We are IntechOpen, the world's leading publisher of Open Access books Built by scientists, for scientists

4,100+

Open access books available

116,000+

International authors and editors

120M+

Downloads

Our authors are among the

Top 1%

most cited scientists

12.2%

Contributors from top 500 universities

Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI)

## Interested in publishing with us? Contact<EMAIL_ADDRESS>
Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com

## **Meet the editor**

Dr Nikolaos M. Sitaras, MD, PhD, is an Associate Professor of Pharmacology, Department of Pharmacology, Medical School, University of Athens, Athens, Greece.

Contents

**Preface IX**

Chapter 1 **Designing, Conducting and Reporting**

Chapter 2 **Innovating Medical Knowledge:**

Maya J. Goldenberg

Chapter 3 **Twenty Lessons to Incorporate**

Madhur Dev Bhattarai

Chapter 4 **A Post-Structuralist View**

Chapter 6 **Evidence Based Information**

Vahideh Zarea Gavgani

Brian Walsh

**Randomised Controlled Trials: A Few Key Points 1**  Hamidreza Mahboobi, Tahereh Khorgoei and Neha Bansal

**EBM Concept and Practices into Medical Education 29**

**Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 11**

**of Evidence-Based Medicine (EBM) 55**

Chapter 5 **Information Mastery – Changing the Paradigm of Patient Care with Patient-Oriented Evidence That Matters (POEM) 79**  Shepard Hurwitz, David Slawson and Allen Shaughnessy

**Prescription (IPs) in Developing Countries 89**

**The Modern Evolution of the Pap Smear 117**

**How Evidence Based Medicine is Changing Our Practice? 99**

Chapter 7 **Changing Attitudes in Obstetrics and Gynecology –**

Hesham Al-Inany and Amr Wahba

Chapter 8 **Evidence-Based Cervical Cancer Screening:**

Justin Lappen and Dana R. Gossett

### Contents

#### **Preface XI**

## Preface

*Evidence-based*, in general, is the term that characterizes many decision making processes in modern society and science. From justice to politics. To medicine.

*Evidence-based medicine* (EBM) was introduced to the best benefit of the patient. It has transformed the *pathophysiological approach* to the *outcome approach* of today's treatments. *Disease- oriented* to *patient- oriented* medicine. And, for some, daily medical practice from *patient oriented* to *case oriented* medicine. Evidence has changed the paternalistic way of medical practice. And gave room to patients, who show a tendency towards partnership.

The only certain in medical science is uncertainty. Therefore, medicine relies more and more to statistics. But the significant does not always dignify the essential. As William Osler quoted, "if it was not for differences among individuals, the Art of Medicine could be Science in addition".

Statistical significance is not enough. Importance is hidden under the clinical influence of evidence. And according to Gertrude Stein, "for a difference to be different it must make a difference".

Although EBM has introduced a different way of thinking in the day to day medical practice, there is plenty of space for implementation and improvement. And the dispute remains: should "Evidence-based Medicine" be the new "Faith-based Medicine"?

> **Dr Nikolaos M. Sitaras**  Athens University, Medical School, Department of Experimental Pharmacology, Athens, Greece

**1**

**Designing, Conducting and Reporting**

Hamidreza Mahboobi1, Tahereh Khorgoei2 and Neha Bansal3

Randomized Controlled Trials (RCTs) are the most valuable study which play an important role in the field of medicine. Other study types including descriptive studies (e.g. case reports, case series, cross-sectional studies) and certain analytical studies (e.g. case control studies, cohort studies) are also important pieces of evidence but RCTs which are designed for evaluation of the interventions in clinical practice are probably the highest level of evidence in the pyramid of Evidence Based Medicine. It is simple, yet the most powerful

RCTs are considered the most powerful evidence that exists. This is most probably due to the fact that 'randomizing' people into two different groups probably takes care of all the confounding factors and equals out all the causes which may affect the final result of the

This is mostly because of their accurate design. This reduces any possibility of bias in the result. Every year, the numbers of RCTs that are published in Medical Journals are increasing and thus, they have a great effect on changing the way medical science is practiced all over the world. Evidence-Based Medicine is highly dependent on the RCTs.

Therefore designing, conducting and reporting RCTs is an important aspect of medical science and all medical professionals should learn these skills. Critical appraisal of RCTs is probably as important as conducting them. All medical professionals need to understand and evaluate RCTs for the possibility of bias or any shortcomings. RCT results translate

**1. Introduction**

study.

tool in modern clinical research.

**2. RCTs: Top of the evidence-pyramid**

**Randomised Controlled Trials:**

**A Few Key Points**

*Student Research Committee,*

*3Seth G.S. Medical College,*

*1,2Iran 3India*

*1Hormozgan University of Medical Sciences,*

*2Hormozgan University of Medical Sciences, Infectious and Tropical Disease Research Center,*

## **Designing, Conducting and Reporting Randomised Controlled Trials: A Few Key Points**

Hamidreza Mahboobi1, Tahereh Khorgoei2 and Neha Bansal3

*1Hormozgan University of Medical Sciences, Student Research Committee, 2Hormozgan University of Medical Sciences, Infectious and Tropical Disease Research Center, 3Seth G.S. Medical College, 1,2Iran 3India*

#### **1. Introduction**

Randomized Controlled Trials (RCTs) are the most valuable study which play an important role in the field of medicine. Other study types including descriptive studies (e.g. case reports, case series, cross-sectional studies) and certain analytical studies (e.g. case control studies, cohort studies) are also important pieces of evidence but RCTs which are designed for evaluation of the interventions in clinical practice are probably the highest level of evidence in the pyramid of Evidence Based Medicine. It is simple, yet the most powerful tool in modern clinical research.

#### **2. RCTs: Top of the evidence-pyramid**

RCTs are considered the most powerful evidence that exists. This is most probably due to the fact that 'randomizing' people into two different groups probably takes care of all the confounding factors and equals out all the causes which may affect the final result of the study.

This is mostly because of their accurate design. This reduces any possibility of bias in the result. Every year, the numbers of RCTs that are published in Medical Journals are increasing and thus, they have a great effect on changing the way medical science is practiced all over the world. Evidence-Based Medicine is highly dependent on the RCTs.

Therefore designing, conducting and reporting RCTs is an important aspect of medical science and all medical professionals should learn these skills. Critical appraisal of RCTs is probably as important as conducting them. All medical professionals need to understand and evaluate RCTs for the possibility of bias or any shortcomings. RCT results translate

Designing, Conducting and Reporting Randomised Controlled Trials: A Few Key Points 3

A simple way of knowing if you should go through the trouble of conducting the

This can be especially difficult to decide when new interventions are heavily dependent on

4.2. Is there preliminary evidence that the intervention is likely to be beneficial (from observational studies), including some appreciation of the size of the likely treatment effect?

However, there is another side of the story. Failure to perform these important trials which should have been conducted may sometimes result in harmful treatments being used continuously without validation and evaluation. For example, neonates were widely treated with high concentrations of oxygen until randomized trials identified oxygen as a risk factor

Other study designs, including non-randomised controlled trials, can detect associations between an intervention and an outcome. But they cannot rule out the possibility that the association was caused by a third factor linked to both intervention and outcome. Double blinding ensures that the preconceived views of subjects and clinicians cannot

Daniel Judah has been thought to have conducted the first and earliest recorded clinical trial which dates back to approximately 600 B.C. He compared the health effects of the vegetarian diet with those of a royal Babylonian diet over a 10-day period. The trial was obviously not even close to the current modern standards set for trials and was majorly flawed with allocation bias, ascertainment bias, and confounding by divine intervention, but

The 19th century saw a steep development curve in the history of clinical trials. In 1836, the editor of the *American Journal of Medical Sciences* wrote an introduction to an article that he considered "one of the most important medical works of the present century, marking the start of a new era of science," and stated that the article was "the first formal exposition of the results of the only true method of investigation in regard to the therapeutic value of remedial agents." This article was the French study on bloodletting in treatment of pneumonia by P. C. A. Louis. Sir Austin Bradford Hill takes all the credit for the modern concepts of randomization trials. The Medical Research Council trials on streptomycin for pulmonary tuberculosis are rightly regarded as a landmark that ushered in a new era of medicine. Since Hill's pioneering achievement, the methodology of the randomized controlled trial has been increasingly accepted and the number of randomized controlled trials reported has grown exponentially. The Cochrane Library already lists more than 150,000 such trials, and they have become the underlying basis for what is currently called

the report has influenced medical decision for now over two millennia.

Such information is needed to estimate sample sizes and justify the expense of a trial.

**4. Justification of your trial: Ask two keys questions**

randomized trial is to ask yourself these two simple questions:

clinicians' skills (surgical procedures7 or "talk" therapies).

for retinopathy of prematurity.

"evidence-based medicine"

systematically bias the assessment of outcomes.

**5. History of randomised controlled trials**

4.1. Is the intervention well enough developed to permit evaluation?

directly into changing clinical practice. Hence, it is important that they are free of bias and are strong in their design and execution.

#### **3. RCTs: The other side of the coin**

However, RCTs are not far from their fair share of disadvantages. They may be the most powerful tool in the world of research but many ethical and practical concerns limit their use.

3.1. Not all randomized trials are unethical. However, a RCT may be ethical but infeasible. This may be due to difficulties in randomization or recruitment. For example, interventions like cancer screening at an early age might have an extremely long follow up with not may positive outcomes.

3.2. Once a convention is set in the community or a particular intervention gains popularity, it is tough convincing the subjects to "experiment" with their alternative options. A recent attempt to conduct a trial of counselling in general practice failed when practitioners declined to recruit patients to be allocated at random.

3.3. Certain populations of people may have certain strong ideologies and preferences. This may also limit recruitment and result in bias outcomes if not accounted for and accommodated within the study design.

3.4. Randomised trials are not always practical for evaluation of rare diseases or rare outcomes or even outcomes which take a long time to develop.

3.5. A successful and valid RCT requires a large sample size because the outcomes generally have smaller effects and a large measurable difference is required when comparing two groups of interventions. So, the larger the sample size, the better the randomized trial but the larger the financial constraints as well as the time required for the trial to be completed.

3.6. They also have a fairly large drop-out rates and a huge population of the sample size is often lost to follow up making it even harder to assess the final results.

3.7. Even with the people who do follow up, not all religiously adhere to the regimen prescribed to them and some may even be totally non-compliant.

3.8. Since they require a lot of time and manpower, they are fairly expensive to conduct. Financial constraints are probably the most common reason for a trial to be shelved.

3.9. Randomized trials have a huge ethical dilemma. If an intervention is considered inferior to the current treatment modality, exposing some patients to it and not others (or exposing one group to placebo and the other to the treatment) is often thought unethical. For example, a non-random study suggested that multivitamin supplementation during pregnancy could prevent neural tube defects in children. Even though the study was seriously flawed, ethics committees were unwilling to deprive patients of this potentially useful treatment, making it difficult to carry out the trial which later showed that folic acid was the effective part of the multivitamin cocktail.

Thus, these randomized trials should only be undertaken if there is an important question which needs to be answered by the physician and other small scale observational or analytical studies justify its conduction.

#### **4. Justification of your trial: Ask two keys questions**

2 Evidence Based Medicine – Closer to Patients or Scientists?

directly into changing clinical practice. Hence, it is important that they are free of bias and

However, RCTs are not far from their fair share of disadvantages. They may be the most powerful tool in the world of research but many ethical and practical concerns limit their

3.1. Not all randomized trials are unethical. However, a RCT may be ethical but infeasible. This may be due to difficulties in randomization or recruitment. For example, interventions like cancer screening at an early age might have an extremely long follow up with not may

3.2. Once a convention is set in the community or a particular intervention gains popularity, it is tough convincing the subjects to "experiment" with their alternative options. A recent attempt to conduct a trial of counselling in general practice failed when practitioners

3.3. Certain populations of people may have certain strong ideologies and preferences. This may also limit recruitment and result in bias outcomes if not accounted for and

3.4. Randomised trials are not always practical for evaluation of rare diseases or rare

3.5. A successful and valid RCT requires a large sample size because the outcomes generally have smaller effects and a large measurable difference is required when comparing two groups of interventions. So, the larger the sample size, the better the randomized trial but the larger the financial constraints as well as the time required for the trial to be completed. 3.6. They also have a fairly large drop-out rates and a huge population of the sample size is

3.7. Even with the people who do follow up, not all religiously adhere to the regimen

3.8. Since they require a lot of time and manpower, they are fairly expensive to conduct.

3.9. Randomized trials have a huge ethical dilemma. If an intervention is considered inferior to the current treatment modality, exposing some patients to it and not others (or exposing one group to placebo and the other to the treatment) is often thought unethical. For example, a non-random study suggested that multivitamin supplementation during pregnancy could prevent neural tube defects in children. Even though the study was seriously flawed, ethics committees were unwilling to deprive patients of this potentially useful treatment, making it difficult to carry out the trial which later showed that folic acid

Thus, these randomized trials should only be undertaken if there is an important question which needs to be answered by the physician and other small scale observational or

Financial constraints are probably the most common reason for a trial to be shelved.

are strong in their design and execution.

