Hss4303b- intro to epidemiology

March 11, 2010 – Clinical Trials

But first

• Your “intent to submit” poster assignment is due today at midnight

• Submitting it on time is part of the poster mark

The Poster Event

Tips for your poster

• It’s like a regular paper, but visually presented• Be specific and answer the question that you ask• Poster presentation is not a science fair, it’s a

collaborative scientific communication exercise -> impress with rigour and honesty, not flash

• Be specific and focused• Everyone will have the same method (literature

review), but be specific about that, too

Overall Marking Scheme

Apr 29MNT gym

However…

• Because there was a screw-up, I will let each of you choose whether you want– 25% midterm and 40% final– 20% midterm and 45% final

• We will do it via online poll, starting tonight and ending next week– If you do not respond, you will receive the default

scheme of 25% midterm and 40% final

How It All Begins

• An idea or observation

• An hypothesis• A research question• Data source• A design• A project!

Say… all the pygmies with Doofus disease I’ve met were all Left-handed!

Maybe left-handed pygmies are more likely to have doofus disease!

What is the prevalence of doofus disease among left- and right-handed pygmies in the valley of Deonandia?

Patient records from the 3 main doofus disease clinics in Greater DeonandiaCross-sectional

cohort design

Statement of the research question• The research question is the statement of the hypothesis and helps to

determine the important parameters or objectives of the study• The parameters or the objectives will provide the answer to the research

question• For example: is intensive therapy, including more frequent injections of

insulin and more frequent monitoring of blood glucose levels, “superior” to standard therapy for diabetes mellitus?

• The possible outcome measures include:– The percentage of patients surviving at a specified time following the initiation

of treatment– A patient’s ability to maintain an active lifestyle– The risk of having a major complication from treatment– The risk of experiencing one of the vascular events associated with diabetes

mellitus– Measurement of hemoglobin which is an indicator of long-term blood glucose

levels– Blood glucose levels at specified points in time

Research Question

• Something that is answerable with a well structured study

• http://www.health.qld.gov.au/ph/Documents/pdu/23393.pdf

• Often we confuse research question with research hypothesis

Research topic: Physical activity and cardiovascular diseaseResearch problem: Is there a link between lack of physical activity

and hypertension?Research question: Will 30 minutes of moderate activity daily

reduce hypertension in office workers?Hypothesis: Thirty minutes of moderate activity daily

in sedentary Queensland Health workers will reduce the median systolic blood pressure by 10mm mercury.

Poster Example• Topic

– Autism and diet• Question

– Is eating cheese within the first few years of life associated with having autism among Ontario boys?

• Method– Literature review of peer-reviewed studies published in English since 1990– Keywords: autism, cheese, diet, male, boys, children

• Results– 15 studies identified, 12 of which were reviewed– 7 found positive association between cheese eating and autism– 5 found no association

• Conclusions/Recommendations– Some evidence for a positive association between cheese eating and autism– Experimental design is recommended to confirm suspicion of causality

Poster Example• Topic

– Autism and diet• Question

– Is eating cheese within the first few years of life associated with having autism among Ontario boys?

• Method– Literature review of peer-reviewed studies published in English since 1990– Keywords: autism, cheese, diet, male, boys, children

• Results– 15 studies identified, 12 of which were reviewed– 7 found positive association between cheese eating and autism– 5 found no association

• Conclusions/Recommendations– Some evidence for a positive association between cheese eating and autism– Experimental design is recommended to confirm suspicion of causality

Null hypothesis• Null hypothesis: the percentage of persons in the standard therapy who

develop diabetic retinopathy during a 5 year period = the percentage of persons in the intensive therapy who develop diabetic retinopathy during a comparable period

• The null hypothesis is stated in the null form: there is no difference between the treatment groups regarding the specified end points

• The purpose of the clinical trial or the study is to test whether the observed outcomes are consistent with the null hypothesis.

• If the observed data are not consistent with the null hypothesis, the null hypothesis is rejected in favor of an alternative hypothesis

• Alternative hypothesis states that there is a difference in the percentage of persons in the standard and intensive therapies who develop diabetic retinopathy

• A number of other end points can be selected that are of interest to the study

Null hypothesis• ________________________

– H0 : π0 = π1 where H0 is the null hypothesis and π0 and π1 are percentages of persons in standard and intensive therapies

– H0: μ0 = μ1 where H0 is the null statement and μ0 and μ1 are the mean values of a biomarker of outcome measurement

• The purpose of the study is to test whether the observed outcomes are consistent with the null statement and to either support or reject the null statement– H0 : π0 ≠ π1

