HESC 401 Epidemiology

Randomized Trials: Some Further Issues

HESC 401 Epidemiology

Objectives

� Describe and be able to calculate efficacy

� Identify and describe three major U.S. randomized trials

� Describe the four phases in testing of new drugs in the U.S.

� Explain ethical issues in relation to randomized trials

� Describe publication bias, factors that contribute towards it, and the outcome that resulted from it

Sample Size � One of the most important issues in any type of study

design is sample size, meaning, “How many subjects do we have to study?”

� This term, sample size, is used often when there are issues with why no association was found between an exposure and outcome.

� This question should be answered before large amounts of money and resources are invested. Only after the study has been completed do investigators realize that they had too few participants at the beginning of the study to obtain meaningful results.

Sample Size

This question of sample size or how many subjects should we include should be answered before large amounts of money and resources are invested. Only after the study has been completed do investigators realize that they had too few participants at the beginning of the study to obtain meaningful results.

Expressing the Results of Randomized

Trials � The risks of death or of developing a disease in each group

can be calculated, and the reduction in risk (efficacy) can then be calculated.

� Efficacy can be expressed in terms of the rates of developing disease in the vaccine and placebo groups.

� Efficacy =(Rate in those who received placebo) – (Rate in those who received _________________ the vaccine)

Rate in those who received the placebo

This tells us the extent of the reduction in disease by use of the vaccine. Risks are often calculated per person-years of observation.

Generalizability of Results

� We reviewed this concept in the previous chapter, but it is an important one. When a trial is carried out, the ultimate objective is to generalize the findings beyond the study population to the general population.

� Two different concepts: internal validity and external validity. This is depicted on the next slide in Figure 8- 8.

Figure 8-8. The external validity of trial is whether the results we found in the trial “apply” or can be generalized to the entire population.

Examples of randomized trials

� The following slides until slide 19 provide examples of three famous randomized trials. There are many others, but these over view RCT’s well.

� 1. The Hypertension Detection and Follow-up Program � 2. The Multiple Risk Factor Intervention Trial

� 3. Study of Breast Cancer Prevention Using Tamoxifen

The Hypertension Detection and

Follow-up Program

� This was a Veteran’s Administration study that demonstrated that treating people who have large increases in blood pressure can reduce their mortality.

� The multicenter Hypertension Detection and Follow- up Program study was designed to investigate the benefits of treating mild to moderate hypertension.

The Hypertension Detection and

Follow-up Program (cont’d)

� Out of 22,994 eligible subjects, 10,940 subjects were randomized either to the stepped care or the referred care group.

� Stepped care- treatment according to a defined protocol in which treatment was changed when a specific decrease in blood pressure did not occur during a certain period of time.

� Referred care- subjects were referred back to their own physicians.

� Mortality was then studied over a 5-year period in both groups.

© 2005 Elsevier

Figure 8-9, from the text showing , the design of the Hypertension Detection and Follow-up Program.

The Hypertension Detection and

Follow-up Program (cont’d)

� Figure 8-10 on the next slide shows that the patients in the stepped care group had lower mortality than those in the referred care group.

Figure 8-10: At every interval during the 5-year follow-up, the stepped care group had lower mortality than the referred care group. The way this curve is represented is interesting because instead of showing % survival on the Y axis, they have shown % mortality, but the interpretation is similar to the survival curves we reviewed.

The Multiple Risk Factor

Intervention Trial

� The MRFIT was a randomized study designed to determine whether mortality from myocardial infarction could be reduced by lifestyle changes and other measures.

� There were two groups: the special intervention group (SI) and the usual care group (UC).

The Multiple Risk Factor Intervention

Trial (cont’d)

� The SI group received stepped care for hypertension and intensive education and counseling about lifestyle changes.

� The UC group received the usual care provided in the community.

� Figure 8-11 on the next slide shows that over an average follow-up period of 7 years, levels of coronary heart disease risk factors decreased more in SI men than in UC men.

Figure 8-11. Lower rates of coronary heart disease risk factors in SI men than UC men.

The Multiple Risk Factor

Intervention Trial (cont’d)

� At the end of the study, however, no statistically significant differences were found between the groups.

Study of Breast Cancer Prevention

Using Tamoxifen

� According to Gordis, “The observation that women treated with, tamoxifen for breast cancer had a lower incidence of cancer in the other breast suggested that tamoxifen might have value in preventing breast cancer.”

� The randomized trial started in 1992.

� By 1997, 13,388 women 35 years of age or older had been enrolled.

� They were randomly assigned to either receive a placebo or 20 mg of tamoxifen per day for 5 years.

Phases in Testing of New Drugs in

the United States � Phase I studies are clinical pharmacologic studies-

small studies of 20 to 80 patients that look at toxicity and pharmacologic effects.

� After the drugs pass Phase I, they pass to Phase II. Phase II studies are clinical investigations of 100-200 patients for efficacy and relative safety.

� Phase III studies are large-scale randomized controlled trials for effectiveness and relative safety, which are often multi-centered.

� As simple as each phase may sound, it could take up to 10 years to even complete one phase and millions of dollars.

Phases in Testing of New Drugs

in the United States (cont’d)

� Once a drug passes Phase III testing, then it can be licensed for marketing.

� However, certain adverse effects of drugs that may not be evident in large clinical trials may become evident only when the drugs is in use by large populations.

� Therefore, Phase IV studies, or post-marketing surveillance, are important for monitoring new agents as they come into general use by the public.

Is Randomization Ethical?

� We reviewed this concept briefly in chapter 7.

� Randomization is ethical only when we do not know whether drug A is better than drug B.

� We are not sure at what point we “know” that one drug is better than the other.

� It is better to know when we have actual adequate evidence to support the conclusion that drug A is better than drug B.

� Another question posed is whether it is ethical to use a placebo.

Registration of Clinical Trials

� Not all results of clinical trials are published.

� This can pose a problem when the results from all published clinical trials are reviewed.

� Example: Clinical trials of a new drug are reviewed, but only those that show beneficial results are published. Those showing negative results that were not published will have an erroneous effect because not ALL studies of the drug have shown a clear benefit. This is called publication bias or non- publication bias.

Registration of Clinical Trials

(cont’d)

� Factors that account for publication bias:

� 1) Journals want to publish results from studies showing dramatic effects rather than results from studies showing no benefit at all from a new drug.

� 2) Companies that develop new drugs and fund studies of these drugs frequently want to keep the results unpublished when they show no benefits, show serious side effects, or when the drug is shown to be less effective than current drugs.

Registration of Clinical Trials

(cont’d)

� This selective reporting of clinical trials was a major risk to public health.

� This led the International Committee of Medical Journal Editors to adopt a policy, which became effective in 2005.

� The policy stated is that ALL clinical trials of medical interventions must be registered in a public trials registry before any participants are enrolled in the study.

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