The Patient’s Voice is Finally Being Heard in Diabetes Drug Research


Applied Clinical Trials

Type 2 diabetes mellitus is one of the Western world’s most common chronic conditions, with global prevalence increasing rapidly.

Type 2 diabetes mellitus (T2DM) is one of the Western world’s most common chronic conditions, with global prevalence increasing rapidly. For people with T2DM, it is important to control the level of glucose in the blood so as to maintain good health and decrease the risk (or at least delay the onset) of complications associated with the condition, including retinopathy, cardiovascular disease, nephropathy and neuropathy. It has long been acknowledged that achieving good control of blood glucose requires that healthcare professionals (HCPs) and patients work together to increase the patients’ knowledge, self-efficacy, and engagement in self-management behaviours, including taking their antihyperglycemic medication. However, adherence to diabetes medication regimens and other aspects of self-management are poor. In recent years, HCPs have recognized that the psychosocial aspects of living with diabetes must be prioritized to maximize the improvement in clinical outcomes; indeed a recent consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) highlights the importance of providing care that is respectful of and responsive to individual patient preferences, needs, and values.

In the past decade there have been a slew of antihyperglycemic medications complete pivotal clinical trials. The purpose of these trials is to establish the safety and efficacy of the medication and to inform marketing authorization decision-making. To this end, efficacy continues to be defined using a glucose-centric model, with primary endpoints based on blood glucose reduction and/or control. However, many newer medications offer additional benefits, including weight loss and blood pressure control. One may assume that this incremental clinical benefit, if well communicated to patients, would increase the utilization of, and adherence to, these newer therapies. However, the same therapies are oftentimes associated with negative side-effects, including gastrointenstinal and urinary complications, as well as unknown long-term safety profiles. All of this data will be utilized by marketing authorization decision-makers and reflected in product labelling if approved, but patients’ perceptions of, and experiences with medication are not routinely reflected in the same labelling. This is a problem for clinicians, prescribers and researchers interested in translational medicine; in establishing safety and efficacy in a trial and extrapolating that to non-trial environments, where we aim to maximise both clinical and psychosocial outcomes, or at least ensure that clinical outcomes are not achieved to the detriment of psychosocial ones. For this we need to gain insights into the patients’ subjective experience of therapy during the pivotal clinical trials.

Patient-Reported Outcome (PRO) questionnaires can be used to collect subjective clinical and psychosocial outcome data directly from the patients in clinical trials in order to describe the patient’s perception of a disease and its treatment(s) without the interpretation of responses by a physician or anyone else. They are particularly relevant and important when eliciting data that can only be captured by asking patients directly about how they feel or function. In looking at the newer classes of medication for T2DM (e.g. DPP-4 inhibitors, GLP-1 receptor analogues, novel insulins, SGLT-2 inhibitors) PRO questionnaires have been used to inform endpoints in most of the pivotal programs. As with the concept of blood glucose, a PRO can contain many related but distinct concepts, including symptoms of diabetes, health-related quality of life, psychological well-being, and treatment satisfaction. Each concept captures a different aspect of an individual’s experiences, thoughts, and feelings about T2DM and/or its treatment, although there is overlap. These, as well as perceived impact of weight, have all been measured as endpoints across the pivotal trials of the newer classes of medication for T2DM.

This PRO data has the potential to offer insights into the subjective experience of therapy and provide an informed perspective of the patients’ experience of treatment, and the associated patient-perceived benefit-to-risk ratio of the medication. Unfortunately, PRO data has not traditionally been held in high esteem in T2DM, partly owing to the traditional glucose-centric model of care, and partly owing to variable scientific credibility in their measurement and lack of clarity in their interpretation. However, in recent years the science of PROs has progressed considerably, with the US and European regulators releasing guidance documents clarifying their expectations of the scientific rigour that should be incorporated into the development and selection of PRO endpoints. A recent PRO extension to the CONSORT statement highlights that well developed PRO instruments can provide reliable and valid data in a manner which is meaningful to trialists, clinicians and patients alike. Despite this, the only PRO data to be reflected in product labelling for any antihyperglycemic mediation for T2DM is blood glucose (based on patient self-recording of objective data). That was, until the European approval of Trulicity® (dulaglutide) in November 2014.

In the clinical efficacy and safety section of the summary of product characteristics for Trulicity®, the European Medicines Agency (EMA) included the following text: "Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily." Demonstrating improvements from baseline in treatment satisfaction with Trulicity®, and showing that this improvement was greater with Trulicity® when compared to exenatide twice daily allows the developer of Trulicity®, Eli Lilly, to summarize with one metric the patients’ appraisal of his or her experience with treatment (i.e., both processes and outcomes), their perception of the relative balance between positive clinical outcomes and negative side-effects of Trulicity®, and their perceived benefit of improved clinical efficacy and reduced injection frequency versus an efficacious comparator. Perhaps most importantly for translational researchers, the data is important for clinical feasibility; a patient who is satisfied with their treatment is more likely to engage and adhere, and will thus therefore derive the maximal therapeutic benefit that the medication can offer.

Such PRO data, taken together with clinical efficacy and safety data, can assist HCPs in providing holistic care in T2DM that is in line with patient preferences, needs and values per the principles of evidence-based medicine. The inclusion of PRO data in the product label demonstrates a regulatory acknowledgement of the relevance of the patient perspective as it pertains to the saturated market of antihyperglycemic medication for T2DM, and gives HCPs confidence in the scientific credibility of the PRO endpoint.

To my mind therefore this is a huge step on the path to which one day, I hope, will yield an even more patient-centric model in which the patients’ perspective becomes a key endpoints in pivotal trials of atihyperglycemic medication for T2DM; perhaps even as part of a composite endpoint; improvement of clinical outcomes in the absence of psychosocial detriment.

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