Overcoming challenges in obesity-related clinical trials 

Weighing scale

Deirdre Albertson, Vice President, Project Management, Cardiovascular/Metabolic Division, ICON, Jack L Martin, MD, FACC, Senior Director, Cardiovascular Therapeutics, Drug Development Solutions, ICON and Simon Bruce, MD VP, Internal Medicine, Drug Development Solutions, ICON, assess the clinical trials landscape for obesity and ask why patient centricity is key to overcoming common challenges in the sector.   

Recent advancements in obesity treatments, exemplified by the approvals of semaglutide and tirzepatide, have spotlighted the field for healthcare providers and developers. With this heightened interest, insight into the current state of obesity research and its future direction is particularly valuable.  

An ICON survey of over 100 drug development professionals in obesity research revealed optimism about future therapies, with a significant shift towards combination treatments for obesity and its comorbidities. While 66% of respondents were confident in the likelihood of success for prospects in their organisations’ obesity pipeline, most respondents (64%) believe the focus of future treatment will be combination therapy, targeting both obesity and its comorbidities, rather than single therapies (17%) such as semaglutide, tirzepatide and retratrutide.  

Some of the current optimism may be related to the nearly two decades of experience we now have with certain incretin hormone therapies based on glucagon-like peptide receptor agonists (GLP-1 RA), which modulate appetite, satiation and food intake and have revolutionised treatment for type 2 diabetes. Semaglutide, a long-acting injectable GLP-1 RA, has shown excellent weight loss efficacy in obese non-diabetic patients, and is being further developed as an oral formulation. Moreover, newer incretin hormone therapies, such as tirzepatide and retratrutide, show further weight loss efficacy by including additional hormone analogs, such as glucose-dependent insulinotropic polypeptide and glucagon, for dual and triple incretin agonist therapy. New potential mechanisms being investigated may address energy expenditure and preservation of lean muscle mass, which also may ultimately add to combination treatment approaches. 

Another notable survey insight is that many survey respondents cited “clinical trials” as the most challenging stage of obesity drug or device development (31% of respondents) — more than twice as many as for the second most challenging stage, regulatory submission and approval (12%). There are many factors that contribute to the difficulty of clinical trials related to obesity, and incorporating patient centricity can help to overcome several significant obstacles. By considering the role of patient centricity in clinical trial design, patient retention and engagement for long-term follow up, researchers and sponsors can better position their obesity-related clinical trials for success. 

Clinical trial design and patient centricity

Integrating patient centricity into trial design is one method of ensuring that it is a principal element of the trial, and that participants will be able to benefit from it. And many survey respondents are making the effort to do just that: Approximately 45% of survey respondents reported employing patient-centric trial design in their obesity-related clinical studies. One design component that can contribute to patient centricity is decentralisation. Full and hybrid decentralised trials (DCTs) have become increasingly feasible and common over the past several years. These allow participants to minimise their number of on-site clinic visits, or, in the case of fully decentralised trials, to enrol and participate without having to necessarily first find a specific investigative site. 

DCTs can make it easier for interested patients to take part in a study by allowing them to self-refer through the use of online screening tools, since common measures – such as height and weight – make it relatively simple for potential participants to determine eligibility. Digital tools, such as heart rate, glucose and exercise monitors in addition to smartphone applications such as e-diaries and patient surveys, can allow participants to provide data to researchers with minimal effort. DCTs can decrease the burden of participation by reducing or eliminating the need to commit time and resources to frequent visits to a centralised clinical trial site.  

Improving retention

Although motivation to participate in weight loss trials is usually not a problem, effective patient retention strategies are vital, especially given the unique challenges of obesity trials, such as side effects and disillusionment among placebo group participants. Emphasising patient centricity by aligning trial processes with participants’ needs and providing continuous support and flexibility can mitigate these challenges.  

For example, many obesity incretin therapies have transient gastrointestinal side effects, including nausea, vomiting and diarrhoea, that require titration and management. Determining the best starting doses and titration patterns is often a goal of early phase clinical development. If the dose is not optimised, these side effects may become too unpleasant and cause participants to choose to exit a trial. Another challenge in maintaining participant engagement is the lack of perceived effectiveness. In many cases, it is easy for patients placed in an obesity drug trial’s placebo arm to figure out that they are not losing weight, and, as a result, they may remove themselves from the trial in pursuit of an effective treatment.  

