The ability of an intervention to produce the desired beneficial effect in expert hands and under ideal circumstances.

What is evidence Based Drug Therapy?

Evidence based drug therapy means integrating the best evidence, the individual characteristics of the patient, and individual clinical expertise, into a decision making process which leads to optimal drug therapy.

It is dependent on the use of randomized controlled trials, as well as systematic reviews (of a series of trials) and meta-analysis,

An experiment performed on human beings in order to evaluate the comparative efficacy of two or more therapies.The randomized controlled trial uses an appropriate control group (placebo or the standard ,a well-established therapy) for comparison with the experimental therapy and random allocation of patients to the experimental and control groups.The randomized controlled trial is generally considered to yield the strongest scientific evidence of efficacy.

Sources of bias to check for in a randomised controlled trial

The efficacy of a drug should ideally be measured in terms of clinical end points that are relevant to patients; if surrogate end points are used they should be valid.

A surrogate end point may be defined as a variable which is relatively easily measured and which predicts a rare or distant outcome of either a toxic stimulus (such as a pollutant) or a therapeutic intervention (a drug or surgical procedure) .

• In the evaluation of pharmaceutical products, commonly used surrogate end points include:

Pharmacokinetic measurements (for example, concentration-time curves of a drug or its active metabolite in the blood stream);In vitro (laboratory) measures such as the mean inhibitory concentration of an antimicrobial against a bacterial culture on agar; Macroscopic appearance of tissues (for example, gastric erosion seen at endoscopy);Change in levels of (alleged) serum markers of disease (for example, prostate specific antigen)

• Features of the ideal surrogate end point

The surrogate end point should be reliable, reproducible, clinically available, easily quantifiable, affordable, and show a "dose-response" effect (the higher the level of the surrogate end point, the greater the probability of disease) It should be a true predictor of disease (or risk of disease) and not merely express exposure to a covariable. The relation between the surrogate end point and the disease should have a biologically plausible explanation

• It should be sensitive—a "positive" result in the surrogate end point should pick up all or most patients at increased risk of adverse outcome

• It should be specific—a "negative" result should exclude all or most of those without increased risk of adverse outcome

• There should be a precise cut off between normal and abnormal values

• It should have an acceptable positive predictive value—a "positive" result should always or usually mean that the patient thus identified is at increased risk of adverse outcome

• It should have an acceptable negative predictive value—a "negative" result should always or usually mean that the patient thus identified is not at increased risk of adverse outcome

• It should be amenable to quality control monitoring

• Changes in the surrogate end point should rapidly and accurately reflect the response to treatment. In particular, levels should normalise in states of remission or cure

Clinical Trials Databases (ClinicalTrials.gov)

This site from the National Institutes of Health (NIH) giving access to several databases containing facts about both public and privately supported clinical studies.

There are several databases available covering: cancer; AIDS; eye diseases; rare diseases; heart, lung and blood diseases; infection, immunologic and allergic diseases (NIAID); alzheimer's disease.

Current Controlled Trials (CCT)

This is a database of ongoing controlled trials which has been developed by Current Controlled Trials Ltd, part of the Current Science Group of companies. It contains a metaRegister of Controlled Trials (mRCT), which aims to provide online access to as comprehensive a listing as possible of ongoing and completed controlled trials in all areas of healthcare. There is also a Controlled Trials Links Register, which links to other online registers of controlled trials..

HerbMed

HerbMed is an evidence-based database that provides hyperlinked access to the scientific data underlying the use of herbs for health. It is maintained by the Alternative Medicine Foundation Inc. There is an alphabetic listing of herbs, in addition to the database function. Six categories of information are provided for each herb: evidence for activity; warnings; preparations; mixtures; mechanisms of action; other, which includes links to pictures.

TRIP Database

The Gwent-based TRIP (Turning Research into Practice) Database amalgamates a number of separate providers of evidence-based material into this one database and has 15,000 links from 61 sources, including peer-reviewed journals as the BMJ, JAMA, NEMJ and others from the BMJ Publishing Group. Each publisher is categorised as either: evidence-based (direct links); evidence-based (indirect links); peer-reviewed journals; guidelines; and other (to accommodate material that doesn't fit into the other categories).

A systematic review is an overview of primary studies that used explicit and reproducible methods.

Methodology for a systematic review of randomised controlled trials

• Advantages of systematic reviews

• Explicit methods limit bias in identifying and rejecting studies

• Conclusions are more reliable and accurate because of methods used

• Large amounts of information can be assimilated quickly by healthcare providers, researchers, and policymakers

• Delay between research discoveries and implementation of effective diagnostic and therapeutic strategies may be reduced .

• Results of different studies can be formally compared to establish generalisability of findings and consistency (lack of heterogeneity) of results.

• Reasons for heterogeneity (inconsistency in results across studies) can be identified and new hypotheses generated about particular subgroups

Cochrane systematic reviews

Are generally considered to be the most reliable sources of evidence of clinical effectiveness.

Cochrane systematic reviews are presented in an unbiased way and updated regularly to include evidence from the latest trials in clinical or complementary medicine.

The Cochrane Collaboration is an international non-profit and independent organisation, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide.

A meta-analysis is a mathematical synthesis of the results of two or more primary studies that addressed the same hypothesis in the same way

Although meta-analysis can increase the precision of a result, it is important to ensure that the methods used for the review were valid and reliable

Pooled odds ratios of eight randomised controlled trials of coronary artery bypass grafting against percutaneous coronary angioplasty, shown in MetaView format.

The BNF is a joint publication of the British Medical Association and the Royal Pharmaceutical Society of Great Britain.

