February 28, 2011
Seminal successes linked to tolerant regulatory oversight, hope
Relatively lenient regulations regarding human subjects protections in the 1950s played an important role in pediatric oncology being the first field of medicine in which doctors simultaneously treated patients and carried out clinical research, according to a pediatric hematologist-oncologist at the Johns Hopkins Berman Institute of Bioethics.
The review, by Yoram Unguru, makes clear that a combination of factors unique to pediatric oncology allowed patient care and experimental research to intertwine successfully—and so, the case may not necessarily serve as a model for other fields. However, Unguru says that his analysis does raise anew some basic questions about whether the two endeavors always present an ethical dilemma, and whether regulatory oversight needs to be strict and rigid in all fields.
“Historical transgressions in human subjects research have been quite stark and even horrifying. So it seems obvious that we need strict and structured oversight in place to prevent them from happening again,” said Unguru, whose review is online on the website for the journal Pediatric Blood & Cancer. “But I’m also curious to see what kind of feedback, good or bad, others might have about this paper.”
The more tolerant regulatory climate during the mid-20th century applied not only to human subjects protections but also to approvals for new treatments, Unguru’s paper points out. This gave physician-investigators considerable freedom to present novel therapies to parents, many of whom were willing to try anything that might prolong their child’s life in the face of an incurable disease.
This was true, he notes, even in the face of “therapeutic misconception or misunderstanding.” That phrase describes the notion that patients—or in the case of pediatric oncology, often parents—misconstrue clinical trials as being more in their immediate medical interest than might actually be the case.
Eventually, though, the work of the physician-investigators led to the first cure of a childhood cancer—acute lymphoblastic leukemia—via the experimental use of multi-agent chemotherapy. Doctors subsequently applied the strategy to other types of childhood cancers, curing them as well, and ultimately, to the treatment of adult cancers.
“That tolerant regulatory oversight contributed to such breakthroughs is historically intriguing,” said Unguru, who is also on the faculty at the Herman and Walter Samuelson Children’s Hospital at Sinai, in Baltimore.
Unguru cites other equally important factors that allowed patient care and research to come together, leading to “countless breakthroughs and advances.” These included the large-scale, multicenter nature of the studies; the highly collaborative and selfless spirit among physician-investigators; the relatively small number of children who develop cancer; and, again, the hope of patients’ parents.
In the United States, about 1.5 million adults developed cancer in 2009, while for those under the age of 20, that figure was approximately 12,500. Hence, because the patient pool was small and scattered throughout the country at the time of his study, physicians needed to collaborate closely and constantly in order to compare notes and come to a consensus about what worked, Unguru says.
Unguru says he was compelled to write the review because of the ongoing debate over whether practice and research should be kept at arm’s length in the clinical setting. Those who insist they should, cite the contrasting nature of their goals: Practice aims to promote the patient’s best interest, whereas research seeks to secure generalizable knowledge to help future patients, with the interests of the research subject receiving secondary consideration.
But given the increasing amount of research being done in the clinical setting, especially among children with cancer, the line between practice and research gets blurrier by the day, he says. Hence, some practitioners question whether such strict division needs to be observed if, in some cases, the aim is to improve care.
“There is fairly good evidence showing that many pediatric oncologists feel the main purpose of clinical trials is to come up with new treatments, and that’s one way they get around this tension of being both a physician and a research investigator,” Unguru said. “I can tell you that I struggle with that tension all the time.”
The article begins by tracing the successful integration of patient care and experimentation in pediatric oncology to 1953, when doctors and researchers were brought under one roof, at the National Cancer Institute’s Clinical Center. This led to collaboration and the introduction of novel chemotherapy methods, epitomizing the notion of “bench to bedside.”
Over the next few years, researchers launched the first randomized clinical controlled trial, or RCT, involving children with cancer, and group efforts such as the Acute Leukemia Task Force were born, Unguru explains. He adds that the task force was responsible for highly successful programs that led to the widespread implementation of multiple-drug chemotherapy regimens that dramatically lengthened remissions among children enrolled in subsequent RCTs.
Hence, experimental treatments were rapidly adopted and seemingly widely accepted as the standard of care in pediatric oncology. Unguru notes that the current survival rate among children with cancer is 80 percent, whereas fewer than 10 percent survived prior to the proliferation of RCTs.
Today, nearly 70 percent of children with cancer enroll in such trials, primarily via their physician-investigators, largely because these studies offer the most promising and cutting-edge treatments.
To read Unguru’s article, go to onlinelibrary.wiley.com/doi/10.1002/pbc.22976/full.