The objectives of a study must be stated in specific terms and collect appropriate data. The endpoints (or outcomes), determined for each study participant, are the quantitative measurements required by the objectives.
An outcome measure or endpoint is the result of a intervention that is used to objectively determine the baseline function of a participant at the beginning of the clinical study. Once the intervention has commenced, the same instrument can be used to determine safety or efficacy. Outcome measures or endpoints should be measurable, which indicates that they are assessed by a numerical value.
Outcome measures are typically classified into three groups: primary, secondary, and exploratory. Their classification is informed by the clinical development plan for the product or intervention.
The primary and secondary endpoints should be pre-specified, meaning they are determined before the start of the study, and they are required by scientific journals and regulators to be analysed and reported in full. All data must be analysed and have results available prior to database lock. If you are unsure about the analysis plan or timeline for a particular endpoint this endpoint should be considered exploratory.
Primary outcome measures are defined by ClinicalTrials.gov as “the outcome measure of greatest importance specified in the protocol, usually the one used in the power calculation. Most clinical studies have one primary outcome measure, but a clinical study may have more than one”. The primary outcome measures the main reason why you are conducting your study.
It is advised to have just one primary outcome measure, however if this is not possible it is important to consider if the outcomes will be treated as co-primary endpoints or multiple primary endpoints. The decision will inform the statistical analysis.
Co-primary endpoints should be used when there are more than one primary endpoint and declare the study success only if both primary endpoints are statistically significant in favour of the experimental intervention. When co-primary endpoints are used, each primary endpoint is tested at significant level of 0.05.
Multiple primary endpoints can be used if there are more than one outcome endpoint. The study would be viewed as successful if either one of the primary endpoints is statistically significant in favour of the experimental treatment. In this case, each primary endpoint is tested at a significant level determined by the method for multiplicity adjustment. In simple terms the significance level (0.05) is divided by the number of endpoints (Bonferroni Method).
Secondary outcome measures are defined by ClinicalTrials.gov as “an outcome measure that is of lesser importance than a primary outcome measure but is part of a pre-specified analysis plan for evaluating the effects of the intervention or interventions under investigation in a clinical study and is not specified as an exploratory or other measure.
A clinical study may have more than one secondary outcome measure. However, ICH-GCP states that “Secondary variables are either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives”. The number of secondary variables should be limited and should be related to the limited number of questions to be answered in the trial. A study conducted after the initial exploratory phase of development can be criticized for having multiple secondary endpoints measuring outcomes not related to the primary aim of the study. Secondary outcome measure should be listed in the protocol in the order of importance in the clinical development program.
Consideration should be given to whether a secondary endpoint may be better identified as an exploratory endpoint. Appropriate secondary endpoints often are used to demonstrate additional effects after success on the primary endpoint or to provide evidence that a particular mechanism underlies a demonstrated clinical effect.
Exploratory outcome measures are typically used as a foundation for future studies and new hypotheses. Exploratory endpoints may also include clinically important events that are expected to occur too infrequently to show a treatment effect.
Atlantia’s Science and Regulatory can help you to classify your study objectives in the context of the regulatory requirements for your product and clinical develop plan. Schedule a meeting with our team to discuss your clinical research program.