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 literature. 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 practitioners 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 estimates 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-

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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 limitations 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

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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. If blind randomization body condition of the dogs to bias the results. For prac- was used to allocate study subjects to treatment and titioners to be sure that the treatment and control control groups, the practitioner can be confident that groups in the study are truly comparable, they must look observed differences between the groups reported in the for the presence and method of randomization in the trial are not due to selection of particular subjects to methods section of the report. If there is no mention of receive a given therapy. randomization, the presence of unequal study groups and a biased result must be considered. Ascertaining the Outcome If randomization is properly done, nobody either The primary concern regarding determining the out- involved in deciding whether a subject is eligible to comes in the trial (i.e., pain score and platelet function enter a trial or responsible for administering the treat- in our example) is that results are not biased by collec-

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tion of more complete or accurate information from one tion is an objective outcome and cannot be affected by study group compared with another (i.e., drug A versus knowledge of the dog’s study group. In contrast, when placebo). Observation bias (by the investigators or care- the outcome of interest is subjective, such as pain score, givers of the dogs) in ascertaining the outcome can exist the use of blinding and a control group minimizes bias in an RCT in that knowledge of a study subject’s treat- in the ascertainment. ment status might, consciously or not, influence identi- Placebo controls also take care of the problem that fication or reporting of relevant events (i.e., pain score). caregivers administering a drug to their dog may be sen- Bias occurs when investigators consciously or subcon- sitized to their dog’s physical condition and may tend to sciously favor one group over another. For example, if ascribe every sign or unusual occurrence to the treat- investigators know which dogs received the treatment, ment. The key to obtaining an unbiased estimate of they may monitor that group more closely and thus deal effect for a treatment with a subjective outcome or a with them differently than they would the control group side effect is to subtract the placebo effect. That is, the

Selection bias is the systematic differences in prognosis or responsiveness to treatment between the treatment and control groups selected for the trial.This can be eliminated with blind randomization of the study subjects. in a way that could seriously affect the outcome of the true effect of the treatment with drug A on pain score is trial. For example, if investigators know that a dog is the measured effect of drug A on the pain score minus receiving drug A, they may be more likely to persistently the measured effect of the placebo on the pain score. If question the dog’s caregiver to give some indication of a the example OA trial did not use a placebo group con- positive response on a pain score than if they know the trol, it would be impossible for the practitioner to tell dog is receiving the placebo. whether the decreased pain score following the treat- Bias can also occur if the dog’s caregiver knows to ment with drug A was due to the actual drug or merely which group their dog belongs. If the dog’s caregiver to the caregivers or investigators belief that the treat- knows that their dog is receiving drug A versus the ment would help. placebo, they are likely to overreport an improved pain score, whereas those who know their dog is in the con- Sample Size Considerations trol group are likely to overreport no improvement (or A trial must have a sufficient sample size (i.e., number perhaps deterioration). This leads to exaggerated esti- of study subjects) to have adequate statistical power or mates of treatment benefits. ability to reliably detect the small to moderate but clini- Blinding of the investigators and caregivers of the cally important differences between study groups (e.g., study subjects prevents these biases.1,2,5 In the title or drug A versus the placebo) that are most likely to abstract of an RCT report, authors often describe the occur.1,2 A trial undertaken with an insufficient number trial as blind. However, the reader often has to go to the of study subjects is of little scientific value. In fact, trials methods section of the report to determine exactly with an inadequate sample size could be scientifically which parties were blind. If either the investigators or harmful if their results are misinterpreted as demon- caregivers of the dogs were not blinded, the practitioner strating that a treatment has no effect when, in fact, the must again interpret the results of the trial knowing that sample size was not sufficient to draw that conclusion. significant biases could be present. The likelihood of For the example OA trial, the null result would have such bias is directly related to the subjectivity of the out- been that the pain score following drug A administra- comes under study. For example, the secondary outcome tion was not different than the pain score following for the example OA trial is platelet function. In this placebo administration in dogs with OA. In our exam- case, observation bias is unlikely because platelet func- ple, the null hypothesis was disproved, so an adequate

