Eugenie Kleinerman, M.D., head of MD Anderson Children's Cancer Hospital, discusses before Congress what can be done to improve children's access to new agents early on.
Part II of: New Drugs Needed in Battle Against Childhood Cancers
As I said before, we have taken our eye off what I believe to be the goal of "cure" to one of "fear of inducing toxicity." Fear of toxicity governs the U.S. Food and Drug Administration (FDA) and paralyzes the pharmaceutical industry from including children early on in Phase I clinical trials.
Unlike adults, children don't have early access to new agents
Phase I trials gradually establish the maximum tolerated dose and define the side effects of the drug at each dose.
These first-in-human Phase I trials are for patients 18 years and older. Once the dose is found, Phase II and III trials investigate the efficacy in specific diseases, and this data, if positive, is used to support approval by the FDA.
Children are not part of this scenario and thus do not have early access. If the company wishes to investigate drug activity in children, it must start the process of Phase I-III all over again, a time-consuming and expensive process.
Risk vs. Hope: Who has the authority to decide?
Inclusion of patients younger than 18 years old in Phase I trials is blocked because of the fear of side effects. However, just like adults, children who would be eligible for Phase I trials are those with cancer that has not responded or has recurred following the most up-to-date, proven therapy regimens.
A tried and successful method for speeding up access for children
I have a modest proposal that I believe will take a small step toward rectifying this inequity.
Phase I trials start by using a low drug dose. After a few patients receive the drug at that dose without adverse effects, the next higher dose is given to another few patients. This goes on until the maximum tolerated dose (MTD) is reached and the toxicity is defined.
What I suggest is that a separate arm be built into Phase I trials for children. The trial can be designed in this way:
- After the first dose level is completed in adult patients and they are entered onto the second dose, pediatric patients would be allowed to enter at dose Level 1.
- Once dose Level 1 is shown to be safe, the next cohort of pediatric
patients would be entered on the dose level that is one step below where
the adults are.
- If the pediatric cohort completes dose Level 1, and the adult cohort
is now on dose Level 6, the next group of pediatric patients would
start at dose Level 5, rather than Level 2.
I suggest this design with confidence. It works.
We showed this at MD Anderson Children's Cancer Hospital in a joint trial with the adult leukemia service where we established the MTD of clofarabine, the one new agent for pediatric cancer that has been approved in 20 years.
The time has come for us to adopt an attitude of "collective responsibility" for identifying ways to increase access and speed up the approval process that involve agents to treat childhood cancer. This is the perfect opportunity for the FDA to take the lead on this important issue and show the way.
Children with cancer are part of our future. Losing this valuable resource is a tragedy.
New Drugs Needed in Battle Against Childhood Cancers