Whether guided by economics or an instinct to shield children from potential harm, the way we bring new pediatric drugs to market does not always serve the best interests of children with life-threatening illness for whom few options exist. As a pediatric oncologist for 40 years, I have witnessed a revolution in cancer treatment, launched by early advances in treating children that later also benefited adults. Today, however, children with intractable disease are too often left behind and denied timely access to breakthroughs in cancer treatment that could save their lives. This must change.
Current practice has children awaiting completion of Phase I safety trials in adults, if not considerably longer, before pediatric trials open. But children are not small adults. They tolerate and respond to medical interventions differently from adults. Moreover, tomorrow’s pediatric drug may prove useful for treating a far more common adult cancer whose connection to the drug seems far-fetched today.
To understand the issue, look no further than asparaginase, a workhorse drug for treating the most common pediatric cancer, and ponatinib, a new drug for adults with leukemia whose maker recently decided to delay a planned pediatric trial while it addresses safety concerns on the adult side.
Asparaginase fueled the breakthrough in treating acute lymphoblastic leukemia and remains a mainstay of treatment today. About 90 percent of US children with the leukemia now survive; as recently as the 1950s and ’60s, virtually none did.
Like many pioneering early chemotherapy agents, asparaginase was tested and used first in children and only later used to treat adults. Subsequent research found that 40 percent of adult patients treated with asparaginase developed potentially dangerous blood clots. Only 4 percent of pediatric patients suffer this side effect. Likewise, asparaginase is substantially more toxic to adult livers than to children’s.
Thus, under today’s standards, asparaginase would never have reached children, in whom it has proven so effective.
Ponatinib was developed for adults with chronic myeloid leukemia whose other therapies have failed or whose leukemia harbors a specific genetic mutation. In October, the Food and Drug Administration suspended sales after some patients developed blood clots that could potentially result in fatal heart attacks and strokes. The FDA in late December cleared the way for Cambridge-based Ariad Pharmaceuticals to resume sales once additional precautions are in place. The issue now facing Ariad and the FDA is whether these side effects in adult patients warrant a continued suspension of the planned pediatric trial. Considering the rarity of clotting events in children, I would argue that the pediatric trial should proceed as planned.
Researchers want to explore ponatinib’s potential to be a better option for some children suffering life-threatening cancer. Does ponatinib pose the same risks for children as it does in adults? Would children’s young bodies be as susceptible to dangerous blood clots? Or would the risk be substantially lower, as it is with asparaginase?
We should not wait until a cancer drug is brought to market for adults, or is well on its way through adult clinical trials, before learning such answers. After enough adult patients have enrolled in a Phase I safety trial to determine that the initial low dose is well tolerated, a parallel pediatric trial should open immediately. If the experimental drug proves unsafe for children, stop the trial.
This approach would make scientific advances available to desperately ill children much sooner. It would help ensure that tomorrow’s asparaginase is not lost for children.
We stand at the edge of revolutionary changes in our understanding of cancer, as we learn that it is defined more by genetics and biological pathways than location of the malignancy. While children and adults may react to the same drug differently, if a pediatric tumor and an adult tumor share the same underlying biology, we should use that knowledge to benefit both. Not only is doing right by children the right thing to do, it may well mean doing right by grown-ups, too.