Defining Vaso-Occlusive Crises in Sickle Cell Disease from the Perspective of the Patient: Development of a New Toolbox to Measure Treatment Outcomes

Background

Historically, outcomes in sickle cell disease clinical trials have relied on counting the number of patient medical contacts as the primary endpoint. However, pain crises often occur at home and are self-treated by the patient without a documented medical contact (Smith et al., 2005). Collecting home-based data using traditional paper diaries is often unreliable even with validated instruments (Coons et al., 2015). The purpose of this effort was to develop a content-valid daily diary (eDiary) using an electronic patient-reported outcome (ePRO) device to allow daily reporting of patients' health status in relationship to crisis and non-crisis days, pain, fatigue, functioning, analgesic medication use, non-medical treatment, and medical contacts.

Methods

The draft eDiary was developed based in part on previous research conducted by Smith et al. in the PiSCES study (2005) and studies by Palermo et al. (2004) and Bakshi et al. (2015). Development methods followed standard qualitative approaches consistent with the FDA PRO guidance and input from regulators. Patients recorded experience of a pain crisis and related healthcare use. Pain and fatigue were measured as single items with an 11-point numeric rating scale (NRS) from 0 = no pain/tiredness to 10 = worst pain/tiredness in a 24-hour recall period. Based on prior development work, the Return to Normal Activity Questionnaire (RNAQ) was included as a measure of functioning. It includes four dimensions of functioning (physical, social, self-care, daily activities) measured on an 11-point NRS. Data on pain medication use and non-medical treatments were also recorded.

In order to confirm the content validity of the eDiary items, one-time one-on-one in-person qualitative interviews with adolescent and adult patients ages 12 - 64 were conducted to ascertain concepts important to patients, to obtain patient input into the development of the items, and to assess scale comprehension and relevance. Interviews followed an open-ended, semi-structured interview guide and included both concept elicitation and cognitive interviewing components. During concept elicitation, participants were asked to describe a "pain crisis," how they perceived the beginning and end of a pain crisis, and what they considered to be a meaningful pain crisis treatment benefit. Using paper screen shots of the eDiary, the cognitive interview portion systematically evaluated the draft instrument, including clarity of instructions, understanding of key terms, interpretation of items, and appropriateness of response options. The eDiary was then piloted in a 6-month non-interventional, longitudinal study. Usability and feasibility of the eDiary and the ePRO device were evaluated at different time points as well as preliminary psychometrics and construct validity.

Results

Seventeen participants (6 adolescents 12-17 years; 11 adults 18-64 years) were interviewed. A pain crisis day was defined as a day when the patient experienced more pain than usual, was unable to do what they would normally do, was more tired than usual, and may require additional pain medication, medical treatment, or contact with a medical provider. Symptom patterns described by patients included pain worse than usual, fatigue, limitations in social, physical, and daily functioning, and seeking medical attention when symptoms become more severe. The most commonly endorsed treatment benefit was shorter duration of a pain crisis (N=16).

Thirty-five patients participated in a non-interventional, longitudinal study and completed interviews on the usability and feasibility of completing the eDiary and using the ePRO device. Overall, respondents found the eDiary easy to complete and the device easy to use, hold, and navigate. Participants were able to enter the data at home without assistance each day.

Conclusions

The eDiary expands the collection of data on SCD pain crises beyond the "classic endpoint" of medical contacts to the real-life scenario that includes pain crises occurring and treated at home. Evidence demonstrates that the eDiary is a relevant measure of pain, fatigue, and functional impairment during a pain crisis in patients with SCD. Usability/feasibility of the eDiary and the ePRO device were rated highly across factors such as ability to complete, convenience, and ease of use. Further testing of the eDiary operating characteristics and construct validation are ongoing.