Journal of Pediatric Gastroenterology & Nutrition:
Steps Toward Harmonization for Clinical Development of Medicines in Pediatric Ulcerative Colitis—A Global Scientific Discussion, Part 1: Efficacy Endpoints and Disease Outcome Assessments
Sun, Haihao*; Vesely, Richard†; Taminiau, Jan†; Szitanyi, Peter†; Papadopoulos, Elektra J.*; Isaac, Maria†; Klein, Agnes‡; Uzu, Shinobu§; Griebel, Donna*; Mulberg, Andrew E.*
*US Food and Drug Administration, Silver Spring, MD
†European Medicines Agency, London, UK
‡Health Canada, Ottawa, Ontario, Canada
§Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
Address correspondence and reprint requests to Andrew E. Mulberg, MD, FAAP, Division of Gastroenterology and Inborn Errors Products, OND/CDER, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (e-mail: Andrew.Mulberg@fda.hhs.gov).
Received 5 September, 2013
Accepted 6 January, 2014
Members of the i-IBD Working Group include primary authors and Jessica Lee, MD; Anil Rajpal, MD; Robert Fiorentino, MD; Klaus Gottlieb, MD; Aisha Peterson Johnson, MD; Zana Handy Marks, MD; Wes Ishihara, BS; Kevin Bugin, MS, RAC of the Division of Gastroenterology and Inborn Error Product in the FDA; Kader Kourad; Catherine Njue; Cora Chen; Talia De Laurenti of Health Canada; Mutsuhiro Ikuma, MD; Yosuke Kobayashi; Keiko Ueda, MD; Hana Sugai; and Akiko Nitta of PMDA. Other members from the FDA are Jean Temeck, MD; William Rodriguez, MD, PhD; Robert M Nelson, MD, PhD; and Suzanne Malli of the Office of Pediatric Therapeutics.
The views expressed in this article are those of the authors and do not necessarily reflect official positions or policies of the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan.
The authors report no conflicts of interest.
Objectives: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally.
Methods: The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials.
Results: There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC.
Conclusions: Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.
See “Pediatric UC Drug Development: A GREAT Idea Now Needs a GRAND Conversation” by Rosh and Hyams on page 677 and “Steps Toward Harmonization for Clinical Development of Medicines in Pediatric UC—A Global Scientific Discussion, Part 2: Data Extrapolation, Trial Design, and Pharmacokinetics” by Mulberg et al on page 684.
Ulcerative colitis (UC) is a chronic inflammatory disease that involves the mucosal surface of the colon, resulting in diffuse friability and erosions with bleeding. Approximately 50% of adult patients have disease confined to the rectosigmoid region (proctosigmoiditis);, in 30% it extends to the splenic flexure (left-sided colitis); and in <20% it extends more proximally and is referred to as extensive colitis (1). In contrast, the symptoms of pediatric UC may be more severe with higher rates of colectomy and 80% of them are extensive colitis (2–4). There is a correlation between disease extent and symptom severity in both adults and children (1). Differences in the extent of endoscopically active colonic disease and signs and symptom severity at presentation between adults and children suggest that it is important to consider whether defining pediatric-specific endpoints to assess clinical outcome in pediatric UC trials is needed.
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 (5). The definitions of study endpoints and disease remission have, however, been diverse and inconsistent across the UC trials performed to date globally in both adult and pediatric populations (5). On the basis of the pediatric trial data submitted to the US Food and Drug Administration (FDA), 3 different disease activity indices, including the Modified Sutherland Ulcerative Colitis Activity Index (MUCAI), Mayo scale score, and Pediatric Ulcerative Colitis Activity Index (PUCAI), were used in the pediatric trials leading to approval of pediatric indications for 2 products (6). The components and definitions of the grading systems are different among the 3 disease activity indices used in the pediatric UC trials (6,7). Although both MUCAI and Mayo score include the mucosal appearance component, the definition of the grading score is different (6,7). The PUCAI does not include the component of the mucosal appearance (7,8). The present use of different indices has presented a hurdle for global drug development in pediatric UC. As of this writing, 3 products (Remicade, Janssen Biotech, Horsham, PA; Colazal, Salix Pharmaceuticals, Raleigh, NC; and Azulfidine Pfizer, New York, NY) have been approved by the FDA, and 1 (Remicade) by European Medicines Agency (EMA) and Health Canada for a pediatric UC indication. No randomized efficacy pediatric UC trial was conducted to support product label in Japan, although the pediatric dosage and administration of Pentasa, Imuran, and Azanin have been approved by the Pharmaceuticals and Medical Devices Agency (PMDA).