Prioritising patient centricity by understanding the patient’s journey and focusing on the patient’s needs is one beneficial strategy to reduce patient participation barriers and increase retention. For example, consistent communication and engagement with patients throughout the trial – such as through proactive patient education on the investigational product – may help to mitigate attrition. In the recent ICON survey, respondents believed that the factors that would most likely improve patient retention were: (1) providing flexibility with regard to appointments to suit the patient’s schedule (36%); (2) customising patient support services (33%); and (3) reducing travel burden, such as through travel stipends (32%). These responses reflect the importance of working with patients to accommodate their specific needs. 

Patient engagement for long-term follow up

For long-term follow up, maintaining engagement is crucial, necessitating innovative approaches for efficient data collection over extended periods. And facilitating this alongside expense concerns is no easy task: 44% of survey respondents cited long-term follow up as the biggest challenge of obesity-related clinical trials. Obesity trials may extend for years due to the importance of compiling an adequate safety database. The significant expense to support long-term trial extensions must result in usable long-term safety and outcome data, and therefore requires a balance between efficiency in trial design/execution and sufficient interaction with subjects to ensure ongoing engagement and retention.  

Maintaining patient engagement over longer periods of time requires measures beyond what may be necessary in initial clinical trials. Digital health technology, including wearable devices and remote data collection, can allow patients to engage with a study remotely, with fewer required site visits. Adherence reminders and check-ins can also be helpful in keeping the clinical trial fresh in the minds of participants. 

An important additional new tool, clinical trial tokenisation, can facilitate collection of even longer-term safety and outcome data beyond the original clinical trial period. Clinical trial participants can consent to tokenisation which, by deidentifying participants’ personal information, allows for continued collection of anonymised data through second-party sources, including electronic health records, even after participants have completed the study. In addition to removing the dependence on patients’ continued participation and the reliability of their recollections, tokenisation can provide deeper insights on trends and patterns over time, bridging the gap between registrational clinical trials and real-world data. 

Other design considerations for success

While patient-centric trial design was the second-most employed design component for respondents’ obesity-related clinical studies, the first was multi-indication studies (50%). Newer therapies for weight loss are being studied and used for obesity-associated indications including diabetes, dyslipidemia with fatty liver, cardiovascular and renal disease. For sponsors interested in the exploration and development of a treatment for multiple indications, such as obesity and comorbidities, employing master protocols in trial design may present efficiencies and flexibility in research. Master protocols offer an overarching set of procedures, which allow for screening across metabolic phenotypes and allocation of subjects into one or more sub-studies testing multiple hypotheses, providing efficiencies in recruitment and study site selection, as well as data and analysis benefits such as sharing of control subjects. 

Basket trials are one example of a design that utilises master protocols. Because they enable a treatment to be tested across a diverse span of diseases that share a commonality, basket trials are well suited for the interconnected therapeutic areas related to obesity. Another design that uses master protocols is a platform trial, which evaluates and compares multiple interventions for one indication through multiple trial arms. These trials are adaptable, allowing researchers to begin additional arms or evaluate results of an arm while the trial is ongoing, allowing sponsors to focus effort and resources on the most promising assets, while dropping trial arms with treatments that prove to be ineffective. 

Taking patient centricity past clinical trials

This condensed overview, alongside ICON’s survey results, underscores the importance of patient-centric approaches throughout the clinical trial and treatment development process for obesity, reflecting industry trends towards more inclusive and efficient research methodologies. But the importance of patient centricity does not end with research. Several of the key barriers to reducing obesity in the general population, as identified by survey respondents, are questions of patient centricity, such as patient education on available treatments (34%). As obesity prevalence grows – with one billion people expected to be living with obesity by the year 2030 – ensuring patient access to and education about new treatments is essential. Even beyond clinical trials, maintaining a patient-centric approach in treatment dissemination will be paramount.  

References  

1: https://www.iconplc.com/insights/therapeutics/endocrine-and-metabolic-disorders/obesity/trends-and-challenges-in-obesity-research  

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