Background

Crohn's disease is characterized by chronic inflammation that can occur anywhere in the gastrointestinal tract, but most often affects the small bowel and colon. Typical symptoms include abdominal pain, chronic diarrhea, and gastrointestinal bleeding. Crohn's disease affects between 400,000 and 600,000 North Americans.¹ Ten percent of Crohn's disease patients are children under the age of 17 years.²

The clinical management of Crohn's disease is complicated. Practice guidelines for Crohn's disease recommend that clinicians take into account the disease location, severity, complications, and extra-intestinal manifestations when choosing a treatment strategy. However, no universal treatment strategy exists.³ The lack of consensus about the best treatment strategy can result in confusion and frustration for the Crohn's disease patient as well as practitioners who treat Crohn's disease patients.

Medications are the preferred treatment for Crohn's disease with surgical interventions reserved for complications of disease or evidence of dysplasia. Medical therapy in Crohn's disease targets intestinal inflammation with the intent of altering the natural history of the disease. Corticosteroids and aminosalicylates such as sulfasalazine have been used since the 1950s. Immunomodulators (6-mercaptopurine, azathioprine, and methotrexate) have been used for the treatment of Crohn's disease since the 1970s, although use of these medications was not routine until the 1990s.⁴ The first biologic tumor necrosis factor (TNF)-alpha inhibitor, infliximab, was approved by the Food and Drug Administration (FDA) for the treatment of Crohn's disease in adults in 1998. The FDA-approved monoclonal antibodies against TNF-alpha inhibitor also include adalimumab and certolizumab pegol.⁵ Another biologic agents used for the treatment of Crohn's disease include natalizumab, a monoclonal antibody against cellular adhesion molecule α4-integrin that is FDA-approved for Crohn's disease in adults.⁵

Our recent systematic review addressed several Key Questions in the management of Crohn's disease (see Table A). In that review, we identified several important gaps in the evidence, as shown in the analytic framework depicted in Figure A.⁶ We used the population, intervention, comparison, outcome, timing, setting (PICOTS) framework to identify gaps from the evidence in relationship to the populations, interventions, comparisons, outcomes, timing, and settings relevant to treatments for Crohn's disease. Several gaps related to the target population (children, non-white, and risk stratification based on patient characteristics). Other gaps related to interventions and comparisons of interest (step up versus top down treatment and head to head comparisons within and between treatment classes), outcomes of interest (mucosal healing, and patient-reported symptoms), or a timing issue (remission beyond 2 years). The objective of this report is to identify and prioritize existing gaps in the synthesized literature pertaining to pharmacological induction and maintenance of remission for patients with Crohn's disease by engaging stakeholders using a modified Delphi method.

Table A

Listing of Key Questions.

Figure A

Analytic framework for identification of potential research gaps in phase 1.

Methods

Stakeholder Engagement

Overview

We used a modified Delphi method to identify and prioritize existing gaps in the published literature on the pharmacologic management of Crohn's disease. The process had seven steps across four phases (Figure B). The Delphi method involved iterative rounds of responses by group members, providing aggregated feedback about all members' responses until consensus is reached. For each round, we used a Web-based assessment tool (SurveyMonkey™, Palo Alto, CA) that presented the list of the research gaps originally proposed by the authors based on the findings of the evidence review. Consensus among stakeholders was defined as agreement in responses of 50 percent or higher in three or more options for each category of research gaps. Gaps that did not achieve 50 percent or greater consensus among the stakeholders on three or more options were returned to the stakeholders, with their compiled feedback to reprioritize. Gaps achieving 50 percent or greater consensus in the following round were used to formulate specific research questions.

Figure B

Outline of steps for identification and prioritization of future research needs in Crohn's disease management.

Phase 1. Identification of Research Gaps

We used the analytic framework (Figure A) to identify potential populations, medication comparisons, and outcomes gaps from the comparative effectiveness review. A Web-based assessment tool was populated with the identified research gaps specific to the induction of remission and, separately, the maintenance of remission. We queried the stakeholders on nine potential populations for whom future research may be a priority (Table B). We also asked the stakeholders about 13 medication comparisons (Table C) and 12 disease-related outcomes (Table D) that could be priorities for future research. For each question about prioritizing research gaps, optional free-text fields were provided for stakeholders to propose their own options.

Table B

Stakeholder identification and prioritization of populations of greatest importance for future research for the induction of remission in patients diagnosed with Crohn's disease.

Table C

Stakeholder identification and prioritization of medication comparisons of greatest importance for future research for the induction of remission in patients diagnosed with Crohn's disease.