In addition, many studies have been conducted to explore whether biomarkers can be used as surrogate endpoints to assess the mucosal inflammation and activity of disease in UC. Biomarkers are measurable characteristics, independent of subjective clinical opinion, that reflect physiological, pharmacological, or disease processes in animals or humans. Changes in biomarkers following treatment may reflect a clinical response to the product and may predict or identify safety problems related to a candidate drug or reveal a pharmacological activity expected to predict an eventual benefit from treatment (9). A surrogate endpoint is a biomarker that is intended to substitute for a clinical endpoint and is expected to predict clinical benefit based on epidemiological, therapeutic, pathophysiological, or other scientific evidence. Surrogate endpoints can be a subset of pharmacodynamic biomarkers. For these reasons, although all surrogate endpoints can be considered biomarkers, it is likely that only a few biomarkers would be appropriate for use as surrogate endpoints (10). The validation of a surrogate endpoint typically requires in-depth clinical insights, empirical evidence, and a meta-analysis of many randomized and well-controlled trials (10).
Harmonization on pediatric-specific endpoints and outcome measurements is needed to facilitate future pediatric UC trials and drug development. The International Inflammatory Bowel Disease (i-IBD) Working Group, which consists of scientific members from the FDA, EMA, Health Canada, and the PMDA of Japan, is an international collaboration developed to advance scientific knowledge on efficacy endpoints, trial design, data extrapolation, and pharmacokinetics (PK) supporting drug development in pediatric IBD, including UC and Crohn disease (CD). The i-IBD Working Group seeks to improve the likelihood that clinical development of safe and effective therapies for the treatment of IBD is successful. The Working Group intends to focus on the immediate need for consensus on efficacy endpoints, biomarkers, trial design, and how to use extrapolation and PK data in pediatric IBD among regulatory authorities, as well as in the scientific and medical community. For the purpose of clarity, the scientific discussions of pediatric UC and CD will be reported separately. This article summarizes scientific discussions of pediatric UC among members of the i-IBD Working Group and provides possible approaches to consider for working toward harmonization of present thinking about drug development in pediatric UC. The views of the i-IBD Working Group expressed in this article are only individual personal opinions or suggestions for drug development in pediatric UC, and do not represent regulatory consensus or official guidelines of the individual agencies. Part 1 of this article presented here focuses only on the discussion of efficacy endpoints, biomarker, and surrogate endpoints in pediatric UC trials. Part 2 of the article, related to discussions of trial designs, extrapolation, and PK studies, will be reported in a separate article.
The members of 4 regulatory agencies (FDA, EMA, Health Canada, and PMDA) discussed their positions and practices based on their evaluations of applications received for drugs intended to treat pediatric UC via monthly teleconferences from January through December 2012. All attempts were made to understand individual approaches of agencies and opinions of experts. The suggestions provided in this article are based, wherever possible, on the evidence published in the medical literature.
A literature review assessing efficacy endpoints, biomarkers, and surrogate endpoints that have been used in pediatric IBD trials was conducted. The electronic database, PubMed/ MEDLINE, was searched. The phrase “pediatric ulcerative colitis/ AND (disease activity indices OR endpoints)” was used for the literature search on the topic of pediatric endpoints. The phrase “inflammatory bowel disease/ AND (disease activity indices or instrument) AND (biomarkers or surrogate endpoints)” was used for the literature search for biomarkers. No language and time restrictions were applied during the search. The last search was conducted on July 2, 2013.
