Improving Trials and Authorization of New Medicine Access for Juvenile Idiopathic Arthritis

Multiple stakeholders were brought together to discuss the challenges surrounding trials, and the testing and authorization of new medicines for juvenile idiopathic arthritis.

The number of pharmacologic treatments for juvenile idiopathic arthritis (JIA) is growing at a rapid pace; however, many issues surround current pediatric trial designs used for the assessment of medications in patients with JIA. In addition, patients who qualify and are willing to participate in these trials is shrinking, which could pose a challenge for research and considering the pace at which treatment options are expanding.

Recently, researchers contended that regulatory agencies, pharmaceutical companies, and other stakeholders must work together to develop and implement novel trial designs so that new medicines for JIA can be authorized and made available to patients in a timelier manner.

Current Challenges in JIA Trials

In the United States, approximately 40% to 60% of children with JIA are not eligible to participate in clinical trials for the testing of new JIA medications because of factors such as having clinically inactive disease (CID) with 1 or more medications at 1- and 2-year follow-ups. Similarly, in the United Kingdom, 38% of patients with JIA were found to have CID at 1-year follow-up, and in Canada, 45% of patients had CID at the 1-year follow-up.

Considering that many children with JIA are exposed to multiple medications in clinical practice, trials that do not adequately account for switching of between medications in a patient often result in inaccurate and misleading data. Other factors cited by researchers as contributors to poor assessment of study results included small patient numbers, limited duration of follow-up, restrictive cohort inclusion criteria, and the absence of comparators.

The medications currently being used to treat JIA were authorized based on data from pediatric placebo-controlled randomized clinical trial results that included all subtypes of JIA. Medications are now being developed for specific JIA categories that are defined as rare diseases, and therefore, according to researchers, the current model that obtains regulatory approval for new JIA medications is no longer feasible.

Researchers cited several methodologic issues with the current testing model for new JIA medications; for instance, the current open-label design has made it difficult for researchers to interpret and generalize outcomes in the resultant responder group, since nonresponders are excluded from the trial after the open-label phase and valuable information is lost or limited, especially with regard to safety. In addition, patients, families, and clinicians have been concerned about abandoning the use of effective medications during trials since this may result in patients missing a window of opportunity when effective treatments may lead to long-term remission.

Current Outcome Measures in JIA Trials

The most common outcomes in JIA trials are flare, disease activity, damage, response to therapy, and several patient-reported outcomes. The JIA American College of Rheumatology (ACR) measure of flare and treatment response are the standard measures for registration trials; however, according to researchers, the JIA ACR measure does not reflect the disease activity level and may not be useful in clinical care because of the requirement of blood test results and certain calculations involving baseline values.

The ACR Provisional Criteria for CID currently standardizes the measurement of inactive disease and remission on and off medication. However, these criteria require additional prospective validation, and the ACR CID definition does not include the patient’s perception of disease status, which researchers consider to be a weakness.

Unmet Needs of Patients, Parents, and Providers

As the list of available medications for JIA continues to grow, researchers stated that the decision-making process for choosing the best medication is becoming more complex. Families and providers have many unanswered questions about JIA medications, including the safety of combining these medications with other medications, the medications that best work for specific JIA categories, and the frequency with which patients need to switch from a certain medication to another.

Patients and their families have stated that they expect clinical trials to produce meaningful and valuable information, especially since multiple effective treatment options for JIA already exist. According to researchers, parents and providers want trials to be patient-centered and provide valuable knowledge, rather than serve as a last resort for patients without health insurance or for whom other JIA treatments have been unsuccessful.

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Proposed Solutions

Representatives of the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have encouraged pharmaceutical companies to implement new trial designs, leverage Bayesian statistical analysis or extrapolation studies when possible, and also, design study plans with guidance and feedback from patients, families, clinicians, and researchers to support the authorization of new JIA medications. Clinical trialists and methodologists have been encouraged to work together to develop study designs superior to the uncontrolled open-label and active-comparator controlled study designs currently being used to test JIA treatments.

The Juvenile Arthritis Disease Activity Score (JADAS) has been proposed as an alternative to the JIA ACR outcome measure because it can be used to convey the level and change in disease activity. JADAS has been used as a secondary outcome in a number of positive registration trials; for trials with a treat-to-target design, the JADAS cutoff for inactive disease can also be used as an outcome.

To improve the evaluation of long-term safety of medications, researchers suggested including all patients starting new study drugs in a disease-based registry regardless of whether they have used other medications or were included in a prior comparator cohort. Currently, researchers indicated that some JIA studies apply unnecessary restrictions, including prohibiting patients from switching from comparator cohorts to study drug cohorts during follow-up.

Researchers also recommended that newly approved medications be studied in the context of disease-based registries for a specific time period, rather than for a specific number of patients. The registries would provide safety data on all patients who are starting study drugs, along with appropriate comparator patients during the same time period. This would help improve the quality of how safety data is collected for medications, and ensure that new drugs are studied extensively enough for researchers to meaningfully assess long-term safety.


Schanberg LE, Ramanan AV, De Benedetti F, et al. Toward accelerated authorization and access to new medicines for juvenile idiopathic arthritis [published online July 16, 2019]. Arthritis Rheumatol. doi:10.1002/art.41043