In this JCO PO Article Insights episode, Miki Horiguchi provides a summary on the article, “TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing and explains what a non-inferiority trial is. 

TRANSCRIPT

Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal’s Editorial Fellow. Today, I'll be providing a summary of the article titled "TARGET: A Randomized Non-Inferiority Trial of a Pre-Test, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing" by Dr. Stacy Loeb and colleagues.

To help you understand the TARGET study design, I'll first explain what a non-inferiority trial is.

One of the most common clinical trial designs we see in clinical papers is the superiority trial. A superiority trial is designed to demonstrate that a new treatment is superior to a control, such as a placebo or a standard treatment, in terms of a primary outcome that is relevant to the study's purpose. In a superiority trial, a statistical test is performed for the null hypothesis that there is no treatment difference between the two arms. If a significant p-value, which is conventionally less than 0.05 is observed, we consider that the probability that the null hypothesis being true is very low, and thus conclude that there is a treatment difference between the two arms. On the other hand, if the p-value is larger than 0.05, we cannot conclude that there is a treatment difference because the probability that the null hypothesis being true is not low enough. Here, it's very important for us to keep in mind that a non-significant p-value does not mean no difference between the two arms.

Therefore, if the study objective is to show that a new treatment has a similar treatment effect to a control treatment, the standard statistical testing approach used in a superiority trial is not appropriate. To meet this specific study objective, utilizing a non-inferiority test is more appropriate. The formulation of a hypothesis in a non-inferiority test is distinct from that in a superiority test. In essence, the null hypothesis is that the new treatment is inferior by more than the predefined margin, whereas the alternative hypothesis argues against this, suggesting that the new treatment is not inferior within this margin. A significant p-value from the non-inferiority test indicates support for the alternative hypothesis, implying that the new treatment is at least as effective as the control treatment considering the predefined margin of non-inferiority. 

There are a couple of points to consider prior to designing a non-inferiority trial. The first is about the justification for using a non-inferiority study. The new treatment must offer a clear advantage other than the treatment effect, such as fewer side effects and lower cost, so that it can be a viable alternative to the control treatment as long as it maintains a certain level of treatment effect that is not inferior to the controls.  

The second point is about the non-inferiority margin. The non-inferiority margin defines the threshold below which the new treatment is deemed non-inferior to the control. The selection of an appropriate margin is pivotal as it profoundly influences the power and sample size of the study, as well as the interpretation of the statistical test results. To ensure the study's objectives are met, the non-inferiority margin must be established during the study design phase. This decision should be informed by clinical expert opinions, findings from previous studies, or regulatory guidelines. 

Now let me move on to the introduction of the TARGET study. The TARGET study was a multicenter, non-inferiority randomized trial to compare the effects of two types of interventions for pre-test genetic education in patients with prostate cancer. The authors developed a patient-driven, web-based education tool that consisted of nine modules with text and videos to deliver genetic testing education. They then assessed its non-inferiority to traditional genetic counseling and the decisional conflict about taking genetic testing. The primary endpoint was the change in the decisional conflict score between pre- and post-intervention. The authors estimated the difference in pre-post change of the score between the two arms and the corresponding one-sided 95% confidence interval. The non-inferiority of the web tool arm on the pre- post change of the score to the genetic counseling arm was assessed based on a pre-specified non-inferiority margin of 4. In this case, if the estimated upper confidence bound for the difference between the two arms is less than the non-inferiority margin, the study confirms the non-inferiority of the web tool to the genetic counseling in terms of the primary outcome.

The non-inferiority margin for this study was determined based on a previously conducted similar study. For the TARGET study, several factors underscore the appropriateness of using a non-inferiority trial. First, the web-based education model is likely to significantly increase convenience compared to traditional genetic counseling, which is delivered in person or through telehealth appointments with the genetic counselor. The introduction of the proposed web tool is expected to reduce logistical burdens for patients, such as those related to transportation and scheduling. Second, from the perspective of healthcare providers, the adoption of the proposed web tool could reduce the workload of genetic counselors, offering a potential solution for a shortage of counselors.

A total of 346 patients were randomly assigned in a 1:1 allocation to either of the two interventions. The primary analysis population was the modified intention-to-treat population, which included 153 on the web tool arm and 162 on the genetic counseling arm. The estimated difference in pre- post-change of the decisional conflict score between the two arms was -0.04 and the upper boundary of the corresponding confidence interval was 2.54, which was less than the predefined non-inferiority margin. The p-value for the non-inferiority test was 0.01. The authors reported results for the secondary endpoints, which included cancer genetics knowledge, attitude toward genetic testing, and satisfaction with genetic counseling. It was also reported that a total of 265 patients took genetic testing, and among the total, pathogenic variants were identified in 42 patients. The authors concluded that the study results support the use of a patient-driven web tool for expanding access to pre-test education for germline genetic testing among patients with prostate cancer. The authors also mentioned some limitations of this study, one of which is the limited racial and ethnic diversity among the study population. Some requirements to access the web-based tool, such as a computer and Wi-Fi access, may raise concerns about widening disparities in access to genetic services for cancer patients. Further studies to examine ways to address these limitations are needed.

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