Current State of Disease Activity Indices Used in Pediatric UC Trials
On the basis of the literature review and regulatory history provided by 4 international agencies that participated in the i-IBD Working Group, 3 different disease activity indices (MUCAI, Mayo score, and PUCAI) have been used in pediatric trials conducted to support drug approval for pediatric UC (6). MUCAI was used in the Colazal pediatric trial submitted to the FDA in 2006, and the Mayo score and PUCAI were used in the Remicade pediatric trial submitted to the FDA, EMA, and Health Canada in 2011. Each of these disease activity indices captured most, but not all, of the key signs and the symptoms (rectal bleeding, diarrhea, lower abdominal cramps, fecal urgency, and sigmoidoscopy appearance) experienced by both adult and pediatric patients with UC (6,7). For example, abdominal pain, an important symptom to young children (8), is only measured by PUCAI. Although PUCAI was developed specifically to assess the disease activities in pediatric patients with UC, the instrument does not comply with good measurement principles as delineated in the FDA Patient Recorded Outcomes Guidance because the PUCAI collects information on concepts such as abdominal pain and stool number using clinician report (11). Because of this design flaw, the PUCAI cannot be considered a well-defined and reliable measure for use as an effectiveness endpoint. The MUCAI and Mayo scores include a mucosal appearance component, whereas PUCAI does not assess the mucosal appearance and is intended to be a noninvasive measure of disease activity. Thus, no preferred primary efficacy endpoints or activity indices were identified because of insufficient data. There is a need to develop singular or multiple, well-defined, reliable, and internationally validated outcome measures to assess signs and symptoms of UC disease activity for use in clinical trials. The consensus of the committee noted that signs and symptom assessment is only 1 component of disease activity, and endoscopic appearance and histological assessment are equally relevant to consider in clinical outcome measurements.
Study Endpoints: Clinical Remission and Mucosal Healing
A total of 10 articles were retrieved and 9 articles relevant to pediatric UC endpoints and disease activity indices were reviewed from the published literature. One article evaluating issues associated with the quality-of-life questionnaire was not reviewed. For demonstrating induction, the i-IBD Working Group accepts the use of clinical remission as a primary endpoint. The definition of clinical remission is, however, different in the PUCAI and Mayo scores; in the case of Remicade, trial outcomes using these 2 indices appear divergent (7).
For the remission maintenance claim, the i-IBD Working Group, except PMDA, accepts the use of singular or multiple, well-defined, reliable, and internationally validated outcome measures to assess clinical signs and symptoms and endoscopic disease activity as primary endpoints. Colonoscopic appearance is the primary measure of disease activity in adult UC. It is recognized that induction and maintenance of symptomatic remission are not sufficient to achieve long-term treatment success, which reinforces the importance of assessing mucosal healing in UC. It has been recommended in the literature to include mucosal healing as a primary endpoint in all new clinical trials (5,12–14).; however, repeated colonoscopies are not generally acceptable for children in clinical practice, especially in the United States, Canada, and Japan, because of adverse effects of sedation used during the procedure.
The Mayo score, which has a component that assesses mucosal appearance, has been used as disease activity index to assess clinical outcomes in pediatric UC (6); however, the Mayo score requires sigmoidoscopy at each assessment and the acceptability of performing frequent sigmoidoscopy in children has been an ongoing debate among the pediatric gastroenterology community globally. The PUCAI is considered to be an effective noninvasive measure of clinical outcomes, supplemented by 1 sigmoidoscopy, by many international key opinion leaders in pediatric IBD and used in clinical trials (8,15–17). This position is, however, not acceptable to the i-IBD Working Group. As described previously, the instrument does not comply with good measurement principles as delineated in the FDA Patient Recorded Outcomes Guidance because the PUCAI collects information on concepts such as abdominal pain and stool number using clinician report. In general, each type of outcome assessment (eg, patient-reported, observer-reported, or clinician-reported) plays a critical role in drug development. The choice of the appropriate type of outcome assessment depends on the context of its use and the goal of measurement. For example, if symptom intensity is the goal of measurement and the patient population can respond themselves, a patient-reported outcome is most appropriate; however, if clinical judgment is required to interpret an observation, a clinician-reported outcome is appropriate. If the concept of interest can only be adequately captured by observation in daily life, and the patient cannot report for him- or herself, then an observer-reported outcome is chosen. There is no universally accepted minimum age appropriate for a child to provide self-report. For children who cannot provide self-report of symptoms, a parent report of observable signs is acceptable. An example of a disease area where an existing outcome measure was not identified is irritable bowel syndrome. In this case, an interim outcome measure was developed even as efforts are underway to develop a new measure.
