FUNDAMENTALS OF CLINICAL TRIALS

Chapter 1 Introduction to Clinical Trials The evolution of the modern clinical trial dates back at least to the eighteenth century [1, 2]. Lind, in his classical study on board the Salisbury, evaluated six treatments for scurvy in 12 patients. One of the two who was given oranges and lemons recovered quickly and was fit for duty after 6 days. The second was the best recovered of the others and was assigned the role of nurse to the remaining ten patients. Several other comparative studies were also conducted in the eighteenth and nineteenth centuries. The comparison groups comprised literature controls, other historical controls, and concurrent controls [2]. The concept of randomization was introduced by Fisher and applied in agricultural research in 1926 [3]. Probably the first clinical trial that used a form of random assignment of participants to study groups was reported in 1931 by Amberson et al. [4]. After careful matching of 24 patients with pulmonary tuberculosis into comparable groups of 12 each, a flip of a coin determined which group received sanocrysin, a gold compound commonly used at that time. The British Medical Research Council trial of streptomycin in patients with tuberculosis, reported in 1948, used random numbers in the allocation of individual participants to experimental and control groups [5, 6]. The principle of blinding was also introduced in the trial by Amberson et al. [4]. The participants were not aware of whether they received intravenous injections of sanocrysin or distilled water. In a trial of cold vaccines in 1938, Diehl and coworkers [7] referred to the saline solution given to the subjects in the control group as a placebo. One of the early trials from the National Cancer Institute of the National Institutes of Health in 1960 randomly assigned patients with leukemia to either 6-azauracil or placebo. No treatment benefit was observed in this double-blind trial [8]. In the past several decades, the randomized clinical trial has emerged as the preferred method in the evaluation of medical interventions. Techniques of implementation and special methods of analysis have been developed during this period. © Springer International Publishing Switzerland 2015 L.M. Friedman et al., Fundamentals of Clinical Trials, DOI 10.1007/978-3-319-18539-2_1 1 Many of the principles have their origins in work by Hill [9–12]. For a brief history of key developments in clinical trials, see Chalmers [13]. The original authors of this book have spent their careers at the U.S. National Institutes of Health, in particular, the National Heart, Lung, and Blood Institute, and/or academia. The two new authors have been academically based throughout their careers. Therefore, many of the examples reflect these experiences. We also cite papers which review the history of clinical trials development at the NIH [14–18]. The purpose of this chapter is to define clinical trials, review the need for them, discuss timing and phasing of clinical trials, and present an outline of a study protocol. Fundamental Point A properly planned and executed clinical trial is the best experimental technique for assessing the effectiveness of an intervention. It also contributes to the identification of possible harms. What Is a Clinical Trial? We define a clinical trial as a prospective study comparing the effects and value of intervention (s) against a control in human beings. Note that a clinical trial is prospective, rather than retrospective. Study participants must be followed forward in time. They need not all be followed from an identical calendar date. In fact, this will occur only rarely. Each participant however, must be followed from a welldefined point in time, which becomes time zero or baseline for that person in the study. This contrasts with a case-control study, a type of retrospective observational study in which participants are selected on the basis of presence or absence of an event or condition of interest. By definition, such a study is not a clinical trial. People can also be identified from medical records or other data sources and subsequent records can be assessed for evidence of new events. With the increasing availability of electronic health records, this kind of research has become more feasible and may involve many tens of thousands of individuals. It is theoretically possible that the participants can be identified at the specific time they begin treatment with one or another intervention selected by the clinician, and then followed by means of subsequent health records. This type of study is not considered to be a clinical trial because it is unlikely that it is truly prospective. That is, many of the participants would have been identified after initiation of treatment and not directly observed from the moment of initiation. Thus, at least some of the follow-up data are retrospective. It also suffers from the major limitation that treatment is not chosen with an element of randomness. Thus associations between 2 1 Introduction to Clinical Trials treatment and outcome are nearly always influenced by confounding factors, some of which are measured (and thus can be accounted for with adjustment) and others unmeasured (that cannot be). Of course, electronic records and registries can work effectively in collaboration with randomization into clinical trials. As exemplified by the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial [19], electronic registries greatly simplified the process of identifying and obtaining initial information on those people eligible for the trial. As noted by Lauer and D’Agostino [20], however, translating this approach into other settings will not be easy. A clinical trial must employ one or more intervention