– H0: μ0 ≠ μ1

The next logical topic is…

• Sample size calculations and Type I and Type II error

• But I’ve arranged for a special guest to come speak about that, so you’ll have to wait:– Dr Nick Barrowman– March 29

Randomized trials• Randomizations are study designs that can be used for

evaluating new approaches to treatment and prevention• Randomized trials can be used in clinical setting or community

setting and refer to treatments and drugs• Randomized trials are used:

– To evaluate new drugs and other treatments of disease– To assess new programs for screening and early detection– To determine new ways of organizing and delivering health care

Randomized trial

• Identify a population• Randomize to receive treatment or observe

behaviour• Follow the randomized group during the study

period. Possible groups (or arms):– Controls with no exposure– Current treatment– New treatment

• Compare the randomized groups

The Randomized Control/Clinical Trial

Study population

randomization

Study group A(get the treatment)

Study group B(get the placebo)

Why do we randomize?Why do we blind?

Randomized trials are primarily used to test efficacy ofnew treatment regimes or new drug therapies

The Randomized Control/Clinical Trial

The RCT is considered the only undeniable method of determining causality. The “gold standard”

Advantages:-extraneous variables are well controlled-temporal relationship is well established-if blinded, conclusions are difficult to argue with

Disadvantages:-cost-doesn’t represent “real world”-ethics

Random assignment

• Each participant has equal chance of being assigned to any group

• Does not presume that each participant in every group is the same

• Unfortunately, does not guarantee equivalence

If people change groups…

• Problems for analysis:– Eliminate participants who change, will reduce

sample size and introduce bias in sample of those who remain

– Analyze according to treatment received (on-protocol analysis), bias in favour of treatment effect

Usually called “per protocol” analysis

Intention to treat

• Principle whereby data are analyzed according to group assignment (the way we intended to treat patients), regardless of how patients were actually treated

“If you randomize, you analyze”… Superior

Control groups

• Use of is most effective strategy for ruling out effects of extraneous variables

• May receive standard intervention, placebo, no intervention

• To draw valid comparisons, must assume reasonable equivalency between experimental and control group

This is why we randomize

Unplanned trial• Ambrose Paré (1510-1590)

– A surgeon during the renaissance period

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.

Planned trial

• James Lind 1747 the story of ‘limeys’

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.

Allocations of subjects to treatment groups (1)

• Case studies (__________________________)– No comparison between treated and untreated

One day when I was a junior medical student, a very important Boston surgeon visited the school and delivered a great treatise on a large number of patients who had undergone successful operations for vascular reconstruction. At the end of the lecture, a young student at the back of the room timidly asked, "Do you have any controls?" Well, the great surgeon drew himself up to his full height, hit the desk, and said, "Do you mean did I not operate on half of the patients?" The hall grew very quiet then. The voice at the back of the room very hesitantly replied, "Yes, that's what I had in mind." Then the visitor's fist really came down as he thundered, "Of course not. That would have doomed half of them to their death." God, it was quiet then, and one could scarcely hear the small voice ask, "Which half?" Dr. E. E. Peacock, Jr

Allocations of subjects to treatment groups (2)

• Case-control studies (________________________)– Historical controls: the control group is selected from past

records of disease treatment• Difference in time and the purpose of the medical record• Ancillary conditions (lifestyle and behaviour) between then and

now• Environmental and other changes including procedural changes

– Historical design is relevant when the disease fatality rates are high and cause of death is not associated with other relevant factors

Simultaneous non-random controls

A sea captain was given samples of anti-nausea pills to test during a voyage. The need for controls was carefully explained to him. Upon return of the ship, the captain reported the results enthusiastically. "Practically every one of the controls was ill, and not one of the subjects had any trouble. Really wonderful stuff." A skeptic asked how he had chosen the controls and the subjects. "Oh, I gave the stuff to my seamen and used the passengers as controls."

What are the problems if any with the selection of controls?