Discussions continue with pediatric gastroenterology thought leaders regarding the development of a validated outcome measure. The PUCAI could be modified to be an alternative to the Mayo score, but it lacks an endoscopic component, which is critical for an assessment of disease activity according to the harmonized opinion. According to the study (n = 48) conducted by Turner et al (8) in 2007, PUCAI is correlated with Mayo score (r = 0.95, P < 0.001) and the colonoscopic appearance in children (r = 0.77, P < 0.001). On the basis of the Turner study (n = 86) in 2009, PUCAI is also correlated with the colonoscopic score in adults (r = 0.73, P < 0.001) (15); however, PUCAI has not achieved universal acceptance as the unique primary endpoint and there are ongoing studies to establish the relationship between mucosal healing and PUCAI clinical activity index (18).
Noninvasive Biomarkers and Pediatric UC
A total of 65 articles were retrieved and 51 articles addressing noninvasive biomarkers, surrogate endpoints, and disease activity indices associated with UC in either adult or pediatric population were reviewed. Fourteen articles relevant to noninvasive biomarkers and surrogate endpoints associated with CD were excluded. Among the 51 articles reviewed, only 1 study was conducted in 148 pediatric patients (62 with UC, 79 with CD, 7 with IBD, and 22 healthy control individuals) (19). This study reported that fecal lactoferrin levels were significantly higher in patients with UC (1880 ± 565 μg/mL) (mean ± SE) or CD (1701 ± 382 μg/mL) than in healthy control individuals <21 years (1.17 ± 0.47 μg/mL, P < 0.001); thus, they are a sensitive and specific marker of inflammation in children and young adults with UC or CD. It also reported that fecal lactoferrin level correlates well with clinical disease activity indices such as physician global assessment and erythrocyte sedimentation rate (19). Some studies have reported that fecal calprotectin is a reliable biomarker of mucosal damage and inflammation in both UC and CD (20). In addition, fecal lactoferrin, calprotectin, and polymorphonuclear-elastase, as well as serum C-reactive protein, have been evaluated in 139 adult patients undergoing diagnostic ileocolonoscopy (42 with UC, 43 with CD, and 53 with IBD) to assess intestinal inflammation in IBD. These 3 fecal markers are believed to differentiate IBD with active endoscopic inflammatory activity from IBD with inactive endoscopic inflammatory activity, and are reportedly superior to C-reactive protein in their diagnostic accuracy (21). Another study has shown that fecal levels of leukocyte markers (myeloperoxidase, eosinophil protein X, and IL-1β) could be objective complements to endoscopic and histopathological evaluations in the daily care of patients with UC (22). The utility of these biomarkers in a pediatric drug development program needs further investigation to justify their use as clinically meaningful endpoints. Other novel noninvasive markers still need to be developed or identified to measure the mucosal healing in pediatric UC.
The overall goal is to optimize the labeling information to enable correct use of the drug. The development of reliable, well-defined, and clinically relevant endpoints that measure tangible benefits for patients in terms of how they feel, function, and survive is essential. Consensus on the efficacy endpoints and assessment of disease activity measurement would facilitate the globalization of pediatric UC trials. Well-defined, reliable, and internationally accepted disease activity index/indices need to be developed or modified from the existing activity indices to fulfill this goal.
Literature review has shown that there is no consistency in the use of primary endpoints and disease activity indices to assess clinical outcome in adult and pediatric UC trials (5,12). Many disease activity indices have been developed, but none have been properly validated with a formal evaluation of their biometric properties such as responsiveness, reliability, and validity (5). Therefore, harmonization of pediatric efficacy endpoints and outcome measurements is needed to facilitate pediatric UC drug development. Endpoint definition also impacts the role that extrapolation may play in the development of drugs for pediatric IBD. If one wished to extrapolate efficacy in UC from adults to children, one must know whether there is a similar response in the 2 populations to intervention with a validated disease activity index. The role of extrapolation in drug development in pediatric UC is discussed in a separate article. In addition, since colonoscopic evaluation is important in assessing UC activity and potential long-term outcome (12–14), it would be meaningful to correlate the clinically reported signs and symptoms of UC as measured by the PUCAI with gross and/or histological evidence of mucosal healing. Insufficient correlation of colonoscopy appearance with other noninvasive indices in the past has limited their use in inflammatory bowel disease (23–26).
The i-IBD Working Group set forth to discuss issues in drug development in UC that may benefit from harmonization. It concluded that outcome measurements in pediatric UC trials must account for both endoscopic disease activity of UC and improvement of signs and symptoms. It was mutually agreed that assessment of signs and symptoms could not be used as a single primary endpoint in pediatric UC trials, but could be used as a coprimary or key secondary endpoint in conjunction with endoscopic parameters of mucosal appearance to assess condition severity. This is a global approach that is now being consistently communicated by regulatory agencies to drug sponsors. Additional work toward validating instruments for outcome assessment should be pursued, including understanding the utility of the components of the Mayo score when considered without endoscopy and of the PUCAI score, and their relationship to treatment benefit.