**3. RCTs: The other side of the coin**

declined to recruit patients to be allocated at random.

outcomes or even outcomes which take a long time to develop.

often lost to follow up making it even harder to assess the final results.

prescribed to them and some may even be totally non-compliant.

was the effective part of the multivitamin cocktail.

analytical studies justify its conduction.

accommodated within the study design.

use.

positive outcomes.

A simple way of knowing if you should go through the trouble of conducting the randomized trial is to ask yourself these two simple questions:

4.1. Is the intervention well enough developed to permit evaluation?

This can be especially difficult to decide when new interventions are heavily dependent on clinicians' skills (surgical procedures7 or "talk" therapies).

4.2. Is there preliminary evidence that the intervention is likely to be beneficial (from observational studies), including some appreciation of the size of the likely treatment effect?

Such information is needed to estimate sample sizes and justify the expense of a trial.

However, there is another side of the story. Failure to perform these important trials which should have been conducted may sometimes result in harmful treatments being used continuously without validation and evaluation. For example, neonates were widely treated with high concentrations of oxygen until randomized trials identified oxygen as a risk factor for retinopathy of prematurity.

Other study designs, including non-randomised controlled trials, can detect associations between an intervention and an outcome. But they cannot rule out the possibility that the association was caused by a third factor linked to both intervention and outcome. Double blinding ensures that the preconceived views of subjects and clinicians cannot systematically bias the assessment of outcomes.

#### **5. History of randomised controlled trials**

Daniel Judah has been thought to have conducted the first and earliest recorded clinical trial which dates back to approximately 600 B.C. He compared the health effects of the vegetarian diet with those of a royal Babylonian diet over a 10-day period. The trial was obviously not even close to the current modern standards set for trials and was majorly flawed with allocation bias, ascertainment bias, and confounding by divine intervention, but the report has influenced medical decision for now over two millennia.

The 19th century saw a steep development curve in the history of clinical trials. In 1836, the editor of the *American Journal of Medical Sciences* wrote an introduction to an article that he considered "one of the most important medical works of the present century, marking the start of a new era of science," and stated that the article was "the first formal exposition of the results of the only true method of investigation in regard to the therapeutic value of remedial agents." This article was the French study on bloodletting in treatment of pneumonia by P. C. A. Louis. Sir Austin Bradford Hill takes all the credit for the modern concepts of randomization trials. The Medical Research Council trials on streptomycin for pulmonary tuberculosis are rightly regarded as a landmark that ushered in a new era of medicine. Since Hill's pioneering achievement, the methodology of the randomized controlled trial has been increasingly accepted and the number of randomized controlled trials reported has grown exponentially. The Cochrane Library already lists more than 150,000 such trials, and they have become the underlying basis for what is currently called "evidence-based medicine"

Designing, Conducting and Reporting Randomised Controlled Trials: A Few Key Points 5

the study at the end along with the reasons for the same. It is useful to note that

All randomized trials usually have similar study design. However, still some differences exist. If classified according to the patient exposure and the response to the intervention, the

This is the most popular design and is based on the comparison of the effects of the intervention in the case group with the control group or another intervention group. The two groups receive a maximum of one intervention. Normally two parallel groups with equal sample size will be selected through a randomized selection. However, at times the number of the two groups isn't equal. It is important that the researcher reports this as well

Randomized trials can also be done by involving more than two groups. It is then known as

Each participant receives all the interventions involved in the trial. The sequential order in which they receive them is decided randomly. This study design however should be limited to stable chronic conditions where the disease profile doesn't fluctuate over time as well as short interventions. Also a key concern in these trials is the adequate washout period

This is a complex design where more answers can be found in a single trial. The two or more interventions are compared between themselves as well as a control group. Since RCTs are

Due to such differences, it is important that the study design is described in detail at the time of reporting the trial. This helps the reader a much better understanding of the research conducted. All the study designs must be considered and the best one chosen at the time of

Usually the study design is fixed once the protocol is submitted and the researchers don't change it till end of the study. However, sometimes there is need to modify the study due to various reasons. It is important that researchers explain the cause of the same and also the

One of the most important issues in RCTs is the intervention. Researchers need to answer

as the ratio of the individuals in the two groups at the time of reporting the trial.

between the two therapies in order to avoid the carry-on effect.

expensive to conduct, it's better that we get more answers in a single trial.

unwillingness of an individual to receive the intervention is an exclusion criterion.

**7.2 Study designs**

following styles exist:

**7.2.1 Parallel design**

a multi-arm parallel RCT.

**7.2.2 Cross-over design**

**7.2.3 Factorial design**

designing one's RCT.

**7.3 Intervention**

outline the changes in the RCT design in detail.

several questions about this aspect before even starting their trial.

### **6. Evidence supporting randomised trials**

Enough evidence exists that a successful RCT is one which is well-designed. These RCTs are superior to other study designs in estimating an intervention's true effect. Meta-analysis of controlled trials shows that failure to conceal random allocation and the absence of double blinding yield exaggerated estimates of treatment effects.

It is also well known that well-matched comparison-group designs may be a good alternative when an RCT is not feasible.

#### **7. Issues in designing and conducting RCTs**

As, mentioned before RCTs are conducted to evaluate the importance of an intervention of any sorts. They can be used to understand the effectiveness of a screening test or the effect of any surgical or medical intervention by comparing the outcomes like mortality or disease recurrence.

Let's discuss several important issues in designing and conducting of RCTs.

#### **7.1 Inclusion and exclusion criteria**

In all study types the researchers need to define their target population and the criteria for inclusion and exclusion of every individual in the study. This forms an important aspect of the trial which needs to be decided before starting the trial.

Accurate definition of the study population in RCTs is extremely important and some key pointers are:

7.1.1. In RCTs, the researcher needs to make an intervention on the study population and it is required that these candidates in the study are eligible for receiving the intervention according to the current guidelines.

7.1.2. If the intervention is contraindicated in a population, then that population meets the exclusion criteria of the study target.

7.1.3. Sometimes it is difficult to assess the effect of an intervention in a large population because that needs a large sample size. So the researcher intervenes on a specific portion of the population (for example a specific sex or age group).

7.1.4. Case selection bias is one of the most important bias in RCTs which can be prevented by using appropriate inclusion and exclusion criteria.

Sometimes, the same criteria can be used as either for inclusion or exclusion from the study. For example, a specific drug reaction can serve as both depending on what the researcher wants to study. It can be an inclusion criterion if the study is about a particular drug and the associated adverse reaction. It can also be an exclusion criterion in case the investigator wants to analyze the efficacy of the drug.

The researchers need to report the exact number of the individuals assessed intending to meet the inclusion criteria, the exact number of individuals included in the study after fulfilling all inclusion and exclusion criteria, the exact number of individuals excluded from the study at the end along with the reasons for the same. It is useful to note that unwillingness of an individual to receive the intervention is an exclusion criterion.

#### **7.2 Study designs**

4 Evidence Based Medicine – Closer to Patients or Scientists?

Enough evidence exists that a successful RCT is one which is well-designed. These RCTs are superior to other study designs in estimating an intervention's true effect. Meta-analysis of controlled trials shows that failure to conceal random allocation and the absence of double

It is also well known that well-matched comparison-group designs may be a good

As, mentioned before RCTs are conducted to evaluate the importance of an intervention of any sorts. They can be used to understand the effectiveness of a screening test or the effect of any surgical or medical intervention by comparing the outcomes like mortality or disease

In all study types the researchers need to define their target population and the criteria for inclusion and exclusion of every individual in the study. This forms an important aspect of

Accurate definition of the study population in RCTs is extremely important and some key

7.1.1. In RCTs, the researcher needs to make an intervention on the study population and it is required that these candidates in the study are eligible for receiving the intervention

7.1.2. If the intervention is contraindicated in a population, then that population meets the

7.1.3. Sometimes it is difficult to assess the effect of an intervention in a large population because that needs a large sample size. So the researcher intervenes on a specific portion of

7.1.4. Case selection bias is one of the most important bias in RCTs which can be prevented

Sometimes, the same criteria can be used as either for inclusion or exclusion from the study. For example, a specific drug reaction can serve as both depending on what the researcher wants to study. It can be an inclusion criterion if the study is about a particular drug and the associated adverse reaction. It can also be an exclusion criterion in case the investigator

The researchers need to report the exact number of the individuals assessed intending to meet the inclusion criteria, the exact number of individuals included in the study after fulfilling all inclusion and exclusion criteria, the exact number of individuals excluded from

Let's discuss several important issues in designing and conducting of RCTs.

**6. Evidence supporting randomised trials**

alternative when an RCT is not feasible.

**7.1 Inclusion and exclusion criteria**

according to the current guidelines.

exclusion criteria of the study target.

wants to analyze the efficacy of the drug.

recurrence.

pointers are:

blinding yield exaggerated estimates of treatment effects.

**7. Issues in designing and conducting RCTs**

the trial which needs to be decided before starting the trial.

the population (for example a specific sex or age group).

by using appropriate inclusion and exclusion criteria.

All randomized trials usually have similar study design. However, still some differences exist. If classified according to the patient exposure and the response to the intervention, the following styles exist:

#### **7.2.1 Parallel design**

This is the most popular design and is based on the comparison of the effects of the intervention in the case group with the control group or another intervention group. The two groups receive a maximum of one intervention. Normally two parallel groups with equal sample size will be selected through a randomized selection. However, at times the number of the two groups isn't equal. It is important that the researcher reports this as well as the ratio of the individuals in the two groups at the time of reporting the trial.

Randomized trials can also be done by involving more than two groups. It is then known as a multi-arm parallel RCT.

#### **7.2.2 Cross-over design**

Each participant receives all the interventions involved in the trial. The sequential order in which they receive them is decided randomly. This study design however should be limited to stable chronic conditions where the disease profile doesn't fluctuate over time as well as short interventions. Also a key concern in these trials is the adequate washout period between the two therapies in order to avoid the carry-on effect.

#### **7.2.3 Factorial design**

This is a complex design where more answers can be found in a single trial. The two or more interventions are compared between themselves as well as a control group. Since RCTs are expensive to conduct, it's better that we get more answers in a single trial.

Due to such differences, it is important that the study design is described in detail at the time of reporting the trial. This helps the reader a much better understanding of the research conducted. All the study designs must be considered and the best one chosen at the time of designing one's RCT.

Usually the study design is fixed once the protocol is submitted and the researchers don't change it till end of the study. However, sometimes there is need to modify the study due to various reasons. It is important that researchers explain the cause of the same and also the outline the changes in the RCT design in detail.

#### **7.3 Intervention**

One of the most important issues in RCTs is the intervention. Researchers need to answer several questions about this aspect before even starting their trial.

