Randomized Controlled Trials. Mahasti Alizadeh MD,MPH

Transcription

1 Randomized Controlled Trials Mahasti Alizadeh MD,MPH

2 Outline Case studies Study design Selection the subjects Intervention and comparison groups Allocation Blinding Outcome Interpretation of results Ethical issues CONSORT checklist 12/8/2015 M.Alizadeh MD,MPH 2

3 Case study Ambroise Paré ( ), Paré lived at a time when the standard treatment for war wounds was the application of boiling oil. 12/8/2015 M.Alizadeh MD,MPH 3

4 At length my oil lacked and I was constrained to apply in its place a digestive made of yolks of eggs, oil of roses and turpentine. That night I could not sleep at my ease, fearing that by lack of cauterization I would find the wounded upon which I had not used the said oil, dead from the poison. I raised myself early to visit them, when beyond my hope I found those to whom I had applied the digestive medicament feeling but little pain, their wounds neither swollen nor inflamed, and having slept through the night. The others to whom I had applied the boiling oil were feverish with much pain and swelling about their wounds. Then I determined never again to burn thus so cruelly the poor wounded. Unplanned Trial 12/8/2015 M.Alizadeh MD,MPH 4

5 A planned trial was described by the Scottish surgeon James Lind in Lind became interested in scurvy, which killed thousands of British seamen each year. 12/8/2015 M.Alizadeh MD,MPH 5

6 I took 12 patients in the scurvy on board the Salisbury at sea. The cases were as similar as I could have them they lay together in one place and had one diet common to them all. Two of these were ordered a quart of cider per day Two others took 25 gutts of elixir vitriol Two others took two spoonfuls of vinegar Two were put under a course of sea water Two others had two oranges and one lemon given them each day Two others took the bigness of nutmeg. The most sudden and visible good effects were perceived from the use of oranges and lemons, one of those who had taken them being at the end of 6 days fit for duty The other was appointed nurse to the rest of the sick. 12/8/2015 M.Alizadeh MD,MPH 6

7 Uses of randomized trials Evaluating new drugs and other treatments of disease, including tests of new health and medical care technology. Trials can also be used to assess new programs for screening and early detection, or new ways of organizing and delivering health services. 12/8/2015 M.Alizadeh MD,MPH 7

8 Design 12/8/2015 M.Alizadeh MD,MPH 8

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10 Using randomization, the patients are then divided into two (or more) groups of comparable prognosis. One group, called the experimental group, is exposed to an intervention that is believed to be better than current alternatives. The other group, called a control (or comparison) group, is treated the same in all ways except that its members are not exposed to the experimental intervention. Patients in the control group may receive a placebo, usual care, or the current best available treatment. The course of disease is then recorded in both groups, and differences in outcome are attributed to the intervention. 12/8/2015 M.Alizadeh MD,MPH 10

11 Sampling External Validity Internal Validity 12/8/2015 M.Alizadeh MD,MPH 11

12 Inclusion criteria Among the usual inclusion criteria is that : Patients really do have the condition being studied. To be on the safe side Study patients must meet strict diagnostic criteria. Patients with unusual, mild, or equivocal manifestations of disease may be left out in the process: restricting generalizability. 12/8/2015 M.Alizadeh MD,MPH 12

13 Exclusion criteria Patients with comorbidity (diseases other than the one being studied) Patients are excluded if they are not expected to live long enough to experience the outcome events of interest. 3. Patients with contraindications to one of the treatments cannot be randomized. 4. Patients who refuse to participate in a trial are 5. Patients who do not cooperate during the early stages of the trial are also excluded. This avoids wasted effort and the reduction in internal validity that occurs when patients do not take their assigned intervention, move in and out of treatment groups, or leave the trial altogether. 12/8/2015 M.Alizadeh MD,MPH 13

14 Random allocation 12/8/2015 M.Alizadeh MD,MPH 14

15 Main purpose of randomization The main purpose of randomization is to prevent any potential biases on the part of the investigators from influencing the assignment of participants to different treatment groups. When participants are randomly assigned to different treatment groups, all decisions on treatment assignment are removed from control of the investigators. Thus, the use of randomization is crucial to protect the study from any biases that might be introduced consciously or subconsciously by the investigator into the assignment process. Another benefit of randomization is that to whatever extent it contributes to comparability, this contribution applies both to variables we can measure and to variables that we cannot measure and may not even be aware of, even though they may be important in interpreting the findings of the trial. 12/8/2015 M.Alizadeh MD,MPH 15

16 Allocating treatment Table of baseline characteristics 12/8/2015 M.Alizadeh MD,MPH 16

17 It is reassuring to see that important prognostic variables are nearly equally distributed in the groups being compared. If the groups are substantially different in a large trial, it suggests that something has gone wrong with the randomization process. Smaller differences, which are expected because of chance, can be controlled for during data analyses 12/8/2015 M.Alizadeh MD,MPH 17

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19 Intervention Generalizability Complexity (normal complexity of real world treatment) Strength 12/8/2015 M.Alizadeh MD,MPH 19

20 Comparison No intervention Usual care Placebo Another intervention 12/8/2015 M.Alizadeh MD,MPH 20

21 Blinding 12/8/2015 M.Alizadeh MD,MPH 21

22 Blinding Single blind Double blind Triple blind Allocation Concealment 12/8/2015 M.Alizadeh MD,MPH 22

23 A trial in which there is no attempt at blinding is called an open trial or, in the case of drug trials, an open label trial. 12/8/2015 M.Alizadeh MD,MPH 23

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25 Outcome Clinical trials may have as their primary outcome a composite outcome, a set of outcomes that are related to each other but are treated as a single outcome variable. For example, in a study of percutaneous repair versus open surgery for mitral regurgitation, the composite outcome was the absence of death, mitral valve surgery, or severe mitral regurgitation 12 months after treatment 12/8/2015 M.Alizadeh MD,MPH 25

26 The disadvantage of composite outcomes is that they can obscure differences in effects for different individual outcomes. In addition, one component may account for most of the result, giving the impression that the intervention affects the others too. All of these disadvantages can be overcome by simply examining effect on each component outcome separately as well as together. 12/8/2015 M.Alizadeh MD,MPH 26

27 In addition to hard outcomes such as survival, remission of disease, and return of function, a trial sometimes measure health-related quality of life by broad, composite measures of health status. 12/8/2015 M.Alizadeh MD,MPH 27

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29 Efficacy and Effectiveness Can treatment help under ideal circumstances? Trials that answer this question are called effcacy trials. Elements of ideal circumstances include patients who accept the interventions offered to them, follow instructions faithfully, get the best possible care, and do not have care for other diseases 12/8/2015 M.Alizadeh MD,MPH 29

30 Second, does treatment help under ordinary circumstances? Trials designed to answer this kind of question are called effectiveness trials. All the usual elements of patient care are part of effectiveness trials. Patients may not take their assigned treatment. Some may drop out of the study, and others find ways to take the treatment they were not assigned. The doctors and facilities may not be the best. In short, effectiveness trials describe results as most patients would experience them. 12/8/2015 M.Alizadeh MD,MPH 30

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32 Intention to treat analysis A related issue is whether the results o fa randomized controlled trial should be analyzed and presented according to the treatment to which the patients were randomized or according to the one they actually received 12/8/2015 M.Alizadeh MD,MPH 32

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34 Interpretation of results 12/8/2015 M.Alizadeh MD,MPH 34

35 CONSORT checklist 12/8/2015 M.Alizadeh MD,MPH 35

36 CONSORT stands for Consolidated Standards of Reporting Trials, encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials (RCTs).

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