Planning a clinical trial programme for medicinal products for chronic constipation: An analysis of the European Medicines Agency Guideline

INTRODUCTION. Chronic constipation is a widespread condition associated with substantial direct and indirect costs for diagnosis and treatment and a significant reduction in the quality of life of patients. There is a need for the development and clinical studies of novel medicinal products for chronic constipation due to the limited availability of effective treatment options and concerns regarding the long-term safety and tolerability of these options. Currently, the Russian Federation and other Member States of the Eurasian Economic Union (EAEU) lack guidelines governing the design and conduct of clinical trials of new medicinal products for chronic constipation.

AIM. This study aimed to analyse the relevant international approaches and methods as a potential basis for drafting a regional guideline for planning clinical trial programmes for novel medicinal products for chronic constipation.

DISCUSSION. This study analysed the main provisions of the European Medicines Agency (EMA) outlined in the Guideline on the evaluation of medicinal products for the treatment of chronic constipation (including opioid-induced constipation) and for bowel cleansing. The authors identified special considerations for conducting pharmacology studies and confirmatory clinical trials (selection of the clinical trial population, design, and duration; selection of primary and secondary efficacy endpoints; and safety assessment). Additionally, the authors highlighted special considerations for confirmatory clinical trials in paediatric and geriatric populations.

CONCLUSIONS. The EMA guideline covers all the requirements that are necessary for designing a clinical trial programme for a novel medicinal product for chronic constipation. Therefore, the EMA guideline can inform the ongoing development of the corresponding guideline for the Russian Federation and other EAEU Member States.

1. Roque M, Bouras E. Epidemiology and management of chronic constipation in elderly patients. Clin Interv Aging. 2015;10:919–30. https://doi.org/10.2147/CIA.S54304

2. Bharucha AE, Pemberton JH, Locke GR. American gastroenterological association technical review on constipation. Gastroenterology. 2013;144(1):218–38. https://doi.org/10.1053/j.gastro.2012.10.028

3. Chu H, Zhong L, Li H, Zhang X, Zhang J, Hou X. Epidemiology characteristics of constipation for general population, pediatric population, and elderly population in China. Gastroenterol Res Pract. 2014;2014:532734. https://doi.org/10.1155/2014/532734

4. Mugie SM, Benninga MA, Di Lorenzo C. Epidemiology of constipation in children and adults: A systematic review. Best Pract Res Clin Gastroenterol. 2011;25(1):3–18. https://doi.org/10.1016/j.bpg.2010.12.010

5. Eoff JC. Optimal treatment of chronic constipation in managed care: Review and roundtable discussion. J Manag Care Pharm. 2008;14(9 Suppl A):1–15. https://doi.org/10.18553/jmcp.2008.14.s8-a.1

6. Maevskaya EA. Chronic constipation: Management tactics based on scientific evidence. Farmateka. 2014;(14):17–23 (In Russ.). EDN: SVQFTF

7. Camilleri M, Ford AC, Mawe GM, Dinning PG, Rao SS, Chey WD, et al. Chronic constipation. Nat Rev Dis Primers. 2017;3:17095. https://doi.org/10.1038/nrdp.2017.95

8. Forootan M, Bagheri N, Darvishi M. Chronic constipation: A review of literature. Medicine (Baltimore). 2018;97(20):e10631. https://doi.org/10.1097/md.0000000000010631

9. Lacy BE, Mearin F, Lin Chang, Chey WD, Lembo, AJ, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–407. https://doi.org/10.1053/j.gastro.2016.02.031

10. Andreyev DN, Zaborovsky AV, Trukhmanov AS, Mayev IV, Ivashkin VT. Evaluation of the functional gastrointestinal diseases concept from standpoints of Rome IV (2016) diagnostic criteria (review). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;27(1):4–11 (In Russ.). https://doi.org/10.22416/1382-4376-2017-27-1-4-11

