publication date: Oct. 14, 2016
Goodman: Too Many PD-1 Trials for Adults, Too Few for Children
By Nancy Goodman
Kudos to The Cancer Letter’s report on the 803 PD-1 or PD-L1 trials. As Rick Pazdur noted, that is just too many resources chasing the same idea for adult cancer studies.
Alas, as of Friday, Oct. 7, clinicaltrials.gov shows only two open trials for a PD-1 or PD-L1 trial for patients 0 to 17 years of age, and both are monotherapies. There are no listed combination trials that are open and accept kids. There are no PD-L2 trials listed that accept kids.
The 160,000 slots for adults to enter PD-1 trials exist because we all know how exciting these drugs are. But, if so, why are there so few trials for which children and young teens would qualify? Shouldn’t kids and teens also get a shot at exciting investigational drugs?
When my son, Jacob, was treated for medulloblastoma, there were so many adult brain cancer trials open. None of them would accept a 10-year-old boy. Even on a compassionate use basis. Perhaps none of these drugs would have conferred a benefit to Jacob. However, I am still sorry that he wasn’t given a chance to at least try.
Sponsors provide no scientific or ethical rationales on the clinicaltrials.gov summaries to explain the eligibility requirements and the prohibition of enrolling children and young teens in trials.
So let’s consider the major impediments to including children on the 803 PD-1 trials:
Would a dead child on a trial slow down PD-1 clinical development?
There is the issue of dead kids on trials. As a mother of a child who died of a pediatric cancer, I can say this. There is the uncomfortable and unspoken concern that a child on a trial could have a new toxicity or die, thereby slowing down the adult drug development. Could a child die in a PD-1 trial, thereby slowing down the other 803 PD-1 trials?
There is no evidence that the FDA has ever penalized a sponsor for a dead kid, absent gross negligence. I cannot find cases of a dead child on a trial resulting in a terminated adult trial—and I’ve spoken to many pharmaceutical companies to find cases.
I would ask those for whom this is a concern to put forward examples so that we can all examine these instances together. The urban myth that a dead kid on a trial will cause the FDA to delay adult development has not be substantiated, and is not a good reason to block terminally ill children from potentially beneficial treatments.
Others argue that it is unethical to put a child on a PD-1 trial early—perhaps because there is new or unknown toxicity that could bring death earlier to a child. With respect to PD-1 drugs, how could it be unethical to include a child on a PD-1 trial, when there are other approved PD-1 drugs that kids are already taking off-label?
For children who are terminally ill, I would argue that the most ethical position is to give the child, the child’s family and the child’s physician the opportunity to weigh the known and unknown risks to assess what the best trial is for that child.
Can we identify new toxicities or different pharmacokinetics for PD-1 drugs for kids that would exclude kids of certain ages from PD-1 trials?
If there are toxicity concerns that would exclude 17 year olds, or 15 year olds, or even 9 year olds from PD-1 trials, then let’s discuss them. In fact, the two pediatric trials for PD-1 drugs that are open presumably addresses this question satisfactorily.
For other classes of drugs, usually, developmental toxicities can be predicted. In addition, pharmacokinetic differences between children and adults can be usually identified by pediatric pharmacologists early in a drug’s clinical development process.
Do we need to prioritize clinical research of PD-1 drugs in kids, given how few kids have cancer?
Some argue that before we put kids on more than the two open PD-1 trials, the 803 open adult trials should be prioritized so that all the trials are completed, science progresses and children are not “used” by being put on trials that will not be completed.
The problem of prioritization for children is a theoretical problem that we should be so lucky as to have. For children with cancer, the problem is not that there are too many unprioritized trials, it is that kids cannot get onto trials.
If children were admitted to trials when there wasn’t a scientific reason to exclude them, then children with cancer would achieve a major win: earlier access to PD-1 drugs. There might even be new efficacy or toxicity data to be found and collected. The two open pediatric trials might have a more difficult time accruing, but these two trials are both monotherapies in an environment of hundreds of combination PD-1 trials.
In other areas of clinical research—such as written requests leading to pediatric exclusivity and post-market studies—prioritization is not required. Let’s not block early access to drugs for kids by raising the flag of prioritization here with PD-1 drugs.
Eventually, if we are very lucky, and if the problem of early access to drugs for children with cancer has been solved, then we will have to come together as a community to start to talk about prioritization. We are years and years away from such a wonderful problem.
I propose two steps to ensure that children are not denied access to potentially life-extending drugs such as PD-1 drugs merely because of convention:
1) Pass the RACE for Children Act (S 3239, HR 5858).
Pursuant to the Pediatric Research Equity Act (PREA), sponsors developing drugs for indications for which there are pediatric populations have certain obligations to undertake pediatric trials. However, PREA does not apply to cancer because cancer indications are defined by organ of tumor origin. In other words, children do not get prostate cancer or breast cancer.
The RACE for Children Act would update PREA: as cancer drugs are now developed by molecular target, RACE would authorize FDA to require sponsors to undertake certain PREA pediatric studies if the molecular target of investigational drugs is relevant to pediatric cancers.
For example, if sponsors studying PD-1 trials are only studying the drugs for adult cancers—breast cancer, lung cancer, ovarian cancer, pancreatic cancer—does it make sense for sponsors not be required to undertake PREA pediatric studies because children do not have these cancers? The RACE for Children Act would require sponsors to undertake PD-1 trials in pediatric cancers for which PD-1 therapies are scientifically relevant.
The RACE for Children Act has solid science. It has been endorsed in a Nature editorial and by over 100 patient groups and hospitals.
Congress should pass the RACE for Children Act as soon as possible.
2) Lower the minimum age of eligibility and put kids and young teens on cancer trials unless there is a scientific or ethical reason not to.
Sponsors should be asked to explain their decision to cut off eligibility for trials at 18 years of age or any other age.
FDA has the authority to make these inquiries about eligibility by age and has begun to do so. Given the promise of these drugs for terminal kids awaiting their approval, and given the practice of use of these drugs on an off-label basis by these kids, FDA is authorized to continue to press companies to explain and justify their eligibility requirements as standard practice.
Moreover, NIH-funded trials should include children and young teens unless there is a scientific or ethical reason not to. Though we, as a society, permit private companies to exclude children and young teens from trials for non-scientific reasons, we should ask government agencies such as NIH and the Department of Defense to refrain from also excluding children from clinical research when there is no scientific rationale.
The author is executive director and founder of Kids v Cancer.