techniques. These may be single or combinations of diagnostic, preventive, or therapeutic drugs, biologics, devices, regimens, procedures, or educational approaches. Intervention techniques should be applied to participants in a standard fashion in an effort to change some outcome. Follow-up of people over a period of time without active intervention may measure the natural history of a disease process, but it does not constitute a clinical trial. Without active intervention the study is observational because no experiment is being performed. Early phase studies may be controlled or uncontrolled. Although common terminology refers to phase I and phase II trials, because they are sometimes uncontrolled, we will refer to them as clinical studies. A trial, using our definition, contains a control group against which the intervention group is compared. At baseline, the control group must be sufficiently similar in relevant respects to the intervention group in order that differences in outcome may reasonably be attributed to the action of the intervention. Methods for obtaining an appropriate control group are discussed in Chaps. 5 and 6. Most often a new intervention is compared with, or used along with, best current standard therapy. Only if no such standard exists or, for several reasons discussed in Chap. 2, is not available, is it appropriate for the participants in the intervention group to be compared to participants who are on no active treatment. “No active treatment” means that the participant may receive either a placebo or no treatment at all. Obviously, participants in all groups may be on a variety of additional therapies and regimens, so-called concomitant treatments, which may be either self-administered or prescribed by others (e.g., other physicians). For purposes of this book, only studies in human beings will be considered as clinical trials. Certainly, animals (or plants) may be studied using similar techniques. However, this book focuses on trials in people, and each clinical trial must therefore incorporate participant safety considerations into its basic design. Equally important is the need for, and responsibility of, the investigator to inform fully potential participants about the trial, including information about potential benefits, harms, and treatment alternatives [21–24]. See Chap. 2 for further discussion of ethical issues. Unlike animal studies, in clinical trials the investigator cannot dictate what an individual should do. He can only strongly encourage participants to avoid certain medications or procedures which might interfere with the trial. Since it may be impossible to have “pure” intervention and control groups, an investigator may not What Is a Clinical Trial? 3 be able to compare interventions, but only intervention strategies. Strategies refer to attempts at getting all participants to adhere, to the best of their ability, to their originally assigned intervention. When planning a trial, the investigator should recognize the difficulties inherent in studies with human subjects and attempt to estimate the magnitude of participants’ failure to adhere strictly to the protocol. The implications of less than perfect adherence are considered in Chap. 8. As discussed in Chaps. 6 and 7, the ideal clinical trial is one that is randomized and double-blind. Deviation from this standard has potential drawbacks which will be discussed in the relevant chapters. In some clinical trials compromise is unavoidable, but often deficiencies can be prevented or minimized by employing fundamental features of design, conduct, and analysis. A number of people distinguish between demonstrating “efficacy” of an intervention and “effectiveness” of an intervention. They also refer to “explanatory” trials, as opposed to “pragmatic” or “practical” trials. Efficacy or explanatory trials refer to what the intervention accomplishes in an ideal setting. The term is sometimes used to justify not using an “intention-to-treat” analysis. As discussed in Chaps. 8 and 18, that is insufficient justification. Effectiveness or pragmatic trials refer to what the intervention accomplishes in actual practice, taking into account inclusion of participants who may incompletely adhere to the protocol or who for other reasons may not respond to an intervention. Both sorts of trials may address relevant questions and both sorts need to be properly performed. Therefore, we do not consider this distinction between trials as important as the proper design, conduct, and analysis of all trials in order to answer important clinical or public health questions, regardless of the setting in which they are done. The SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials) [25], as well as the various International Conference on Harmonisation (ICH) documents [26] devote considerable attention to the quality of trials, and the features that make for high quality. Poorly designed, conducted, analyzed, and reported trials foster confusion and even erroneous interpretation of results. People have argued over what key elements deserve the most attention versus those that expend resources better used elsewhere. However, unless certain characteristics such as unbiased assignment to treatment of sufficient numbers of adequately characterized participants, objective and reasonably complete assessment of the primary and secondary outcomes, and proper analysis are performed, the trial may not yield interpretable results. Much of the rest of this book expands on these issues. Clinical Trial Phases In this book we focus on the design and analysis of randomized trials comparing the effectiveness and adverse effects of two or more treatments. Several steps or phases of clinical research, however, must occur before