Clinical Trial Endpoints and Important Outcomes for the Sickle Cell Disease Community
Crawford J Strunk, Regina Hartfield, Joel Nepomuceno, Edward Donnell IvyAbstract
Background
Sickle cell Disease (SCD), the most common monogenic disorder in the US affecting nearly 160,000 people[1] was first reported in the literature in 1910.[2] It was not until 1998, however, that hydroxyurea was first approved to treat SCD.[3] Since then, only three other disease modifying medicines, L-glutamine, crizanlizumab, and voxelotor have been approved.[4] These medicines had to show evidence of either an improvement in vaso-occlusive crisis (VOC) rate[5,6], or, as in the case of voxelotor[7], an improvement of hemoglobin that was felt to be a surrogate marker for improvement in organ function. Despite the suc cess of these approved therapies, several other promising treatments failed to meet their primary endpoints of improved rate of VOC.[8] Osunkwo et al demonstrated in the SWAY study that patient reported outcomes (PROs) are important to people living with sickle cell disease.[9, 10] FDA and other regulatory bodies and the pharmaceutical industry appear to be at odds related to how to translate PROs into clinically relevant and important endpoints and on how to engage the sickle cell community to determine what is meaningful to them. Sickle Cell Disease Association of America, Inc., (SCDAA) developed and conducted this survey to help determine clinically important and meaningful endpoints to the sickle cell community.
Methods
The SCDAA Chief Medical Officer and Vice Chief Medical officer, in anticipation of the American Society of Hematology (ASH) scientific workshop on clinical trial endpoints and disease scoring system, developed the survey to obtain information regarding what clinical trial endpoints may be meaningful to the sickle cell community. After the questions were vetted by the communications team, SCDAA president and membership engagement manager, the survey was posted to the SCDAA website. The questions were both demographic and clinical trial related. Patients were asked to provide information on age, number of ED/hospitalization visits per year, and if they were a warrior. Questions related to clinical trials included whether a reduction of pain episodes should be included as a clinical trial endpoint, symptom related outcomes, organ specific concerns, previous participation in clinical trials and reasons why people did not participate in clinical trials. Consent was not obtained explicitly; if SCD warriors or caregivers responded to the survey, consent was presumed. Responses to questions are categorized by the number of respondents to each question variable using descriptive statistics.
Results
A total of 42 people responded to the survey. Of the respondents, 41 were people living with SCD. Ages ranged from 18 to older than 60, with 14 respondents between 31-40. Twenty-three respondents were seen by a hematologist in a comprehensive sickle cell center. Most (32) had a primary care provider but less than half (20) of respondents worked full time; more than half (25) have used acute care 3 times or less in a year’s time. More than half of respondents (23) thought a reduction of VOC was an important endpoint in clinical trials. Regarding symptoms that are most important to measure, the top three answers were joint/bone pain (34), fatigue (27), and Inability to concentrate on tasks (16). The top three sickle cell related problems people were most concerned about were chronic pain from bone or joint disease (30), kidney disease/failure (26), and lung/breathing problems (21). Of the respondents, 11 were involved in a clinical trial. The top reasons why people did not want to participate were that it would interfere with work or other responsibilities (14), fear of the side effects of the drug or therapy (14), and unawareness of clinical trials (10) or that the research site was too far from home/transportation issues (10).
Conclusions
This is the first survey by the SCDAA of the SCD community regarding endpoints in SCD. Limitations of this survey include a small sample size and not using a validated questionnaire. However, this survey reinforces data previously published and suggests that while half of people living with SCD would like to continue to use a reduction in VOC as a valid endpoint, other important endpoints such as fatigue, chronic pain, and brain fog should be considered as part of patient reported endpoints in any study involving the sickle cell community. This survey could serve as a guide to future clinical trial development with warrior-driven endpoints in mind.