11. Tack J, Müller-Lissner S, Stanghellini V, Boeckxsta­ens G, Kamm MA, Simren M, et al. Diagnosis and treatment of chronic constipation — a European perspective. Neurogastroenterol Motil. 2011;23(8):697–710. https://doi.org/10.1111/j.1365-2982.2011.01709.x

12. Dukas L, Willett WC, Giovannucci EL. Association between physical activity, fiber intake, and other lifestyle variables and constipation in a study of women. Am J Gastroenterol. 2003;98(8): 1790–6. https://doi.org/10.1111/j.1572-0241.2003.07591.x

13. Haug TT, Mykletun A, Dahl AA. Are anxiety and depression related to gastrointestinal symptoms in the general population? Scand J Gastroenterol. 2002;37(3):294–8. https://doi.org/10.1080/003655202317284192

14. Bordin DS, Kucheryavy YuA, Andreyev DN. Chronic constipation: Urgency of the problem and modern possibilities of therapy. Effective Pharmacotherapy. 2019;15(36):76–80 (In Russ.). https://doi.org/10.33978/2307-3586-2019-15-36-76-80

15. Tucker DM, Sandstead HH, Logan GM Jr, Klevay LM, Mahalko J, Johnson LK, et al. Dietary fiber and personality factors as determinants of stool output. Gastroenterology. 1981;81(5):879–83. PMID: 6269944

16. Ostroumova OD, Shakhova EYu, Kochetkov AI. Drug-induced constipation. Russian Journal of Evidence-based Gastroenterology. 2020;9(1):20–31 (In Russ.). https://doi.org/10.17116/dokgastro2020901120

17. Trukhan DI, Degovtsov EN, Drokina OV. Patient with constipation syndrome at the ambulatory-polyclinic reception: Actual aspects of differential diagnosis and treatment. Medical Council. 2021;(5):142–53 (In Russ.). https://doi.org/10.21518/2079-701X-2021-5-142-153

18. Sbahi H, Cash BD. Chronic constipation: A review of current literature. Curr Gastroenterol Rep. 2015;17(12):47. https://doi.org/10.1007/s11894-015-0471-z

19. Nyam DC, Pemberton JH, Ilstrup DM, Rath DM. Long-term results of surgery for chronic constipation. Dis Colon Rectum. 1997;40(3):273–9. https://doi.org/10.1007/bf02050415

20. Rao SS. Constipation: evaluation and treatment of colonic and anorectal motility disorders. Gastroenterol Clin North Am. 2007;36(3):687–711. https://doi.org/10.1016/j.gtc.2007.07.013

21. van der Schoot A, Drysdale C, Whelan K, Dimidi E. The effect of fiber supplementation on chronic constipation in adults: An updated systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(4):953–69. https://doi.org/10.1093/ajcn/nqac184

22. Basilisco G, Coletta M. Chronic constipation: A cri­tical review. Dig Liver Dis. 2013;45(11):886–93. https://doi.org/10.1016/j.dld.2013.03.016

23. Davani-Davari D, Negahdaripour M, Karimzadeh M, Seifan M, Monkam M, Masoumi SJ, et al. Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods. 2019;8(3):92. https://doi.org/10.3390/foods8030092

24. Ivashkin VT, Maev IV, Abdulganieva DI, Alekseenko SA, Gorelov AV, Zakharo­va IN, et al. Practical recommendations of scientific society for the study of human microbiome and the Russian gastroenterological association on use of probiotics, prebiotics, synbiotics and functional foods in treatment and prevention of gastroenterological diseases in children and adults. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(2):65–91 (In Russ.). https://doi.org/10.22416/1382-4376-2021-31-2-65-91

25. Le Nevé B, de la Torre AM, Tap J, Derrien M, Cotillard A, Barba E, et al. A fermented milk product with B. Lactis CNCM I-2494 and lactic acid bacteria improves gastrointestinal comfort in response to a challenge diet rich in fermentable residues in healthy subjects. Nutrients. 2020;12(2):320. https://doi.org/10.3390/nu12020320

