Who is Smart Enough for a #RareDisease Clinical Trial?

Posted Tuesday October 14, 2014 by Melissa

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:

  1. A threshold of test cooperation and ability to obtain a valid score.
  2. A lower threshold number given that many children will still be able to validly test and score below a 55.
  3. An age bracketed score window, given the age norming of neurocognitive assessments, such that the threshold would lower by age to account for the age norming, e.g., maybe 55 at age 3, 50 at age 4-5, 45 at age 6, etc.
  4. Qualification based only on verbal and nonverbal components of a cognitive assessment, given that the visual-spatial domain is notably and consistently deficient in boys with Hunter Syndrome and pulls down their overall score dramatically.
  5. A parallel arm of children who otherwise qualify for the trial via safety criteria, but for the neurocognitive assessment a lower or no applicable threshold.

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.

But wait.

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.

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8 Responses to “Who is Smart Enough for a #RareDisease Clinical Trial?”

  1. Meredith Pinchak // October 14, 2014 at 10:04 am

    Sad, but true. I have watched my son loose more skills than I care to admit. He can still walk, give high 5’s, and hugs, but I doubt I will ever hear “I love you, mommy” ever again. We were denied because he was deemed “untestable”.

  2. Many will die in the mean time. They just weren’t smart enough, someone said. – Those two sentences had me in tears. Took me back to when we took Matthew to Children’s Hospital Oakland and had him tested for the NHS. Not long into the testing they sat me down and told me that they did not want to “waste anymore of my time” and that I should just take Matthew and go do something fun so that the trip was not wasted. Needless to say, my son was not smart enough, and that was evident to all of them right away. He was only 4 at the time but neurologically this monster of a disease had already taken a huge toll on him, it was like trying to test a 2 year old. I left there in tears and brokenhearted for my child. If he could not test for the NHS then there was no hope for the trial. I was so angry at the whole situation, still am. I am angry that the boys that need this trial drug the very most will most likely never get it, and if they do, it will be to little to late. Because as Melissa says “they just were not smart enough”, never mind the fact that they are not smart enough because of this horrible disease and that this drug that they are not “smart enough” to have could help them with that exact issue. I am not hopeless but I am realistic, and I feel in my heart that in 3-4 years if and when this drug is finally available to everyone, it will be to late for my child. The whole thing just pisses me off!!! This was a great article Melissa!! Thank you so much for all that you do for our community and our boys – when I grow up I want to me just like you 🙂 <3

  3. This should be given to every child all over the world, how they can decide which child should have it and which shouldn’t is barbaric, between not living in America and not passing silly tests, where the child is out of his comfort zone as is, is totally unfair. Doesn’t my child’s life matter? Because I’m not an American or he didn’t pass a test, is that ok for him to die a slow painful death,while we his family watch knowing shire could have helped? There are only 2000 in the world with hunters, give them all a fair chance at fighting this God forsaken disease. All our kids need to have this chance, a b c’s or no a b c’s ….Ethan s mommy, Ger in Galway Ireland

  4. I agree 100% with everything Melissa said in this write. There are many boys who are falling under the 55, and for different reasons. Sometimes they “are not smart enough” and other times there are behavior issues that hinder their ability to test at all on day, and the next day they may do fine, which is exactly what happened with my son, Zain Semones. When he initially tested, I had to bribe him with Reese cups and orange soda to make it through testing. He was still stubborn and did not test to his fullest potential, scoring a 49. I, the geneticist, and as well the developmental doctor knew that Zain could have done much better. He was accepted in spite of the 49 and so we moved forward with a “no drug…6 month wait” computer pick for Zain. At baseline, he wouldn’t test.. he absolutely refused! He and the developmental doctor had a mind game going that day, and boy did he give her a run for her money! She ultimately concluded …(her words)>>> “I learned more about Zain today than any ole test could have ever shown me!”. She was so impressed with his ability to stand off with her, structurally and consciously. So, yes, there needs to not only be a broader score criteria, but as well they need coverage in the testing strategies to work around days like this, that most of our boys have! A few days after this second testing, Zain had the LP done and his pressure was 40.5, which ultimately excluded him from the trial, robbing him of his place he had earlier been granted in Phase I of the trial. I can only hope that while we live out this agonizing wait for FDA approval, that he maintains enough skill to “be smart enough” to get the drug…if they will allow him to get it with having a shunt!

  5. Shire has made so many missteps and hit so many snags and delays that the Phase 1 safety phase has been going on for almost 5 years now. While we HAVE THE SAME GOAL of ultimate swift FDA approval so all boys can benefit from the drug on the market, our children are losing skills, quality of life and their lives in front of our eyes. There needs to be more urgency and better designed trials for rare disease. Including but not limited to: parent consultation and representation from our Hunter Syndrome community, a broad allowance of compassionate use for those in greatest need who are excluded from the trial. This is my boy in the video and he is the perfect candidate to get IT or any other breakthrough treatment, but it needs to come soon. He walks, talks, sleeps, tests, can reason, manipulate, negotiate and play basketball like a rock star. Yet it is still surreal 2 months later that he didn’t fall in that arbitrary narrow band meeting the perfect storm of age discriminating criteria on the horrid DAS II test. So now what, we wait 3 excruciating long years, pray it gets approved in a swift manner and he gets it at age 10 when it will likely have diminished benefit. Thank you Melissa for this important post.

  6. Those of you who have known us for a while may remember me trying to get Dan into this trial some years back. Even before its onset, I had Dan in front of the right people and made sure they knew he was there, we were willing to participate, and most importantly that he was still “smart enough.” They watched him so close. Told me he was perfect. Just needed to wait for the trail to open. Hope. He was about the age of the beautiful boy in the video during that time. At that age, he was using simple sentences, and he could tell you how to spell his name. He could draw lines, crisscrosses, and circles on request. He could name pretty much any color, shape, animal, or food you put in front of him. Could dress himself from head to toe with minimal assistance, and was about half potty trained. Could adapt items to use as “tools” to get get items that were out of reach. He could sort and match items like he was getting paid a cookie per item. And damned if he couldn’t figure out how to get into anything and everything you didn’t want him to get into. Other mothers of boys with Hunter Syndrome would look at him and just marvel at his high level of functioning for the ripe old age of 6 (because after all, that is about mid-life expectancy for these boys). But in the eighteen or so months that they were watching him before the trial opened, even though he was doing so well, had not lost any skills, and was even still slowly gaining skills… he had gotten too old. For every month that ticked by, he became less and less smart in their eyes. Until one day he passed that line, and he was no longer perfect for them, because his age officially made him not smart enough.
    Now at 12yrs old, it hurts me too much to think about all the things I miss watching him do and say to even go into detail. His IQ is no longer testable because he can’t cooperate and no longer understand the majority of the tasks they want him to perform. Playtimes are being replaced by naptimes. Sentences are being replaced by vocalizations and one or two words phrases. All because some asshole assigned a number to my baby and said he wasn’t smart enough. It was like being told he was dying all over again. I’ve done my best to come to terms with it and I find things to tell myself to try and bring comfort and reason to the situation.
    But I will never forget what that day felt like. Or how that phone call went. And as much as I try to ignore it, it still hurts every damn day.

  7. Excellent presentation Melissa. You are very gifted.

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