Design of Small Clinical Trials

The design and conduct of any type of clinical trial require three considerations: first, the study should examine valuable and important biomedical research questions; second, it must be based on a rigorous methodology that can answer a specific research question being asked; and third, it must be based on a set of ethical considerations, adherence to which minimizes the risks to the study participants (Sutherland, Meslin, and Till, 1994). The choice of an appropriate study design depends on a number of considerations, including:

the ability of the study design to answer the primary research question; o whether the trial is studying a potential new treatment for a condition for which an established, effective treatment already exists; o whether the disease for which a new treatment is sought is severe or life-threatening;

the probability and magnitude of risk to the participants;

the probability and magnitude of likely benefit to the participants;

the population to be studied-its size, availability, and accessibility;

and

how the data will be used (e.g., to initiate treatment or as preliminary data for a larger trial).

Because the choice of a study design for any particular trial will depend on these and other factors, no general prescription can be offered for the design of clinical trials. However, certain key issues are raised when random- ized clinical trials (RCTs) with adequate statistical power are not feasible and when studies with smaller populations must be considered. The utility of such studies may be diminished, but not completely lost, and in other ways may be enhanced.

To understand what is lost or gained in the design and conduct of studies with very small numbers of participants, it is important to first consider the basic tenets of clinical trial design (Box 2-1).

KEY CONCEPTS IN CLINICAL TRIAL DESIGN

Judgments about the effectiveness of a given intervention ultimately rest on an interpretation of the strength of the evidence arising from the data collected. In general, the more controlled the trial, the stronger is the evidence. The study designs for clinical trials can take several forms, most of which are based on an assumption of accessible sample populations. Clinical trials of efficacy ask whether the experimental treatment works under ideal condi-

BOX 2-1
Important Concepts in Clinical Trial Design
Does the trial measure efficacy or effectiveness?
A method of reducing bias (randomization and masking [blinding])
Inclusion of control groups
- Placebo concurrent controls
- Active treatment concurrent controls (superiority versus equivalence trial)
- No-treatment concurrent controls
- Dose-comparison concurrent controls
- External controls (historical or retrospective controls)
Use of masking (blinding) or an open-label trial
- Double-blind trial
- Single-blind trial
Randomization
- Use of randomized versus nonrandomized controls
Outcomes (endpoints) to be measured: credible, validated, and responsive to change
Sample size and statistical power
Significance tests to be used


tions. In contrast, clinical trials of effectiveness ask whether the experimental treatment works under ordinary circumstances. Often, trials of efficacy are not as sensitive to issues of access to care, the generalizability of the results from a study with highly selective sample of patients and physicians, and the level of adherence to treatment regimens. Thus, when a trial of efficacy is done with a small sample of patients, it is not clear whether the experimental intervention will be effective when a broader range of providers and patients use the intervention. On the other hand, trials of effectiveness can be problematic if they produce a negative result, in which case it will be unclear whether the experimental intervention would fail under any circumstances. Thus, the issue of what is preferred in a small clinical study-a trial of efficacy or effectiveness-is an important consideration.

In the United States, the Food and Drug Administration (FDA) over- sees the regulation and approval of drugs, biologics, and medical devices. Its review and approval processes affect the design and conduct of most new clinical trials. Preclinical testing of an experimental intervention is performed before investigators initiate a clinical trial. These studies are carried out in the laboratory and in studies with animals to provide preliminary evidence that the experimental intervention will be safe and effective for humans. FDA requires preclinical testing before clinical trials can be started. Safety information from preclinical testing is used to support a request to FDA to begin testing the experimental intervention in studies with humans.

Clinical trials are usually classified into four phases. Phase I trials are the earliest-stage clinical trials used to study an experimental drug in humans, are typically small (less than 100 participants), and are often used to deter- mine the toxicity and maximum safe dose of a new drug. They provide an initial evaluation of a drug's safety and pharmacokinetics. Such studies also usually test various doses of the drug to obtain an indication of the appropriate dose to be used in later studies. Phase I trials are commonly conducted with nondiseased individuals (healthy volunteers). Some phase I trials, for example, those of studies of treatments for cancer, are performed with indi- viduals with advanced disease who have failed all other standard treatments (Heyd and Carlin, 1999).

