FDA Draft Guidance for Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet: Comments by the Society for the Study of Celiac Disease

Abstract

In light of the commentary published in Gastroenterology by Goldkind et al,1Goldkind L. et al.Gastroenterology. 2023; 164: 317-319Abstract Full Text Full Text PDF Scopus (2) Google Scholar we would like to present the comments offered by the Society for the Study of Celiac Disease (SSCD) to the US Food and Drug Administration (FDA) regarding its draft guidance for developing drugs for adjunctive treatment to a gluten-free diet. The SSCD is an organization of medical, scientific, and allied health professionals, formed to advance research in celiac disease and gluten-related disorders and to improve clinical care, including diagnosis and treatment. The SSCD thanks the FDA for providing expectations for the development of therapies for adjunctive treatment to a gluten-free diet. We support the development of such guidance as facilitating the development of nondietary therapies for celiac disease, for which the unmet need is substantial. The burden of persistent symptoms and/or enteropathy, the inevitability of gluten exposure, and the burdensome nature of the gluten-free diet are key issues that the scientific and patient communities have and will continue to emphasize. We recognize the difference between guidance for drug development and the ultimate target patient population for the drug after its testing and approval; indeed, those with ongoing enteropathy together with symptoms represent a relatively small subset of those people with celiac disease who are looking for and would benefit from nondietary therapies. Here, we summarize some specific concerns related to the draft guidance:•Although the term gluten-free diet is commonly invoked as the treatment for celiac disease, it is important to note that the removal of all gluten is not a realistic goal of treatment in celiac disease.2Silvester J.A. et al.Gastroenterology. 2020; 158: 1497-1499.e1Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Rather, the goal of clinical care is balancing adequate disease control with minimizing the burden and quality-of-life impact of the gluten-free diet.3Wolf R.L. et al.Dig Dis Sci. 2018; 63: 1438-1448Crossref PubMed Scopus (86) Google Scholar The largest clinical unmet need for treatments in celiac disease is not for control of symptoms in patients who are truly not exposed to gluten but for improved disease control in spite of ongoing efforts at gluten avoidance.•The requirement for improvement or resolution of histology (lines 194–202) at 24 or 52 weeks may preclude the development of therapies that improve gluten-induced symptoms in the face of stable enteropathy. Villus architecture in celiac disease may heal slowly and, in some cases, may persist for years, even with the strictest attempts at gluten avoidance. This is particularly a concern in older adults. As such, there should be some flexibility in expectation of the magnitude of expected healing in the face of variables such as a patient’s age and the duration of disease. As has been noted in presentations to the FDA,4US Food and Drug Administration https://www.fda.gov/drugs/news-events-human-drugs/gastroenterology-regulatory-endpoints-and-advancement-therapeutics-vi-great-vi-workshop-celiacGoogle Scholar markers of immunologic response, such as serum interleukin 2, may be an alternative measure of biologic disease modification in this indication that is more responsive than histology.5Cartee A.K. et al.Am J Gastroenterol. 2022; 117: 319-326Crossref PubMed Scopus (4) Google Scholar•The draft guidance recommends using a clinically accepted histologic scale such as the Marsh-Oberhuber classification (lines 94–98). This scale is occasionally used in clinical practice for the diagnosis of celiac disease (with villus atrophy or villus blunting without a classification more commonly used), but it has less reproducibility than the villus height/crypt depth ratio, a tool that is increasingly used by investigators because of its responsiveness to change, fine scaling, and utility as a continuous variable.6Adelman D.C. et al.Am J Gastroenterol. 2018; 113: 339-347Crossref PubMed Scopus (52) Google Scholar Furthermore, the Marsh-Oberhuber classification collapses 2 parameters, intraepithelial lymphocyte count and villus architecture, whose responsiveness are not highly correlated and have both different biologic mechanisms and clinical importance.•The draft guidance includes the recommendation for dietitian involvement during the treatment period of a candidate drug. Assessment by an expert dietitian is not standardized, nor is availability widespread. A more broadly defined dietary counseling session (as opposed to the involvement of a registered dietitian with specialized expertise in the gluten-free diet) directed at gluten avoidance may be more practical. We believe that intensive dietitian involvement throughout a trial may raise the likelihood of type 2 error in trials, but involvement to a more modest extent is appropriate.•There is a substantial unmet need for children and adolescents with celiac disease, groups for whom unique considerations for diagnosis and monitoring are at play. This was a prominent component of the Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics conference hosted by the FDA in July 2021; we hope and expect that this draft guidance will be adapted for pediatric and adolescent populations.4US Food and Drug Administration https://www.fda.gov/drugs/news-events-human-drugs/gastroenterology-regulatory-endpoints-and-advancement-therapeutics-vi-great-vi-workshop-celiacGoogle Scholar We look forward to partnering with the FDA as the development of nondietary therapies for celiac disease proceeds. Society for the Study of Celiac Disease (SSCD) Executive Council: Benjamin Lebwohl, MD, MS, President; Ritu Verma, MD, President-Elect; Ciaran Kelly, MD, Past President; Daniel Leffler, MD, MS, Secretary; Vanessa Weisbrod, Treasurer; Anne Roland Lee, EdD, RDN, LD, Councilor; Maureen Leonard, MD, MMSc, Councilor; and Amelie Therrien, MD, MSc, Councilor. Society for the Study of Celiac Disease (SSCD) Writing Committee: Daniel Adelman, MD; Marilyn Geller; and Joseph Murray, MD. Regulatory and Clinical Expert Perspective of the 2022 FDA Draft Guidance “Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet”GastroenterologyVol. 164Issue 3PreviewThe US Food and Drug Administration (FDA) has published the draft guidance “Celiac disease: developing drugs for adjunctive treatment to a gluten-free diet.”1 The guidance intends to promote clinical development of drugs and biologics for the treatment of celiac disease (CeD) as an adjunct to a gluten-free diet (GFD) in adults, based on current understanding of the natural history of the disease. A successful guidance document will promote robust evidence of meaningful benefit and lead to practicable, successful CeD drug development in clinical trials. Full-Text PDF ReplyGastroenterologyVol. 164Issue 3PreviewWe appreciate the valuable addition that the Society for the Study of Celiac Disease1 offers in response to the US Food and Drug Administration (FDA) regarding their draft guidance on celiac disease. This letter to the editor enhances the current regulatory discussions on the path forward in the development of therapies for patients with celiac disease. Their views synergize with our concerns that we have presented in the journal.2 Areas of particular congruence are the risks of requiring histologic improvement as defined in the guidance in patients already fully attempting to follow a gluten-free diet. Full-Text PDF