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number of study subjects must have completed the trial. Had it not been disproved Assessed for eligibility (n = ...) (i.e., the conclusion of the trial was that drug A was not Excluded (n = ...) better than the placebo in decreasing pain scores), the practitioner would need to Randomized (n = ...) look at the methods section of the report to determine whether this is a true null Allocated to treatment (n = ...) result or the study was merely Allocated to control group (n = ...) underpowered. The methods section should describe how the sample size was determined. If it Compliant (n = ...) Compliant (n = ...) Noncompliant (n = ...) Noncompliant (n = ...) does not, the practitioner can- Lost to follow-up (n = ...) Lost to follow-up (n = ...) not be certain that a null result is not due merely to an inadequate number of animals enrolled in the trial. Analyzed (n = ...) Analyzed (n = ...) Excluded from analysis (n = ...) Excluded from analysis (n = ...) EVALUATING RESULTS Tracking Study Subjects Figure 3. Flow of study subjects through a randomized controlled clinical trial. Through the Trial Numbers in each section should be reported. For practitioners to assess the validity of results and whether they are applicable to their patients, they must dogs were assessed for eligibility but only 70 were ran- be able to follow the flow of study subjects through the domized in the trial, 130 dogs would be considered non- trial. This is relatively easy to do if a flow diagram of participants. If a lot of the nonparticipation is because of subject progress through the phases of the trial is reasons other than not fitting the inclusion and exclusion included in the results section of the report (Figure 3). criteria, the participating experimental population (Figure If a diagram is not included, the practitioner must glean 2) becomes an even more select subset of the reference this information from the text of the results section. population for reasons that may not be identified. A trial should report the number of study subjects assessed for Number of Animals Assessed for Eligibility eligibility that did not participate and ideally offer some Versus Number of Animals Randomized details about the nonparticipants so practitioners can People who choose to participate in a clinical trial are assess the presence and extent of differences between par- very likely to differ from nonparticipants in ways that ticipants and nonparticipants. This aids in judging can impact the outcome of the trial. This is particularly whether the results of the participants are representative true if a large percentage of those offered enrollment in of the larger population and, ultimately, of the patients in a trial decline and the participants in the trial become a a clinician’s practice. select subgroup for reasons not apparent in the inclusion criteria. Whether the subgroup of participants is repre- Number of Animals Randomized Versus Number sentative of the entire potential participant pool does of Animals Allocated to the Study Groups not affect the validity of results for that subgroup but If a valid randomization technique is used, it is very may affect how applicable the results are to the popula- likely that the number of study subjects allocated to tion of patients a practitioner sees. For example, if 200 each of the two study groups will not be exactly 50% of

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the total number randomized. When computer ran- groups more alike, thereby decreasing the ability of the domization or a randomization table is used to allocate trial to detect any true differences between groups. For study subjects to groups, it is common for one study example, if seven of the 36 dogs in the drug A group do group to have slightly more subjects enrolled than the not receive drug A according to the protocol and five of other. For example, if 70 dogs are randomized in the the 34 dogs in the placebo group are administered drug OA trial, it would be typical for 36 to be assigned to the A (or some other over-the-counter analgesic) by their drug A treatment group and 34 to be assigned to the caregivers at their own initiative, the two groups (i.e., placebo group (or vice versa). It would be more unusual drug A and placebo) become very similar in their expo- for exactly 35 dogs to be assigned to each group. If prac- sure to drug A (or pain medication in general); conse- titioners notice in the results section that an equal num- quently, any true magnitude of effect of drug A may be ber of animals were assigned to each study group, they obscured. Thus the interpretation of any trial result should look closely at the methods section to determine must take into account the extent to which there was the method of randomization. If a clear method is not adherence to the treatment regimen. described, the reader should wonder whether alternate If a null result of a trial (i.e., no difference between assignment to the treatment and control groups was drug A and the placebo groups) is found in light of a used rather than true randomization. Alternate assign- significant number of those enrolled not complying ment always results in exactly 50% of the subjects in with the protocol, the study may be underpowered (i.e., each of the two study groups (assuming an even number not enough compliant subjects in each group) to detect

