Rethinking Risk-Benefit in Sickle Cell Disease Therapy

Alan Anderson, MD

Pfizer’s decision last fall to withdraw voxelotor (Oxbryta) from the worldwide market is an example of how companies make risk-benefit calculations about medicines, and how those decisions vary widely from one category to another.

Cancer drugs have their own set of standards.

The risk-benefit calculus routinely accommodates uncertainty and severe side effects, if the medicine offers a modest and temporary clinical benefit, given the life-threatening nature of many cancers.

Sickle cell disease is a different story. Decisions to advance or shelve a drug candidate often appear to be driven by a more risk-averse model.

This is odd, because sickle cell disease dramatically reduces quality of life and results in a 30-year reduction in life expectancy. This different calculus for cancer and sickle cell disease patients is especially concerning when considering that sickle cell disease research and development suffers from chronic underinvestment and historical stigmatization.

Patients with sickle cell disease have never been given the R&D resources or clinical support they deserve. These patients have a debilitating, chronic illness. Their treatment options are few.

Pfizer released a statement on Sept. 25 that concerns over Oxbryta’s long-term safety profile and questions about its overall clinical benefit were key reasons for its market removal. However, these explanations seem at odds with the evidence from the HOPE clinical trials, which showed a significant, sustained improvement in hemoglobin levels, reduction in hemolysis, and a reassuring safety profile (NEJM article, June 2019).

Moreover, since FDA approval in November 2019, many U.S. physicians have reported tangible clinical benefits and manageable side effects in patients treated with Oxbryta.

This disconnect between Pfizer’s stated rationale and both the trial data and real-world experience raises questions about whether factors other than the established clinical performance are driving the decision to pull the medication from the market. It was also surprising that no alternatives were made available to clinicians, including the addition of warnings to the label or the development of a compassionate use program for patients with no other options.

When a medication like Oxbryta is removed from the market with little warning or input from the community it serves, the consequences are far-reaching. This decision, and others like it, limit the ability of clinicians to engage in detailed, patient-specific discussions about the trade-offs inherent in therapy choices. These conversations are standard practice in oncology.

Cancer patients are routinely informed that aggressive treatments come with high risks, yet the potential benefits may justify these risks. By applying a balanced risk-benefit framework to sickle cell disease, pharmaceutical companies could empower physicians to provide tailored, nuanced care, fostering informed decision-making even amid uncertainty.

Furthermore, the rapid removal of an effective drug like Oxbryta undermines trust among patients, clinicians, and advocacy groups. A more inclusive process that incorporates these voices can ensure that decisions are made with a full understanding of the lived realities of patients, whose needs and perspectives are often marginalized. Such an approach not only aligns with ethical imperatives but also has the potential to drive innovation by fostering a more collaborative environment among industry, regulators, and the community.

The case of Oxbryta should serve as a wake-up call: pharmaceutical companies must recognize that a one-size-fits-all approach to risk evaluation is inadequate.

Instead, embracing a more balanced and inclusive strategy will enable physicians to have the kind of comprehensive, informed bedside discussions that are the hallmark of oncology care. By adopting a nuanced risk-benefit framework for sickle cell disease treatment, we would honor the principle that every patient deserves the best possible chance at improved quality of life.

Alan R. Anderson, MD, Associate Professor of Pediatrics, University of South Carolina School of Medicine; Medical Director, Lifespan Sickle Cell Center of Excellence, Prisma Health, Greenville, SC