Designing, Conducting and Reporting Randomised Controlled Trials: A Few Key Points 7

participants are needed in order to show the difference in a particular outcome in a

Sample size should be determined using sample size calculator software or the standard formula. It is recommended to consult a statistician for calculation of the study sample

Randomization is what gives the RCTs its strength. In RCTs patients are randomly assigned into the two or more study groups and each individual has an equal chance to be assigned to any group. The clinician, the investigators or the patient have no choice in the allocation. This prevents the selection bias. Random allocation ensures no systematic differences between intervention groups in factors, known and unknown, that may affect outcome. No other study design allows this kind of a balance. It is crucial that the investigators pre define the allocation guidelines and stick by it till the end of the trial. It is extremely important that the guidelines are not modified at any point in the trial. Randomization can be done in

The easiest method to do randomization of the sample is 'simple randomization'. In this method, individuals are assigned equally to the groups using a random process, for example, a computer generated list of random numbers. Other methods like blocked randomization and stratified randomization are more complex, less common and are usually used for very specific trials. Blocked randomization aims to numerical balance between groups and stratified

Blinding means that the person is not aware of what group he/she is in and what treatment or placebo he/she is receiving. According to the various levels of blinding like blinding the participants, researchers, outcome assessors and statisticians, RCTs are divided into four types: open label, single blinded, double blinded and triple blinded RCTs. Due to confusions and discrepancies about who exactly was blinded in the single and double and triple blinded studies, The 2010 CONSORT guidelines specify that authors should not use these terms. It is required to report the details of the blinding like "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing

Blinding obviously helps to prevent personal bias in the study which is a huge concern in conducting a RCT. Every effort should be made to reduce any bias as much as possible. In case the study population is neonates, researchers may decide not to use blinding because of the differences in interventions like oral or IV feeds. The most prevalent type of blinding is the double blinded design where the investigator and the patient are both unaware of the

The most common statistical tests used for all type of papers are descriptive. These tests include mean and standard deviation for quantitative variables and frequency and

randomization aims to balance characteristics between the groups.

certain statistical significance?

**7.6 Randomization**

several different methods.

**7.7 Blinding**

outcomes) and how."

details of who is in which group.

**7.8 Statistical analysis**

size.

An intervention can be a drug or device. It can be used for prevention or treatment. For drugs it is important to carefully determine the dosage, timing, duration and administration route. All information about the drug needs to be provided to the reader at the time of reporting. Even the manufacturer of the drug or device can be mentioned for the sake of complete reporting and easy reproducibility of the trial if required.

Even very small differences either in the type, dosage, duration or the route of administration may lead to a significant difference in the outcomes. The intervention should be obvious in order to give the possibility of comparison to other study to the researchers as well as a chance to reproduce the results if required.

#### **7.4 Outcome/ Results**

Probably the most important think we are looking for in a randomized trial article are the outcomes or the results. These can be divided into primary and secondary outcomes. They should have been determined before even starting the study.

Primary outcome is the main intervention outcome. Other study outcomes aer put in the category of secondary outcomes. For example the drug side effects are usually put in that category.

Another important issue in the outcomes is the 'measures' used to measure these outcomes. The outcomes may be laboratory test results. For these outcomes, it is important to list the methodology for the measurement, kits used for the same as well as the manufacturer where they are produced.

Other type of outcome is the clinical outcome. For this, it is important to mention the guidelines used by the researcher for the determination of the variable as well as the name of that person (e.g. General physician, specialists or medical students).

It is recommended that before selection of the primary and secondary outcomes the researchers reviews the literature thoroughly and chooses the similar outcomes in similar studies. This is important for comparing the results of the evidence already out there with their study.

An advantage of designing a trial with clearly pre-determined inclusion criteria/exclusion criteria, intervention and outcomes which are similar to other studies, is the possibility of collecting these data to form a meta-analysis which gives us even more clarity and consolidates all the evidence to give a final conclusion.

#### **7.5 Sample size**

A small sample size is unable to show all differences between case and control group. As we mentioned before, the effects are usually small and thus, we need to demonstrate large results to show sizable difference and this is why we need a large sample size. However, large sample sizes need more time and budget. There are also issues with recruitment and reaching out to large populations. Sample size should be determined after a thorough literature review and full access to previous studies in populations similar to the current study and also after determination of the power of the study. The sample size is the answer to the power of the study and simply answers the question: how many participants are needed in order to show the difference in a particular outcome in a certain statistical significance?

Sample size should be determined using sample size calculator software or the standard formula. It is recommended to consult a statistician for calculation of the study sample size.

#### **7.6 Randomization**

6 Evidence Based Medicine – Closer to Patients or Scientists?

An intervention can be a drug or device. It can be used for prevention or treatment. For drugs it is important to carefully determine the dosage, timing, duration and administration route. All information about the drug needs to be provided to the reader at the time of reporting. Even the manufacturer of the drug or device can be mentioned for the sake of

Even very small differences either in the type, dosage, duration or the route of administration may lead to a significant difference in the outcomes. The intervention should be obvious in order to give the possibility of comparison to other study to the researchers as

Probably the most important think we are looking for in a randomized trial article are the outcomes or the results. These can be divided into primary and secondary outcomes. They

Primary outcome is the main intervention outcome. Other study outcomes aer put in the category of secondary outcomes. For example the drug side effects are usually put in that

Another important issue in the outcomes is the 'measures' used to measure these outcomes. The outcomes may be laboratory test results. For these outcomes, it is important to list the methodology for the measurement, kits used for the same as well as the manufacturer

Other type of outcome is the clinical outcome. For this, it is important to mention the guidelines used by the researcher for the determination of the variable as well as the name

It is recommended that before selection of the primary and secondary outcomes the researchers reviews the literature thoroughly and chooses the similar outcomes in similar studies. This is important for comparing the results of the evidence already out there with

An advantage of designing a trial with clearly pre-determined inclusion criteria/exclusion criteria, intervention and outcomes which are similar to other studies, is the possibility of collecting these data to form a meta-analysis which gives us even more clarity and

A small sample size is unable to show all differences between case and control group. As we mentioned before, the effects are usually small and thus, we need to demonstrate large results to show sizable difference and this is why we need a large sample size. However, large sample sizes need more time and budget. There are also issues with recruitment and reaching out to large populations. Sample size should be determined after a thorough literature review and full access to previous studies in populations similar to the current study and also after determination of the power of the study. The sample size is the answer to the power of the study and simply answers the question: how many

complete reporting and easy reproducibility of the trial if required.

well as a chance to reproduce the results if required.

should have been determined before even starting the study.

of that person (e.g. General physician, specialists or medical students).

consolidates all the evidence to give a final conclusion.

**7.4 Outcome/ Results**

where they are produced.

category.

their study.

**7.5 Sample size**

Randomization is what gives the RCTs its strength. In RCTs patients are randomly assigned into the two or more study groups and each individual has an equal chance to be assigned to any group. The clinician, the investigators or the patient have no choice in the allocation. This prevents the selection bias. Random allocation ensures no systematic differences between intervention groups in factors, known and unknown, that may affect outcome. No other study design allows this kind of a balance. It is crucial that the investigators pre define the allocation guidelines and stick by it till the end of the trial. It is extremely important that the guidelines are not modified at any point in the trial. Randomization can be done in several different methods.

The easiest method to do randomization of the sample is 'simple randomization'. In this method, individuals are assigned equally to the groups using a random process, for example, a computer generated list of random numbers. Other methods like blocked randomization and stratified randomization are more complex, less common and are usually used for very specific trials. Blocked randomization aims to numerical balance between groups and stratified randomization aims to balance characteristics between the groups.

#### **7.7 Blinding**

Blinding means that the person is not aware of what group he/she is in and what treatment or placebo he/she is receiving. According to the various levels of blinding like blinding the participants, researchers, outcome assessors and statisticians, RCTs are divided into four types: open label, single blinded, double blinded and triple blinded RCTs. Due to confusions and discrepancies about who exactly was blinded in the single and double and triple blinded studies, The 2010 CONSORT guidelines specify that authors should not use these terms. It is required to report the details of the blinding like "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."

Blinding obviously helps to prevent personal bias in the study which is a huge concern in conducting a RCT. Every effort should be made to reduce any bias as much as possible. In case the study population is neonates, researchers may decide not to use blinding because of the differences in interventions like oral or IV feeds. The most prevalent type of blinding is the double blinded design where the investigator and the patient are both unaware of the details of who is in which group.

#### **7.8 Statistical analysis**

The most common statistical tests used for all type of papers are descriptive. These tests include mean and standard deviation for quantitative variables and frequency and

Designing, Conducting and Reporting Randomised Controlled Trials: A Few Key Points 9

Randomised controlled trials are the most rigorous way of determining whether a causeeffect relation exists between treatment and outcome and for assessing the cost effectiveness

9.2. Patients and trialists should remain unaware of which treatment was given until the study is completed-although such double blind studies are not always feasible or

9.4. Patients are normally analysed within the group to which they were allocated, irrespective of whether they experienced the intended intervention (intention to treat

9.5. The analysis is focused on estimating the size of the difference in predefined outcomes

Given that poor design may lead to biased outcomes, investigators should strive for methodological rigour and report their work in enough detail for others to assess its

Stolberg HO et al. Fundamentals of Clinical Research for Radiologists. AJR 2004;183:1539–

Afshar Z, et al. Research Mentorship Program (RMP) to Enhance the Research

Mahboobi H, et al. Current form of randomized controlled trials. Annals of Pediatric

Mahboobi H, et al. Designing a Research Mentorship Program (RMP) to enhance research

Productivity in a Psychiatric Hospital: First Report. Electronic Physician.

productivity at Ebne-Sina psychiatric hospital. Australasian Medical Journal.

9.3. All intervention groups are treated identically except for the experimental treatment

Australasian New Zealand Clinical Trial Registry

Clinical Research Information Service (CRIS) , Republic of Korea

 Brazilian Clinical Trial Registry Chinese Clinical Trial Registry

Clinical Trial Registry – India

 EU Clinical Trial Registry German Clinical Trial Registry Iranian Registry of Clinical Trials Japan Primary Registries Network

**9. Summary**

appropriate

analysis)

quality.

**10. References**

1544.

2011;3(4):442-445.

2010;1(2):180-2.

Cardiology. 2011;4(1):90.

between intervention groups.

Cuban Public Registry of Clinical Trials

of a treatment. Some key pointers at a glance are: 9.1. Random allocation to intervention groups

percentage for qualitative variables. They also use Chi-square test or Exact fisher test for comparison and the T tests are also commonly used. Other descriptive statistical tests are less commonly used. However, researchers may need other statistical tests for subgroup analysis and adjusted analysis.

Two main ways to analyze RCTs are per protocol analysis and intent to treat analysis. In per protocol analysis, analysis will be done based on the groups which the patients are assigned into, but in intent to treat analysis the analysis is based on receiving treatment or not.

Some RCTs need large sample sizes and may continue for a long time. The researchers may decide to cease the study if significant difference was observed in important study outcomes. For example if a specific drug be associated with significant increase in a side effect, then the study should be stopped. Also if a significant improvement be observed during the study, the researchers can stop the study. To reach this aim interim analysis can be done. But the number of interim analysis, the time, the individuals who will do it and the conditions in which the study will stop should be clear.

#### **8. Clinical trial registry**

All RCTs need to be registered in international clinical trial registry databases before starting enrolment of study participants. Once the researchers register their clinical trial in a clinical trial registry database they will receive a unique trial registry number.

Almost all medical journals request their authors mention their trial registry number in the abstract of their paper. The editors of these journals avoid publication of RCTs without trial registry number even if they have high quality in study design and writing.

According to the registry database where the researchers register their clinical trial, detailed information about the trial is needed by them.

This information includes: Title, purpose, condition which the study is studying in detail, type, name and dosage and all other information about the intervention, study type, allocation, endpoints and outcomes, intervention model, masking (Blinding), the number of patient enrolled in the study, study start and completion dates, inclusion and exclusion criteria etc.

RCT registration has several benefits. They are a good source of previous trials and it is possible to search and reach the content of the registered RCTs easily.

During the registration the researchers needs to review all important issues in the study design and methodology of the research. This helps them to reduce bias in their design and consider all aspect of the RCT design.

All RCTs need to obtain the ethics approval of the committee of the institute or the hospital where they want to conduct the trial. This practice will guarantee that all the RCTs published in the top-notch high impact medical journals are validated and ethically correct.

