Developing a Clinical Research Protocol:  The Survival Guide

Opportunities are available for you to pursue a thesis project in either basic or clinical research. Clinical research is less completely "controllable," and is therefore more subject to potential confounders and sources of bias. However, clinical research offers the advantage of more direct clinical relevance. Whatever topic you choose, you can likely find a qualified advisor in the medical school. But an advisor knowledgeable in your area of interest may or may not have a strong background in research methods. On the chance that they do not, you should be prepared to follow a systematic process in the development of your project to be sure the results are what you intend.

Be advised that data do not make a thesis. Without an excellent hypothesis, defined outcome measure(s), and good methodology, collected data cannot lead to meaningful insights. Above all, a good thesis depends on an excellent hypothesis. It is more than coincidence that a “thesis” is derived from the underlying “hypo-thesis.”

The following sequence is recommended for the development of a clinical research or epidemiology thesis project. Don’t wait for your advisor to bring up each component; they may never do so. You should be assertive in addressing the following items before you begin the actual research. If you and your advisor are uncertain about or want help with any of the steps below, there are experts in methodology available for consultation (See section on Secondary Thesis Advisors). Be sure to obtain such a consult early. There is little that methods can offer once the data have been collected.

1. Start with a good question. In general, “good” or “excellent” is best defined as a question for which the answer matters either to other researchers in the field, practicing clinicians, or patients. Remember, you will likely do just as much work to answer a question which has “below average” interest to others as you will in answering a question which others will call important.
2. Convert the question to a hypothesis by asserting a position. This will lead directly to a consideration of measures, both of exposure and outcome.
3. Generate measures of exposure and outcome. This step is facilitated by a review of the pertinent literature. How have other researchers defined/measured the exposure and/or outcome? The effort to generate meaningful measures will generally require a return to the hypothesis for refinement, and narrowing (i.e., express the hypothesis in terms of the specific exposure of interest, and the specific outcome anticipated).
4. Once a reasonable hypothesis developed, a protocol should be constructed. How can the hypothesis be tested? The first requirement is that a comparison be made. Here, too, a search of the literature for methods will be helpful. Choosing the right control group is challenging, and subtle. Once the comparison group is chosen, the magnitude of expected difference should be estimated, as a basis for determining sample size (power calculation). In clinical research, standard methods include cohort studies (prospective, or retrospective; the randomized controlled clinical trial is a sub-category of the prospective cohort study) that assemble groups on the basis of exposure/intervention, and follow for outcome; and case-control studies that assemble groups on the basis of the outcome and assess for previous exposures. We urge you to use one of the three.
5. In light of the design you deem most appropriate, revise your measures of exposure and outcome as required. For example, in a prospective study, you can choose how to measure factors of interest, whereas in a retrospective study you will need to rely on measures obtained in the past, or the subjects’ recall.
6. Once your measures are established, determine the appropriate sample size and the methods of analysis. A plan for data collection and management should also be developed. Consultation with a statistician may be helpful at this stage. Now is the time to assess feasibility. Specifically, the following questions should be addressed: Can enough people be obtained for the study? Can the outcome events be observed and suitably analyzed?
7. The research should only begin after steps 1-6 are dealt with successfully. Again, there are no methods that can transform a vague question and data into a methodologically rigorous study after the fact. Good methods must come first.

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