Primary Question and Hypothesis Testing in Randomized Controlled Clinical Trials

By Luo, Jiangtao | General Psychiatry, June 2016 | Go to article overview

Primary Question and Hypothesis Testing in Randomized Controlled Clinical Trials


Luo, Jiangtao, General Psychiatry


Summary: We briefly reviewed and provided cautions about some of the fundamental concepts used in the design of medical and public studies, especially primary question, hypothesis testing and sample size in this short note. We also talked about some of the extensions and development in the recent years.

Keywords: hypothesis, randomize, clinical trial, primary question

[Shanghai Arch Psychiatry. 2016; 28(3): 177-180.

1. Primary and secondary questions

Medical research is always about answering scientific questions related to treatments or preventions of diseases in special population of patients, who are defined by inclusion and exclusion criteria and treatments or preventions are performed among them. These questions are often divided into primary and secondary questions. Usually we have only one primary question in a study and it is the key and central question that we want to answer. We should state our primary question in advance rather than define it during our trial process later. Our study should be designed to answer the primary question and our sample size calculation should be based on it. It is unacceptable if a proposal lacks clear statement about primary question. Some research questions are important in public health and clinical practice, but we cannot answer them all due to limited technology and resources. So answerable is another criterion in choosing primary question. Therefore, at the design stage we must choose a primary question that we are able to answer via clinical trials. For example, in a study on 'Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia' [1], the primary question is to find the treatment difference between ibrutinib and chlorambucil for 'previously untreated older patients with CLL or small lymphocytic lymphoma'. All the other research questions are secondary.

Secondary questions are closely related to the primary question. A study may have several secondary questions, which must be stated in advance or at design stage. We do not recommend mining data after the trial although data mining has become increasingly important in other settings. The number of secondary questions should be limited as well. Otherwise we may not have sufficient power to answer truly important questions and effectively control false positive rate. In Physicians' Health Study [2], the primary question is total mortality rate between aspirin and placebo groups. The secondary question is fatal and nonfatal myocardial infarction.

Once the primary question has been determined, the next step is to define the primary outcome that is used to describe the primary question. We must pay special attention to primary outcome and it must be evaluated in each of all study participants in the same way. Also the evaluation must be unbiased. Our recommendation is to use double blind, hard endpoint, and independent assessment. All study participants should have primary outcomes when the study ends [3, 4].

2. Hypothesis testing

The methods for answering scientific questions from data collected in clinical trials belong to statistical inference. An important part of statistical inference is hypothesis testing, the foundation of which was laid by Fisher, Neyman, and Pearson among others [5]. Hypotheses consist of null hypothesis ([H.sub.0]) and alternative hypothesis ([H.sub.1]). The [H.sub.1] is our scientific hypothesis, which is what we want to collect data for. To test if [H.sub.1] is true, we start from [H.sub.0], our straw man, since we usually already know from our pilot data, animal model or other approaches that [H.sub.1] is true. So we assume that [H.sub.0] is true and show that the probability that the observed data satisfies the null [H.sub.0] is very small (<0.05, usually). Thus, the null [H.sub.0] is opposite to the scientific hypothesis, the alternative [H.sub.1], such as [H.sub.0]: cure rate for the standard therapy is equivalent to that for the experimental intervention vs. …

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