ASH and FDA Unveil New Recommendations to Guide Clinical Development of Sickle Cell Disease Therapies

Joint FDA/ASH Led Initiative Highlights Importance of Using Patient Reported Outcomes and Biomarkers in Clinical Trials to Advance SCD Therapies 

The American Society of Hematology (ASH) today 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 – published in two companion papers in the current issue of Blood Advances – are the result of seven expert and patient led panels convened by ASH and the U.S. Food and Drug Administration (FDA) to improve the design of clinical trials for new SCD therapies, including promoting broader use of patient reported outcomes and biomarkers as clinical endpoints.

Sickle cell disease is the most common inherited red blood cell disorder in the United States, and it affects millions of people worldwide. In people living with SCD, the red blood cells, which are normally round, become crescent or sickle-shaped which contributes to the vaso-occlusive crises these patients experience. People with SCD suffer from an array of physical complications, including acute pain crises, joint and organ damage, impaired cognitive function, and a reduced life expectancy. In addition to the immense physical burden they must endure, people with SCD are often stigmatized due to a poor understanding among healthcare professionals and the general public of the life-limiting effects of the disease. Supporting SCD research and access to care efforts for all people living with the disease is a chief priority for ASH.

While the molecular basis of SCD has been well understood for decades, there are currently only four FDA approved treatments for this debilitating condition. Bone marrow transplant is a cure for some individuals with SCD, but it is not an option for everyone. Although two new treatments for SCD have recently been approved, and many others – including potentially curative gene therapies – are in development, medical experts and FDA officials agree there is a need for uniformity around clinical trial endpoints to ensure these new therapies deliver a meaningful benefit from the patient’s perspective. “There are a number of investigational drugs in development that target different manifestations of SCD,” said Julie Panepinto, MD, MSPH, FAAP, 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. “However, there are no clear standardized endpoints for evaluating the effect of therapies on clinical outcomes and patient well-being.”

Dr. Panepinto said that amid the burgeoning effort to develop curative SCD therapies, clinical research should incorporate endpoints that are not only measurable, but also relevant and directly beneficial to the patient based on their preferences and experience.

“What’s happening in SCD is really exciting and many of us feel we are on the cusp of identifying multiple disease-modifying therapies,” Dr. 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.”

Ann Farrell, MD, Director of the FDA’s Division of Hematology Products and co-chair of the workshop, points out that the scientific understanding and the treatment of SCD have evolved to a point that the endpoints used to evaluate earlier SCD treatments are now inadequate.

“These changes have greatly impacted the discussion the Agency is having with the pharmaceutical industry as new clinical trials are designed,” said Dr. Farrell. “We need endpoints that better reflect the patient experience of their disease in the current healthcare system.”

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 development of new endpoints as a focus for future research. Led by Drs. Panepinto and Farrell, the panels conducted extensive literature reviews, assessed available evidence, and used expert judgement to identify which existing endpoints can be incorporated into SCD clinical trials and what additional data are needed. 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 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, peri-operative and pregnancy-related mortality, as well as PROs from children and their caregivers relating to growth and development. 

The published recommendations represent the most comprehensive review of science to date in the treatment of SCD and will be a valuable reference for academic researchers seeking funding for scientific studies and pharmaceutical companies looking to identify endpoints for specific clinical trials. 

“The papers document the wide-ranging discussions held by researchers, patients, caregivers, international experts, pharmaceutical industry and government to understand where we are in terms of defining clinical trial endpoints for current use and those for future development that will serve patients best,” said Dr. Farrell. She also noted the initiative identified several opportunities to incorporate the patient voice in clinical practice to help better understand how effective current medical treatments are.

The workshop was modeled after an earlier ASH/FDA initiative that focused on leukemia and myeloma, and was generously supported solely by the philanthropic support from numerous individual donors who contributed to the ASH Foundation’s Sickle Cell Disease Initiative Fund and by the Doris Duke Charitable Foundation.

In 2016, ASH launched a multifaceted initiative to address the burden of disease both in the United States and globally. For this initiative, ASH has developed clinical guidelines for SCD management and care, expanded education and training efforts, advocated with policymakers to enhance and expand federal SCD programs, and founded the Sickle Cell Disease Coalition. In addition to these efforts, the ASH Research Collaborative (ASH RC) SCD Clinical Trials Network was developed with the mission to improve outcomes for individuals with SCD by expediting SCD therapy development and facilitating innovation in clinical trial research. It provides the infrastructure for identifying patient cohorts for trials, matching trial sponsors with sites, facilitating recruitment of eligible patients, and ensuring optimally designed trials and an efficient, coordinated approach. Through patient engagement and optimized clinical trial execution, the Clinical Trials Network is helping to bring new and more effective therapies to individuals with SCD. 

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

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The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, and Blood Advances (www.bloodadvances.org), an online, peer-reviewed open-access journal.

Contact:  
Andrea Fischer, American Society of Hematology 
afischer@hematology.org; 202.823.4884