The Burden of Proof

Kids helping kids helping science—that’s the promise of pediatric clinical trials
Robert Truog
Robert Truog

Harvard Medicine
By Elizabeth Cooney

Four doctors file into Becca’s hospital room on their daily rounds, thirteen days after the teenager received a stem cell transplant. They rub their hands with sanitizing gel, then proceed to listen to her chest. The stethoscope they use stays in her room; when not in use, it hangs from the IV pole. An array of hair bows pinned next to cheerleading pictures on one wall leads a doctor to venture that Becca’s room could win a best-decorated contest.

The 15-year-old says she always wears a bow in her hair. Not losing her hair to chemotherapy is perhaps the most tangible sign of the gentler approach doctors are taking to treat her rare disease. Dyskeratosis congenita is an inherited disorder in which telomeres—the protective caps on the ends of chromosomes—are not properly maintained, a situation that can lead to changes in the controls on cell division. Becca’s rapidly dividing cells burn out quickly, leading to bone marrow failure. Because her cells do not repair damage as well as they should, she is more susceptible to cancer and organ failure.

The chemotherapy or radiation typically used to prepare a body for a bone marrow transplant is extraordinarily harsh, and Becca’s condition makes her even more vulnerable to the aggressive nature of these conventional tools. To help her body accept the donated stem cells, doctors instead gave Becca immunosuppressive drugs only. In other studies, this approach has shown that the more robust cells will outcompete the leftover damaged cells and will survive.

One of Becca’s doctors wears two hats: clinician and researcher. He oversees her care—and the research study’s protocol. Becca is one of five participants in the pilot study.

Her parents wouldn’t have it any other way. Their unease with having their daughter be one of only a handful of patients in the world to receive this alternative treatment was calmed when they learned that their daughter’s doctor is an expert in her disease. Today, the disease neither of them had heard of until Becca’s diagnosis four months ago has become their own object of study. They know her dates and diagnoses; they understand there is a 10 percent risk that her body won’t accept the transplanted cells or be able to produce its own. They check her online patient portal daily to see what her blood counts are, willing her absolute neutrophil count above 500, the threshold of transplant success.

“You just watch the numbers and pray,” her mother says. “There’s nothing else you can do. Whether you believe in God or not, you pray.”

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In the Balance

Fears over harming vulnerable children in the name of research, however, may have produced unintended consequences.

“We protected children so long from research experiments,” says Susan Kornetsky, director of clinical research compliance at Boston Children’s Hospital, “that each time we prescribed a drug for them for which there was no pediatric data, we actually subjected children to an uncontrolled experiment. You had to select a drug tested only in adults, and then take your best guess that maybe it would work the same way in children.” As a member of her hospital’s institutional review board (IRB), Kornetsky is responsible for reviewing research protocols to ensure they meet regulatory and ethical standards.

The enrollment of children in research studies has risen throughout the past decade. Among children under the age of 15 who are diagnosed with cancer, roughly six out of every ten participate in clinical trials. This rather robust enrollment rate may be attributed to the fact that the relative rarity of cancer in children means that the 15,000 children diagnosed with the disease annually in the United States will more likely be cared for at academic medical centers, focal points for clinical research. Among adults diagnosed with cancer, fewer than one in twenty participate in clinical trials.

IRB panels must weigh the likelihood that a child will be put in jeopardy or reap a benefit by participating in a research trial. If no other treatment will work, the balance tilts toward benefit. If, however, other treatments are available, federal regulations say the anticipated risk and benefit to the child in the trial must be equivalent to those from alternative approaches. That standard does not exist for adults.

“That’s where the regulations and ethics get a bit fuzzy,” says Robert Truog, director of the HMS Center for Bioethics and the HMS Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics at Boston Children’s. “If a child can benefit from the research, then that’s a justification for exposing that child to more than minimal risk in a research study. But if you have good reason to believe that the treatment is beneficial, then you should be using it as a treatment and not limiting its use through clinical trial. By definition, when you’re doing clinical research, you don’t know whether what you are about to do is going to be beneficial or harmful.”


Read the full article "The Burden of Proof" in the Spring 2015 issue of Harvard Medicine magazine.
Photo credit: John Soares