Disease Activity Indices Used in the Pediatric UC Trials
Table 2 compares the components of disease activity indices and definitions of the grading systems used in pediatric UC trials. Although both MUCAI and Mayo Score include the endoscopic mucosal appearance component, the grading score is defined differently. The PUCAI does not include mucosal assessment and is intended to be a noninvasive measure of disease activity.
As shown in Table 3, rectal bleeding, diarrhea, lower abdominal cramps, fecal urgency, and sigmoidoscopic appearance are considered the key signs and symptoms in the patients with UC (5). Each of the 3 existing disease activity indices used in pediatric UC trials measures most, but not all, of the key signs and symptoms of pediatric UC. For example, although all 3 instruments assess rectal bleeding and diarrhea, no instrument measures urgency and incontinence, which are very important to patients (5,12). Abdominal pain, an important symptom to young children (13), is captured only in PUCAI.
Assessment of the Disease Activity Indices Used in the Pediatric UC Trials
MUCAI is a modification of the Sutherland UC Disease Activity index, and thus it is similar but not identical to the primary efficacy endpoint used in the adult trial. The MUCAI used concrete signs (rather than symptoms) that the parent or the child can observe. For example, rather than using the term “diarrhea,” which is often ill-defined by patients, the MUCAI uses “number of stools per day,” which is an easily quantifiable variable. The other clinical sign assessed by the MUCAI is rectal bleeding, which can be easily identified by a patient or parent. In addition, the MUCAI includes mucosal appearance and a global rating of disease activity, which is assessed by the physician.
The Mayo score also consists of 4 categories (rectal bleeding, stool frequency, physician assessment, and endoscopic appearance) that are rated from 0 to 3 and give rise to a total score ranging from 0 to 12 (Table 2). It is the most commonly used instrument in placebo-controlled clinical trials for UC (1,10,14–17). Unlike the MUCAI, the Mayo stool frequency subscore is not an absolute stool count number, but is scored relative to “normal” for that subject, which may introduce interobserver variation. Additionally, the percentage of blood content–estimated patients may also introduce interobserver variation. Thus, a PRO component that assesses episodes of rectal bleeding not associated with stool may need to be considered. Further refinement of this endpoint may need to be considered.
The PUCAI was developed as a noninvasive disease activity index for pediatric UC and is reported to be correlated with colonoscopy (r = 0.77) (13). It is a physician-administered measure that focuses on 6 key signs and symptoms of UC: abdominal pain, rectal bleeding, stool consistency, number of stools per 24 hours, nocturnal stools (any event causing awakening), and activity level, which gives a maximum score of 85 (Table 2). The item selection of the PUCAI was performed by a group of 36 experts in pediatric inflammatory disease. The item weighting was performed by regression modeling using a prospective cohort of 157 pediatric patients with UC with a physician global assessment of disease activity as the anchor. A physician-based rather than a patient-based approach was used in the PUCAI during the instrument development process because the developers believe that disease activity is best judged by experienced physicians (13).
Because physicians obtain and interpret the information, the PUCAI is a proxy report, not a PRO or ObsRO. Additionally, the source of the information, that is, whether it is the child or caregiver, is unclear and can be variable. The extent to which the physician completing the assessment includes his or her own interpretation is unclear. The lack of standardization in measurement introduces variability and results in concepts of measurement (disease activity, response, and remission) being variably defined. Furthermore, unobservable concepts such as pain can only be assessed via direct report; if direct report is not feasible, such concepts must be assessed indirectly based on observable signs. The ability of the individual to ignore pain (PUCAI abdominal pain item) may be related to various other factors unrelated to the disease. In addition, the PUCAI lacks an adequate age-appropriate interviewer script and response rating criteria for the physician interviewer. Published work by Lee et al in 2011 demonstrated strong agreement between PUCAI scores obtained directly from patients and those completed by physicians. Additionally, a comparison study of noninvasive disease activity indices conducted in 86 adults with UC has demonstrated that PUCAI correlated with colonoscopic score better than partial Mayo score (0.74 vs 0.69, respectively) (11). Whether a patient-based PUCAI could complement existing instruments in both clinical and research settings remains to be confirmed in multiple clinical trials or in a registration setting (18). Therefore, there are features of PUCAI that, if addressed, could improve its ability to serve as an efficacy endpoint in a clinical trial to evaluate a product for the treatment of UC in the pediatric population.
