Paediatric clinical trial designs are in urgent need of reform because they are currently failing to meet the needs of children and young people with juvenile idiopathic arthritis (JIA), experts report.

Commonly used trial designs are plagued by ethical issues and, in many cases, do not provide the information needed for making evidence-based decisions on treatment, according to a viewpoint published in The Lancet Rheumatology, based on the views of patient and parent members of the CLUSTER Consortium Champions network.

“With an increasing array of different medications at our disposal, clinicians are faced with a myriad of options, but evidence to better inform these decisions is lacking,” the authors said.

“Current trial design aims to answer whether a drug is safe and effective. However, the crucial question for most children and young people with juvenile idiopathic arthritis and their families is which drug is right for them,” and “current studies, comparing one medication to placebo, cannot answer this vital question,” they argued.

The authors highlighted several problem areas within the current JIA research landscape, starting with ethical concerns surrounding the administration of placebo medicines to children when effective alternative treatments are available.

While randomised placebo-controlled withdrawal clinical trials somewhat address this issue by reducing placebo exposure—as only those who initially respond to trial medication are subsequently randomised to placebo or continued active treatment—their design still has critical flaws.

“First, valuable information about non-responding participants could be lost, which has implications for interpreting the clinical efficacy of the drug.” Similarly, “there is little information generated on comparative safety, as all participants receive the study drug,” they stressed.

Also, the apparent impact of the drug might be reduced by continued efficacy into the placebo phase.

Crucially, “patients, parents, and clinicians feel strongly that withdrawing efficacious medication is unacceptable and might risk missing the window of opportunity during which continuation of effective treatment could result in long-term remission,” they emphasised.

Also of note, while flare – a key trial endpoint – is considered to be sensitive to even small changes in disease activity, thus ensuring that children can re-start trial agents at the earliest opportunity, the CLUSTER Consortium Champions feel the definition is “weighted towards clinical markers of active disease rather than patient-reported factors, such as increased pain or fatigue”.

Additionally, clinical markers of active disease “could occur at a stage when joint damage is already underway”, they pointed out.

Placebo concerns

The group also emphasised the importance of ensuring that clinical trial designs are acceptable to patients and their families to minimise enrolment issues, particularly in areas such as JIA, where the pool of potential trial participants is small.

“Patients and families have notably reported that avoiding placebo would substantially increase their desire to enrol in a clinical trial,” the authors stressed.

The group also highlighted a nearly 10-year delay between the availability of a novel treatment for adults and its availability for children, meaning that many new therapies are currently prescribed off-label for younger patients.

“Although ethical considerations are often barriers to paediatric studies, which are often not possible without some data available in adults, the subsequent delay to accessing potentially beneficial medication could be considered equally unethical,” the authors said.

“For childhood conditions such as juvenile idiopathic arthritis for which there is a small timeframe available to prevent irreversible damage, this dilemma is particularly pertinent,” it was noted.

The authors believe the solution for JIA is precision medicine with “a strategic pharmacological approach based on the clinical, biochemical, genetic, and psychosocial elements of a disease, rather than the current approach, which is based on clinical phenotype alone”.

Progress in JIA clinical research will also require urgent reform of trial designs. These should include exploring head-to-head studies with limited use of placebo and, essentially, the involvement of patients and patient representatives at a much earlier stage than is currently the norm to ensure that outcomes truly reflect patients’ needs.

According to the authors, “many aspects of current trial design in paediatric rheumatology are unacceptable for children and families.”

“Urgent reform in both our approach to studying novel medications in children and young people and the licensing of novel agents is needed to ensure limited resources for research are maximised, and trials deliver more meaningful outcomes for children and young people with juvenile idiopathic arthritis”, they stressed.