Capturing what isn't measured: in-trial interviews in pediatric rare disease

Rare diseases in children are often heterogeneous by nature, meaning that one child can experience the same rare disease in an entirely different way from another child with the same diagnosis. That makes it difficult to assess change within a clinical trial, and equally difficult to develop patient-centered clinical outcome assessments (COAs) that are relevant and comprehensive without being burdensome.

Over the last two decades, both paediatric clinical trials in rare diseases and the use of patient-focused COAs in those trials have seen a welcome rise. Parents, and their children where they are able, are usually provided with standardized, validated measures to report the child's symptoms and the impact of the disease. Many of these measures are considered to have content validity, as they have undergone appropriate patient-level or parent-level testing to confirm that the concepts they cover are relevant and important to patients.

What parents notice, and what the measures miss

Even so, pharmaceutical companies often receive letters from parents at the end of a trial describing changes they noticed in their children. Those changes are frequently so small that no COA captures them. Where a measure does capture them, the change may be too small to be considered clinically meaningful. Parents, though, consistently report that these small changes are meaningful to them and to their child.

Two examples show what this looks like in practice.

In one study in a progressive neurological disease, a child held their parent's gaze for seven seconds, far longer than the one second they had managed before. The parent said this made them feel more connected to their child, and made the difficult job of caring for a child with a rare disease that bit easier. No measure in the trial assessed the concept of a gaze being held for longer.

In another trial, a parent noted that their child learned to say "no" during the study. That was the single word they most wanted their child to learn, because it gave the child some autonomy over their own body. Measures may assess the ability to communicate in general, but adding one word to a child's vocabulary is unlikely to translate into a change on a communication scale.

From parents' letters to systematic evidence

In the past, this kind of information was gleaned only from letters that parents took it upon themselves to write to the trial sponsor. Those letters may or may not have been read, and decisions were rarely taken on the basis of them, because they were not collected systematically.

Over the last decade, in-trial interviews have become a helpful way to collect that information systematically: how the clinical trial went for the family, and whether the changes the child experienced were meaningful in the child's life and in their parents' lives. Interview content is often tied to the measures included in the trial. In-trial interviews can also provide a systematic way to assess smaller changes in concepts that current COAs do not yet cover, and to give meaning to the changes that are experienced.

When the interviews take place matters

Interviews are often conducted solely at the end of the trial, known as "exit interviews." These can be hugely valuable in providing context to the changes children experience, linking those changes to practical daily changes in how the child feels and functions. Concepts that are important to families but not currently measured can also surface, which is useful information for future trials.

• Exit interviews in Phase III trials aid interpretation of these pivotal trials.
• Exit interviews in earlier phase trials help guide drug development and COA strategy.
• Baseline and mid-point interviews provide insight into the child's journey through the trial as it happens.

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Meaningful change, understood on the patient's terms

In-trial interviews offer a way to make sure meaningful changes are better understood and properly patient-focused.

In pediatric rare disease, meaningful change is not always a large change on a scale. Sometimes it is seven more seconds of eye contact, one new word, or a little more autonomy. In-trial interviews help ensure those changes are not simply noticed, but captured, understood and inform decisions.