine, whose philosophical origins extend back to mid-19th century Paris and earlier, remains a demanding issue for clinicians, public health practitioners, purchasers, planners, and the public. Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. Individual clinical expertise means the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice (Sackett e al, 1996).
“EBM is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” (Sackett et al, 1996). David Sackett goes on to say, “Evidence based medicine is not restricted to randomised controlled trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions”.
The importance of scientific evidence is best observed when previous literature, medical rationale, patient preferences and practitioner experience are combined (Ellrodt et al, 1997). This combination intends to provide the patient with the best-known standard of care.
The main drawback for evidence-based medicine (Tonelli , 2001) is the fact that studies of populations are not necessarily relevant when a medical practitioner is treating a single patient. (See Beyond EBM below)

The Scientific Method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge (Goldhaber & Nieto, 2010).
The scientific method is the method of choice when gathering medical evidence. It follows a strict structure to ensure that evidence gathering is standardised, regardless of the type of evidence gathering used. Its goal is to test a given hypothesis (theory) (Kramer, 1987). These steps must be repeatable, to guard against mistake or confusion in any particular experimenter.
The process is as follows:

· Define the question

· Gather information and resources

· Form hypothesis

· Perform experiment and collect data

· Analyse data

· Interpret data and draw conclusions

· Publish results

· Retest

Types of Evidence
There are many types of evidence gathering tools used in medicine. They all use the scientific method and are subject to rigorous scrutiny if they report a hypothesis as true.

Systematic Review
A systematic review is a summary of research (often in the biomedical or health care context) that uses explicit methods to perform a thorough literature search and critical appraisal of individual studies to identify the valid and applicable evidence. A systematic review is a literature review focused on a single question, which tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. An understanding of systematic reviews and how to implement them in practice is becoming mandatory for all professionals involved in the delivery of health care.
While systematic reviews are regarded as the strongest form of medical evidence, a review of 300 studies found that not all systematic reviews were equally reliable, and that their reporting could be improved by a universally agreed upon set of standards and guidelines (Moher et al, 2007).
A further study by the same group found that of 100 guidelines reviewed, 4% required updating within a year, and 11% after 2 years. 7% of systematic reviews needed updating at the time of publication (Shojania et al, 2007).

Randomized Controlled Trials
A randomized controlled trial (RCT) is a type of scientific experiment most commonly used in testing healthcare services (such as medicine or nursing) or health technologies (such as pharmaceuticals, medical devices or surgery). According to Lachin (1998), “RCTs are considered the most reliable form of scientific evidence in healthcare because they eliminate spurious causality and bias”.
In an open trial, the researcher knows the full details of the treatment, and so does the patient. These trials are open to challenge for bias, and they do nothing to reduce the placebo effect. However, sometimes they are unavoidable, particularly in relation to surgical techniques, where it may not be possible or ethical to hide from the patient which treatment he or she received. Usually this kind of study design is used in bioequivalence studies.
In a single-blind trial, the researcher knows the details of the treatment but the patient does not. Because the patient does not know which treatment is being administered (the new treatment or another treatment) there might be no placebo effect. In practice, since the researcher knows, it is possible for them to treat the patient differently or to subconsciously hint to the patient important treatment-related details, thus influencing the outcome of the study.
A major difficulty in dealing with trial results comes from commercial, political and/or academic pressure. Most trials are expensive to run, and will be the result of significant previous research, which is itself not cheap. There may be a political issue at stake (compare MMR vaccine) or vested interests (compare homeopathy). In such cases there is great pressure to interpret results in a way, which suits the viewer, and great care must be taken by researchers to maintain emphasis on clinical facts (Lachin et al, 1988).

Cohort Study
A cohort study or panel study is a form of longitudinal study used in medicine and social science. It is one type of study design and should be compared with a cross-sectional study.
A cohort is a group of people who share a common characteristic or experience within a defined period (e.g., are born, leave school, lose their job, are exposed to a drug or a vaccine, etc.). Thus a group of people who were born on a day or in a particular period, say 1948, form a birth cohort. The comparison group may be the general population from which the cohort is drawn, or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation, but otherwise similar. Alternatively, subgroups within the cohort may be compared with each other.
In medicine, a cohort study is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute a hypothesis strengthens confidence in it. Crucially, the cohort is identified before the appearance of the disease under investigation. The study groups, so defined, are observed over a period of time to determine the frequency of new incidence of the studied disease among them. The cohort cannot therefore be defined as a group of people who already have the disease. Distinguishing causality from mere correlation cannot usually be done with results of a cohort study alone (Breslow & Day, 1987).