Table D

Stakeholder identification and prioritization of populations of greatest importance for future research for the maintenance of remission in patients diagnosed with Crohn's disease.

Phase 2. Prioritization of Research Gaps

The stakeholders were given a copy of the executive summary of the evidence review and were asked to independently identify the three highest priority populations, medication comparisons, and outcomes for future research for both induction of remission and maintenance of remission using the Web-based system.

Phase 3. Consensus Building

Responses from the completed feedback forms were compiled and analyzed for agreement. Categories that did not achieve consensus as defined above on three or more options were sent back to the stakeholders in a revised form of the original Web-based assessment tool with the complied responses from the previous round in an attempt to build consensus.

Phase 4. Research Question Development

Research questions were developed based on feedback from stakeholders that achieved consensus during the second and third rounds. The stakeholders were presented with their compiled feedback from the second and third phases along with the research questions developed. They were asked to provide feedback on the clarity, utility, study design feasibility, ongoing studies addressing the questions, and priority of the research questions.

Results

The stakeholders' responses about the gaps in evidence concerning populations, medication comparisons, and outcomes varied for the induction of remission and the maintenance of remission of Crohn's disease. Therefore, results from the stakeholder prioritization are presented first as future research needs for the induction of remission and then for the maintenance of remission.

Maintenance of Remission

All stakeholders prioritized children as an important population for future research on the maintenance of Crohn's disease remission. Fifty percent of stakeholders agreed that non-responders to biologics, and patients with complications are important populations to study in future research (Table D).

Among medication comparisons for maintenance of remission, two medication comparisons, with variation only in the single-medication control arm (TNF-alpha inhibitor and thiopurine versus thiopurine only or TNF-alpha inhibitor only), achieved consensus during the first round (Table E). Compiled stakeholder responses regarding medication comparisons from the first consensus round were sent to the stakeholders with a request to evaluate and again prioritize the medication comparisons. During the second round, four stakeholders (60%) identified one medication comparison (TNF-alpha inhibitor and thiopurine versus TNF-alpha inhibitor) as a top priority for future research, while three stakeholders (50%) identified a previously low-ranked medication comparison (one TNF-alpha inhibitor versus another TNF-alpha inhibitor) as a top priority for future research on the induction of remission in Crohn's disease. The medication comparison originally agreed upon by 50 percent of stakeholders during the first round failed to achieve consensus during the second round, and was not included in our final list of research questions (Table E).

Table E

Stakeholder identification and prioritization of medication comparisons of greatest importance for future research for the maintenance of remission in patients diagnosed with Crohn's disease.

Discussion

All stakeholders indicated that future research was needed for the induction of remission using monotherapy of one TNF-alpha inhibitor against another TNF-alpha inhibitor. Equally so, this intervention was given second highest priority by the stakeholders among the research questions developed. Our stakeholders identified head-to-head comparison of combination therapy of TNF-alpha inhibitors and thiopurine against monotherapy of a TNF-alpha inhibitor for the maintenance of remission in Crohn's disease as a high priority for future research. Based on stakeholder feedback, it is clear that combination therapy consisting of a TNF-alpha inhibitor and thiopurine for maintenance of remission is extremely important for future research; however, there is some ambiguity regarding the best monotherapy comparison as thiopurine achieved our criterion for consensus in the first round (50%) but failed to do so in the second round (33%). However, this monotherapy intervention was the one given highest priority by our group of stakeholders.

Children were unanimously considered a high priority for all future research in the field of Crohn's disease. It was noted by one stakeholder that when assessing outcomes for children, the Pediatric CDAI should be used. It was agreed that the outcomes of highest priority are mucosal healing, patient reported outcomes, CDAI, and steroid reduction for studies of the induction and/or maintenance of remission of Crohn's disease.

In a recent report, Cheifetz and colleagues engaged gastroenterologists to prioritize future comparative effectiveness research topics in inflammatory bowel disease.⁷ The authors reported that an “anti-TNF agent alone versus anti-TNF agent with thiopurine in patients with moderate to severe Crohn's disease failing thiopurine” was their sixth highest research priority among all inflammatory bowel disease related research questions. In addition, they reported that the “efficacy and safety of long-term immunomodulation versus anti-TNF therapy in Crohn's disease…” was their eighth highest research priority. Likewise, their findings reported the need to accept mucosal healing as a primary outcome.⁷ These results support our findings about high priority interventions and outcomes for future research. However, our stakeholders unanimously agreed that children are the highest priority for future research while Cheifetz identified adults as a higher priority.