Biomarkers and their role as surrogate endpoints should continue to be investigated for their utility and role in expediting pediatric drug development. The qualification procedures from the FDA and EMA can help to have clear guidelines and a way forward for a regulatory acceptance as validates as fit for purpose (27,28). Mucosal healing has been proposed as a primary endpoint to assess long-term treatment outcome in UC trials since it is associated with better quality of life, fewer hospitalizations, fewer surgeries, longer time to clinical relapse, and reduction in dysplasia or cancer. The components of mucosal healing, that is, endoscopic appearance and histological evidence of inflammation to clinical benefit in children, remain to be elucidated. The importance of histological disease activity to long-term complications, that is, dysplasia and cancer risk, is well-known and accepted. Long-term risks for cancer development are related to the long-term management of mucosal inflammation, although 1 exacerbation poses an increased long-term risk for colonic cancer development (29). Although mucosal appearance can be directly assessed by endoscopy, there is a concern in Japan as to whether the endoscopy is well received in children because of risks of sedation and clinical practice paradigms and should be avoided in pediatric UC research completely. Clearly, there was divergence in this topic from the United States, Canada, and Europe, but Japan agreed that this was a point for further discussion. In Canada, colonoscopy in the pediatric population is more frequently used to assess treatment failure than therapeutic success. Validated substitutes for assessing mucosal appearance are needed to reduce endoscopy burden in children. Convergence on this perspective on the role of colonoscopy to be part of a clinical development program under general anesthesia is preferred by the pediatric gastroenterology community, but there may be variability in this practice globally, including Japan. This would be ethically acceptable only if provided as part of the child's clinical evaluation of response and not as a research-only endpoint.
The future potential role of fecal calprotectin and lactoferrin may be as noninvasive biomarkers in IBD, particularly UC (20). In the future, suitable biomarkers may need to be considered as substitutes for the endoscopic component of the disease activity indices for outcome measurement in pediatric IBD trials. Further confirmatory work to support the role of these biomarkers as surrogate endpoints awaits investigation.
In conclusion, the i-IBD Working Group offers the following perspectives, as shown in Table 1, on trial endpoints in an effort to enhance globalization of drug development in pediatric UC. For demonstration of induction, clinical remission measured by the Mayo disease activity score has been acceptable; however, as induction typically lasts 8 weeks, endoscopic appearance and histological improvement may not yet be shown, and thus endoscopy may pose an unnecessary burden for children. Timing of endoscopy related to the pharmacodynamic effect of the individual molecular entity is important to clarify in earlier stages of drug development. The judicious use of endoscopy based on the individual mechanism of action and durability of the therapeutic agent is important to consider in a pediatric development program. For demonstration of the maintenance of remission, clinical evaluation of signs and symptoms and endoscopy for mucosal healing evaluation including biopsy are important. If the Mayo score is used, endoscopic assessment, including assessment of gross and histological evidence of mucosal disease activity, should be ideally incorporated, but there was no global harmonization on this point. Additional data are needed to support the use of the PUCAI alone for assessing maintenance of remission; thus, it will be important to continue to obtain outcome information using the PUCAI, the Mayo score, and endoscopy for the foreseeable future.
Additional perspectives include a preference for assessment of clinical remission over clinical response for evaluation of induction for drug development, and justify the critical role of use of colonoscopy as a component of the outcome assessment for purposes of identifying the endoscopic and histological disease activity. The use of independent central reading with video monitoring of endoscopy is becoming more generalized and should be considered for use in pediatric clinical trials. The acceptability of these positions was acceptable to all agencies except PMDA for the role of colonoscopy for the evaluation of UC disease activity. At the present time, biological markers could be used as exploratory endpoints to assess efficacy. Understanding the role of biomarkers and their relationship to UC disease activity will advance our understanding of UC.
The authors thank Dr Julie Beitz of the US Food and Drug Administration for valuable editing and insightful input during the manuscript preparation.
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biomarkers; disease outcome assessments; endpoints; pediatric ulcerative colitis; surrogate endpoint
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