The International Clinical Trial Registry Platform (ICTRP) has introduced ten primary registries in its registry network which can register the clinical trial with their profile and the link to their website

#### **9. Summary**

8 Evidence Based Medicine – Closer to Patients or Scientists?

percentage for qualitative variables. They also use Chi-square test or Exact fisher test for comparison and the T tests are also commonly used. Other descriptive statistical tests are less commonly used. However, researchers may need other statistical tests for subgroup

Two main ways to analyze RCTs are per protocol analysis and intent to treat analysis. In per protocol analysis, analysis will be done based on the groups which the patients are assigned

Some RCTs need large sample sizes and may continue for a long time. The researchers may decide to cease the study if significant difference was observed in important study outcomes. For example if a specific drug be associated with significant increase in a side effect, then the study should be stopped. Also if a significant improvement be observed during the study, the researchers can stop the study. To reach this aim interim analysis can be done. But the number of interim analysis, the time, the individuals who will do it and the

All RCTs need to be registered in international clinical trial registry databases before starting enrolment of study participants. Once the researchers register their clinical trial in a clinical

Almost all medical journals request their authors mention their trial registry number in the abstract of their paper. The editors of these journals avoid publication of RCTs without trial

According to the registry database where the researchers register their clinical trial, detailed

This information includes: Title, purpose, condition which the study is studying in detail, type, name and dosage and all other information about the intervention, study type, allocation, endpoints and outcomes, intervention model, masking (Blinding), the number of patient enrolled in the study, study start and completion dates, inclusion and exclusion

RCT registration has several benefits. They are a good source of previous trials and it is

During the registration the researchers needs to review all important issues in the study design and methodology of the research. This helps them to reduce bias in their design and

All RCTs need to obtain the ethics approval of the committee of the institute or the hospital where they want to conduct the trial. This practice will guarantee that all the RCTs published in the top-notch high impact medical journals are validated and ethically correct. The International Clinical Trial Registry Platform (ICTRP) has introduced ten primary registries in its registry network which can register the clinical trial with their profile and the

into, but in intent to treat analysis the analysis is based on receiving treatment or not.

analysis and adjusted analysis.

**8. Clinical trial registry**

criteria etc.

link to their website

conditions in which the study will stop should be clear.

information about the trial is needed by them.

consider all aspect of the RCT design.

trial registry database they will receive a unique trial registry number.

possible to search and reach the content of the registered RCTs easily.

registry number even if they have high quality in study design and writing.

Randomised controlled trials are the most rigorous way of determining whether a causeeffect relation exists between treatment and outcome and for assessing the cost effectiveness of a treatment. Some key pointers at a glance are:

9.1. Random allocation to intervention groups

9.2. Patients and trialists should remain unaware of which treatment was given until the study is completed-although such double blind studies are not always feasible or appropriate

9.3. All intervention groups are treated identically except for the experimental treatment

9.4. Patients are normally analysed within the group to which they were allocated, irrespective of whether they experienced the intended intervention (intention to treat analysis)

9.5. The analysis is focused on estimating the size of the difference in predefined outcomes between intervention groups.

Given that poor design may lead to biased outcomes, investigators should strive for methodological rigour and report their work in enough detail for others to assess its quality.

#### **10. References**

**2**

**Innovating Medical Knowledge: Understanding Evidence-Based**

Because few would object to evidence-based medicine's (EBM) principal task of basing medical decisionmaking on the most judicious and up-to-date evidence, the debate over this prolific movement may seem puzzling. Who, one may ask, could be against evidence (Carr-Hill, 2006)? Yet this question belies the sophistication of the evidence-based movement. This chapter presents the evidence-based approach as a socio-medical phenomenon and seeks to explain and negotiate the points of disagreement between supporters and detractors. This is done by casting EBM as more than the simple application of research findings to clinical care and improved health outcomes, but rather an umbrella term that harnesses a specific set of pedagogical objectives (some rather radical) under a name that makes it difficult to

EBM is most popularly defined as the "conscientious and judicious use of current best evidence in the healthcare of individuals and populations" (Sackett et al., 1996b). EBM's influential doctrine first appeared in the *Journal of the American Medical Association* as a brief

*A new paradigm for medical practice is emerging. Evidence based medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision-making and stresses the examination of evidence from clinical research. EBM requires new skills of the physician, including efficient literature searching and the application of the formal rules of evidence (Evidence Based Medicine Working Group*

EBM rose quickly into prominence in medicine, with virtually every area of healthcare now subscribing to the evidence based mantra. This is a considerable feat for a discipline that is described in the EBM manifesto as largely reliant on conventions and habits of thought and

Yet amidst the hubris, there is a sort of obviousness to EBM that has prompted critics to

polemic authored by the Evidence Based Medicine Working Group:

charge EBM with offering "nothing new" (Benitez-Bribiesca, 1999):

**1. Introduction**

argue against.

*[EBMWG], 1992).*

practice.

**Medicine as a Socio-Medical**

**Phenomenon**

Maya J. Goldenberg *University of Guelph,*

*Canada*

## **Innovating Medical Knowledge: Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon**

Maya J. Goldenberg *University of Guelph, Canada*

#### **1. Introduction**

10 Evidence Based Medicine – Closer to Patients or Scientists?

Mahboobi H, et al. Evidence-based medicine for medical students. Aust Med J. 2010;1:190-

Mahboobi H, et al. Have we something to replace evidence based medicine? Annals of

Mahboobi H, et al. Mentorship in Medical Students researches. Electronic Physician 2011;

Marcinkiewicz M et al. The Impact of the Internet on the Doctor-Patient Relationship.

Schulz KF et al. CONSORT 2010 Statement: updated guidelines for reporting parallel

3.

3(4):414-415.

Cardiac Anaesthesia. 2011;14(3):246.

Australasian Medical Journal 2009; 2(5):1-6.

group randomised trials. Ann Int Med 2010;152.

Because few would object to evidence-based medicine's (EBM) principal task of basing medical decisionmaking on the most judicious and up-to-date evidence, the debate over this prolific movement may seem puzzling. Who, one may ask, could be against evidence (Carr-Hill, 2006)? Yet this question belies the sophistication of the evidence-based movement. This chapter presents the evidence-based approach as a socio-medical phenomenon and seeks to explain and negotiate the points of disagreement between supporters and detractors. This is done by casting EBM as more than the simple application of research findings to clinical care and improved health outcomes, but rather an umbrella term that harnesses a specific set of pedagogical objectives (some rather radical) under a name that makes it difficult to argue against.

EBM is most popularly defined as the "conscientious and judicious use of current best evidence in the healthcare of individuals and populations" (Sackett et al., 1996b). EBM's influential doctrine first appeared in the *Journal of the American Medical Association* as a brief polemic authored by the Evidence Based Medicine Working Group:

*A new paradigm for medical practice is emerging. Evidence based medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision-making and stresses the examination of evidence from clinical research. EBM requires new skills of the physician, including efficient literature searching and the application of the formal rules of evidence (Evidence Based Medicine Working Group [EBMWG], 1992).*

EBM rose quickly into prominence in medicine, with virtually every area of healthcare now subscribing to the evidence based mantra. This is a considerable feat for a discipline that is described in the EBM manifesto as largely reliant on conventions and habits of thought and practice.

Yet amidst the hubris, there is a sort of obviousness to EBM that has prompted critics to charge EBM with offering "nothing new" (Benitez-Bribiesca, 1999):

Innovating Medical Knowledge:

**3. What's new about EBM?**

investigating this alleged paradigm change.

**3.1 Is EBM a new paradigm?**

Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 13

underlying evidence will provide superior patient care" (EBMWG, 1992). While the ethical imperative to improve patient care remained central, the promise to decrease medical uncertainty by systematic evaluation of the efficacy of current practices was particularly appealing to health care administrators and policy analysts facing a crisis situation with respect to escalating healthcare costs and spending. Added to the gamut of methodologies for data collection and analysis first recommended by Cochrane was the use of emerging information technologies to synthesize the large quantities of published studies, proliferate information, and increase accessibility. The combined picture of EBM as ethically driven to improve patient care, fiscally responsible, and technologically up-to-date likely drove the rapid integration of the movement into medicine, where just over twenty years since the Evidence Based Medicine Working Group formed, EBM is now common parlance within health care. Academic centres and journals dedicated to EBM's advancement have been established with much fanfare, and the evidence-based movement has stretched beyond the health sciences to business management (Kovner et al., 2000; Kovner & Rundall, 2006), public health (McGuire, 2005), speech pathology (Reilly et al., 2004), occupational therapy (Von Zweck, 1999) social work (Cournoyer, 2004; Howard et al., 2003; Grinnell & Unrau, 2010), education (Council for Exceptional Children, 2011; Horner et al., 2005; Slavin, 2002), and other social science disciplines. It is even generating attention as a promising new approach to bioethics ("evidence-based ethics") (Roberts, 2000; Strech, 2008; the rare criticism is found in Goldenberg, 2005). The term "evidence-based everything" has been

used to describe the enthusiasm for this movement (Mykhalovskiy & Weir, 2004).

grounded in the empirical sciences, which bases its claims on observational evidence.

Despite the fanfare, it is not immediately obvious that EBM offers something new to medical practice. In response to EBM's demand that medical decisions ought to be based on stringent empirical evidence, critics ask, hasn't modern medicine *always* been evidencebased? Quite surely, by being founded on natural science, biomedicine has always been

The critics are correct to think that EBM's empirical commitments are not new to medicine's ideal practices (regardless of whether or not they are actually practiced). However, proponents have denied the charge that EBM is "old hat" (Sackett et al., 1996b), and have even been grandiose in their descriptions of EBM as being a "new paradigm" promising to "revolutionize" medicine (EBMWG, 1992). This description suggests the evidence based approach to offer something radically different from previous approaches, and so it is worth

To illustrate the unique workings of EBM, the new paradigm of medicine, the Evidence

*A junior medical resident working in a teaching hospital admits a 43-year old previously well man who experiences a witnessed grand mal seizure. He had never had a seizure before and had not had any recent head trauma…Findings on physical examination are normal. The patient is given a loading dose of phenytoin intravenously and the drug is continued orally. A computed tomographic head scan is completely normal, and an electroencephalogram shows only non-*

Based Medicine Working Group presented the following clinical scenario:

*"Evidence based medicine," one chemist said to me, "What other kind of medicine could there possibly be?" and a consultant physician said gruffly: "We have always practiced evidence based medicine" (Hope, 1995).1*

The EBM pioneers equivocated on the movement's innovation and conservatism. It was described as both a "new paradigm" (EBMWG, 1992) and a historically-supported approach "whose philosophical origins extend back to mid-19th century Paris and earlier" (Sackett et al., 1996b). Yet it will be demonstrated in this chapter that although EBM is not best understood as a new "paradigm" or a radical departure from biomedicine, it offers methodological innovation that has shifted how we pursue, collect, and evaluate medical knowledge.

Beginning with a historical account of the origins of EBM, a focus on three key methodological innovations employed by EBM will be used to advance the argument that EBM's original contribution to medicine, or what separates EBM from other approaches, is the priority it gives to certain forms of evidence, specifically evidence from randomized controlled trials. EBM offers a shift in the sort of evidence that is most highly valued for diagnosis, therapy, and prognosis questions, as heavy emphasis is placed on experimental controls and quantified measures, thus diminishing the previous status of clinical experience and observational studies significantly. This commitment represents not only methodological change, but also a novel regard of the reliability of various forms of medical knowledge. EBM offers a new answer to medicine's fundamental normative question: how ought we to practice medicine?

#### **2. The origins of evidence-based medicine**

The origins of the evidence-based medicine movement are traceable back to a series of lectures given by epidemiologist Archie Cochrane in the early 1970s, where he argued that many popularly used medical practices were of unknown or questionable safety and efficacy (Ashcroft, 2004). In these lectures, which were later compiled in *Effectiveness and Efficiency: Random Reflections on Health Services* (Cochrane, 1972), he detailed the injury, waste, and failure to improve care that ensued from widespread acceptance and use of unestablished medical interventions. He maintained that treatments should be evaluated using unbiased methods like the randomized controlled trial, and that health care professionals should regularly update their knowledge base (Ashcroft, 2004). Aschcroft has noted the strong ethical imperative behind Cochrane's recommendations, as they were rooted in concern to do no harm, to do one's best for one's patients, and to do so justly by eliminating waste (Ashcroft, 2004).