– Simultaneous nonrandomized controls: select controls in a nonrandomized manner

• Selection of control based on the days of admission, or the order of admission

• Such a criteria is nonrandom because of the ability to predict the next control

• The goal of randomization is to eliminate the possibility that the investigator will know what the assignment of the next patient would be

• BCG vaccination against tuberculosis in New York City

Results of a trial of BCG vaccine (day of admission)Table 7-1. Results of a Trial of Bacillus Calmette-Guérin Vaccination: I

    Tuberculosis Deaths

  No. of Children No. %

Vaccinated 445 3 0.67

Controls 545 18 3.30

All children were included i.e. those who responded to the invitation to participate in the studyThere was a bias in the sample

• Randomization procedures– Balance– Bias

• Selection bias• Accidental bias

• Methods of randomization:– Coin tossing to determine the next subject– Permuted block randomization– Table of random numbers– Urn randomization– Covariate adaptive– Outcome adaptive– Allocation concealment

• Sequentially numbered opaque sealed envelopes• Sequentially numbered containers• Centrally controlled

Blinding

• Techniques to reduce experimental bias by keeping the participants and/or investigators ignorant of group assignments and research hypotheses– If both, called double blinding

Blinding

• To blind participants, must offer placebo condition– Often not possible; therefore blind investigator

and measurement team• Single-blind study

• As assessments become more subjective, need for blinding increases

Biases

• There are alllllll sorts of biases possible in RCTs

Two Types of RCT Bias

• Hawthorne Effect– Tendency for people to try harder just ‘cause

they’re being watched

• Rosenthal Effect– Tendency for experimenter to affect the

experiment by giving unintentional (often non-verbal) cues to subjects

Two Types of RCT Bias

• Hawthorne Effect– Coined by Landsberger in 1955 at Hawthorne

Works (workers more productive in light)

• Rosenthal Effect– Also called Pygmalion effect (form of self-fulfilling

prophecy)

Placebo

• “I please”– Term first used in medicine in 1785

• Tension with Hippocratic Oath• What is placebo effect?• Sometimes called “physiological effect

produced by placebo”. Why?• How is it relevant for some alternative

therapies like homeopathy?

The Paradox of the PlaceboBy Deonandan and Barrowman BMJ 16 June 2004

While the proposal by Fergusson et al (1), regarding post hoc assessment of the success of blinding in RCTs, is problematic, it does suggest an intriguing dimension of the so-called placebo effect. If the intervention being studied in the RCT is truly more efficacious than placebo, then, as noted in several of the response letters (2,3,4), blinding can be invalidated through patients correctly guessing their allocation by gauging their individual responses to treatment (leaving aside the issue of side effects). In such a scenario, improvement due to the treatment intervention is perhaps compounded by further improvement brought on through the expectation of improvement, once blinding has been effectively broken.

This effect might be most pertinent in trials of depression drugs, where continuous subjectively-assessed outcomes are typically used and where placebo effects may therefore occur (5). A patient randomized to receive the drug begins to feel better, correctly guesses his or her allocation, then possibly benefits further from the very expectation of improvement. In short, the positive effects of expectation might be more pronounced in the treatment group and less pronounced in the placebo group.

The individual assessing outcomes might be similarly affected, since he or she might also correctly guess the patient's allocation. In studies with serial assessments, future assessments could then be biased.

For treatments that show dramatic results, RCTs may overestimate the actual size of the treatment effect relative to placebo. It may then be more appropriate to speak of testing the whole treatment experience, rather than purporting to test the specific effectiveness of the intervention alone.

http://w

ww

.bmj.com

/cgi/eletters/bm

j.37952.631667.EEv1#62926

The CONSORT Statement

• Proposed by David Moher of CHEO

The CONSORT Statement comprises a 22-item checklist and a flow diagram, along with some brief descriptive text. The checklist items focus on reporting how the trial was designed, analyzed, and interpreted; the flow diagram displays the progress of all participants through the trial.

The CONSORT Statement

• Diagram:

• http://www.consort-statement.org/consort-statement/flow-diagram/

• Enrollment, Allocation, Follow-up and Analysis

The CONSORT Statement• Degree of random allocation• Rationale• Sample size• Outcome measures• Stopping rules• Statistical analysis methods• Baseline characteristics• Adverse events• generalizability

Some key com

ponents

Jadad Score

• Defined by Alejandro Jadad-Bechara in 1996• Jadad: “[RCT] is one of the simplest, most

powerful and revolutionary forms of research”1.Was the study described as randomized?2.Was the study described as double blind?3.Was there a description of withdrawals and

dropouts?

An RCT paper receives a Jadad score of 0 to 5

Criticisms of Jadad Score

• Too simplistic• Too much reliance on blinding

Then why are Jadad and CONSORT so important?

Cochrane Collaboration

• The Cochrane Collaboration is a group of over 10,000 volunteers in more than 90 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies. The results of these systematic reviews are published as "Cochrane Reviews" in the Cochrane Library.

– Wikipedia

Cochrane Collaboration

• Founded by Iain Chalmers in 1993– Minimize bias– Provide and maintain best evidence via systematic

reviews– Heavy reliance on RCTs– EBM is at its heart

www.cochrane.org