Clinical Operations Project Manager, Kayentis

Ally Hochman

Arthritis is a general term categorized by acute or chronic inflammation of the joints. The condition may cause a variety of symptoms, most commonly pain, stiffness, decreased range of motion, and joint deformities. The pathology of arthritis is not limited to the joint itself and can extend to the surrounding connective tissues and structures throughout the body having a global impact on ones’ quality of life.

Clinical research in arthritis often includes clinical outcome assessments (COAs), such as patient-reported outcomes (PROs), clinician-reported outcomes (ClinROs) and observer-related outcomes (ObsROs). While objective measures are a necessity, the extent of the patient experience cannot be captured simply with a physical exam, lab tests, or imaging. Only including these types of assessments would provide a limited understanding of the overall condition, which could lead to reduced therapeutic advancements, treatments that do not fully manage patient symptoms, and restricted scope of research that is not targeted to patient needs. PROs allow patients to be active participants in the research conducted and contribute their insight as it relates to their health condition. Additionally, regulatory bodies are increasingly looking at COAs to guide patient-focused research and decision making.

Of the many PROs used in arthritis research, some questionnaires are centered around specific symptoms such as fatigue, pain, and perceived physical function. Others are more specific to the subset of arthritis being studied. Collecting and assessing PROs allows the full breadth of symptoms and disease impact to be quantified. Of most importance, PROs allow for research to focus on what matters most to patients with the condition being studied.

Fatigue is a common symptom expressed by patients diagnosed with arthritis often accompanied with an inflammatory disease process and/or chronic pain. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) aims to assess patients’ self-report regarding their level of fatigue and the impact that their activities of daily living. This 13-item questionnaire is used in patients diagnosed with rheumatoid arthritis, psoriatic arthritis, and osteoarthritis, as well as a multitude of other chronic health conditions.

 The visual analog scale (VAS) offers a way for patients to quantify their pain using a horizontal line rating their pain from no pain on the left to the worst their pain can be on the right. This simple method is transferrable to different locations of pain and different disease types. For example, knee pain VAS may be used in a patient with osteoarthritis while back pain VAS categorizes the intensity of inflammatory back pain that can present in arthritis types such as juvenile idiopathic, reactive, and psoriatic arthritis. The VAS is often included under other PROs when measuring the extent of disease impact. For instance, the patient global assessment for psoriatic arthritis pain uses several VAS scales for musculoskeletal and dermatological manifestations of psoriatic arthritis.

Furthermore, research has shown a link between pain severity and mental health in patients with arthritis. High pain levels are correlated with increased depression and anxiety. Additionally, anxiety and depression can lower one’s threshold for pain, creating a cycle of poor health, pain, and a negative impact on mental health. By using PROs to examine pain, researchers can not only examine pain levels and how those levels change in response to treatment but can also use that information to inform care focusing on comprehensive management and overall well-being. 

 As indicated, a key focus of arthritis research is assessing patients’ perception of their own health and their quality of life. The Health Assessment Questionnaire-Disability Index (HAQ-DI) assesses activities such as walking, eating, dressing, grip, and reach to allow patients to explain how their disease is impacting activities of daily living. The Short Form-36 (SF-36) is another PRO that is widely used to analyze health-related quality of life. Both have been used in rheumatoid arthritis and a variety of other chronic health conditions to assess changes in quality of life. Use of PROs that analyze quality of life and how patients are experiencing their disease is vital to provide patients with a voice to explain their symptoms, as well as how their disease impacts their ability to live a fulfilled life.

Some PROs allow for a more comprehensive collection of data related to the patients’ disease activity. The Clinical Disease Activity Index (CDAI) is a composite index that assesses disease activity based on joint swelling, tenderness, and the patient and physician’s global assessment. The GRAppa Composite ScorE (GRACE) is another composite score specific to psoriatic arthritis that looks at joints, skin, function, pain, and quality of life. The data collected from multiple variables to form the composite score allows researchers to view different aspects of the disease objectively and subjectively, depending on the patients’ insight to evaluate their disease progression and response to treatment. Using these types of PROs across a trial can provide valuable information on symptom range and related trends.

 In arthritis and other inflammatory and immune-mediated conditions, symptoms can vary not only from patient to patient, but can change day to day in the same patient. In certain types of arthritis, there may be periods where symptoms are more intense, and times where symptoms are less noticeable. Due to this fluctuation, it can be difficult for patients to accurately recount their symptoms. A diary format takes this into consideration by allowing for data to be collected in real time. Many of the PROs referenced can be formatted as eDiaries to be accessed by patients remotely. For example, PROs focused on fatigue or pain can evaluate the change in these symptoms overtime, how well patients respond to intervention, and ultimately lead to more individualized care as these symptoms are tracked, assessed, and analyzed.

eCOA systems have been shown to enhance legibility, logic, attributability, accuracy, and timeliness of data capture, as well as allow for both on- and off-site data collection. Remote data collection can decrease geographic barriers and add flexibility for study participants. Symptoms of arthritis, such as pain, fatigue, and physical limitations, can be disruptive and difficult for patients to manage. As such, these symptoms can greatly interfere with patients’ quality of life and ability to perform activities of daily living, including traveling on-site for a study visit. In the event the patient is unable to come in for their visit due to these barriers, there is the adaptability for electronic data collection to be done remotely. This increases the likelihood of data to be collected within the visit window, prevents data loss, and supports patients continued participation in the trial.