Cochrane's programmatic outline was revitalized in 1990 by a group of professors of clinical epidemiology, medical informatics, and biostatistics at McMaster University in Canada, who called themselves the "Evidence Based Medicine Working Group". They introduced the phrase "Evidence Based Medicine" in a ubiquitous 1992 manifesto as a "new paradigm" in medical education and practice (EBMWG, 1992). In the document, the ethical promise was made that the virtuous clinician "whose practice is based on an understanding of the

 1 Hope is a supporter of EBM who maintains that one sign of a movement being important is when its detractors indignantly maintain that it is nothing new.

underlying evidence will provide superior patient care" (EBMWG, 1992). While the ethical imperative to improve patient care remained central, the promise to decrease medical uncertainty by systematic evaluation of the efficacy of current practices was particularly appealing to health care administrators and policy analysts facing a crisis situation with respect to escalating healthcare costs and spending. Added to the gamut of methodologies for data collection and analysis first recommended by Cochrane was the use of emerging information technologies to synthesize the large quantities of published studies, proliferate information, and increase accessibility. The combined picture of EBM as ethically driven to improve patient care, fiscally responsible, and technologically up-to-date likely drove the rapid integration of the movement into medicine, where just over twenty years since the Evidence Based Medicine Working Group formed, EBM is now common parlance within health care. Academic centres and journals dedicated to EBM's advancement have been established with much fanfare, and the evidence-based movement has stretched beyond the health sciences to business management (Kovner et al., 2000; Kovner & Rundall, 2006), public health (McGuire, 2005), speech pathology (Reilly et al., 2004), occupational therapy (Von Zweck, 1999) social work (Cournoyer, 2004; Howard et al., 2003; Grinnell & Unrau, 2010), education (Council for Exceptional Children, 2011; Horner et al., 2005; Slavin, 2002), and other social science disciplines. It is even generating attention as a promising new approach to bioethics ("evidence-based ethics") (Roberts, 2000; Strech, 2008; the rare criticism is found in Goldenberg, 2005). The term "evidence-based everything" has been used to describe the enthusiasm for this movement (Mykhalovskiy & Weir, 2004).

#### **3. What's new about EBM?**

12 Evidence Based Medicine – Closer to Patients or Scientists?

The EBM pioneers equivocated on the movement's innovation and conservatism. It was described as both a "new paradigm" (EBMWG, 1992) and a historically-supported approach "whose philosophical origins extend back to mid-19th century Paris and earlier" (Sackett et al., 1996b). Yet it will be demonstrated in this chapter that although EBM is not best understood as a new "paradigm" or a radical departure from biomedicine, it offers methodological innovation that has shifted how we pursue, collect, and evaluate medical

Beginning with a historical account of the origins of EBM, a focus on three key methodological innovations employed by EBM will be used to advance the argument that EBM's original contribution to medicine, or what separates EBM from other approaches, is the priority it gives to certain forms of evidence, specifically evidence from randomized controlled trials. EBM offers a shift in the sort of evidence that is most highly valued for diagnosis, therapy, and prognosis questions, as heavy emphasis is placed on experimental controls and quantified measures, thus diminishing the previous status of clinical experience and observational studies significantly. This commitment represents not only methodological change, but also a novel regard of the reliability of various forms of medical knowledge. EBM offers a new answer to medicine's fundamental normative question: how

The origins of the evidence-based medicine movement are traceable back to a series of lectures given by epidemiologist Archie Cochrane in the early 1970s, where he argued that many popularly used medical practices were of unknown or questionable safety and efficacy (Ashcroft, 2004). In these lectures, which were later compiled in *Effectiveness and Efficiency: Random Reflections on Health Services* (Cochrane, 1972), he detailed the injury, waste, and failure to improve care that ensued from widespread acceptance and use of unestablished medical interventions. He maintained that treatments should be evaluated using unbiased methods like the randomized controlled trial, and that health care professionals should regularly update their knowledge base (Ashcroft, 2004). Aschcroft has noted the strong ethical imperative behind Cochrane's recommendations, as they were rooted in concern to do no harm, to do one's best for one's patients, and to do so justly by

Cochrane's programmatic outline was revitalized in 1990 by a group of professors of clinical epidemiology, medical informatics, and biostatistics at McMaster University in Canada, who called themselves the "Evidence Based Medicine Working Group". They introduced the phrase "Evidence Based Medicine" in a ubiquitous 1992 manifesto as a "new paradigm" in medical education and practice (EBMWG, 1992). In the document, the ethical promise was made that the virtuous clinician "whose practice is based on an understanding of the

1 Hope is a supporter of EBM who maintains that one sign of a movement being important is when its

*medicine" (Hope, 1995).1*

ought we to practice medicine?

eliminating waste (Ashcroft, 2004).

detractors indignantly maintain that it is nothing new.

**2. The origins of evidence-based medicine**

knowledge.

*"Evidence based medicine," one chemist said to me, "What other kind of medicine could there possibly be?" and a consultant physician said gruffly: "We have always practiced evidence based*

> Despite the fanfare, it is not immediately obvious that EBM offers something new to medical practice. In response to EBM's demand that medical decisions ought to be based on stringent empirical evidence, critics ask, hasn't modern medicine *always* been evidencebased? Quite surely, by being founded on natural science, biomedicine has always been grounded in the empirical sciences, which bases its claims on observational evidence.

> The critics are correct to think that EBM's empirical commitments are not new to medicine's ideal practices (regardless of whether or not they are actually practiced). However, proponents have denied the charge that EBM is "old hat" (Sackett et al., 1996b), and have even been grandiose in their descriptions of EBM as being a "new paradigm" promising to "revolutionize" medicine (EBMWG, 1992). This description suggests the evidence based approach to offer something radically different from previous approaches, and so it is worth investigating this alleged paradigm change.

#### **3.1 Is EBM a new paradigm?**

To illustrate the unique workings of EBM, the new paradigm of medicine, the Evidence Based Medicine Working Group presented the following clinical scenario:

*A junior medical resident working in a teaching hospital admits a 43-year old previously well man who experiences a witnessed grand mal seizure. He had never had a seizure before and had not had any recent head trauma…Findings on physical examination are normal. The patient is given a loading dose of phenytoin intravenously and the drug is continued orally. A computed tomographic head scan is completely normal, and an electroencephalogram shows only non-*

Innovating Medical Knowledge:

ties to the biomedical tradition.

unequivocal conclusions.

deny) the evidence/judgment divide (Downie et al., 2000).

Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 15

Understanding the unique circumstances of the individual case is thought to involve a form of practical knowledge or judgment quite different from the *technical* knowledge offered by EBM. The "grey zones" of practice (Naylor, 1995), that is, areas where the evidence from randomized trials about risk-benefit ratios of competing clinical options is incomplete, inconclusive, or contradictory and so clinical judgment must be relied on,2 are repeatedly argued to be missing from EBM's formulaic knowledge base (Tanenbaum, 1993). Indeed, EBM struggles to account for the interpretive dimensions of clinical care, as evidence-based decisionmaking is largely an effort to standardize and rationalize the application of evidence to clinical care. It is no wonder that critics fail to be persuaded by EBM's conciliatory efforts, such as making the first principle of EBM "*evidence is never enough*" in the authoritative *Users' Guides to the Medical Literature*  textbook (Guyatt & Rennie, 2002). It is also worth asking: if evidence is not the fundamental

In light of these grey zones, EBM is charged with creating and sustaining the idea that *evidence* and *practice* are opposing concepts (Pope 2003; Wood et al., 1998). Other dualisms reinforced in the EBM literature include technical vs. experiential/intuitive knowledge, empirical vs. theoretical knowledge, evidence based vs. patient-centred care, and, of course, EBM vs. its biomedical predecessor, which is inappropriately referred to as "traditional medicine".3 Adherence to these artificial bifurcations seems to misdirect the EBM debate, as they promote undue polarization between EBM and its biomedical alternatives. For instance, the references to pre-EBM as "traditional medicine" in some of the early EBM programmatic literature (EBMWG, 1992; Sackett et al, 1996b) is an obvious misnomer, as the term typically refers to folk and alternative healing practices. The selection of this inappropriate term was presumably deliberate, as it permitted the EBM originators to emphasize what they alleged to be the widespread tendency of clinical medicine to operate without sufficient evidentiary support to establish the efficacy of their practices. Pre-EBM biomedicine was therefore "traditional" insofar as it is unscientific or at least insufficiently scientific. Some support for this claim has been found in the phenomenon of small area variations of healthcare practice among different geographical regions (Parchman, 1995). However invoking "traditional medicine" is polemical (and distracting) in its misrepresentation of biomedicine, as it cannot account for biomedicine's modern scientific framework, its significant technological advances and achievements, and, of course, EBM's

Despite not invoking revolution (or comparable large-scale upheaval) in medical practice, it will now be demonstrated that EBM brings something new to medicine. The critics who deny this claim likely do so because they misunderstand EBM to be asking for no more than rigorous empirical research in medicine. But the term "evidence based" amounts to much more. While the evidence based approach certainly does call for rigorous empirical research in medicine, this call is accompanied by novel accounts of what counts as valid evidence

2 Among the procedures cited by Naylor to be in the "grey zone" are: carotid endarterectomy, upper gastrointestinal (GI) endoscopy, hysterectomy, and percutaneous transluminal coronary angioplasty. Randomized controlled trials have been done in these areas, but the results have not produced

3 Accompanying these imposed bifurcations are, of course, efforts at integration, such as "evidencebased patient centred care" (Borgmeyer, 2005), and "evidence-based patient choice" (Hope, 1996; Edwards & Elwyn, 2001; Parker, 2001). The literature also includes an effort to overcome (or possibly

base of medicine, are we still practicing evidence *based* medicine?

*specific findings. The patient is very concerned about his risk of seizure recurrence. How might the resident proceed (EBMWG, 1992)?*

The Working Group explain that the resident practicing *"the way of the past"* (pre-EBM) would consult the senior resident, who, supported in his view by the attending physician, informs her that the risk of seizure recurrence is high, although its precise risk factor is unknown to him. He instructs the resident to relay this information and the related precautions to the patient. The resident does as she is told and the patient, still fearful, is discharged (EBMWG, 1992). In *"the way of the future"*, however, the EBM-trained resident asks herself whether she knows the prognosis of a first seizure and, realizing that she does not, proceeds to the library and conducts a literature search on the *Grateful Med* (now *PubMed*) search engine. Her search on the medical subject headings "epilepsy", "prognosis", and "recurrence" retrieves twenty-five titles, of which one is deemed by the resident to be directly relevant. Exercising the critical appraisal skills that she learned in medical school, she reviews the paper, deems the study and its conclusions to be valid, and returns to her patient after only thirty minutes. She conveys the risk of recurrence over time post-incident, and recommends follow-up with his family physician. The patient leaves "with a clear idea of his likely prognosis" (EBMWG, 1992).

In their comparative analysis of EBM and its biomedical predecessor, Sehon and Stanley argue that the EBM programmatic literature's likening of its approach to a Kuhnian paradigm shift is a gross exaggeration (Sehon & Stanley, 2003). The authors contend that EBM is not a new paradigm because Kuhn described such a large-scale scientific revolution as involving dramatic changes of worldview and even a different world in which scientists must operate (Kuhn, 1996). A Kuhnian paradigm is an "entire constellation of beliefs, values, techniques, and so on shared by the members of a given community" (Kuhn, 1996). The new paradigm will be *incommensurable*, to some extent, with the previous paradigm, a condition that is not met with the evidence based approach in comparison to biomedicine's "basic science approach", which involves "studying the physiological mechanisms of the body and the biochemical properties of drugs" (Sehon & Stanley, 2003).

When EBM is suggested to be a new paradigm, this fosters the impression that an entire set of beliefs, values, and techniques are being discarded, "and that the whole world of medical research and clinical practice is completely different than it was in the days before EBM" (Sehon & Stanley, 2003). This impression is certainly false. Furthermore, the language of paradigms suggests that health care practitioners must make a "stark choice" between EBM and "traditional" biomedicine, where one can "accept the new regime and completely reject the old, or defensively hold onto the old and dismiss EBM entirely" (Sehon & Stanley, 2003). Aside from not being a productive atmosphere in which to hold a critical debate about EBM, this polarization exaggerates the merits, demerits, and differences between EBM and its biomedical "predecessor".

