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Tripartite Estimands for Adherence Causal Inference in Clinical Trials, With Applications for the Development of COVID-19 Treatments

Tripartite Estimands for Adherence Causal Inference in Clinical Trials, With Applications for the Development of COVID-19 Treatments

Arman Sabbaghi

Statistics, Purdue University

09 September 2021

In most clinical trials, patients are randomized to an experimental treatment and a control treatment in order to assess the efficacy of the former. Clinical trials generally have a prescriptive set of procedures for the conduct of the trial, which is called a protocol. For ethical and medical reasons, patients may not be able to follow the defined protocol and dosing. Specifically: 1.patients may have adverse events during the trial, 2.patients or their physicians may decide to discontinue their study medication, regardless of whether they are experiencing any benefit from the treatment, 3.patients or their physicians may feel that there is insufficient improvement in their condition (or even worsening) and likewise decide to terminate further use of their study medication, 4.personal circumstances that may keep a patient from continuing to participate in a clinical trial (e.g. moving out of town, family matters that take precedence such as the illness of a family member), or 5.patients may not be able to adhere to the protocol schedule - they miss visits, they forget to take their medication, they withdraw consent to take a battery of tests during the trial.Each of the disruptions to the planned clinical trial protocol as described above (as well as others that can occur in clinical trials) can obscure or confound the effect of both experimental and control treatments being studied.Estimating the so-called direct treatment effects is quite difficult and not as direct due to the biases that must be accounted for from the above disruptions. The proposed Tripartite Estimands framework circumvents the biases incurred by incorporating non-adherence to the above disruptions into the model for the outcomes of the different treatments, yielding results that capture a more comprehensive view of the treatment effects. While the Tripartite Approach can be useful in many clinical trial settings, it may have particular utility for the thousands of ongoing clinical trials of new medications NOT for COVID-19 that have experienced substantial disruptions due to the COVID-19 epidemic. For example, many trials were ongoing at the beginning of 2020 (in diabetes, pain, cancer, rheumatoid arthritis, asthma, etc.), and when the pandemic hit, many of the patients in these studies either 1.could not get to the study site for treatment due to quarantine or the site being closed 2.could not get their study medication because supply chains were severely disrupted or 3.actually contracted COVID-19 and had to discontinue their study medication or drop-out of the study in which they were enrolled.

[{ "PostingID": 4720, "Title": "SANOFI-EFC12261", "Description": "A 24-week, Open-label, Randomized, 2-arm Parallel Group, Multinational, Multi-center Clinical Trial to Compare the Efficacy and Safety of Lixisenatide Injected Prior to the Main Meal of the Day Versus Lixisenatide Injected Prior to Breakfast in Type 2 Diabetic Patients Not Adequately Controlled on Metformin" }]

Statistical Analysis Plan