this comparison can be implemented. Classically, trials of pharmaceutical agents have been divided into 4 1 Introduction to Clinical Trials phases I through IV. Studies with other kinds of interventions, particularly those involving behavior or lifestyle change or surgical approaches, will often not fit neatly into those phases. In addition, even trials of drugs may not fit into a single phase. For example, some may blend from phase I to phase II or from phase II to phase III. Therefore, it may be easier to think of early phase studies and late phase studies. Nevertheless, because they are in common use, and because early phase studies, even if uncontrolled, may provide information essential for the conduct of late phase trials, the phases are defined below. A good summary of phases of clinical trials and the kinds of questions addressed at each phase was prepared by the International Conference on Harmonisation [26]. Figure 1.1, taken from that document, illustrates that research goals can overlap with more than one study phase. Thus, although pharmacology studies in humans that examine drug tolerance, metabolism, and interactions, and describe pharmacokinetics and pharmacodynamics, are generally done as phase I, some pharmacology studies may be done in other trial phases. Therapeutic exploratory studies, which look at the effects of various doses and typically use biomarkers as the outcome, are generally thought of as phase II. However, sometimes, they may be incorporated into other phases. The usual phase III trial consists of therapeutic confirmatory studies, which demonstrate clinical usefulness and examine the safety profile. But such studies may also be done in phase II or phase IV trials. Therapeutic use studies, which examine the drug in broad or special populations and seek to identify uncommon adverse effects, are almost always phase IV (or post-approval) trials. Phase I Studies Although useful pre-clinical information may be obtained from in vitro studies or animal models, early data must also be obtained in humans. People who participate in phase I studies generally are healthy volunteers, but may be patients who have already tried and failed to improve on the existing standard therapies. Phase I studies attempt to estimate tolerability and characterize pharmacokinetics and Therapeutic TYPE OF STUDY Therapeutic Therapeutic Exploratory Human Pharmacology TIME I II III IV PHASES OF DEVELOPMENT INDIVIDUAL STUDY objectives design conduct analysis report Confirmatory Use Fig. 1.1 Correlation between development phases and types of study [26] Clinical Trial Phases 5 pharmacodynamics. They focus on questions such as bioavailability and body compartment distribution of the drug and metabolites. They also provide preliminary assessment of drug activity [26]. These studies may also assess feasibility and safety of pharmaceutical or biologic delivery systems. For example, in gene transfer studies, the action of the vector is an important feature. Implantable devices that release an active agent require evaluation along with the agent to assess whether the device is safe and delivers the agent in appropriate doses. Buoen et al. reviewed 105 phase I dose-escalation studies in several medical disciplines that used healthy volunteers [27]. Despite the development of new designs, primarily in the field of cancer research, most of the studies in the survey employed simple dose-escalation approaches. Often, one of the first steps in evaluating drugs is to estimate how large a dose can be given before unacceptable toxicity is experienced by patients [28–33]. This is usually referred to as the maximally tolerated dose. Much of the early literature has discussed how to extrapolate animal model data to the starting dose in humans [34] or how to step up the dose levels to achieve the maximally tolerated dose. In estimating the maximally tolerated dose, the investigator usually starts with a very low dose and escalates the dose until a prespecified level of toxicity is obtained. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If no specified level of toxicity is observed, the next predefined higher dose level is used. If unacceptable toxicity is observed in any of the three participants, additional participants, usually three, are treated at the same dose. If no further toxicity is seen, the dose is escalated to the next higher dose. If additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar. Some [32, 35–37] have proposed more sophisticated designs in cancer research that specify a sampling scheme for dose escalation and a statistical model for the estimate of the maximally tolerated dose and its standard error. The sampling scheme must be conservative in dose escalation so as not to overshoot the maximally tolerated dose by very much, but at the same time be efficient in the number of participants studied. Many of the proposed schemes utilize a step-up/step-down approach; the simplest being an extension of the previously mentioned design to allow step-downs instead of termination after unacceptable toxicity, with the possibly of subsequent step-ups. Further increase or decrease in the dose level depends on whether or not toxicity is observed at a given dose. Dose escalation stops when the process seems to have converged around a particular dose level. Once the data are generated, a dose response model is fit to the data and estimates of the maximally tolerated dose can be obtained as a function of the specified probability of a toxic response [32]. Bayesian approaches have also been developed [38, 39]. These involve methods employing continual reassessment [35, 40] and escalation with overdose control [41]. Bayesian methods involve the specification of the investigators’ prior opinion