Numerous commentators have characterized the EBM debate as dredging up the hoary "art versus science" dispute regarding the nature of modern clinical medicine. The critics worry that EBM overemphasizes the latter at the expense of the former. Sullivan and MacNaughton, for example, comment that

*the doctor does not deal with illnesses alone but with people who are ill, and for each individual the illness is unique in terms of his or her experience of it and in its presentation to the doctor (Sullivan & MacNaughton, 1996).*

The Working Group explain that the resident practicing *"the way of the past"* (pre-EBM) would consult the senior resident, who, supported in his view by the attending physician, informs her that the risk of seizure recurrence is high, although its precise risk factor is unknown to him. He instructs the resident to relay this information and the related precautions to the patient. The resident does as she is told and the patient, still fearful, is discharged (EBMWG, 1992). In *"the way of the future"*, however, the EBM-trained resident asks herself whether she knows the prognosis of a first seizure and, realizing that she does not, proceeds to the library and conducts a literature search on the *Grateful Med* (now *PubMed*) search engine. Her search on the medical subject headings "epilepsy", "prognosis", and "recurrence" retrieves twenty-five titles, of which one is deemed by the resident to be directly relevant. Exercising the critical appraisal skills that she learned in medical school, she reviews the paper, deems the study and its conclusions to be valid, and returns to her patient after only thirty minutes. She conveys the risk of recurrence over time post-incident, and recommends follow-up with his family physician. The patient leaves "with a clear idea of his likely prognosis" (EBMWG, 1992).

In their comparative analysis of EBM and its biomedical predecessor, Sehon and Stanley argue that the EBM programmatic literature's likening of its approach to a Kuhnian paradigm shift is a gross exaggeration (Sehon & Stanley, 2003). The authors contend that EBM is not a new paradigm because Kuhn described such a large-scale scientific revolution as involving dramatic changes of worldview and even a different world in which scientists must operate (Kuhn, 1996). A Kuhnian paradigm is an "entire constellation of beliefs, values, techniques, and so on shared by the members of a given community" (Kuhn, 1996). The new paradigm will be *incommensurable*, to some extent, with the previous paradigm, a condition that is not met with the evidence based approach in comparison to biomedicine's "basic science approach", which involves "studying the physiological mechanisms of the

When EBM is suggested to be a new paradigm, this fosters the impression that an entire set of beliefs, values, and techniques are being discarded, "and that the whole world of medical research and clinical practice is completely different than it was in the days before EBM" (Sehon & Stanley, 2003). This impression is certainly false. Furthermore, the language of paradigms suggests that health care practitioners must make a "stark choice" between EBM and "traditional" biomedicine, where one can "accept the new regime and completely reject the old, or defensively hold onto the old and dismiss EBM entirely" (Sehon & Stanley, 2003). Aside from not being a productive atmosphere in which to hold a critical debate about EBM, this polarization exaggerates the merits, demerits, and differences between EBM and its

Numerous commentators have characterized the EBM debate as dredging up the hoary "art versus science" dispute regarding the nature of modern clinical medicine. The critics worry that EBM overemphasizes the latter at the expense of the former. Sullivan and

*the doctor does not deal with illnesses alone but with people who are ill, and for each individual the illness is unique in terms of his or her experience of it and in its presentation to the doctor*

body and the biochemical properties of drugs" (Sehon & Stanley, 2003).

biomedical "predecessor".

MacNaughton, for example, comment that

*(Sullivan & MacNaughton, 1996).*

*the resident proceed (EBMWG, 1992)?*

*specific findings. The patient is very concerned about his risk of seizure recurrence. How might*

Understanding the unique circumstances of the individual case is thought to involve a form of practical knowledge or judgment quite different from the *technical* knowledge offered by EBM. The "grey zones" of practice (Naylor, 1995), that is, areas where the evidence from randomized trials about risk-benefit ratios of competing clinical options is incomplete, inconclusive, or contradictory and so clinical judgment must be relied on,2 are repeatedly argued to be missing from EBM's formulaic knowledge base (Tanenbaum, 1993). Indeed, EBM struggles to account for the interpretive dimensions of clinical care, as evidence-based decisionmaking is largely an effort to standardize and rationalize the application of evidence to clinical care. It is no wonder that critics fail to be persuaded by EBM's conciliatory efforts, such as making the first principle of EBM "*evidence is never enough*" in the authoritative *Users' Guides to the Medical Literature*  textbook (Guyatt & Rennie, 2002). It is also worth asking: if evidence is not the fundamental base of medicine, are we still practicing evidence *based* medicine?

In light of these grey zones, EBM is charged with creating and sustaining the idea that *evidence* and *practice* are opposing concepts (Pope 2003; Wood et al., 1998). Other dualisms reinforced in the EBM literature include technical vs. experiential/intuitive knowledge, empirical vs. theoretical knowledge, evidence based vs. patient-centred care, and, of course, EBM vs. its biomedical predecessor, which is inappropriately referred to as "traditional medicine".3 Adherence to these artificial bifurcations seems to misdirect the EBM debate, as they promote undue polarization between EBM and its biomedical alternatives. For instance, the references to pre-EBM as "traditional medicine" in some of the early EBM programmatic literature (EBMWG, 1992; Sackett et al, 1996b) is an obvious misnomer, as the term typically refers to folk and alternative healing practices. The selection of this inappropriate term was presumably deliberate, as it permitted the EBM originators to emphasize what they alleged to be the widespread tendency of clinical medicine to operate without sufficient evidentiary support to establish the efficacy of their practices. Pre-EBM biomedicine was therefore "traditional" insofar as it is unscientific or at least insufficiently scientific. Some support for this claim has been found in the phenomenon of small area variations of healthcare practice among different geographical regions (Parchman, 1995). However invoking "traditional medicine" is polemical (and distracting) in its misrepresentation of biomedicine, as it cannot account for biomedicine's modern scientific framework, its significant technological advances and achievements, and, of course, EBM's ties to the biomedical tradition.

Despite not invoking revolution (or comparable large-scale upheaval) in medical practice, it will now be demonstrated that EBM brings something new to medicine. The critics who deny this claim likely do so because they misunderstand EBM to be asking for no more than rigorous empirical research in medicine. But the term "evidence based" amounts to much more. While the evidence based approach certainly does call for rigorous empirical research in medicine, this call is accompanied by novel accounts of what counts as valid evidence

<sup>2</sup> Among the procedures cited by Naylor to be in the "grey zone" are: carotid endarterectomy, upper gastrointestinal (GI) endoscopy, hysterectomy, and percutaneous transluminal coronary angioplasty. Randomized controlled trials have been done in these areas, but the results have not produced unequivocal conclusions.

<sup>3</sup> Accompanying these imposed bifurcations are, of course, efforts at integration, such as "evidencebased patient centred care" (Borgmeyer, 2005), and "evidence-based patient choice" (Hope, 1996; Edwards & Elwyn, 2001; Parker, 2001). The literature also includes an effort to overcome (or possibly deny) the evidence/judgment divide (Downie et al., 2000).

Innovating Medical Knowledge:

*Horwitz, 1997).*

**4.1 The hierarchy of evidence**

Sackett et al. maintain that for questions of therapy,

randomized controlled trial, and (3) outcomes measures.

providing little if any evidence for the value of intervention (see Fig. 1).

**A Hierarchy of Strength of Evidence for Treatment Decisions**

Single observational study addressing patient-important outcomes

Fig. 1. *Users' Guide to Medical Literature* hierarchy of evidence (Rennie & Guyatt, 2002)

While EBM has evolved over time, most notably in its self-regard from a (polemical) "new paradigm" to a more tempered technique for clinicians to manage vast quantities of research information (for example, Haynes, 2002), the core belief that evidence belongs in fixed hierarchical order with the systematic review of randomized controlled trials always on top remains unshaken (Upshur et al., 2001). In the evaluation of treatment effects, for example, a large, well-designed, randomized trial is considered more reliable than those findings from non-randomized prospective or retrospective studies (Sackett, 1997). Similar schemes have been developed for the ranking of evidence in other clinical categories such as prognosis, aetiology, and diagnosis (Centre for Evidence-Based

Systematic reviews of randomized controlled trials

N of 1 randomized controlled trial

capacity, bone density, and so forth) Unsystematic clinical observations

Single randomized trial

Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 17

trials. The RCT is consistently ranked at the top of the hierarchy of evidence, thus confirming the former's privileged position (Feinstein & Horwitz, 1997). For instance,

The analysis in the next three sections will further examine the novel contents of EBM captured in its methodological privileging of (1) the hierarchy of evidence, (2) the

The hierarchy of evidence captures EBM's basic methodological and epistemic commitments in a fairly straightforward ranking of methods. EBM proponents strongly hold that the trustworthiness or validity of evidence is a function of the design of the study from which the evidence is obtained (Sackett, 1989, 1997; Sackett et al., 1991; Solomon & McLeod, with the Canadian Task Force on the Periodic Health Examination, 1994), and so the desire to use only the "best evidence from clinical research" in the management of individual patients (Sackett et al, 1996b, 1997) has resulted in intricate classificatory schemes for ranking the value of different types of studies. Among the numerous published formulations, there is a consistent placement of randomized controlled trials or the systematic review of these trials at the top, retrospective studies well down the list, and clinical anecdotes are seen as

Systematic review of observational studies addressing patient-important outcomes

Physiologic studies (studies addressing blood pressure, cardiac output, exercise

*we should try to avoid the nonexperimental approaches, since they routinely lead to false-positive conclusions about efficacy…The randomized trial, and especially the systematic review of several randomized trials…has become the "gold standard" (Sackett et al, 1996b, as cited in Feinstein &*

and what qualifies as the most rigorous methods of empirical research. Rather than a revolution or paradigm change, EBM represents an important *shift* in biomedical thinking and practice that is a significant alternative to its biomedical predecessor. Specifically, EBM offers a shift in the sort of evidence that is most highly valued for diagnostics, prognostics, and therapeutics, in its emphasis on experimental controls and quantitative research, which undermines previous regard of clinical experience and observational studies significantly (Sehon & Stanley, 2003). At minimum, this shift is signified by a change from a medical model grounded in basic science to a novel statistically-based medicine (Henry, 2006). EBM's hierarchy of evidence is at the service of outcomes research, which uses a cluster of statistical and epidemiological methods for analyzing the therapeutic effectiveness of clinical interventions (Gifford, 1996). This commitment to highly controlled data and methods of statistical analysis that were previously used only for population-based research (such as public health) represents not only methodological change, but also a novel regard of the reliability of various forms of medical knowledge.

#### **4. The novel contents of EBM**

The unique content offered to medicine by EBM remains difficult for many to grasp. Hardly anyone can disagree with the goal of getting clinicians to make "conscientious, explicit, and judicious use of current best evidence" for decisions in patient care. Any expressions of doubt about EBM activities are usually greeted with vigorous accusations of disregarding "today's harsh realities", or ignoring "what happens in clinical medicine" (Sackett et al., 1996a). Furthermore, critics are frequently denounced for erroneous beliefs that EBM only uses evidence from randomized controlled trials, that it involves "merely the mindless application of the results of megatrials", and that "other forms of evidence are heavily discounted" (Rosenberg & Donald, 1995). Feinstein and Horwitz have wisely suggested that much of the confusion surrounding what EBM actually stands for lies in the distinction between the contents of EBM itself and its application in clinical practice. It is only when this distinction is blurred that many clinicians claim EBM to offer "nothing new" (Feinstein & Horwitz, 1997). Many practitioners have seen little novelty in EBM because they regularly assemble evidence, develop clinical judgment, read medical literature, attend medical meetings, and have discussions with one another. These activities seem entirely compatible with the statement that the practice of EBM consists of "integrating individual clinical expertise with the best available external clinical evidence from systematic research" (Sackett et al., 1996b). The activities surrounding the practice of EBM also seems fairly standard, as the data informing evidence-based practice "is not restricted to randomized trials and meta-analyses" (Sackett et al., 1996b). It contains "clinically relevant research, often from the basic sciences of medicine" and it includes studies of diagnostic tests, prognostic markers, and "the efficacy and safety of the therapeutic, rehabilitative and preventive regimes" (Sackett et al., 1996b). With this description of what is done when EBM is *practiced* and with the overt acknowledgement by the EBM originators that EBM is rooted in the medical thought of mid-nineteenth century France, specifically "the call for external evidence expressed in Paris 150 years ago by Louis, Bichat and Magendie" (Sackett et al., 1997), clinicians can easily conclude that EBM is not particularly novel, and may wonder why it has stirred so much fuss and controversy (Feinstein & Horwitz, 1997).

