Introduction to Evidence-Based Practice



Literature Search

Evaluating the Evidence

the evidence

4. Appraise that evidence for its validity (closeness to the truth) and applicability (usefulness in clinical practice)

Step 1: Evaluating the Validity of a Therapy Study

We have now identified current information which can answer our clinical question. The next step is to read the article and evaluate the study.

There are three basic questions that need to be answered for every type of study:

  • Are the results of the study valid?
  • What are the results?
  • Will the results help in caring for my patient?

This tutorial will focus on the first question: are the results of the study valid? The issue of validity speaks to the "truthfulness" of the information. The validity criteria should be applied before an extensive analysis of the study data. If the study is not valid, the data may not be useful.

The evidence that supports the validity or truthfulness of the information is found primarily in the study methodology. Here is where the investigators address the issue of bias, both conscious and unconscious. Study methodologies such as randomization, blinding and accounting for all patients help insure that the study results are not overly influenced by the investigators or the patients.

Evaluating the medical literature is a complex undertaking. This session will provide you with some basic criteria and information to consider when trying to decide if the study methodology is sound. You will find that the answers to the questions of validity may not always be clearly stated in the article and that clinicians will have to make their own judgments about the importance of each question.

Once you have determined that the study methodology is valid, you must examine the results and their applicability to the patient. Clinicians may have additional concerns such as whether the study represented patients similar to his/her patients, whether the study covered the aspect of the problem that is most important to the patient, or whether the study suggested a clear and useful plan of action.

Note: The questions that we used to test the validity of the evidence are adapted from work done at McMaster University. See the References/Glossary unit: 'Users' Guides to the Medical Literature.'

Read the following article to determine if the article meets the criteria for validity.

Massie BM, Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Dec 4;359(23):2456-67. PubMed PMID: 19001508. You can view a copy of the article that is marked to show you where the validity information is found.

Are the results valid?

These questions address the issues of validity and the methodology of the study:

Did intervention and control groups start with the same prognosis?

1. Were patients randomized?

The assignment of patients to either group (treatment or control) must be done by a random allocation. This might include a coin toss (heads to treatment/tails to control) or use of randomization tables, often computer generated.

Research has shown that random allocation comes closest to insuring the creation of groups of patients who will be similar in their risk of the events you hope to prevent. Randomization balances the groups for known prognostic factors (such as age, weight, gender, etc.) and unknown prognostic factors (such as compliance, genetics, socioeconomics, etc.).  This reduces the chance of over-representation of any one characteristic within the study groups.

More information: Treatment allocation in controlled trials: why randomise? Douglas G Altman & J Martin Bland BMJ 1999;318:1209-1209 (1 May)

Massie article: Study procedures: Eligible patients were treated with single-blind placebo for 1 to 2 weeks before randomization; those who successfully completed this run-in phase and whose condition remained clinically stable were randomly assigned in a 1:1 ratio to receive irbesartan or matching placebo. The randomization schedule was implemented with the use of an interactive voice-response system. [page 2457]

2. Was group allocation concealed?

The randomization sequence should also be concealed from the clinicians and researchers of the study to further eliminate conscious or unconscious selection bias. Concealment (part of the enrollment process) ensures that the researchers cannot predict or change the assignments of patients to treatment groups. If allocation is not concealed it may be possible to influence the outcome (consciously or unconsciously) by changing the enrollment order or the order of treatment which has been randomly assigned. Concealed allocation can be done by using a remote call center for enrolling patients or the use of opaque envelopes with assignments.  This is different from blinding which happens AFTER randomization.

More information: Concealing treatment allocation in randomised trials Douglas G Altman & Kenneth F Schulz BMJ 2001;323:446-447 (25 August)

Massie article: Study procedures: The randomization schedule was implemented with the use of an interactive voice-response system. [Page 2457] This methodology would conceal the randomized allocation scheme.

