Breakthrough Immunotherapies Seem Like a Dream Come True for Children with Leukemia

Guest Post: Nancy Jecker, Aaron Wightman, Abby Rosenberg, Doug Diekema

Paper: From protection to entitlement: selecting research subjects for early phase clinical trials involving breakthrough therapies

A breakthrough therapy to cure cancer in children suffering from acute lymphoblastic leukemia (ALL) is a dream for many families.  New immunotherapies appear to make this dream a reality. Such therapies use a person’s own immune cells to recognize and combat their disease. In the largest study to date of ALL patients treated with a form of immunotherapy known as Chimeric Antigen Receptor (CAR) T-Cell therapy, a 93% remission rate was reported. Such results are a glimmer of hope for those whose prognoses were previously considered very poor.

However, the good news is tempered by the fact this potentially lifesaving experimental therapy may not be available to everyone who might benefit. And demand is growing as word spreads. Since CAR T-cell therapy for ALL is available only through clinical trials, do patients have a right to participate? How should we choose among medically suitable candidates?

We have faced these questions before. Most recently, with ZMapp to treat Ebola Virus Disease, azidothymidine (AZT) to treat HIV and AIDS, and Immunitab (Gleevac) to treat Chronic Myleogenous Leukemia. Are patients suffering from devastating, life-threatening diseases entitled to breakthrough therapies?

In a recent paper, we argue that benefit is a continuum, from the complete uncertainty associated with standard research, to an intermediate stage where evidence of benefit mounts and reaches a peak, to a final stage of clearly demonstrated benefit that is sufficient to gain approval for clinical applications. Somewhere along this continuum, patients begin to have an ethical claim to access, which becomes more apparent and weighty as evidence of benefit accumulates.  With breakthrough therapies, evidence of benefit emerges rapidly and in an especially striking way during early stages of research.  Although benefits to research participants are possible with any experimental therapies, with breakthrough therapies, such benefits are not only possible but plausible.

Breakthrough therapies must consider not only how to protect subjects from unknown harms of research, but also how to fairly distribute access to clinical trials. When benefits to research subjects appear more likely, the line between research and health care begins to blur.   This was precisely the point made by HIV and AIDS activists who advocated for “drugs in bodies,” claiming that with a potentially breakthrough therapy available, “giving a placebo to someone with a life-threatening illness is unethical.”

We explore this shift, from protection to entitlement, and argue for a 3-stage approach to selecting among eligible study participants using 4 criteria: likelihood and magnitude of medical benefit, sickest first, and lottery.

Prioritizing individuals with the greatest possible medical benefit is justified to offset the increased risks of study participation. Not only is there a risk of serious and unknown harms, there are also unique vulnerabilities if research subjects believe there is “nothing to lose” because they face almost certain death without access to experimental treatment.

Sickest first is justified because it saves the greatest number of lives, since those who are sickest may not survive long enough to have another shot at a lifesaving experimental treatment.  Sickest first can also be defended by arguing that those who are worst off or have the greatest need deserve priority. When no ethically relevant differences among research candidates remain, a random method, such as a lottery, should be used.

We are just beginning to face the ethical challenges immunotherapies and other breakthrough therapies raise. Future ethical challenges include how we should select which clinical trials will receive immunotherapy products when demand from scientists studying an immunotherapy exceeds product availability.

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