The novelty lies, however, in the organization and privileging of information. While a wide range of evidentiary sources are permitted in evidence-based practice, the evidence collected for EBM itself is confined almost exclusively to RCTs and meta-analyses of those trials. The RCT is consistently ranked at the top of the hierarchy of evidence, thus confirming the former's privileged position (Feinstein & Horwitz, 1997). For instance, Sackett et al. maintain that for questions of therapy,

*we should try to avoid the nonexperimental approaches, since they routinely lead to false-positive conclusions about efficacy…The randomized trial, and especially the systematic review of several randomized trials…has become the "gold standard" (Sackett et al, 1996b, as cited in Feinstein & Horwitz, 1997).*

The analysis in the next three sections will further examine the novel contents of EBM captured in its methodological privileging of (1) the hierarchy of evidence, (2) the randomized controlled trial, and (3) outcomes measures.

#### **4.1 The hierarchy of evidence**

16 Evidence Based Medicine – Closer to Patients or Scientists?

and what qualifies as the most rigorous methods of empirical research. Rather than a revolution or paradigm change, EBM represents an important *shift* in biomedical thinking and practice that is a significant alternative to its biomedical predecessor. Specifically, EBM offers a shift in the sort of evidence that is most highly valued for diagnostics, prognostics, and therapeutics, in its emphasis on experimental controls and quantitative research, which undermines previous regard of clinical experience and observational studies significantly (Sehon & Stanley, 2003). At minimum, this shift is signified by a change from a medical model grounded in basic science to a novel statistically-based medicine (Henry, 2006). EBM's hierarchy of evidence is at the service of outcomes research, which uses a cluster of statistical and epidemiological methods for analyzing the therapeutic effectiveness of clinical interventions (Gifford, 1996). This commitment to highly controlled data and methods of statistical analysis that were previously used only for population-based research (such as public health) represents not only methodological change, but also a novel regard

The unique content offered to medicine by EBM remains difficult for many to grasp. Hardly anyone can disagree with the goal of getting clinicians to make "conscientious, explicit, and judicious use of current best evidence" for decisions in patient care. Any expressions of doubt about EBM activities are usually greeted with vigorous accusations of disregarding "today's harsh realities", or ignoring "what happens in clinical medicine" (Sackett et al., 1996a). Furthermore, critics are frequently denounced for erroneous beliefs that EBM only uses evidence from randomized controlled trials, that it involves "merely the mindless application of the results of megatrials", and that "other forms of evidence are heavily discounted" (Rosenberg & Donald, 1995). Feinstein and Horwitz have wisely suggested that much of the confusion surrounding what EBM actually stands for lies in the distinction between the contents of EBM itself and its application in clinical practice. It is only when this distinction is blurred that many clinicians claim EBM to offer "nothing new" (Feinstein & Horwitz, 1997). Many practitioners have seen little novelty in EBM because they regularly assemble evidence, develop clinical judgment, read medical literature, attend medical meetings, and have discussions with one another. These activities seem entirely compatible with the statement that the practice of EBM consists of "integrating individual clinical expertise with the best available external clinical evidence from systematic research" (Sackett et al., 1996b). The activities surrounding the practice of EBM also seems fairly standard, as the data informing evidence-based practice "is not restricted to randomized trials and meta-analyses" (Sackett et al., 1996b). It contains "clinically relevant research, often from the basic sciences of medicine" and it includes studies of diagnostic tests, prognostic markers, and "the efficacy and safety of the therapeutic, rehabilitative and preventive regimes" (Sackett et al., 1996b). With this description of what is done when EBM is *practiced* and with the overt acknowledgement by the EBM originators that EBM is rooted in the medical thought of mid-nineteenth century France, specifically "the call for external evidence expressed in Paris 150 years ago by Louis, Bichat and Magendie" (Sackett et al., 1997), clinicians can easily conclude that EBM is not particularly novel, and may wonder

why it has stirred so much fuss and controversy (Feinstein & Horwitz, 1997).

The novelty lies, however, in the organization and privileging of information. While a wide range of evidentiary sources are permitted in evidence-based practice, the evidence collected for EBM itself is confined almost exclusively to RCTs and meta-analyses of those

of the reliability of various forms of medical knowledge.

**4. The novel contents of EBM**

The hierarchy of evidence captures EBM's basic methodological and epistemic commitments in a fairly straightforward ranking of methods. EBM proponents strongly hold that the trustworthiness or validity of evidence is a function of the design of the study from which the evidence is obtained (Sackett, 1989, 1997; Sackett et al., 1991; Solomon & McLeod, with the Canadian Task Force on the Periodic Health Examination, 1994), and so the desire to use only the "best evidence from clinical research" in the management of individual patients (Sackett et al, 1996b, 1997) has resulted in intricate classificatory schemes for ranking the value of different types of studies. Among the numerous published formulations, there is a consistent placement of randomized controlled trials or the systematic review of these trials at the top, retrospective studies well down the list, and clinical anecdotes are seen as providing little if any evidence for the value of intervention (see Fig. 1).

#### **A Hierarchy of Strength of Evidence for Treatment Decisions**

Fig. 1. *Users' Guide to Medical Literature* hierarchy of evidence (Rennie & Guyatt, 2002)

While EBM has evolved over time, most notably in its self-regard from a (polemical) "new paradigm" to a more tempered technique for clinicians to manage vast quantities of research information (for example, Haynes, 2002), the core belief that evidence belongs in fixed hierarchical order with the systematic review of randomized controlled trials always on top remains unshaken (Upshur et al., 2001). In the evaluation of treatment effects, for example, a large, well-designed, randomized trial is considered more reliable than those findings from non-randomized prospective or retrospective studies (Sackett, 1997). Similar schemes have been developed for the ranking of evidence in other clinical categories such as prognosis, aetiology, and diagnosis (Centre for Evidence-Based

Innovating Medical Knowledge:

"gold standard".

Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 19

further question of whether the randomized controlled trial rightfully deserves the title of

Regarded as a maverick among his peers, Cochrane strongly promoted the controversial view that randomized controlled trials offer the best test for the effects of medical interventions and could thereby correct ineffectiveness and even harms perpetrated by contemporary medical practice (this was another heretical claim) (Pope, 2003). With time, this view came to be accepted and randomized trials became "a yardstick by which other sources of information were judged and ranked within a hierarchy of evidence" (Pope, 2003). The introduction of randomized trials to medical research has been credited by Iain Chalmers, one of the original founders of the Cochrane Collaboration who was knighted in 2000 for his activism in cumulating evidence in medical research, and others for revolutionizing therapeutic development and increasing the life expectancy of patients from three to seven years over the past half century (Chalmers, 1998). When substantial uncertainty exists about treatment effects, it is widely thought to be not only scientifically correct to answer it in a study with the smallest amount of built-in bias, but also most ethical to expose patients to alternative treatment options based on chance only and not upon the biased opinion of a physician (Edwards et al., 1998; Frazier & Mosteller, 1995; Freedman, 1997; Lilford & Jackson, 1995).

Many EBM critics point to the "experiential nature" of medical practice for being not only inextricable from but also inappropriately maligned by the evidence based approach (Tanenbaum 1993; Williams & Garner, 2002). However, supporters of EBM insist that experiential knowledge is worth minimizing because experience allows for the repetition of mistakes. EBM proponents point to the data available suggesting human fallibility and bias in drawing conclusions based on uncontrolled experience (Dawson & Arkes, 1987; MacCoun, 1998). Others argue that investigators with relationships or experience with a subject form expectations with respect to treatment outcomes that make them less able to produce objective reviews of scientific evidence than non-experts trained in critical appraisal of evidence (Oxman & Guyatt, 1993). A logical deductive framework for interpretation of evidence is therefore argued to be needed if we are to avoid practicing medicine based on uncontrolled experience, which may do more harm than good (Sackett, 1989). The nature of research is meant to reduce uncertainty, even if it cannot be completely eliminated. Yet what randomized controlled trials gain in experimental certainty (internal validity), they lose in applicability to the clinical context (external validity) (Cartwright, 2007). The EBM hierarchy

indicates a strong presumption in favour of internal validity in experimental design.

The randomized controlled trial design is better geared for certain kinds of intervention questions than others. These trials are ideal for the direct comparison between simple treatments such as two single drugs, and so the pronounced "hegemony of the double-blind randomized controlled trial" (Charlton, 1991) can both undermine research into the use of complex interventions and result in a failure to meet the complex needs of individual patients. Regarding the former, the critics worry that because randomized controlled trial design is increasingly favoured, and because the expectation to provide "best evidence" of effectiveness before implementing interventions is growing, complex interventions are by default less likely to be supported over time (DeVries & Lemmens, 2006). As a result, behavioural, psychosocial, community based, and multiple-component interventions lose out in favour of individual patient-based treatments (Dieppe, 1998; Tallon et al., 2000) and resultant public health policy-setting increasingly focuses on individuals rather than on

Medicine, 2006; Sackett et al., 1997). At the bottom of each of these clinical scales is evidence obtained from case reports and personal experience.

The logic behind the ranking of evidence is simple: randomization is the best method for distinguishing between the effects of active treatment from the effects of known and unknown potentially biasing influences (Peto & Baigent, 1988). It follows that we should make every effort to identify and catalogue these studies. And this is exactly what is happening. EBM proponents initially endorsed the teaching of critical analysis skills in medical schools so that physicians could properly assess the quality of a study (EBMWG, 1992). The hierarchy of evidence is one of the tools used in this task. It was quickly realized, however, that more advanced informatics were needed in order for clinicians to manage the massive amount of research data available. The Cochrane Collaboration has undertaken the monumental task of identifying and evaluating well over a million randomized controlled trials (U.S. Cochrane Center, 2002). Systematic reviews and metaanalyses of randomized trials in specific areas of medicine are now widely available on EBM databases and in EBM journals.

The privileging of "hard" evidence—the quantified data generated by randomized controlled trials—over knowledge generated from clinical experience (EBMWG, 1992) and qualitative measures (Gray, 1997) speaks to an epistemic distrust of subjective or personal experience, which cannot guard against biasing influences. Methodologies like blinding, randomization, placebo-control, the use of large subject populations, and replication of results serve to abstract from values to reveal empirical facts. Of the types of trials available, clinical trials offer the strongest and clearest support for any claim that a treatment is effective because they allow scientists to control extraneous variables and test one factor at a time (Schick & Vaughn, 2002). The hierarchy of evidence is, by the founders' own admission, based on levels of certainty, where the quantified and the scientific forms of evidence are placed on top because they are understood to be most resistant to sceptical refutation (Sackett et al., 1991).

The central goal behind the EBM movement is quality of care, and this goal serves as the grounds for encouraging medical practice that utilizes the latest and best evidence. Evidence-based practices, including the ranking of evidence, are thought to enhance effective and efficient clinical decision-making. But, critics argue, "effectiveness" need not be limited to clinical- or cost-effectiveness. It could also refer to patient-based outcomes indicating satisfaction with the treatment provided. The hierarchy prioritizes evidence of clinical effectiveness and necessarily excludes subjective perceptions (Malterud, 1995, 2001; Rogers 2002). Yet patient narratives and the interpretive features of clinical practice are thought by many to be crucial features of quality healthcare (Greenhalgh & Hurwitz, 1998; Greenhalgh, 1999; Malterud 2001; Silva et al., 2011).