Observation bias is the systematic differences in obtaining information about the study subjects once they have been entered in the trial.This can be eliminated by blinding the investigators, data collectors, and caregivers of animals enrolled in the trial. of total animals). As discussed earlier, this method is a true difference between the study groups, even if an subject to great selection bias when two eligible animals appropriate number were originally randomized. If a present for enrollment at the same time. positive result of a trial (i.e., drug A decreases the pain score significantly more than the placebo) is found in Number of Animals That Do Not light of a significant number of those enrolled not com- Comply in Each Study Group plying with the protocol, the treatment is likely very By definition, an RCT requires the active participa- effective but may not be practical because there is a lot tion and cooperation of the study subjects and their of noncompliance for some reason. For example, drug A caregivers. After the agreement to participate, there may may be very effective in decreasing the pain score in be deviation from the protocol for a variety of reasons, dogs with OA, but if it must be administered five times including the development of side effects, forgetting to per day, noncompliance is likely to be high. It may not administer the medication, or caregivers choosing to be practical for the practitioner to recommend use of obtain alternative treatment for their dogs on their own. drug A, no matter how effective it may be, if the treat- To the extent that study subjects in the control group ment regimen is so difficult that it is likely to be receive therapy or those in the treatment group do not accepted and used in only a small proportion of dogs actually receive their assigned regimen, the two study with OA. For these reasons, compliance data should be groups become very similar in terms of exposure to the reported with reasons for deviation from the protocol treatment. Thus the effect of noncompliance in any for individual subjects. Knowing that 100% compliance study subject makes the treatment and comparison in a trial would be very unusual, practitioners need to

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consider whether only compliant study subjects were single study subject during a trial. If the trial report does analyzed for the report if no compliance information is not address loss to follow-up at all, it is impossible to reported. This can lead to very biased results, which are gauge how much bias may be associated with the results. discussed later. Number of Animals Analyzed Number of Animals Lost to Follow-Up It is important for practitioners to know how many of In addition to the need for uniform ascertainment of the original animals randomized to each study group outcome between groups is the requirement for com- had outcomes analyzed. This again has to do with the plete follow-up of study subjects over the duration of bias that is introduced into results because subjects lost the trial. As the period of time over which subjects must to follow-up cannot be included in the analysis. It also be followed increases, maintaining complete ascertain- has to do with the bias that is introduced when non- ment of outcomes becomes more difficult. A number of compliant subjects are not analyzed in the group to subjects in both groups may be lost to follow-up by the which they were randomized, which is discussed later in end of the study period. If the proportion of outcomes this article. that are not ascertained is large or differs among the study groups, the result could be an under- or overesti- Baseline Data mate of the effect of the drug. One important early step in evaluating results of a If the proportion lost to follow-up is large (i.e., 30% trial is to compare the relevant characteristics of the to 40%), it should raise serious doubts about the validity treatment and control groups to ensure that balance was of the study results.1 However, the more difficult issue achieved. Although randomization tends to distribute for interpretation is that even if the rate of loss is not both known and unknown factors evenly among study that extreme, the probability of loss may be related to groups, if the sample size is small, randomization may the treatment, outcome, or both. For example, if care- not always result in groups that are alike with respect to givers are aware of which study group their dog is en- every factor except the treatment under study. For exam- rolled in, they may be more likely not to return for ple, if the age, sex, and bodyweight of the dog have an follow-up evaluations if their dog is receiving the impact on how well it will respond to treatment with placebo than if it is receiving drug A. It would also be drug A, the breakdown of age, sex, and bodyweight of likely for caregivers of dogs that are not doing well the dogs in the drug A group versus the placebo group while enrolled in the trial (i.e., pain scores remain high) should be presented so that practitioners can feel com- not to return for follow-up evaluation because they want fortable that randomization did indeed work and the to seek alternative therapy. Not determining the out- two groups are comparable. If by chance the groups do come of these cases can introduce a significant amount not appear comparable, the imbalances can be con- of bias in the study. Exactly how much is impossible to trolled in the analysis using statistical techniques that determine directly. would be reported in the methods section. Most RCTs An indirect approach used to describe the extent of reported in veterinary medicine are relatively small, bias introduced by losses to follow-up is to calculate making it very important for the baseline characteristics estimates of treatment effect, assuming the most ex- of the group to be reported. If this information is not treme situations. For example, one estimate would be reported, it is impossible for the practitioner to know based on the assumption that all those lost to follow-up whether randomization was effective in delivering com- from the drug A group had improved pain scores, while parable groups for analysis, and the possibility of selec- none lost from the placebo group did. The second tion bias (as discussed earlier) exists. extreme would be that none lost from the drug A group had improved pain scores, while all lost from the Intention-to-Treat Analysis placebo group did. The results of these calculations pro- When the results of a clinical trial are evaluated, it is vide a range within which the true effect of the drug important for practitioners to assess which study sub- lies. Ideally, the author(s) of the study reports these cal- jects were included in the analysis. Some investigators culations (often called a sensitivity analysis) or at least remove subjects that did not comply with the study pro- provides the information necessary for readers to make tocol from the analysis; however, the exclusion of any this assessment themselves.6 It is unusual not to lose a randomized study subject from the analysis can lead to

