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Evaluating and Interpreting Clinical Trials

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Evaluating and Interpreting Clinical Trials Article #2 CE Evaluating and Interpreting Clinical Trials Dorothy Cimino Brown, DVM, DACVS University of Pennsylvania ABSTRACT: For the practicing veterinarian, selecting the best treatment for patients can be challeng- ing. The “gold standard” for determining the efficacy of a treatment is the randomized controlled clinical trial (RCT) reported in the veterinary medical or pharmaceutical liter- ature. With the time constraints placed on busy practitioners, the temptation is to review the trial objectives and then the conclusions. However, it is important for practi- tioners to be able to critically review the methods and results of RCTs to determine whether the conclusions are justified by the data and whether a change in their practice based on those conclusions may benefit their patients. eports of randomized controlled clinical enroll a limited number of subjects to deter- trials (RCTs) are the “gold standard” by mine the safety, dose, or toxicity of the treat- Rwhich practitioners and others make deci- ment of the condition for which it is intended. sions about treatment efficacy. Therefore, the Phase III trials are large clinical trials of an RCT, more than any other methodology, can intervention that in phases I and II has been have a powerful and immediate impact on patient shown to be efficacious with tolerable side care. This article reviews the basic components of effects. Phase III trials compare the effect and the methods and results for conducting RCTs value of the treatment versus a control group of and describes the influence of those components subjects; these trials are designed to provide on the interpretation of trial results. With this definitive evidence for the efficacy of the treat- understanding, practitioners can critically review ment. Phase III trials can provide unbiased esti- information presented to them in the veterinary mates of an intervention’s specific effects and medical and pharmaceutical company literature change the way practitioners manage their and make informed decisions for their patients. patients. Whether they are truly unbiased esti- mates that have applicability to patients in any DEFINING A CLINICAL TRIAL given practice depends on the many features of A clinical trial is a rigorously controlled test the trials discussed in this article. of a new intervention on subjects. The term intervention is used in the broadest sense to EXAMPLE TRIAL FOR DISCUSSION include prophylactic, diagnos- To make the discussion clearer and more Send comments/questions via email tic, and therapeutic agents applicable, we will refer to a (fictitious) specific [email protected] and procedures. This article RCT report as an example. This is a report of or fax 800-556-3288. focuses on therapeutic agents the beneficial effects of drug A in dogs with Visit CompendiumVet.com for (i.e., new drugs). osteoarthritis (OA). The authors conclude that, full-text articles, CE testing, and CE Clinical trials progress in based on a “double-blind, randomized, placebo- test answers. phases. Phase I and II trials controlled clinical trial,” dogs with OA receiv- COMPENDIUM 752 October 2005 Evaluating and Interpreting Clinical Trials CE 753 Dogs with OA Reference population General group to which the results of a trial are expected to be applicable Intervention Control Drug A Placebo Experimental population Outcome Actual group in which • Pain score the trial is conducted • Platelet function Figure 1. Schematic appearance of the trial. Study Nonparticipants participants ing drug A have “significant pain relief.” In addition, the authors conclude that drug A has “no significant effect on platelet function, unlike other drugs in its class.” Fig- Treatment Comparison ure 1 is a schematic appearance of the trial. group group We will refer to this example as we highlight the basic components of the reporting of the methods and results of RCTs and describe the influence of those compo- Figure 2. Population hierarchy for a randomized nents on the interpretation of trial results. controlled clinical trial. EVALUATION OF METHODS Study Population ing all other methods are appropriate, the trial results For the conclusions of a trial to be useful to practi- are very valid for the experimental population of the tioners, the study subjects in the trial (e.g., dogs with report. What practitioners must decide is whether the OA) should be representative of the patients seen rou- results of the trial can be generalized to the population tinely in their practice. This can be determined by eval- of dogs that they treat on a regular basis. If the answer is uating inclusion and exclusion criteria in the methods yes, a generally similar result to that reported in the trial section of the report. Narrow inclusion and exclusion may be expected. If the answer is no, more variable criteria confine enrollment in the study