#### **4.2 Randomized controlled trials: The "gold standard" of medical research**

The methodological debates that make up the bulk of the EBM literature revolve around the general question whether or not the refined focus on clinical evidence (as prioritized in the EBM hierarchy of knowledge), or the search for secure knowledge in general, improves our ability to decipher best practices and therefore prescribe the most effective treatments. Alternatively, the methods may leave out too many important features of clinical care that are not readily measurable through evidence-based approaches. This leads to the important

Medicine, 2006; Sackett et al., 1997). At the bottom of each of these clinical scales is

The logic behind the ranking of evidence is simple: randomization is the best method for distinguishing between the effects of active treatment from the effects of known and unknown potentially biasing influences (Peto & Baigent, 1988). It follows that we should make every effort to identify and catalogue these studies. And this is exactly what is happening. EBM proponents initially endorsed the teaching of critical analysis skills in medical schools so that physicians could properly assess the quality of a study (EBMWG, 1992). The hierarchy of evidence is one of the tools used in this task. It was quickly realized, however, that more advanced informatics were needed in order for clinicians to manage the massive amount of research data available. The Cochrane Collaboration has undertaken the monumental task of identifying and evaluating well over a million randomized controlled trials (U.S. Cochrane Center, 2002). Systematic reviews and metaanalyses of randomized trials in specific areas of medicine are now widely available on

The privileging of "hard" evidence—the quantified data generated by randomized controlled trials—over knowledge generated from clinical experience (EBMWG, 1992) and qualitative measures (Gray, 1997) speaks to an epistemic distrust of subjective or personal experience, which cannot guard against biasing influences. Methodologies like blinding, randomization, placebo-control, the use of large subject populations, and replication of results serve to abstract from values to reveal empirical facts. Of the types of trials available, clinical trials offer the strongest and clearest support for any claim that a treatment is effective because they allow scientists to control extraneous variables and test one factor at a time (Schick & Vaughn, 2002). The hierarchy of evidence is, by the founders' own admission, based on levels of certainty, where the quantified and the scientific forms of evidence are placed on top because they are

The central goal behind the EBM movement is quality of care, and this goal serves as the grounds for encouraging medical practice that utilizes the latest and best evidence. Evidence-based practices, including the ranking of evidence, are thought to enhance effective and efficient clinical decision-making. But, critics argue, "effectiveness" need not be limited to clinical- or cost-effectiveness. It could also refer to patient-based outcomes indicating satisfaction with the treatment provided. The hierarchy prioritizes evidence of clinical effectiveness and necessarily excludes subjective perceptions (Malterud, 1995, 2001; Rogers 2002). Yet patient narratives and the interpretive features of clinical practice are thought by many to be crucial features of quality healthcare (Greenhalgh & Hurwitz, 1998;

understood to be most resistant to sceptical refutation (Sackett et al., 1991).

**4.2 Randomized controlled trials: The "gold standard" of medical research**

The methodological debates that make up the bulk of the EBM literature revolve around the general question whether or not the refined focus on clinical evidence (as prioritized in the EBM hierarchy of knowledge), or the search for secure knowledge in general, improves our ability to decipher best practices and therefore prescribe the most effective treatments. Alternatively, the methods may leave out too many important features of clinical care that are not readily measurable through evidence-based approaches. This leads to the important

Greenhalgh, 1999; Malterud 2001; Silva et al., 2011).

evidence obtained from case reports and personal experience.

EBM databases and in EBM journals.

further question of whether the randomized controlled trial rightfully deserves the title of "gold standard".

Regarded as a maverick among his peers, Cochrane strongly promoted the controversial view that randomized controlled trials offer the best test for the effects of medical interventions and could thereby correct ineffectiveness and even harms perpetrated by contemporary medical practice (this was another heretical claim) (Pope, 2003). With time, this view came to be accepted and randomized trials became "a yardstick by which other sources of information were judged and ranked within a hierarchy of evidence" (Pope, 2003). The introduction of randomized trials to medical research has been credited by Iain Chalmers, one of the original founders of the Cochrane Collaboration who was knighted in 2000 for his activism in cumulating evidence in medical research, and others for revolutionizing therapeutic development and increasing the life expectancy of patients from three to seven years over the past half century (Chalmers, 1998). When substantial uncertainty exists about treatment effects, it is widely thought to be not only scientifically correct to answer it in a study with the smallest amount of built-in bias, but also most ethical to expose patients to alternative treatment options based on chance only and not upon the biased opinion of a physician (Edwards et al., 1998; Frazier & Mosteller, 1995; Freedman, 1997; Lilford & Jackson, 1995).

Many EBM critics point to the "experiential nature" of medical practice for being not only inextricable from but also inappropriately maligned by the evidence based approach (Tanenbaum 1993; Williams & Garner, 2002). However, supporters of EBM insist that experiential knowledge is worth minimizing because experience allows for the repetition of mistakes. EBM proponents point to the data available suggesting human fallibility and bias in drawing conclusions based on uncontrolled experience (Dawson & Arkes, 1987; MacCoun, 1998). Others argue that investigators with relationships or experience with a subject form expectations with respect to treatment outcomes that make them less able to produce objective reviews of scientific evidence than non-experts trained in critical appraisal of evidence (Oxman & Guyatt, 1993). A logical deductive framework for interpretation of evidence is therefore argued to be needed if we are to avoid practicing medicine based on uncontrolled experience, which may do more harm than good (Sackett, 1989). The nature of research is meant to reduce uncertainty, even if it cannot be completely eliminated. Yet what randomized controlled trials gain in experimental certainty (internal validity), they lose in applicability to the clinical context (external validity) (Cartwright, 2007). The EBM hierarchy indicates a strong presumption in favour of internal validity in experimental design.

The randomized controlled trial design is better geared for certain kinds of intervention questions than others. These trials are ideal for the direct comparison between simple treatments such as two single drugs, and so the pronounced "hegemony of the double-blind randomized controlled trial" (Charlton, 1991) can both undermine research into the use of complex interventions and result in a failure to meet the complex needs of individual patients. Regarding the former, the critics worry that because randomized controlled trial design is increasingly favoured, and because the expectation to provide "best evidence" of effectiveness before implementing interventions is growing, complex interventions are by default less likely to be supported over time (DeVries & Lemmens, 2006). As a result, behavioural, psychosocial, community based, and multiple-component interventions lose out in favour of individual patient-based treatments (Dieppe, 1998; Tallon et al., 2000) and resultant public health policy-setting increasingly focuses on individuals rather than on

Innovating Medical Knowledge:

(Relman, 2009).

knowledge that *does* enter into consideration.

Understanding Evidence-Based Medicine as a Socio-Medical Phenomenon 21

Taken together, the numerous controls utilized to guard against bias and promote efficiency in medical research limits the relevancy of, and may even distort, the "best evidence from clinical research" in the management of individual patients. While there are differences of opinion regarding the challenges posed in making clinical evidence applicable, EBM fails to engage significantly with this problem. EBM's penchant for methodological rigour may be at odds with the ad hoc nature of clinical practice. Tanenbaum has suggested that the precision of "best evidence" is fundamentally irreconcilable with its clinical relevance, given the particularity of patients and the significant improvisational dimensions of clinical practice (Tanenbaum, 1995). Shaughnessy et al. refer to this improvisational feature as "clinical jazz" (Shaughnessy et al., 1998). The debate over randomized controlled trials highlight that the problem of evidence in EBM does not only concern what knowledge is missing from the evidence based decisionmaking framework, but also the nature of the

**4.3 Outcomes measures: Clinical effectiveness and the quality movement in medicine**  EBM was introduced to healthcare in the wake of what has been famously described as the "third revolution" in health care (Relman, 1988),4 a turn toward assessment and accountability in light of escalating health care costs creating a "crisis" situation in health care spending throughout the industrialized world. Patients and payers widely subscribed to a "waste theory" that described physicians wasting healthcare money on poorly performing diagnostics and treatments (Tanenbaum, 1994a). Furthermore, the documentation of notable geographical variations in practice that could not be explained by local organizational and financial arrangements caused alarm (Clancy & Eisenberg, 1988). Health care advocates wanted the consistent practice of only the best health care interventions. The "best" was determined by the "end results" or "outcomes" of medical practice. The urgency with which the public demanded that physicians pay attention to medical outcomes led to what soon became known as the "outcomes movement" in health policy (Epstein, 1990). Evaluating clinical effectiveness was seen as a fiscally responsible means of only financing the most promising therapies and research. EBM facilitated the

clinical data that outcomes research requires in order to evaluate best practices.

Outcomes research refers to all activity directed towards the assessment of outcomes, analysis of effectiveness, and quality assurance (Epstein, 1990). It uses statistical analysis of clinical data to determine associations between particular therapeutic interventions and particular results (Tanenbaum, 1994a). Unlike laboratory research which measures definable clinical events like lipid lowering or blood pressure, outcomes research can employ patientderived endpoints, the outcomes that patients care about (Clancy & Eisenberg, 1988). Common themes in outcomes research are: safety, effectiveness, equity, efficiency, timeliness, and patient centeredness (Institute of Medicine, 2001). The benefits of outcomes research to healthcare include better informed patients and providers, the development of clinical guidelines that reflect those assessments, and wiser purchasing of health care technologies (Agency for Health Care Research and Quality, n.d.). This move towards

4 Relman later lamented that this "third revolution" was never realized due to lack of government initiative by any of the US governmental administrations elected since the 1988 writing of his editorial

groups (Davey-Smith et al., 2001). Speaking more abstractly, numerous philosophers of science deny that there is any universal method in science, randomized trial or otherwise (Cartwright, 2007; Urbach, 1993; Worrall, 2002).

In the arena of individual patient care, critics argue that because EBM guidelines are derived from controlled trials of simplified clinical situations using criteria that often exclude other complicating serious conditions, the evidence may not be applicable to complex clinical situations. The "gold standard" of clinical research is widely thought to have a problem of generalizability of its results to individual patient care (Britton et al., 1998; Culpepper & Gilbert, 1999; Feinstein & Horwitz, 1997). Even Cochrane recognized that while the RCT can measure effectiveness, its results may not be directly replicable in clinical practice (Cochrane, 1972), and so Dingwall et al. seem correct in their suggestion that Cochrane's ideas have been used somewhat selectively in EBM (Dingwall et al., 1988, as cited in Pope, 2003). The problem of generalizability begins with the narrow eligibility criteria for randomized trials, which limit conclusions about a treatment's effectiveness to patients who fulfill those criteria (Feinstein & Horwitz, 1997). To demonstrate optimal efficacy, randomized controlled trials often use relatively homogenous subject populations (Djulbegovic et al., 2000). Patients excluded from such trials can differ substantially from study patients in a variety of ways that could influence treatment outcomes (i.e. disease severity, comorbid conditions, gender, race) (Britton et al., 1998; Tanenbaum, 1995). Furthermore, the time periods covered in clinical trials and the measures used to assess outcomes frequently differ from those used to assess the success of a therapy in actual practice. In an effort to be efficient, clinical trials typically use the shortest time possible for determining valid results, employing surrogate endpoints rather than clinically relevant outcomes. Surrogate endpoints are physiological or biochemical markers that can be ascertained quickly and taken to be predictive of clinically meaningful endpoints such as how a patient feels, functions, or survives—that take much longer to observe. They are "surrogate" insofar as they are outcome measures that are not of direct practical importance but are believed to reflect outcomes that are clinically relevant. For example, cholesterol studies frequently use cholesterol reduction as a surrogate for reduced mortality. Direct demonstration of mortality reduction requires lengthy trials using large subject populations, while cholesterol reduction is known to be strongly associated with mortality benefits, and can be measured easily in smaller numbers of patients. Similarly, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks (Bandolier, n.d.).

Yet the requirement that surrogate endpoints reliably predict the overall effect of the clinical outcome frequently fails in practice (Fleming & DeMets, 1996). The disease process can affect the clinical outcome through several causal pathways that are not mediated by the surrogate. Therefore the effect of the intervention on these pathways will be different from the effect on the surrogate (Fleming & DeMets, 1996). It is more likely, however, that "the intervention affects the clinical outcome by unintended, unanticipated, and unrecognized mechanisms of action that operate independently of the disease process" (Fleming & DeMets, 1996). Fleming and DeMets argue that surrogate endpoints frequently mislead regarding the actual effects that treatments have on health outcomes. For instance, although lipid levels are widely seen to be important predictors of cardiovascular-related mortality, there is debate over the relationship between lipid lowering and reduction in overall mortality. The Coronary Drug Project in the 1970's showed clofibrate and niacin to decrease cholesterol levels, however neither agent reduced total mortality (Fleming & DeMets, 1996).

groups (Davey-Smith et al., 2001). Speaking more abstractly, numerous philosophers of science deny that there is any universal method in science, randomized trial or otherwise