Making pediatric IBD research trials “GREAT”
On Sept. 20 and 21, 2012, I participated in the FDA-sponsored GREAT (Gastroenterology Regulatory Endpoints and Advancement of Therapeutics) Workshop in College Park, MD, focusing on inflammatory bowel disease (IBD).
Overall it was a very positive experience. What was clear was that for the GREAT workshop to be great, it will need to be followed by considerable work and cooperation between all the invested parties.
The first day concerned pediatric IBD and was divided into three sessions — “evaluating efficacy in pediatric trials,” “defining and measuring treatment benefit” and “pediatric dosing.” The presenters and panel for each session included pediatric gastroenterologists experienced in clinical trials, senior representatives of pharma, staff and leadership from FDA and NIH, and a young woman with Crohn’s disease who acted as the lay community spokesperson.
This blogger, along with Joel Rosh, MD, from Goryeb Children’s Hospital in Morristown, NJ, started off the program with a historical perspective on pediatric clinical trials in IBD, which were characterized as usually underpowered for efficacy and occurring many years after the drug being evaluated had been approved for adult use. This late-to-the-dance phenomenon creates significant issues for recruitment and retention as it is much simpler for patients and families to use commercial drugs rather than undergo the hardships of a clinical trial.
First, some background. There is no such thing as a “professional” pediatric clinical trial patient. Most children considered for such studies have severe disease with a duration measured in only a few years. This situation has led the FDA to want to use extrapolation from adult trials to assist in regulatory approval for children. However, extrapolation can only occur if three basic premises are met:
- Is the course of the basic disease being studied sufficiently similar in adults and children?
- Is the response to therapy sufficiently similar in adults and children?
- Do adults and children have a sufficiently similar exposure-response relationship?
If the answer to all of these questions is “yes,” then all that is required are pharmacokinetic (pK) studies in children aimed at achieving drug levels similar to those in adults, and safety trials at the effective dose. We know that the metabolism of many drugs used in children is different than in adults and thus not only pK, but pharmacodynamic (PD) studies, are usually required. If PD studies are also required, then a drug may qualify for partial extrapolation. Safety can never be extrapolated and controlled short term and long term studies will always be required.
With these issues in mind, the session moved to the huge question of whether current measures of disease activity used in pediatric clinical trials — the Pediatric Crohn’s Disease Activity Index (PCDAI) and the Pediatric Ulcerative Colitis Activity Index (PUCAI) — meet FDA’s criteria for endpoint adequacy. FDA categorizes endpoints as patient reported outcomes, clinician reported outcome, observer reported outcome, biomarkers (not influenced by human input, e.g., fecal calprotectin, CRP), or actual survival.
Children present particular challenges as clinical trial participants. Age-dependent maturity may affect their reliability as observers and they are often accompanied by a parent who may have a different impression of disease severity. Additionally, repeated invasive tests, such as colonoscopy, are particularly problematic in children. There was considerable discussion and not universal agreement as to whether current pediatric IBD severity indices meet FDA’s standard. I think it would be fair to say that practicing clinicians are more satisfied with current indices than is the FDA.
What there was agreement about, however, was that there clearly needs to be objective evidence of disease improvement in addition to any patient-reported outcome. The presence of concomitant functional GI disorders, such as irritable bowel, or anatomic abnormalities, such as stricture, make the need clear for objective data in the opinion of this writer.
The last session turned to dosing from the viewpoints of the Center for Drug Evaluation and Research, industry, FDA and experienced clinicians. There was general agreement that adequate pK/PD studies were essential once adult experience was leveraged and that, particularly for biologics, assessment of immunogenicity was crucial. Inadequacies of historical assays for the latter were discussed. The concept of tailoring therapy as a function of an individual’s drug metabolism as the path of the future treatment paradigms was emphasized by clinicians.
I think it would be fair to say that all present were impressed by the level of discussion and the collegiality amongst the participants. Everyone left with a better sense of the work that needs to be done to arrive at mutually agreeable guidelines for future pediatric IBD trials.