Availability of complex assessments in a straightforward system eases the burden of data collection for sites and patients. ePROs can be programmed according to the needs of the trial per protocol, and of the individual patient. Some researchers may choose to study multiple disease subsets within the same trial design. In this case, the ePROs can be specified with programmed triggers to allow for completion of the measures depending on the patients’ pathology. For example, if a trial is to include both patients with rheumatoid and psoriatic arthritis and using the FACIT-Fatigue and GRACE questionnaires mentioned, the eCOA platform should be programmed such that only patients with psoriatic arthritis should be presented with the option to complete the GRACE. Patients with psoriatic arthritis and rheumatoid arthritis should both have the FACIT-Fatigue available for completion.

Certain PROs are used in arthritis research, such as the CDAI and other disease activity scores (DAS) that weigh factors such as patient feedback, lab results, and joint swelling and tenderness, include score calculations to measure disease activity and response. These scores can be calculated automatically in an electronic solution and be available in real time for sites to review and monitor the data.

Depending on the trial design, eDiaries may be utilized to capture data directly from patients. eDiaries can be programmed with patient engagement tools such as reminder alert systems and allow for data capture in real time. This is especially important in the arthritis types with patterns of flare-ups and remission to assure the diary data is being collected as timely and accurately as possible.

As symptoms change over time, patients may not accurately recall their experience later. The use of daily electronic PRO diaries in arthritis has been shown to reduce recall bias and improve the quality of PRO data collection. Electronic diaries and ePROs can be implemented according to a pre-defined schedule, with only the expected questionnaire opening at the determined time slot. For instance, if the recall period is one week prior to the next study visit, the eDiary can be programmed to only open seven days prior to the defined visit date. By programming the ePROs and eDiary so only the correct questionnaires are available at the correct time, there is a decreased risk of capturing unwanted data. 

The use of ePROs in arthritis involves careful consideration and appropriate management to ensure success throughout the duration of the trial. When implementing ePROs, the device design and interface should be user friendly, programmed as specified in the protocol, and the patient experience must be prioritized.

Arthritis management focuses on reducing pain, minimizing joint damage, and improving function and quality of life. Therefore, the ePRO design needs to support those goals. The ePROs should be concise and easy to use with minimal scrolling and typing required by the patient. Features such as interview mode can be added to allow for ePRO completion through dictation, which can minimize joint strain.

Best practice includes user acceptance testing (UAT) for sponsors to review that the ePROs meet the needs of the specific trial. Study teams, clinical sites, and patients must be properly trained in using the technology and training materials should be readily available to refer to as needed. Site teams should be familiar with assistive devices commonly used and able to support the patients’ use of these tools when using a provisioned device or smartphone. Site teams must also be trained in the full capabilities of the ePROs that have been designed specifically for this patient population.

Examples of training options include investigator meeting presentations and demonstrations for clinical staff, online training using material provided by the eCOA solution providers, and videos to be reviewed by relevant staff. It is recommended that refresher trainings are conducted, as recruitment can occur several weeks after the initial training sessions or site staff can change during the course of the study.

Project management teams with clinical experience and eCOA expertise can support the implementation, training, and management of these ePROs. Clinical project managers successfully meet client needs due to their familiarity with medical terminology and arthritis pathology, research requirements, and protocol adherence. These teams are necessary to assess, mitigate, and manage trial-related risks, anticipate challenges sites and patients may face throughout the trial, and provide guidance and solutions.

Clinical project managers work directly with sites to provide strategies to support arthritis patients, such as reinforcing options for remote data collection or interview mode and listening to patient feedback. By having a direct link to the sites, project management teams can understand the arthritis patients’ experience and are able to develop specific strategies to support and improve their experience. These strategies are aimed to support the goals of arthritis treatment by improving functionality of the ePROs to reduce patient stress and minimize any impact on the patients’ joints. Clinical project managers are also essential in assuring timelines are met and support in inspection readiness and in reaching key trial milestones.

Data management activities must be conducted throughout the trial to assure data quality. Full audit trails should be available for review, relevant edit checks implemented, and the data cleaned to account for any inconsistencies. As the data from ePROs and eDiaries is becoming more relevant for clinical trials in arthritis, and even becoming a primary endpoint in a rising number of trials, it is vital the data is comprehensive and its integrity and quality are maintained. In an electronic portal, the data can be easily viewed to support clinical trial monitoring and query management. The electronic portal should also be able to integrate with interactive response technology (IRT) systems for efficiency, decreased costs, and increased data accuracy.

Global research in arthritis continues to focus on developing trials to provide new drugs and advancements to current treatment options. PROs are increasingly being reviewed to determine efficacy and exploratory outcomes within the research context.

However, the content of PROs used in both the clinical and research setting must be continually reviewed and improved upon. New PROs must be developed to ensure they are asking the right questions and addressing topics that matter most to patients with arthritis. Implementing new PROs is a lengthy process, but certain initiatives, such as the NIH funded Patient-Reported Outcomes Measurement System (PROMIS), are actively working to develop and validate PROs for research and clinical practice.

Technology must also advance alongside these developments by continuing to be patient-focused. This includes ongoing integration of ePROs and eDiaries in clinical protocols and the addition of other functions, such as interview mode and televisit capabilities, that will reduce the burden and, as such, improve the patient’s trial journey. Technology adapted to focus on patient engagement, support study teams, and provide quality data will lead to more efficient patient-centered research, better outcomes, and improved care for arthritis patients.

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