The Phase II/III Shire intrathecal idursulfase clinical trial requires a child to test between a score of 55 and 85 on the DAS II neurocognitive assessment (essentially, an IQ test). Neurocognitive assessments are age-normed, i.e., scores are obtained by comparing the abilities of a child with those of an average child his or her age. Thus, a three-year-old child who answers the exact same questions correctly will score higher than a six-year-old child with those same correct answers because the three-year-old is better when compared to his or her peers.
However, the six-year-old can still perform at the same level, can still be accurately measured, and has no reasonable difference other than the age difference and how that affects his score, thus, he is considered much “less smart” than his peers.
The selection of a bottom threshold of 55 almost certainly eliminates most boys with Hunter Syndrome past the age of five or six, and many even before that, not because they can’t complete the test, or answer questions, but simply because their age has caused their score to be lower – the age norming factor.
As such, I have consistently suggested and advocated for different cognitive inclusion criteria for this and other Hunter Syndrome trials:
As a comparison, ever since the beginning of the trial, Case has improved in understanding and in ability. His writing improved, his counting improved, his word recognition improved. But his cognitive number has declined. Not because he has lost any skills whatsoever (the opposite, in fact), but because he has gotten older, and while he has improved, he hasn’t improved as quickly as his peers.
In fact, Case, performing above and beyond any ability he had prior to the trial, is scoring in the range of a 60. He is seven years old. He is doing AMAZINGLY for a boy with Hunter Syndrome, but he himself would only barely qualify were he to test for the new trial phase.
He can write his name, count to 100, swim underwater, play computer games, climb rock walls, read sight words… and because he is seven years old, he scores a 60, give or take.
There are a number of boys who have significant abilities, including the ability to perform on a cognitive test, which we understand is a viable concern given the need to show the drug works, but because they are five, or six, or seven, or eight, their score might only be a 40. And that, my friends, is the only reason they will not get this drug before they lose those skills.
Here is a video of one such boy. These same skills that he shows would qualify him for the trial if he were only about three or four years old. As a six year old, his age normed score did not all him to qualify and thus, by the time this drug gets through the next phase of the trial, he will probably lose most or all of these skills.
I call upon FDA, Shire, and other companies doing clinical research in Hunter Syndrome, to seriously consider their lower threshold for inclusion criteria in clinical trials for our boys. Understand the way neurocognitive assessments are scored in our boys, the challenges for them to even participate, and the limitations. Consider the alternatives outlined above. It will not only allow for broader enrollment that better represents the community you seek to help, but it will allow for faster enrollment of trials, and more well-rounded evaluations of therapies.
But without such changes, while we all wait the three to four years for FDA approval, parents such as his will watch their boys lose these skills that brought them to a 40. The ability to talk, to play basketball, to recognize shapes and colors, to count, to name their family members.
Many will die in the mean time.
They just weren’t smart enough, someone said.
To compare to a more common disease:
“Your daughter has cancer.”
You enter the hospital thinking that she just has a headache and end up with a horrible, horrible reality. You walk down the stairs from the doctor’s office and the echo of your footsteps takes on an entirely new and hollow tone.
Life is forever changed.
You slowly process what this diagnosis means. The change to your “normal” life. Changes in routine. Visions, side effects, and reactions to real illness. The possibility of death.
Slowly, you begin to slug it out day after day in this new life, watching your child become a shadow of what she was before. But all is not lost. She can still do many things that she loves. She reads to you. She tells you she loves you. She sings. She laughs.
The important things are still there. They are made all the more significant by the absence of the things you realize never really mattered to begin with.
But slowly those meaningful things begin their disappearing act as well. You realize that all that matters is now at risk.
The doctor meets you one day in the cancer ward and says there is hope.
Now that’s the word that you’ve longed to hear.
There’s a new medication specifically for her type of cancer. Just for her. And it is almost certain to put her in remission.
Of course, you’re elated. And hopeful. The doctor had just said yesterday that your daughter was deteriorating and would likely succumb to the cancer if something didn’t change.
“Now, all she has to do for us to start this medication is take this test,” the doctor said.
Test? What kind of test? A blood test?
“If she’s smart enough, she can get the medication,” he notes. “But sadly, if she’s not very bright, we can’t give it to her. And to be honest, without it, she’ll probably die.”
She takes the test the next day and a few hours later, the doctor walks in, a heavy chart in his hand and look on his face.
“I’m so sorry to tell you that she’s just not smart enough. She can’t get the medication.”
And so, your daughter will die. Not because she couldn’t be saved. Not because there was a particular risk to her.
But because she just wasn’t smart enough.
Welcome to our clinical trial.