Impact of Different Clinical Remission Definitions on the Clinical Outcome
In the pediatric Remicade trial, the baseline disease activity was measured by both PUCAI and Mayo score. All enrolled patients received Remicade 5 mg/kg intravenous infusion at weeks 0, 2, and 6. At week 8, these patients were evaluated for clinical remission rate measured by both PUCAI and Mayo score. Clinical remission was defined by Mayo score of ≤2 with no individual subscore >1, whereas it was defined by PUCAI as a score <10. As shown in Table 4, 24 of 60 patients (40%) were in clinical remission when assessed by Mayo score, whereas 17 of 51 patients (33%) were in clinical remission when assessed by PUCAI. This observation indicates that different endpoint measures with different definitions of the treatment outcome may affect the clinical trial outcome.
Alternate endpoints were used in the Colazal pediatric trial. Alternate endpoints were also used as a secondary endpoint, but not as a primary endpoint in the Remicade pediatric trial. There is lack of consistency in the definition of primary efficacy endpoints assessing treatment outcome in adult and pediatric UC registration trials. The reason for the inconsistency may be historical precedence, evolving science, and availability of clinical outcome measures. There is currently no consensus on endpoints and clinical outcome measures to assess the clinical outcome in pediatric UC. In addition, different clinical remission definitions may affect the clinical or trial outcomes. Standardized outcome concepts and remission definitions for use as trial endpoints to define treatment benefit are needed to facilitate the pediatric UC drug development.
Using qualitative research in patients and caregivers, an instrument should have adequate content validity (evidence that the score represents the concept of interest and that the item response options, and item weights are appropriate and interpretable) for the target population. In establishing content validity, it is important to identify the lower age limit at which children can understand the questions and provide reliable and valid responses. Multiple versions specific to appropriate age ranges within the targeted patient population (not just a single form) will need to be considered. More important, observer (including caregiver) reports should only include those events or behaviors that can be observed. Taking the example of pain, observers cannot validly rate a child's pain intensity but can report on behaviors and observable signs thought to be caused by pain.
Instrument items should be specific and conceptually simple, representing the concepts that define treatment benefit in the targeted subpopulations. Diagnostic tools do not necessarily capture concepts most important for measuring treatment benefit. Ratings of pain on the basis of “can be ignored” or “cannot be ignored” are discouraged because such responses are affected by many other variables other than the intensity of the symptom. Therefore, a PRO that includes a simple rating of abdominal pain intensity (eg, worst pain intensity in past 24 hours) should be considered. Similarly, it is not feasible for patients to estimate the percentage of stool content that consists of blood; thus, a PRO instrument that assesses concepts, such as number of bloody stools and episodes of rectal bleeding not associated with stool, should be considered.
The collaboration of interested parties, including international regulatory bodies, pharmaceutical industry, academia, and patient groups, in the development of adequate outcome measures in pediatric UC is highly encouraged. To facilitate the development of publicly available scientific tools to address unmet needs such as this, the FDA has initiated a drug development tool qualification program that provides a framework for the development and regulatory acceptance of scientific tools, including clinical outcome assessments, intended for well-specified clinical trial contexts of use (19).
In summary, no existing outcome measures are adequate to measure pediatric UC treatment outcome. No preferred primary efficacy endpoints were identified. To optimize the information for labeling and the correct use of the drug, clinical trials designed to evaluate the efficacy of medical therapies require clearly defined outcome endpoints and a well-recognized definition of disease remission. Consensus on definition of successful treatment outcome (disease response and/or remission) would facilitate pediatric drug development. A well-designed, reliable, and globally recognized outcome measure that measures signs and symptoms in children with UC is needed for expediting pediatric drug development. An age-appropriate set of tools to be completed by an observer or the child, as appropriate, should be based on a firm understanding of disease definition according to clinically meaningful subgroups, and other aspects of the context of use, to ensure content validity. Endoscopic mucosal and histological examination may need to be considered as 1 outcome measurement as the community is actively evaluating the critical role of mucosal healing, which should encompass both gross and microscopic evidence of disease activity. Whether these concepts can best be assessed for by a combination of PRO, ClinRO, and biomarkers, or through the use of individually scored signs and symptoms, remains a topic for further discussion.
The authors thank Drs Donna Griebel, Julie Beitz, Laurie Burke and Ashley Slagle for their review and perspectives shared throughout this process of compiling and reviewing the data and discussion.
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Keywords:© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
clinical outcome measure; disease activity index; pediatric specific endpoints; pediatric ulcerative colitis