Determining the Primary Endpoint in Clinical Research

The purpose of clinical studies is to scientifically address an unmet clinical or regulatory need in the treatment of patients. Informing clinical practice and policy, the outcomes ultimately aim to improve health care. Working in a client centric manner, RQM+ helps navigate important trial nomenclature within your intended clinical investigation. This piece is concerned with explaining what a primary endpoint is and taking you through the thoughts that define a good primary endpoint. 

Definition and purpose 

The outcome measure that answers the reason for conducting a study is the primary endpoint. The term endpoint is distinct from the use of the term in animal research, where it describes the point at which to ethically end the study for the individual experimental animal. In clinical research, the primary endpoint operationalizes the design of the study and determines the meaningfulness of the study for policymakers (McLeod et al., 2019).

The primary endpoint translates the study´s hypothesis into a measurable, treatment-relevant entity and is defined prior to the start of study.  Its discriminatory reflection of the allocated treatment is seen as the sine qua non to assign success to the conduct of a study. However, this assumes a sufficiently powered study (Pocock and Stone, 2016). Surrogacy and compositeness of primary endpoints may be required to adequately depict realistically achievable outcomes in a trial or investigation (Weintraub et al., 2015; Gómez et al., 2014; Pocock et al., 2015). The statistics and medical writing team at RQM+ can advise on these issues. 

Descriptors of a primary endpoint

The primary endpoint can be developed using SMART categories (Purna Singh et al., 2022) and characteristically is all of the following:

• sensitive to change,
• clinically relevant,
• measurable using a validated method,
• of limited variability in the population of interest,
• objective,
• achievable at the timepoint of collecting relevant data.

The selection of a primary endpoint is typically clinician driven but adequately trained staff at RQM+ (medicine & science) will be able to assist in your deliberations. The target outcome may be replaced by a linked intermediate outcome, termed surrogate.  Careful consideration is required to demonstrate alignment of the surrogate parameter with the primary endpoint and justify its patient-relevant meaningfulness (Ciani et al., 2023). 

A primary endpoint should be complemented by patients´ own assessments of health-related quality of life in the shape of patient reported outcomes as a secondary endpoint (Pavlovic et al., 2014; Andrade, 2015). Efforts to standardize patient reported outcomes are increasingly being made and should be included where possible (e.g., Coens et al., 2020; Tong et al., 2022). RQM+ will research developments in your therapeutic area for you.

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Standardized definitions of endpoints 

In the interest of comparative meaningfulness of the outcomes of clinical studies, endpoints are being more accurately defined to effect precision-guided adaptation of clinical practice (e.g., Reddel et al., 2009; Buggy et al., 2018; Hicks et al., 2018; Kilickap et al., 2018; Battelino et al., 2023). It is important to use these definitions as they become available to allow accelerated compilation of evidence of treatment from randomized controlled trials and ideally from complementable outcomes of real-world evidence studies (LoCasale et al., 2021). Where subjective endpoints are standardisable using patient reported outcomes, patient engagement and involvement in clinical research may be increased (Myles et al., 2018). Staying abreast of these technical developments is a key remit of RQM+'s medical writing team, which you will directly benefit from when engaging with us.

Endpoint adjudication

Sometimes, subjective evaluations are needed to decide whether the clinical event corresponds to the attainment of the primary endpoint (Seltzer et al., 2017; Facile et al., 2022). Then, clinical endpoint adjudication by an independent Endpoint Adjudication Committee in clinical trials may become necessary. Clinical Research Organizations have formulated a statement on the independence of such committees where they are necessary (Spitzer et al., 2022) and RQM+ will refer to this.

Sample size calculation

Definition of the endpoint informs the sample size, meaning that the sample size is calculated based on the endpoint and assumptions made that relate to the variation in the intended study population. Secondary endpoints, by contrast, do not input in the sample size calculation but are designed to generate evidence that is supportive of the primary endpoint (McLeod et al., 2019). This is why patients' own assessment of their quality-of-life works best as secondary endpoint to the investigation.

Of note, the size of the sample depends not only on the variability of the outcome measure. It is also influenced by the effect size (or minimal clinically relevant difference), the power of the study and p-value (Gupta et al., 2016), typically draws on similar previous studies for the event rate and includes inflation by an estimated dropout rate (Kadam and Bhalerao, 2010). The medical writing team at RQM+ will assist you in identifying relevant key references for your intended investigation. We will also research for you the dropout rate for your envisaged patient population, duration, and type of intervention and discuss with you the possibility of conducting an interim analysis. When pre-specified, an interim analysis may yield an adjustment of the sample size (Ciolino et al., 2023) and inform you early of the likely success of your investigation as planned. A statistical analysis plan operationalizes the analytical approach and statistical methodology (Stevens et al., 2023) and is drafted by RQM+ according to your study specifics.  

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Analysis of potential covariates

When the primary endpoint is chosen, it is important to consider so-called baseline covariates: these are variables which have or may have an association with your chosen primary outcome measure. Adjustment for these covariates improves the efficiency of the analysis because it avoids a conditional bias from chance covariate imbalance (EMA, 2013). This statistical adjustment needs to be prespecified (Pocock and Stone, 2016) and is routine to RQM+'s statisticians.

Randomization is thought to lead to a balancing of potential confounders (given a large enough sample size), allowing causal inference of a treatment effect.  However, typically, rather than balancing confounders, randomization seeks to ensure an even distribution of potential confounding causes. The concept of confounding causes rather than confounding factors is fundamentally important because it also influences how we think about a possible selection bias in observational studies (Fuller, 2019).

Conclusion

When conducting a clinical investigation, standards within the normative framework (regulations and ethics) of designing, conducting, and reporting clinical studies must be followed. The primary endpoint measures the primary outcome of a study and may map to one of several categories: safety, effectiveness / efficacy, performance (clinical / technical), clinical benefit. Its choice and attainment are relevant to treatment, health care policy and/or regulatory approval.

Regulatory bodies may themselves shape the suitability of surrogate endpoints (Kordecka et al., 2019). Policymakers, however, are but one group of stakeholders in clinical studies. It is viewed as desirable by clinicians that patients themselves input into the meaningfulness of primary endpoints through their representations (Bundgaard et al., 2022). In fact, more recently, participants in clinical research are appreciated as emancipated partners who inform study design and feasibility and whose data contribute to answering health care questions (Faulkner et al., 2023).  RQM+ can advise on these novel aspects.

Compositeness of primary endpoints is viewed critically generally and by RQM+ because composite primary endpoints are seldom in equipoise in terms of severity, frequency, and importance to the patient (Palileo-Villanueva and Dans, 2020). Secondary endpoints, however, are valuable as supportive, additional measures of relevance to the primary endpoint (Vetter and Mascha, 2017) and you may tap into RQM+'s ample experience across many therapeutic areas. 

Stay tuned next week for our technical brief on, "Insight into RQM+ Consultation: How the most appropriate study design is determined." Subscribe to our blog to be notified when it is published!

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