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biased results. Once study subjects are randomized to a Randomized study group (i.e., drug A versus the placebo), their subsequent health experience must be assessed and analyzed Allocated to intervention Allocated to control group along with that of all others in that group, regardless of whether there is compliance Compliers Noncompliers Loss to Compliers Noncompliers follow-up with their assigned regimen. In all circumstances, the optimal comparison for estimat- Analyzed Analyzed ing the true benefit from the treatment protocol is to ana- Figure 4. Flow of randomized study subjects to final analysis. lyze by the intention to treat (not whether they were actually treated). In other words, “once randomized, always analyzed”1,2,7,8 (Figure 4). ference between groups is statistically significant (i.e., P In most trials, perfect compliers represent some frac- < .05). If the 95% CI is presented (e.g., 1.3 to 2.8), the tion of the total study population. Although the goal is reader can see that the best estimate of increased risk of to study the actual effect of the treatment (drug A), ran- elevated pain score is 1.9; however, the reader can be domization is done only on the basis of offering the 95% confident that the true relative risk is no less than treatment. To preserve the power of randomization, the 1.3 and no greater than 2.8. It is particularly important data must be analyzed on this basis. Only the entire to look for the CI when interpreting the results of stud- groups allocated by randomization are truly comparable. ies that are not statistically significant. A narrow CI Subsequent analyses can certainly be reported based on (i.e., 0.8 to 1.2) would add support to the belief that that subgroup of study subjects that actually received there is actually no true increased risk, whereas a wide their assigned treatment; however, if this is reported, it interval (i.e., 0.8 to 8.2) suggests that the sample size is important for practitioners to realize that it is impos- was not sufficient to have adequate statistical power. sible to achieve balance in the distribution of unknown factors that had originally been achieved through ran- EFFICACY VERSUS EFFECTIVENESS domization and that the results of the subgroup of com- In veterinary medicine, RCTs are designed to test a pliers may be biased. biologic question on a relatively homogeneous population of animals (e.g., does drug A significantly decrease the P Values Versus Confidence Intervals pain score of middle-aged, large-breed dogs with cox- The size of the P value is a function of two factors: ofemoral OA and no other underlying diseases?). These the magnitude of the difference between the groups and types of trials are generally called efficacy trials. They test the size of the sample.1 Consequently, even a very small the true biologic effect of a treatment under optimal cir- difference may be statistically significant if the sample cumstances. They do not test the true effectiveness of a size is sufficiently large; conversely, a large effect may treatment in usual care, which is the effect a drug has not achieve statistical significance if there is a small when widely used in practice. The true effectiveness of a sample size. To overcome this problem, a related but far treatment cannot be determined until it is used in a het- more informative measure to evaluate the role of chance erogeneous population of thousands of animals. in the reported results may be the confidence interval (CI). For the OA example, in evaluating the relationship CONCLUSION between drug A and pain in dogs, the report may say The RCT is the most reliable methodology for assess- that dogs in the placebo group have a 1.9 times greater ing the efficacy of treatments in veterinary medicine. risk (i.e., relative risk = 1.9) of an elevated pain score However, a number of issues in the design and conduct compared with dogs receiving drug A and that this dif- of the trial as well as the analysis must be carefully con-