26. Stanghellini V, Vandeplassche L, Kerstens R. Best response distribution of 12-week treatment with prucalopride (RESOLOR) in patients with chronic constipation: Combined results of three randomised, double-blind, placebo-controlled phase III trials. Gut. 2011;60:159–60. https://doi.org/10.1136/gut.2011.239301.338

27. Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(1):1–35. https://doi.org/10.1038/ajg.2008.122

28. Luzina EV. The safety of application of laxatives. Russian Medicine. 2014;20(5):41–4 (In Russ.). EDN: SZVCUN

29. Karpukhin OYu, Eleev AA, Kutyreva MP, Yusupova AF, Khannanov AA. The use of original radiopaque markers in diagnosis of chronic constipation. Koloproktologia. 2016;(2):6–11 (In Russ.). https://doi.org/10.33878/2073-7556-2016-0-2-6-11

30. Rao SS, Hatfield R, Soffer E, Rao S, Beaty J, Conkin JL. Manometric tests of anorectal function in healthy adults. Am J Gastroenterol. 1999;94(3):773–83. https://doi.org/10.1111/j.1572-0241.1999.00950.x

31. Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. Childhood functional gastrointestinal disorders child/adolescent. Gastroenterology. 2006;130(5):1527–37. https://doi.org/10.1053/j.gastro.2005.08.063

32. Pakhomovskaya NL, Tatianina OF, Lazareva TYu. Functional constipation in children. Medical Council. 2022;(1):106–13 (In Russ.). https://doi.org/10.21518/2079-701X-2022-16-1-106-113

33. Koppen IJN, Lammers LA, Benninga MA, Tabbers MM. Management of functional constipation in children: Therapy in practice. Paediatr Drugs. 2015;17(5):349–60. https://doi.org/10.1007/s40272-015-0142-4

34. Gordon M, Naidoo K, Akobeng AK, Thomas AG. Cochrane Review: Osmotic and stimulant laxatives for the management of childhood constipation (review). Evid Based Child Health. 2013;8(1):57–109. https://doi.org/10.1002/ebch.1893

35. Kuizenga-Wessel S, Benninga MA, Tabbers MM. Reporting outcome measures of functional constipation in children from 0 to 4 years of age. J Pediatr Gastroenterol Nutr. 2015;60(4):446–56. https://doi.org/10.1097/MPG.0000000000000631

36. Kuizenga-Wessel S, Heckert SL, Tros W, van Etten-Jamaludin FS, Benninga MA, Tabbers MM. Reporting on outcome measures of functional constipation in children — a systematic review. J Pediatr Gastroenterol Nutr. 2016;62(6):840–6. https://doi.org/10.1097/mpg.0000000000001110

37. Koppen IJN, Saps M, Lavigne JV, Nurko S, Taminiau J, Di Lorenzo C, Benninga MA. Recommendations for pharmacological clinical trials in children with functional constipation: The Rome Foundation Pediatric Subcommittee on Clinical Trials. Neurogastroenterol Motil. 2018;30(4):e13294. https://doi.org/10.1111/nmo.13294

38. Маев ИВ, Самсонов АА, Дичева ДТ, Андреев ДН. Обстипационный синдром. Медицинский вестник МВД. 2012;(4):42–5. Mayev I, Samsonov A, Dicheva D, Andreyev D. Obstipation syndrome. MIA Medical Bulletin. 2012;(4):42–5 (In Russ.). EDN: PAWRDH

39. Fosnes GS, Lydersen S, Farup PG. Drugs and constipation in elderly in nursing homes: What is the relation? Gastroenterol Res Pract. 2012;2012:290231. https://doi.org/10.1155/2012/290231

40. Fleming V, Wade WE. A review of laxative therapies for treatment of chronic constipation in older adults. Am J Geriatr Pharmacother. 2010;8(6):514–50. https://doi.org/10.1016/s1543-5946(10)80003-0