Sickle Cell Disease Therapies: ASH and FDA Guideline

The American Society of Hematology (ASH) has released the most comprehensive set of recommendations to date aimed at establishing uniformity and global standards for clinical trial endpoints used to evaluate new therapies for sickle cell disease (SCD). The new recommendations have been published in Blood Advances.

Sickle cell disease (SCD) is among the most common genetic diseases in the United States, affecting approximately 100,000 people. For people suffering from sickle cell disease, red blood cells become crescent or sickle-shaped, instead of round, contributing to the vaso-occlusive crises this patient population experiences.

Some of the physical complications include acute pain crises, joint and organ damage, impaired cognitive function, and a reduced life expectancy.

During the American Society of Hematology (ASH) 2019 annual meeting, investigators released a comprehensive new set of recommendations that establish uniformity and global standards for clinical trial endpoints to evaluate sickle cell disease therapies. Currently, there are only 4 FDA approved treatments for sickle cell. Bone marrow transplants are also a cure for a portion of sickle cell patients, but not everyone. There are other therapies being worked on in the pipeline, including potentially curative gene therapies.

“There are a number of investigational drugs in development that target different manifestations of SCD,” Julie Panepinto, MD, MSPH, Professor of Pediatric Hematology, Medical College of Wisconsin/Children's Wisconsin, co-chair of ASH's Guideline Oversight Committee, and co-chair of the workshop said in a statement. “However, there are no clear standardized endpoints for evaluating the effect of therapies on clinical outcomes and patient well-being.”

Panepinto said clinical research should generally incorporate endpoints that are both measurable and directly beneficial to the patient based on their preferences and experiences.

“What's happening in SCD is really exciting and many of us feel we are on the cusp of identifying multiple disease-modifying therapies,” Panepinto said. “The field is exploding, so we want to be sure we are measuring relevant endpoints for researchers, clinicians, and patients because that helps us advance the field and get new therapies approved.”

In order to address the global burden of SCD, ASH and the FDA convened seven panels of clinicians, investigators, and people with SCD in a two-day workshop to bring uniformity and standards to existing endpoints, identify gaps, and propose the development of new endpoints as a focus for future research. The panel conducted extensive literature reviews, assessed available evidence, and used expert judgement to identify existing endpoints that can be incorporated into clinical trials.

The panels focused on the following areas:

• Patient-reported outcomes (PROs) – the panel suggested that future trials should measure the impact in three key domains: crisis and non-crisis pain; affect (including emotional impact, sleep quality and fatigue), and function (social, physical and cognitive).


• Pain (non-PROs) – this panel recommended measuring healthcare utilization, analgesic use, and physical function as a complementary measure to PROs on pain.


• The brain – the panel reviewed and identified diagnostic modalities to assess neurological risk, document stroke, and measure cognition and educational attainment.


• End-organ considerations – the panel stressed the need to use biomarkers and endpoints that capture the progression of renal and cardiopulmonary disease.


• Biomarkers – this panel overlapped with other panels addressing various disease manifestations, highlighting the importance of developing and validating a broader array of biomarkers that can measure the response to therapy.


• Measurements of cure – given this is a relatively new area of research, the panel identified the need to develop appropriate biomarkers to evaluate the effect of curative therapies and to capture and share these data in a central repository to help advance the scientific understanding and broader use of these treatments.


• Care in low-resource settings – this panel noted an opportunity to accelerate clinical trials in regions with a high prevalence of SCD, such as sub-Saharan Africa. They also recommended capturing data on early childhood, perioperative and pregnancy-related mortality, as well as PROs from children and their caregivers relating to growth and development.

The pathophysiology of Sickle cell disease is complex, with contributions from multiple pathways. No single pharmacologic therapy has been able to completely suppress the adverse outcomes of Sickle cell disease, although several therapies, acting on different pathways, have shown the ability to provide varying degrees of improvement in outcomes in clinical practice and trials.

Papers in Blood Advances:

• End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain


• End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings