What does “better” mean and who gets to decide that?

April 17, 2020

Dr. Cara O’Neill, Chief Science Officer for Cure Sanfilippo Foundation, posed this question regarding study endpoints to an audience of before the audience of research scientists, biotech leads and industry partners, physicians, U.S. Food & Drug Administration (FDA) staff, and patient advocates at the WORLD Symposium 2020, a conference regarding lysosomal storage diseases held this past February. 


How we choose to define what ‘better’ means sets a trajectory for everything we do,” said O’Neill, a pediatrician who has worked in private practice and academic settings and mother of a daughter with Sanfilippo Syndrome.

Headshot of Dr. Cara O'Neill, Chief Science Officer of Cure Sanfilippo Foundation, a thought leader in evolving Sanfilippo study endpoints“So who’s asking the research questions?,” questioned O’Neill. “Often they are coming from a medical or regulatory perspective and they’re very focused on the basic science. And too often assumptions get made about what are the important aspects of the disease and what are the important symptoms to treat. These assumptions get made without the benefit of the real world experience of the patients that are on the other side of innovation they are creating.”

“Consider for a minute how many pharmaceutical executives, basic science researchers or even clinicians sometimes have spent real, meaningful time in daily life with the patients they’re trying to help,” she challenged.

“Have you gone to dinner with a family who is now struggling to feed their child because they’re forgetting how to chew and swallow their food? Have you spent the weekend at someone’s house whose child doesn’t sleep for 48-72 hours and is loudly banging around, running through the house, yet everyone still has to get up and go about their day – go to work, go to school?”

“I’m assuming most of you haven’t, and that’s to be expected. It’s not a criticism, it’s just a fact,” she clarified. “[A fact] we need to remember because when people in powerful positions or decision-making positions are making those critical go/no-go decisions on clinical trials or trial designs, they may be making that without the input of the patient community. And in doing that, they only have half the information.

Drawing an example from the Autism community, she illustrated the importance of patient/caregiver perspective in the design of study endpoints, “We know with Autism [that] “stimming” or repetitive movements are classic of the condition and are commonly used as endpoints in clinical trials. But during the patient-focused drug development meeting, participants stood up and said, ‘Hey, stimming is not my most significant symptom or my child’s or my loved one’s most significant symptom. Sometimes it’s actually helpful. We want to be able to have that behavior still, it helps us cope. Instead we’d rather you focus on things like communication and speech. Understanding nonverbal gestures, understanding facial expressions. Those are the things that are important to us.’ So you see a very clear mismatch here in the goals and objectives. That’s something we’ve seen happen in the Sanfilippo community, as well.” 

O’Neill shared how information from parents and caregivers, such as the data from Cure Sanfilippo Foundation’s Caregiver Preference Study for Sanfilippo Syndrome, can be used to evaluate the benefits of potential therapy treatments and develop study endpoints for Sanfilippo.

She praised the FDA, including Dr. Janet Woodcook, director of the FDA’s Center for Drug Evaluation and Research, for improving patient engagement and facilitating ways for that to shape study endpoints.

The Caregiver Preference Study for Sanfilippo Syndrome has been a work in progress by the Foundation for the past 18 months, collecting data from 219 MPS-III caregivers across 14 different countries on their children, ages 1 to 40, to help researcher develop better study endpoints. The study’s early results are finding that the caregiver community feels the end points of cognitive IQ points, developmental quotients don’t reflect what their child can do and don’t reflect important aspects of life with Sanfilippo Syndrome.


“So what is meaningful change? posed O’Neill to the audience.“Just simply maintaining current function or slowing the rate of decline.”

She shared quotes directly from caregivers in the study’s focus groups regarding Sanfilippo study endpoints:

  • “I don’t care if it’s not a cure to keep him at where he is right now would be amazing. I would do anything for that.”
  • “Our expectations and what we would like to get from treatments for Sanfilippo are relatively small. Some of those small things have a big impact on us”
  • “I’ve heard some researchers say, ‘Well, would you really want your son to continue to live longer with the mental deficiency?’ Yes. Is he happy? Is he laughing? Is he watching a show? I don’t care if he has a mental deficiency, as long as he’s not in pain.”
  • “I’ll take that she can sit and enjoy doing something for a few…three more minutes than before. I’ll even take an intensive medical procedure to get six more months. I’ll take any of it and I think any of it will be good for her.”
  • “Here’s what I think: I don’t even care if skills are maintained. I just don’t want her to be pain.”

“We all need to be aware of this broad implicit societal bias against people who have intellectual disabilities, particularly children, and just make sure that that’s not entering into our communications, entering into the decisions we make at work, what we choose to study, who we choose to help and how aggressively we choose to help them,” urged O’Neill.

Regarding past clinical trials and their study endpoints, O’Neill questioned, “Maybe we just didn’t pick the right endpoints to show efficacy in trials that failed. We have to understand that [Sanfilippo Syndrome] is a heterogeneous disease, like most rare diseases. And out of the core symptoms, one patient may have more bowel movements symptoms and another patient may have more sleep disturbance. They’re all impacting quality of life, but different, and we need to have our endpoints be able to allow for that heterogeneity and still pick up on differences.”

“We also need to think about as she mentioned more-inclusive trial designs. Instead of trying to get all of our patients to fit into a preferred endpoint like cognitive testing, which may be great for infants and under two-years-old, but not great for the 95% of the living population with this disease currently. So, we need to have our endpoints fit our population rather than vice versa.”

O’Neill closed by sharing her positive outlook, “We’ve come a really long way in the last six years since I started just my observation, since I started coming to this conference. It’s really amazing, the progress that’s happening. We’re not there yet, at least in Sanfilippo, we still don’t have our first treatment. There’s a lot of promise. We’re going to get there.”

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