Outcomes Research
Outcomes research is the method by which the effectiveness of a health care system, unit or individual treatment is measured. The measurements used may be objective measures, such as blood pressure readings, or subjective measures, such as the severity of pain. It allows for a somewhat objective measure of the outcomes of clinical practice (Kane, 2005).

Ecological Studies
Ecological studies are studies in which associations are sought between a disease and certain ecological attributes of the population. Ecological studies may reveal an increased incidence of disease in certain areas of a country, at a certain time of year, among migrant workers, among people of a certain occupation or people of a certain social class (Zuur et al, 2005).

A case series (also known as a clinical series) is a medical research study that tracks patients with a known exposure or examines their medical records for exposure and outcome. A case series can be retrospective or prospective and usually involves a smaller number of patients than more powerful case-control studies or randomized controlled trials.
A case series is a type of observational study. Case series may be consecutive or non-consecutive, depending on whether all cases presenting to the reporting authors over a period of time were included, or only a selection (Jabs, 2005).

Expert Opinion
This is the knowledge available to experts in their field based on experience and training. It is considered the least valuable source of medical evidence and the experts are required to update and improve their knowledge by studying medical evidence higher up the valued chain (Szklo and Nieto, 2006)

The ranking of medical evidence is as follows:

· Systematic Review

· Randomised Controlled Trial

· Cohort Study

· Case-control study

· Outcomes research

· Ecological study

· Case-series

· Expert opinion

Beyond EBM
Translational Research
Translational medicine is a medical practice based on interventional epidemiology. It is regarded as a natural progression from Evidence-Based Medicine. It integrates research from the basic sciences, social sciences and political sciences with the aim of optimising patient care and preventive measures which may extend beyond healthcare services. In short, it is the process of turning appropriate biological discoveries into drugs and medical devices that can be used in the treatment of patients (Lean et al, 2008). Translational Research is the basis for Translational Medicine. It is the process which leads from evidence based medicine to sustainable solutions for public health problems.

Systems Biology and Whole Systems Research
Systems biology is the study of an organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions, which give rise to life. These interactions are ultimately responsible for an organism´s form and functions. Systems biology describes the study of complex systems, with emphasis on how interactions between components of biological systems underlie the behaviour of the system as a whole. It is typified by the generation and testing of models of complex processes (generally quantitative and computational) to explain and predict biological phenomena, and combines iterative cycles of theory, modelling and experiments (Ashall et al, 2009; Toettcher et al, 2009). In order for a systems perspective to be fully appreciated, however, we must first recognise the reductionist nature of medical science and understand its limitations (Ahn et al, 2006).

Several concepts have emerged in systems biology to describe properties occurring at the systems level. One prominent concept is robustness, defined as the ability to maintain stable functioning despite various perturbations (Stelling et al, 2004; Kitano, 2006). Natural systems specifically demonstrate an uncanny penchant for robustness, which, as many have argued, is necessary for natural systems to survive and procreate (Keller, 2000). Robustness is attained by five described mechanisms: feedback control, structural stability, redundancy, modularity, and adaptation (Ioannou & Sun, 1995). Biological systems across all scales, from cells to organisms, rely on a combination of these mechanisms to maintain a semblance of stability. The human body is no exception.

Complementary and alternative medicine (CAM) often consists of whole systems of care (such as naturopathic medicine or traditional Chinese medicine (TCM)) that combine a wide range of modalities to provide individualised treatment. The complexity of these interventions and their potential synergistic effect requires innovative evaluative approaches. Model validity, which encompasses the need for research to adequately address the unique healing theory and therapeutic context of the intervention, is central to whole systems research (WSR).
WSR must hold qualitative and quantitative research methods in equal esteem to realize their unique research contribution. Whole systems are complex and therefore no one method can adequately capture the meaning, process and outcomes of these interventions (Verhoef et al, 2005).

