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Revealing the missing evidence: Randomised real-life studies in basal insulin therapy

Published on 10/07/17 at 11:14am

Sanofi’s Riccardo Perfetti, Head of Global Diabetes, and Jukka Westerbacka, Medical Director, Global Medical Affairs, discuss how the significance of data accrued through real-life studies is becoming more widely recognised and their differences to traditional clinical settings. They further review Sanofi’s currently ongoing trials and how they are helping to better establish the safety profile of their basal insulin.

What is real-world evidence?

Real-world data (RWD) comprises the raw information about patient characteristics, the care they receive, patient-reported outcomes (PROs), healthcare resources consumed, and the outcomes achieved during actual medical practice. Sources of RWD include patient registries, observational and randomised studies that reflect real-world clinical practice, health surveys, PRO analyses, resource utilisation research and retrospective examination of health records/claims databases. While the terminology of real-world evidence (RWE) typically refers to the knowledge created when answering specific research questions utilising data derived from the routine practice of medicine, it has recently been adapted to include analytic projects initiated without a pre-specified hypothesis.

While randomised controlled trials (RCTs) provide a gold standard of evidence on safety and efficacy, the need for RWE reflects the inherent limitations of RCT study designs. The trials are usually performed in highly selected populations, in clinical settings that do not reflect the day-to-day experience of real-life patients and with levels of care and support that exceed what is available in everyday clinical practice. As an example of participant selection, an RCT in diabetes might select individuals with type 2 diabetes (T2DM) on prior basal-bolus insulin with glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) and a basal insulin dose of >42 U/day, while excluding those who had used oral antihyperglycaemic drugs other than metformin in the last three months. Thus, the ‘external validity’ of results from RCTs may be limited to a defined subset of the people with diabetes that a clinician may see daily. If RCTs are not readily ‘generalisable’ to the types of individual with diabetes that are seen in daily practice, then their results might not always be useful for decision making. Real-life studies (RLS) include more representative patient populations that are not limited by factors such as, body mass index, upper limit of HbA1c, prior hypoglycaemia, age, or concomitant medications; clinical parameters that may be used to exclude people from RCTs. In addition, RLS can include individuals that are often excluded from RCTs such as those with severe comorbidities, pregnant or lactating women, and children. In such groups, clinical evidence from RCTs may be scarce, and RWE can provide very useful information. Finally, RWE describes patient and healthcare practitioner behaviour that takes place outside of the constraints associated the clinical trial infrastructure, which typically alter adherence and compliance.

Decision makers have an increasing interest in real-world evidence

Owing to the inherent limitations of RCTs, decision makers such as prescribers, regulators, payers and patients are increasingly turning to RWE on safety and effectiveness to justify the use of particular treatments as well as reimbursement conclusions. Composite clinical endpoints, such as the proportion of individuals who achieve HbA1c targets without experiencing hypoglycaemia, can also help guide treatment choices. PROs and attainment of metrics such as Healthcare Effectiveness Data and Information Set (HEDIS) can demonstrate care quality. Healthcare resource utilisation can determine the impact of treatment choices on cost of care. In support of this, the US Food and Drug Administration have stated that they will publish draft guidance on how RWE can be used to support premarketing and post-marketing safety and efficacy assessments.

Features of real-life studies in diabetes

A strength of RLS is the ability to characterise effectiveness of diabetes interventions in large multinational populations. In the A1chieve study, which has enrolled over 65,000 participants, mean baseline HbA1c was surprisingly poor (9.5 %, 80.3 mmol/mol), however, switching to or initiating a basal insulin analogue resulted in improvements in HbA1c of around 2 % (21.9 mmol/mol) over six months and a decrease in hypoglycaemia risk in those switching from non-analogue insulins. A critical limitation of this study is the lack of a comparator arm and this obviously compromises the quality of the data and the possibility for a rigorous interpretation of the findings. Indeed, most RLS conducted to date have been neither prospective, randomised nor interventional, which limits the conclusions that can be drawn from the studies. Conversely, the Gla-300 RLS programme aims to expand the clinical evidence on the effectiveness and safety of this basal insulin in a real-world setting, thereby permitting the results of these studies to be generalisable and help to inform patient, physician choices and decisions.

Real-world evidence supporting insulin glargine 300 U/mL

In contrast to previous RWE in diabetes, the state-of-the-art RWE programme supporting Gla-300 includes both retrospective analyses as well as prospective studies with both randomised interventional and matched control study designs.

Retrospective analyses

Retrospective analyses will be performed to examine the benefits of switching from insulin glargine 100 U/mL (Gla-100) to the longer acting Gla-300 (non-comparative), changing to or initiating Gla‑300 versus Gla-100 (comparative), and the potential benefits of Gla-300 versus other basal insulins including Gla-100, insulin detemir and insulin degludec. Retrospective analyses have identified that individuals with T2DM on a range of basal insulins (Gla-100, insulin detemir, and neutral protamine Hagedorn) can benefit from switching to Gla-300, which results in significant reductions of HbA1c of between 0.64 % and 0.96 % (7 mmol/mol and 10.5 mmol/mol) as well as reductions in hypoglycaemia risk of up to 77% and reduced health resource utilisation.

Prospective registry

The Diabetes Unmet Needs with basal insulin Evaluation registry has collected data on the management of individuals with T2DM who started treatment with a long-acting basal insulin within the last 12 months or were newly initiated on basal insulin treatment. One aim of the study was to investigate the potential association between the achievement of glycaemic targets and hypoglycaemic events. As hypoglycaemia may be related to other unfavourable clinical and health economical outcomes, multiple secondary endpoints were also assessed to describe the potential impact of the event (e.g. weight gain, fear of hypoglycaemia, and healthcare resource utilisation). The Hypoglycemia Fear Survey questionnaire was also used to identify concerns about low blood sugar and the techniques that individuals use to avoid this.

Randomised, prospective and interventional RLS           

The FDA have recently stated that “…one of the most important advances in clinical trial methodology may be the broadening of the application of randomisation outside of more typical venues for clinical trials, such as academic research centres”. Such randomised RLS are currently being undertaken with Gla-300 with the ACHIEVE Control (US), REACH Control (Europe and Latin America) and REGAIN Control (Europe and Latin America) studies. The aim of these analyses is to answer questions regarding Gla-300 versus other basal insulins (including Gla-100) that are difficult to answer with standard RCTs, such as:

1). Do the pharmacokinetic and pharmacodynamic profiles of Gla-300 enable more individuals to achieve HbA1c targets?

2). Do PROs indicate greater treatment satisfaction and persistence with Gla-300?

3). Does achievement of HbA1c goals with a lower risk of hypoglycaemia with Gla-300 than Gla-100 in RCTs translate into decreased resource use or associated healthcare costs?

The primary endpoint of ACHIEVE Control is the proportion of participants achieving individualised HbA1c targets (HEDIS criteria) without hypoglycaemia. Both REACH Control and REGAIN Control have change in HbA1c as their primary endpoint. Key secondary outcomes include hypoglycaemia (incidence and rate), persistence with insulin treatment, HbA1c‑target achievement, weight change, basal insulin dose, need for treatment intensification, PROs, and healthcare utilisation. ACHIEVE Control will obtain data using the Hypoglycaemia Patient Questionnaire Global Effectiveness Scale, while the REACH Control and REGAIN Control studies will utilise the Hypoglycemia Control Subscale. All three studies will assess patient satisfaction using the Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) and Change (DTSQc) version. ACHIEVE Control will investigate healthcare resource utilisation in terms of hospitalisations, accident and emergency visits, and general practitioner/specialist visits.

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