3. Were patients in the study groups similar with respect to known prognostic variables?

The treatment and the control group should be similar for all prognostic characteristics except whether or not they received the experimental treatment. This information is usually displayed in Table 1, which outlines the baseline characteristics of both groups.  This is a good way to verify that randomization resulted in similar groups.

Massie article: Table 1: The study groups did not differ significantly in baseline characteristics. [Page 2460]

Was prognostic balance maintained as the study progressed?

4. To what extent was the study blinded?

Blinding means that the people involved in the study do not know which treatments were given to which patients. Patients, researchers, data collectors and others involved in the study should not know which treatment is being administered. This eliminates bias and preconceived notions as to how the treatments should be working. When it is difficult or even unethical to blind patients to a treatment, especially a surgical treatment, then a "blinded" clinician or researcher is needed to interpret the results.

More information: Blinding in clinical trials and other studies Simon J Day & Douglas G Altman BMJ 2000;321:504 (19 August)

Massie article:  Patients were blinded using a matched placebo. All investigators and committee members who were involved in the conduct of the study (except for members of the data and safety monitoring board) were unaware of study-group assignments. Data analysts were blinded.  The sponsors or a contract research organization collected the trial data, which were then analyzed at the Statistical Data Analysis Center at the University of Wisconsin, Madison, independently of the sponsors and according to a predefined statistical analysis plan. Adjudicators were blinded. Deaths and hospitalizations were adjudicated by members of an independent end-point committee who were unaware of study-group assignments and used pre specified criteria. [Page 2458]

Were the groups prognostically balanced at the study's completion?

5. Was follow-up complete?

The study should begin and end with the same number of patients in each group. Patients lost to the study must be accounted for or risk making the conclusions invalid. Patients may drop out because of the adverse effects of the therapy being tested. If not accounted for, this can lead to conclusions that may be overly confident in the efficacy of the therapy.  Good studies will have better than 80% follow-up for their patients. When there is a large loss to follow-up, the lost patients should be assigned to the "worst-case" outcomes and the results recalculated. If these results still support the original conclusion of the study then the loss may be acceptable.

Massie Article: The mean follow-up time was 49.5 months, and the trial included 16,798 patient-years of follow-up. At the end of the study, vital-status data were not available for 29 patients (1%) in the irbesartan group and 44 patients (2%) in the placebo group. [Page 2459]

6. Were patients analyzed in the groups to which they were first allocated?

Anything that happens after randomization can affect the chances that a patient in a study has an event. Patients who forget or refuse their treatment should not be eliminated from the study results or allowed to “change groups”. Excluding noncompliant patients from a study group may leave only those that may be more likely to have a positive outcome, thus compromising the unbiased comparison that we got from the process of randomization. Therefore all patients must be analyzed within their assigned group. Randomization must be preserved.  This is called "intention to treat" analysis.

More information: The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study. Nüesch E. et al. BMJ. 2009 Sep 7;339:b3244

Massie article:   Statistical analysis: Data from all patients who underwent randomization were analyzed according to the intention-to-treat principle. [Page 2458]  In addition, Table 2 shows results for primary outcomes that includes all patients in the trial. [Page 2463]

7. Was the trial stopped early?

Stopping a trial early may provide an incomplete picture of the real effect of an intervention.  Trials ended early may compromise randomization if they stop at a “random high” when prognostic factors may temporarily favor the intervention group.  When study size and the number of events are small, stopping early may overestimate the treatment effective.

Massie article:  The study was not stopped early.

Are the results of this study valid?

Yes. This study methodology appears to be sound and the results should be valid.

Key validity issues for studies of Therapy:

  • randomization 
  • concealed allocation
  • baseline similarities
  • blinding
  • follow-up complete
  • intention-to-treat

Guyatt, G. Rennie, D. Meade, MO, Cook, DJ.  Users' Guide to Medical Literature: A Manual for Evidence-Based Clinical Practice, 2nd Edition 2008.

Next - Step 2: What are the results?

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Revised July 2010