It is published biannually under the

authority of a Joint Formulary Committee which comprises representatives of the two professional bodies and of the UK Health Departments.

Clinical guidelines are systematically- developed statements designed to help practitioners and patients decide on appropriate healthcare for specific clinical conditions and/or circumstances.Good guidelines can change clinical practice and influence patient outcome.Guidelines reduce unacceptable or undesirable variations in practice and provide a focus for discussion among health professionals and patients.

• Good clinical guidelines should be:-• Valid – leading to the results expected of them.• Reproducible – if using the same evidence, other

guideline groups would come to the same results.• Cost-effective – reducing the inappropriate use of

resources.• Representative/multidisciplinary – by involving

key groups and their interests.• Clinically applicable – patient populations affected

should be unambiguously defined.• Flexible – by identifying the expectations relating to

recommendations as well as patient preferences.• Clear – unambiguous language, which is readily

understood by clinicians and patients, should be used.

• Guidelines on the web• http://www.nice.org.uk• National Institute for Clinical Excellence.• http://www.sign.ac.uk• The Scottish Intercollegiate Guidelines Network

(SIGN) develops and publishes evidence-based clinical practice guidelines for use by the health service in Scotland. This website also includes SIGN’s criteria for the appraisal of guidelines.

• http://www.healthcentre.org.uk/hc/library/guidelines.htm

• UK and worldwide guidelines available on the Internet (not necessarily formally appraised or reviewed).

• http://www.suffolk-maag.ac.uk/guidelines• A general practice development group has

been established in Suffolk to, among other tasks, examine all proposed guidelines to see whether they are sensible and relevant to Suffolk before they are introduced.

• http://text.nlm.nih.gov/ftrs/pick?collect=ahcpr&t=924522691

• Clinical guidelines published by the US Health Agency, but not fully available

• on the web.

• http://www.sghms.ac.uk/phs/hceu/nhsguide.htm

• The Health Care Evaluation Unit’s Critical Appraisal instrument is available on

• the Internet. Its aim is to encourage the systematic development of clinical

• guidelines in the UK and to provide a structured and transparent approach

• to their appraisal

Therapeutic index provides a very crude measure of the safety of any drug .its main limitations are:-1-It is based on animal toxicity data , which may not reflect forms of toxicity that are important clinically.2-It takes no account of idiosyncratic toxic reactions.

• The NNT is the number of patients to whom a clinician would need to administer a particular treatment to prevent 1 patient from having an adverse outcome over a predefined period of time

• If, for example, the NNT for a treatment is 10, the practitioner would have to give the treatment to 10 patients to prevent 1 patient from having the adverse outcome over the defined period

• E.g. How many people with myocardial infarction would you have to treat with ß-blockers for 2 years to prevent 1 death?

In a recent study of pain relief by antidepressants drugs compared with placebo , the findings were:-

For benefit [a defined level of pain relief], NNT=3.

For minor unwanted effects, NNT=3.

For major adverse effects, NNT=22.

Therefore for 100 patients treated with the drugs , on average 33 will experience pain relief, 33 will experience minor unwanted effects & 4 or 5 will experience major adverse effects, information which is helpful in guiding therapeutic choice.

The number of patients who would have to receive the treatment for 1 of them to experience the adverse effect ;calculated as 100 divided by the absolute risk increase

(a) Relative risk (RR)= Event rate (Drug) / Event rate (Placebo)

(b) Relative risk reduction (RRR) = 1- relative risk x 100

(c) % Absolute risk reduction (ARR) = % Event rate (Placebo) - % Event rate (Drug)

(d) Number needed to treat (NNT) = 100/ % absolute risk reduction.

BOX 1-1What Is a Clinical Trial?A clinical trial is defined as a prospective study comparing the effect and value of intervention(s) against control in human beings (Friedman, Furberg, and DeMets, 1996).

A controlled experiment having a clinical event as an outcome measure and done in a clinic or clinical setting and involving persons having a specific disease or health condition (Meinert, 1996). An experiment is a series of observations made under conditions controlled by the scientist. A clinical trial is an experiment testing medical treatments on human participants (Piantadosi, 1997). The term clinical trials may be applied to any form of planned experiment which involves patients and is designed to elucidate the most appropriate treatment of future patients with a given medical condition (Pocock, 1984).

an experiment performed on human beings in order to evaluate the comparative efficacy of two or more therapies. The randomized controlled trial, which uses an appropriate control group (placebo or sham treatment or the standard well-established therapy) for comparison with the experimental therapy and random allocation of patients to the experimental and control groups, is generally considered to yield the strongest scientific evidence of any well-designed trial.

• The Cochrane Collaboration is an international non-profit and independent organisation, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist, Archie Cochrane..

• The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library

Table 1: An example of similar relative risks but different absolute risk reductions(4), (7)

Placebo# of

patients

Drug# of

patients

RelativeRisk

Relative Risk

Reduction

AbsoluteRisk

Reduction

NumberNeeded to Treat

Total

Event

Total

Event

RR (a) RRR (b) ARR (c) NNT (d)

3178

1038

3810

854

(854/3810)/(1038/3178)=0.

69

(1-0.69)x100=31%

32.6%-22.4%=10.

2%

100/10.2=10

2030

842051

56(56/2051)/

(84/2030)=0.66

(1-0.66)x100=34%

4.1%-2.7%=1.4

%

100/1.4=71

(a) Relative risk (RR)= Event rate (Drug) / Event rate (Placebo)(b) Relative risk reduction (RRR) = 1- relative risk x 100(c) % Absolute risk reduction (ARR) = % Event rate (Placebo) - % Event rate (Drug)(d) Number needed to treat (NNT) = 100/ % absolute reduction