Individualized versus standardized risk assessment in patients at high risk for adverse drug reactions (IDrug) - study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Elderly patients are particularly vulnerable to adverse drug reactions, especially if they are affected by additional risk factors such as multimorbidity, polypharmacy, impaired renal function and intake of drugs with high risk potential. Apart from these clinical parameters, drug safety and efficacy can be influenced by pharmacogenetic factors. Evidence-based recommendations concerning drug-gene-combinations have been issued by international consortia and in drug labels. However, clinical benefit of providing information on individual patient factors in a comprehensive risk assessment aiming to reduce the occurrence and severity of adverse drug reactions is not evident. Purpose of this randomized controlled trial is to compare the effect of a concise individual risk information leaflet with standard information on risk factors for side effects. METHODS/DESIGN: The trial was designed as a prospective, two-arm, randomized, controlled, multicenter, pragmatic study. 960 elderly, multimorbid outpatients in general medicine are included if they take at least one high risk and one other long-term drug (polymedication). As high risk "index drugs" oral anticoagulants and antiplatelets were chosen because of their specific, objectively assessable side effects. Following randomization, test group patients receive an individualized risk assessment leaflet evaluating their personal data concerning bleeding- and thromboembolic-risk-scores, potential drug-drug-interactions, age, renal function and pharmacogenetic factors. Control group patients obtain a standardized leaflet only containing general information on these criteria. Follow-up period is 9 months for each patient. Primary endpoint is the occurrence of a thromboembolic/bleeding event or death. Secondary endpoints are other adverse drug reactions, hospital admissions, specialist referrals and medication changes due to adverse drug reactions, the patients' adherence to medication regimen as well as health related quality of life, mortality and resulting costs. DISCUSSION: Despite extensive evidence of risk factors for adverse drug reactions, there are few prospective trial data about an individualized risk assessment including pharmacogenetic information to increase patient safety. By conducting a health economic analysis, we will evaluate if the application of an individualized drug therapy in daily routine is cost-effective. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00006256 , date of registration 09/01/15.

Choosing Appropriate Estimands in Clinical Trials.

Lack of adherence to study protocol and missing data are often unavoidable in clinical trials, and both increase the need to differentiate between the ideal treatment effect if the medication is taken as directed and the treatment effect in presence of the actual adherence pattern. In this regard, estimands have become the focus of attention. An estimand is simply that which is being estimated. In the context of treatment benefit, an estimand may address either efficacy or effectiveness aspects. Defining the estimand of interest is an essential step to take before deciding on trial design and primary analysis. The choice of estimand has consequences for various other factors to be considered during any clinical trial's planning phase. This study presents a process chart including all aspects to consider during planning. After deciding on the primary estimand, the trial design should be specified, followed by the primary analysis. Both should appropriately address the chosen estimand. Finally, sensitivity analyses should be taken into account. Provided are suggestions for all the planning steps involved, especially on choosing between efficacy and effectiveness, and relevant examples from clinical practice to illustrate them. It is recommended that one bear in mind the process chart during planning of any clinical trial and give reasonable justification for each decision in the study protocol.