Phase II trials are often aimed at gathering preliminary data on whether a drug has clinical efficacy and usually involve 100 to 300 participants. Frequently, phase II trials are used to determine the efficacy and safety of an intervention in participants with the disease for which a new intervention is being developed.

Phase III trials are advanced-stage clinical trials designed to show conclusively how well a drug works. Phase III trials are usually larger, frequently multi-institutional studies, and typically involve from a hundred to thousands of participants. They are comparative in nature, with participants usually assigned by chance to at least two arms, one of which serves as a control or a reference arm and one or more of which involve new interventions. Phase III trials generally measure whether a new intervention extends survival, or improves the health of participants receiving the intervention and has fewer side effects.

Some phase II and phase III trials are designed as pivotal trials (sometimes also called confirmatory trials), which are adequately controlled trials in which the hypotheses are stated in advance and evaluated. The goal of a pivotal trial is to attempt to eliminate systematic biases and increase the statistical power of a trial. Pivotal trials are intended to provide firm evidence of safety and efficacy.

Occasionally, FDA requires phase IV trials, usually performed after a new drug or biologic has been approved for use. These trials are postmarketing surveillance studies aimed at obtaining additional information about the risks, benefits, and optimal use of an intervention. For example, a phase IV trial may be required by FDA to study the effects of an intervention in a new patient population or for a stage of disease different from that for which it was originally tested. Phase IV trials are also used to assess the long-term effects of an intervention and to reveal rare but serious side effects.

One criticism of the classification of clinical trials presented above is that it focuses on the requirements for the regulation of pharmaceuticals, leaving out the many other medical products that FDA regulates. For example, new heart valves are evaluated by FDA on the basis of their ability to meet predetermined operating performance characteristics. Another device is the intraocular lens whose performance must be satisfied in a prespecified grid. Medical device studies, however, rely on a great deal of information about the behavior of the control group that often cannot be obtained or that is very difficult to obtain in small clinical trials because of the small number or lack of control participants.

A much more inclusive and general approach that subsumes the four phases of clinical trials is put forth by Piantadosi (1997), who defines the four phases as (1) early-development studies (testing the treatment mechanism), (2) middle-development studies (treatment tolerability), (3) comparative (pivotal, confirmatory) studies, and (4) late-development studies (extended safety or postmarketing studies). This approach is more inclusive than trials of pharmaceuticals; it includes trials of vaccines, biological and gene therapies, screening devices, medical devices, and surgical interventions.

The ethical conduct of a clinical study of the benefits of an intervention requires that it begin in a state of equipoise. Equipoise is defined as the point at which a rational, informed person-whether patient, provider, or re- searcher-has no preference between two (or more) available treatments (Freedman, 1987; Lilford and Jackson, 1995). When used in the context of research, equipoise describes a state of genuine uncertainty about whether the experimental intervention offers greater benefit or harm than the control intervention. Equipoise is advocated as a means of achieving high scientific and ethical standards in randomized trials (Alderson, 1996). True equi- poise might be more of a challenge in small clinical trials, because the degree of uncertainty might be diminished by the nature of the disorder, the lack of real choices for treatment, or insufficient data to make a judgment about the risks of one treatment arm over another.

A primary purpose of many clinical trials is evaluation of the efficacy of an experimental intervention. In a well-designed trial, the data that are collected and the observations that are made will eventually be used to over- turn the equipoise. At the end of a trial, when it is determined whether an experimental intervention has efficacy, the state of clinical equipoise has been eliminated. Central principles in proving efficacy, and thereby eliminating equipoise, are avoiding bias and establishing statistical significance. This is ideally done through the use of controls, randomization, blinding of the study, credible and validated outcomes responsive to small changes, and a sufficient sample size. In some trials, including small clinical studies, the elimination of equipoise in such a straightforward manner might be difficult. Instead, estimation of a treatment effect as precisely as necessary may be sufficient to distinguish the effect from zero. It is a more nuanced approach, but one that should be considered in the study design.

Adherence to an ethical process, whereby risks are minimized and voluntary informed consent is obtained, is essential to any research involving humans and may be particularly acute in small clinical trials, in which the sample population might be easily identified and potentially more vulner- able. Study designs that incorporate an ethical process may help in reducing concerns about some of problems in design and interpretation that naturally accompany small clinical trials.

Charles H. Evans, Jr., and Suzanne T. Ildstad. Small Clinical Trials: Issues and Challenges (2001)