to a small subset results may be expected. of patients with the disease, which may impose limita- tions on how useful the results are to a practitioner. In Assignment to Treatment Versus our example, the study concluded that drug A has a Control Groups beneficial effect in dogs with OA (i.e., the reference The RCT is the “gold standard” method of evaluating population); however, the inclusion criteria for the trial new and existing treatments because of its ability to were middle-aged, large-breed dogs with coxofemoral minimize bias. One way to minimize bias in the assign- OA and no other underlying conditions (i.e., the experi- ment to a treatment or control group is through ran- mental population; Figure 2). Although drug A domization. Randomization implies that each study appeared to be very beneficial in this subset of dogs with subject has the same chance of being placed in either OA, practitioners are likely to see more variable results the treatment or control group. This means that with an in their practices when administering the drug to dogs adequate sample size, the study groups (i.e., treatment of varying ages and sizes, with varying joints affected by and control) tend to be comparable with respect to all OA, and with underlying diseases. This is not to say variables except for the treatment being studied. Selec- that the reported results of the trial are not valid; assum- tion bias occurs when study subjects with one or more October 2005 COMPENDIUM 754 CE Evaluating and Interpreting Clinical Trials influencing factors appear more frequently in one study ment will know the assigned group. This is known as group than in another. For example, if younger age is blinding. When a system of assignment is known, there associated with a better outcome in dogs with OA and is potential for bias. For example, if the first two eligible the proportion of younger study subjects is greater in the dogs with OA (i.e., a 4-year-old dog and an 8-year-old treatment group than in the control group, then even if dog) present at the same time with different prognoses the treatment and control are equally effective, there and, according to the randomization list, dog 1 is to would be an observed benefit of the treatment that did receive drug A and dog 2 is to receive the placebo, an not really exist. Using our trial example of middle-aged investigator may, consciously or not, enter them into the (4- to 8-year-old) dogs reported in the OA trial, if 50% study in the order that would allow the dog with the of the dogs in the drug A group were 4 to 5 years of age better potential outcome (i.e., the 4-year-old dog) and only 10% were 7 to 8 years of age, and the opposite to receive the treatment. If a large proportion of study were true in the placebo group (i.e., 50% were 7 to 8 subjects are entered in this way, a serious imbalance in years of age, and 10% were 4 to 5 years of age), the drug the treatment groups with respect to factors affecting A group would appear to do much better than the the outcome under study would result.1,2 Ideally, the placebo group, not necessarily because the drug was that randomization list should be kept by a third party much more effective than the placebo but because the (usually a pharmacy) that dispenses the drug or placebo dogs in the drug A group tended to be much younger, to the investigators without them knowing into which Because of its ability to reduce bias (i.e., systematic errors), the randomized controlled clinical trial is the “gold standard” for evaluating drug efficacy. and younger dogs do better. Randomization can take group the dog is being placed. In short, blinding miti- care of this problem by ensuring that a 4-year-old dog is gates the influences of expectation or other human just as likely to be placed in the drug A group as in the predilections.3,4 placebo group. If blinding of the group allocation is not reported or is The beauty of randomization is that not only known reported not to have been done, the practitioner must factors (e.g., age) are evenly distributed between groups again interpret the results of the trial knowing that sig- but also factors that are unsuspected by the investigators nificant selection bias could be present. When allocation because of limitations of biologic knowledge at the time to a treatment or control group is done by a method the trial is initiated. For example, if it were discovered 2 other than blind randomization, the burden of proof is years after our example trial was reported that thin dogs on the investigator/author of the trial report to show do better than obese dogs, the results of the trial would that all possible biases in allocating study subjects to a still be valid because randomization would have roughly group or influencing effects of known or unknown fac- equally allocated the obese and thin dogs between the tors that may differ between the study groups did not two study groups, thus negating the potential for the account for the observed result.
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