7.3 - Other Considerations

Among adult cancer patients in the USA, less than 3% of these patients participate in clinical trials. (Gotay, 1991) Since the process of clinical trials leads to improvements in cancer therapy over time, it would seem that cancer patients would be motivated to participate in increasing numbers over time. But this has not happened. Most diseases, except for AIDS and some pediatric conditions, exhibit similar types of participation rates. The three general reasons for lack of participation are categorized as physician-, patient-, or administrative-related.

The reasons physicians give for failing to enroll patients in clinical trials are the perception that the trial may compromise the physician-patient relationship and the difficulties with informed consent. Many consent forms are cumbersome, intimidating, and not written at an appropriate reading level. The 'experts' say that these documents should be written at an 8th-grade reading level. Using plain language is important. Also, many patients are mistrustful of the medical establishment, although they may trust their individual physicians. Often, ethnic minority groups express even stronger concerns about participation in clinical trials.

There is a distinction between an efficacy trial and an effectiveness trial. In an efficacy trial, the study cohort is relatively homogeneous and the objective is to test a biological question. In an effectiveness trial, the study cohort is relatively heterogeneous and the objective is to assess effectiveness of a treatment. An effectiveness trial tends to be very large and expensive but has much more external validity because of broad eligibility criteria and a heterogeneous population. Most clinical trials are effectiveness studies.

Example Section

An example of an efficacy study is the trial conducted by the Asthma Clinical Research Network (ACRN), entitled “Dose of Inhaled Corticosteroids with Equisystemic Effects (DICE).” The primary objective of the trial was to investigate dose-response effects of various inhaled corticosteroids (ICS) on cortisol production by the adrenal glands. Subjects with mild-moderate asthma were recruited. There were many exclusion criteria, such as obesity, pregnancy or lactation, no oral or injectable steroids during the past twelve months, no ICS or nasal steroids during the past six months, and no topical steroids during the past two months. Subjects were randomized to either one of six different ICS (n = 24 per group) or placebo (n = 12). ICS dose was doubled on a weekly basis (0d, 1d, 2d, 4d, and 8d, where d is a pre-selected low dose for each ICS). Subjects stayed overnight at a hospital at the end of each week, during which blood was drawn hourly and analyzed to determine the concentration of cortisol.

This study was examining a very specific biological question. The primary objective of the trial was to establish whether increasing the dose for each ICS yields a decrease in plasma cortisol (adrenal suppression). The researchers were interested in looking at dose response curves. The DICE trial was not powered to compare the dose-response curves of each ICS.

DICE is strictly an efficacy trial with very narrow eligibility criteria. Furthermore, the protocol specified that the intent-to-treat paradigm would not be followed. Subjects were dropped post-randomization if they received other forms of steroids, became pregnant, or were non-compliant with dose schedules and/or visit schedules.

On the other hand, over the past 20 years, there has been great interest in the gender and ethnic composition of cohorts in clinical trials. Part of this interest is due to ensuring external validity of the results of the trials. For many years caucasian males were the only patients recruited for the purpose of assuring homogeneity. This has been broadened by both the FDA and NIH in their application process. The broader eligibility requirements will help to ensure broader external validity.

The NIH typically requires one-half female participation and one-third ethnic minority participation in CTE trials that it sponsors. Obviously, there are exceptions to this based on the disease of interest. Required representation in clinical trials, however, could be a hindrance to acquiring new knowledge if it consumes too many resources.