The American Recovery and Reinvestment Act of 2009 outlined several research priorities specific to the treatment of Crohn's disease⁸ that have been endorsed by the AGA⁹ including the introduction of biologics into the treatment algorithm for inflammatory diseases, including Crohn's disease. With respect to outcomes of interest, there are still conflicting opinions within the AGA regarding the utility of mucosal healing as a primary endpoint.^10,11 Despite these recent conflicts, it is suggested from our stakeholders and other recent reports,^{7, 12, 13} that mucosal healing should be considered as a primary endpoint.

There were a few limitations to our research needs identification process. The investigators on the original systematic review were actively involved in the identification of research gaps in this study which allowed for potential investigator bias, such that internal experts developed both the Key Questions for the original comparative effectiveness review and identified potential gaps in the literature reviewed. This potential bias was mitigated by allowing stakeholders to independently identify other populations, medication comparisons, or outcomes for future research using a free-text option during each consensus round. A second limitation was that the complexity of the concepts in this topic may be a barrier for some patient stakeholders to contribute. To ensure that our information was accessible to a patient stakeholder, we identified a certified health educator, who possessed the requisite clinical knowledge to provide meaningful feedback from a patient's perspective. We also found that the responses from the patient stakeholder were consistent with those from the other expert stakeholders used in other surveys.

Conclusion

Children are a high priority for future research on the induction and maintenance of remission in patients diagnosed with Crohn's disease. Stakeholders identified substantial need for further research on the use of TNF-alpha inhibitors for induction and maintenance of remission of Crohn's disease. The stakeholders also identified an important need to report outcomes of mucosal healing, patient reported outcomes, CDAI and steroid reduction when conducting induction and maintenance of remission trials for Crohn's disease.

References

1.

Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of crohn's disease in population-based patient cohorts from north america: A systematic review. Aliment Pharmacol Ther. 2002;16(1):51–60. [PubMed: 11856078]

2.

Bousvaros A, Sylvester F, Kugathasan S, et al. Challenges in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2006;12(9):885–913. [PubMed: 16954808]

3.

Lichtenstein GR, Hanauer SB, Sandborn WJ. Practice Parameters Committee of American College of Gastroenterology. Management of crohn's disease in adults. Am J Gastroenterol. 2009;104(2):465, 83. quiz 464, 484. [PubMed: 19174807]

4.

Korelitz BI. A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: Origins at the mount sinai hospital. Mt Sinai J Med. 2000 May;67(3):214–26. [PubMed: 10828907]

5.

New Drug Application & Biologic License Application Efficacy Supplements (Approved CY 2008). [Internet]; c2008 [cited 2012 January]. http://www​.fda.gov/downloads​/Drugs/DevelopmentApprovalProcess​/HowDrugsareDevelopedandApproved​/DrugandBiologicApprovalReports​/EfficacySupplementApprovals​/UCM081900.pdf.

6.

Hutfless S, Almashat S, Berger Z, et al. Comparative Effectiveness Review No. 131. Rockville, MD: Agency for Healthcare Research and Quality; Jan, 2014. Pharmacologic Therapies for the Management of Crohn's Disease. (Prepared by the Johns Hokins University Evidence-based Practice Center under Contract No. 290-2007-10061.) AHRQ Publication No. 14-EHC012-EF. www​.effectivehealthcare​.ahrq.gov/reports/final.cfm. [PubMed: 24696887]

7.

Cheifetz AS, Melmed GY, Spiegel B, et al. Setting priorities for comparative effectiveness research in inflammatory bowel disease: Results of an international provider survey, expert rand panel, and patient focus groups. Inflamm Bowel Dis. 2012;18(12):2294–30. [PubMed: 22337359]

8.

Initial national priorities for comparative effectiveness research. National Academies Press: National Academies Press; 2009.

9.

AGA policy statement on comparative effectiveness research. American Gastroenterological Association; 2010.

10.

Higgins PDR. Mucosal healing is not ready to be the primary endpoint. American Gastroenterological Association; 2010.

11.

Siegel CA. Mucosal healing should be a primary endpoint. American Gastroenterological Association; 2010. american gastroenterological association.

12.

Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in crohn's disease. Inflamm Bowel Dis. 2009;15(9):1295–301. [PubMed: 19340881]

13.

Casellas F, Barreiro de Acosta M, et al. Mucosal healing restores normal health and quality of life in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2012 Apr 17 [PubMed: 22517240]