Clinical trials hypothesis testing

Clarke R, Collins R. 1998. Can dietary supplements with folic add or vitamin B6 reduce cardiovascular risk Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk 5 249-55. 

All clinical trials should have a pre-specified research question, which may be stated in the form of a primary hypothesis (or possibly a few primary hypotheses). An objective outcome measure or measures should also be clearly identified, such as the results of a biochemical test or the score on a validated scale. This allows statistical tests to be applied in order to assess the likelihood that any differences in response between treatment groups resulted from the active treatment and were not due to chance. 

The objective of clinical trials is to demonstrate the safety and effectiveness of the drug compared to placebo or control. The statistical method normally used is known as hypothesis testing. 

The therapeutic benefits and risks of a medicine, and therefore the choice of treatment for an individual patient, stem from evidence from a series of clinical trials. Taken together, these trials should reflect all likely therapeutic situations. From time to time, a particular problem arises that generates a new hypothesis. In order to obtain an answer to the specific question, we sometimes restrict the population sample to study subjects who do not possess a number of variables that may confound the outcome. In this manner, we move away from the realities of everyday clinical practice to an idealised, but artificial, environment. This is justifiable if the restriction is logical and if, with it, the hypothesis testing can be successfully completed. Otherwise, the issue may never be settled. 

Probiotics are the first compounds tested to treat allergic disease, which are based on the concept of the hygiene hypothesis. The preliminary results have shown that the use of probiotics reduces the risk of the development of atopic eczema however, additional clinical trials are needed before their approval for use in a wider population. Other immunomodulatory compounds derived from bacteria (CpGs), mycobacteria and helminths are also being tested to prevent allergic disease. 

This chapter introduces basic concepts in statistical analysis that are of relevance to describing and analyzing the data that are collected in clinical trials, the hallmark of new drug development. (Statistical analysis in nonclinical studies was addressed earlier in Chapter 4.) This chapter therefore sets the scene for more detailed discussion of the determination of statistical significance via the process of hypothesis testing in Chapter 7, evaluation of clinical significance via the calculation of confidence intervals in Chapter 8, and discussions of adaptive designs and of noninferiority/equivalence trials in Chapter 11. 

The requirement to show statistical significance in therapeutic confirmatory trials places a certain importance on a priori hypothesis testing. However, as we have seen, there is much more to clinical research than p-values. Piantadosi (2005) commented on this issue as follows ... 

Workman, R, et al. (2006) Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. Journal of the National Cancer Institute, 98, 580-598. 

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