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sidered to ensure that valid conclusions are made. In 3. Observation bias can be eliminated by addition, practitioners must determine whether the a. using subjective endpoints such as pain score. reported results are applicable to the patients they rou- b. blinding the investigators, data collectors, and care- tinely treat in their practice. Much of this information is givers of the animals enrolled in the trial. c. doing a sensitivity analysis. not presented in the abstract of a report, and practition- d. reporting the number of study subjects assessed for ers must delve deeper into the methods and results of the eligibility that did not participate. trial to make a truly informed decision for their patients. 4. An RCT can provide an unbiased estimate of a REFERENCES drug’s efficacy by 1. Hennekens CH, Buring JE: Epidemiology in Medicine, ed 1. Philadelphia, Lip- a. using an intention-to-treat analysis. pincot Williams & Wilkins, 1987, p 383. b. blinding the randomization. 2. Piantadosi S: Clinical Trials: A Methodologic Perspective. New York, John Wiley c. blinding the investigators, data collectors, and care- & Sons, 1997, p 590. givers of animals enrolled in the trial. 3. Kramer MS, Shapiro SH: Scientific challenges in the application of random- d. all of the above ized trials. JAMA 252:2739–2745, 1984. 4. Juni P, Altman DG, Eggar M: Assessing the quality of controlled clinical tri- 5. Which statement regarding randomization is als. Br Med J 323:42–46, 2001. true? 5. Halpern SD: Evaluating preference effects in partially unblinded, randomized a. Regardless of sample size, randomization ensures that clinical trials. J Clin Epidemiol 56:109–115, 2003. the study groups are comparable with respect to all 6. Hollis S: A graphical sensitivity analysis for clinical trials with non-ignorable missing binary outcome. Stat Med 21:3823–3834, 2002. variables except for the treatment being studied. 7. Ruiz-Canela M: Intention to treat analysis is related to methodological quality. b. Randomization protects against observation bias. Br Med J 320:1007, 2000. c. Randomization is the only way to evenly distribute 8. Moher D, Schulz KF, Altman D: The CONSORT statement: Revised recom- unknown factors between study groups. mendations for improving the quality of reports of parallel-group randomized d. Randomization ensures that study groups have the trials. JAMA 285:1987–1991, 2001. same number of participants enrolled.

6. For practitioners to determine whether study ARTICLE #2 CE TEST subjects in a reported trial are representative of This article qualifies for 2 contact hours of continuing CE their patients, they need to evaluate the education credit from the Auburn University College of a. inclusion criteria. Veterinary Medicine. Subscribers may purchase individual b. exclusion criteria. CE tests or sign up for our annual CE program. Those c. number of study subjects assessed for eligibility that who wish to apply this credit to fulfill state relicensure did not participate. requirements should consult their respective state d. all of the above authorities regarding the applicability of this program. 7. Which term describes the general group to To participate, fill out the test form inserted at the end which the results of a clinical trial are expected of this issue or take CE tests online and get real-time to be applicable? scores at CompendiumVet.com. a. reference population b. experimental population 1. The RCT is the “gold standard” for evaluating c. participants drug efficacy because of its ability to d. nonparticipants a. reduce bias. 8. Which statement is true? b. compare two groups of study subjects. a. Randomization implies that each study subject has c. restrict inclusion criteria to a small subset of patients the same chance of being placed in either the treat- with the disease of interest. ment or control group. d. control the compliance of study participants. b. The primary concern in determining the outcome of a trial is that only the data from study subjects com- 2. Selection bias can be eliminated by pliant with the protocol are collected. a. blinding the caregivers of animals enrolled in the trial. c. When very narrow inclusion and exclusion criteria b. blind randomization of the study subjects. are used, the results of the trial will likely not be valid. c. having an adequate sample size. d. Observation bias is of greatest concern when data d. following the flow of study subjects through the trial. on objective endpoints are collected.

COMPENDIUM Test answers now available at CompendiumVet.com October 2005 764 CE Evaluating and Interpreting Clinical Trials

9. Which statement is true? a. If a large percentage of those offered enrollment in a trial decline, the results of the study are likely to be invalid. b. A trial must have a sufficient sample size to have adequate statistical power to reliably detect the important differences between study groups. c. If the number of study subjects lost to follow-up is large or differs among the study groups, the result is always an overestimate of the effect of the drug. d. A sensitivity analysis is used to determine whether enough study subjects were enrolled in the trial.

10. Which statement is true? a. The abstract of a clinical trial report provides all the information practitioners need to make a truly informed decision for their patients. b. RCTs test the true effectiveness of a treatment in usual practice (i.e., the effect of a drug when it is widely used in practice). c. The size of the P value is a function solely of the magnitude of the difference between the groups. d. Once study subjects have been randomized to a study group, their subsequent health experience must be assessed and analyzed along with that of all others in that group, regardless of whether there is compliance with their assigned regimen.

COMPENDIUM October 2005