There are reasons why the standards of evaluating Western medicine are not suitable for testing traditional Chinese medicine (TCM), which are explicit in the therapeutic objective and principles of TCM. TCM aims to correct maladjustments and restore the self-regulatory ability of the body, and not to antagonize specific pathogenetic targets. Maladjustments in a disease can be classified into several ‘patterns’ according to TCM theory. Multiple diseases might share one ‘pattern’ and be treated by the same herbal formula whereas one disease might display several different ‘patterns’ and be treated by multiple formulae.
These principles are supported by evidence that multi-system changes in one pattern can be modulated by a herbal formula. The approaches used in systems biology and pharmacogenetics are similar to the practices of TCM. But a combined approach using specific parameters associated with modern medicine, the general condition of individuals, as outlined by TCM, and pattern stratification of diseases can be employed to re-evaluate and refine herbal formulae applications (Jiang, 2005).

CAM Research
Contrary to the assertions of many researchers and alternative practitioners, established methodologies (eg, experimental trials, observational epidemiology, social survey research) and data-analytic procedures (eg, analysis of variance, logistic regression, multivariate modelling techniques) are quite satisfactory for addressing the majority of study questions related to alternative medicine, from clinical research on therapeutic efficacy to basic science research on mechanisms of pathogenesis and recovery (Levin et al, 1997).

Botanicals and EBM
Evidence-Based Botanical Medicines
Botanicals and other herbal products are a valuable source for the development of therapeutic agents. Approximately one fourth of prescription drugs contain active ingredients derived from plants, including several chemotherapeutic agents (paclitaxel, docetaxel), camptothecin (irinotecan, topotecan), and vinca alkaloids (vincristine, vinorelbine) (Gupta et al, 2005). Despite the long history of using herbal medicines, only a few have been evaluated with a strict scientific research approach. It is not necessary to rely solely on randomised controlled trials for evidence of efficacy. Although randomised controlled trials can provide the highest-ranking evidence among all trial categories, sometimes a single case report can provide valuable evidence. If possible, determination of the pharmacologically active components of botanical medicines can demonstrate benefit (Cheng et al, 2010).

Modern Botanical Extraction Methods
Botanicals and herbal preparations are medicinal preparations, containing a single or two or more medicinal plants (Ong, 2004). Modern extraction methods mean that botanical medicines are significantly stronger than the traditional water extraction. Concentrations are from a six to one ratio up to a 98% pure isolate. For example, supercritical fluid extraction (SFE) has gained wide acceptance in recent years as an alternative to conventional solvent extraction for separation of organic compounds (Lang & Wai, 2001).
Other methods of extraction are micelle-mediated extraction, solid-phase micro-extraction, pressurised-liquid extraction, microwave-assisted extraction, solid-phase extraction, and surfactant-mediated extraction (Huie, 2002).

Despite its ancient origins, evidence based medicine remains a relatively young discipline whose positive impacts are just beginning to be validated (Bennett et al, 1987; Shin et al, 1993) and it will continue to evolve. These programmes, and their evaluation, will provide further information and understanding about what evidence based medicine is and is not.
While it is true that evidence-based medicine (EBM) has made some useful contributions to contemporary medical practice, notably in the systematic use of randomised controlled trials in the study of therapeutic interventions, it is nonsense to claim that it has played a major role in the successes of modern medicine (such as vaccines, antibiotics, steroids, anaesthetics, surgical techniques) which arose from developments in the basic medical sciences. To some of its critics, in its disparagement of theory and its crude number crunching, EBM marks a return to ‘empiricist quackery’ in medical practice (Fitzpatrick, 2000).

No one can rationally criticise the use of the scientific method to determine medical outcomes, however the means by which one determines what is medicine and what is not, is the issue. What has been labelled ‘autistic reductionism’ seems to have dominated medical research over the last twenty years but it is not universally accepted as the only means by which medical efficacy can be evaluated. In complex situations, such as patients with co-morbidities or in evaluating botanical medicines, a more systematic, integrative approach is required, a multi-level approach.
For frontline healthcare professionals, an open mind is crucial to providing clinical recommendations on concurrent treatments of conventional medicine and complementary and alternative medicine. Reading research publications is one way to get up-to-date findings. Reporting and discussing any suspicious herb-drug interaction cases with peers would also be a big contribution for the development of research studies on herb-drug interaction. For patients, professional advice should be sought first before undertaking any concurrent treatment. Good communication between patients and doctors is of the utmost importance for developing an optimal treatment strategy.


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