Approaches to clinical development of combination medicines in the Russian Federation and the Eurasian Economic Union in view of the requirements of the current legislation

In recent years, there has been an increasing interest in the development of combination medicines (fixed drug combinations) containing two or more active ingredients in a single dosage form. Therefore, there is an urgent need to develop an optimal programme of pre-authorisation clinical trials for combination medicines. The aim of the paper was to summarise modern science-based approaches to clinical development of combination medicines and identify possible ways of their practical implementation, taking into account the requirements of the current legislation. The author reviewed scientific publications devoted to creation of fixed drug combinations and analysed the regulatory documents defining regulatory requirements for pre-authorisation clinical studies of medicines in the Eurasian Economic Union, the Russian Federation, and other countries. Based on the results of the analysis the author described the general regulatory requirements for planning clinical studies of combination medicines for the purpose of their subsequent authorisation in the Russian Federation (via the national procedure) and the Eurasian Economic Union (via the centralized procedure). The pre-authorisation clinical development programme should be designed individually for each combination medicine. The selection of an optimal clinical trial strategy will make it possible to obtain sufficient information on the efficacy and safety of a combination medicine for its subsequent authorisation.

1. Vrijens B, Antoniou S, Burnier M, de la Sierra A, Volpe M. Current situation of medication adherence in hypertension. Front Pharmacol. 2017;8:100. https://doi.org/10.3389/fphar.2017.00100

2. Wirtz VJ, Kaplan WA, Kwan GF, Laing RO. Access to medications for cardiovascular diseases in low- and middle-income countries. Circulation. 2016;133(21):2076–85. https://doi.org/10.1161/CIRCULATIONAHA.115.008722

3. Sylvester KW, Cheng JW, Mehra MR. Esomeprazole and aspirin fixed combination for the prevention of cardiovascular events. Vasc Health Risk Manag. 2013;9:245–54. https://doi.org/10.2147/VHRM.S44265

4. Roberts DN, Miner PB. Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease. Drug Healthc Patient Saf. 2011;3:1–8. https://doi.org/10.2147/DHPS.S7329

5. Devabhaktuni M, Bangalore S. Fixed combination of amlodipine and atorvastatin in cardiovascular risk management: patient perspectives. Vasc Health Risk Manag. 2009;5(1):377–87. PMID: 19475775

6. McDonagh M, Peterson K, Thakurta SG, Dana T. Drug Class Review: Fixed Dose Combination Drug Products for the Treatment of Type 2 Diabetes and Hyperlipidemia: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2007 Oct. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20496342

7. Steinberg H, Anderson MS, Musliner T, Hanson ME, Engel SS. Management of dyslipidemia and hyperglycemia with a fixed-dose combination of sitagliptin and simvastatin. Vasc Health Risk Manag. 2013;9:273–82. https://doi.org/10.2147/VHRM.S44330

8. Canbakan B. Rational approaches to the treatment of hypertension: drug therapy –monotherapy, combination, or fixed-dose combination? Kidney Int Suppl. 2013;3(4):349–51. https://doi.org/10.1038/kisup.2013.75

9. Volpe M, Tocci G. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic. Vasc Health Risk Manag. 2012;8:371–80. https://doi.org/10.2147/VHRM.S28359

10. Bahiru E, de Cates AN, Farr MR, Jarvis MC, Palla M, Rees K, et al. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev. 2017:6;3:CD009868. https://doi.org/10.1002/14651858.CD009868.pub3

11. Ramjan R, Calmy A, Vitoria M, Mills EJ, Hill A, Cooke G, et al. Systematic review and meta-analysis: Patient and programme impact of fixed-dose combination antiretroviral therapy. Trop Med Int Health. 2014;19(5):501–13. https://doi.org/10.1111/tmi.12297

12. Schaecher KL. The importance of treatment adherence in HIV. Am J Manag Care. 2013;19(12 Suppl):s231–7. PMID: 24495293

13. Soriano V, Fernandez-Montero JV, de Mendoza C, Benitez-Gutierrez L, Pena JM, Arias A, et al. Treatment of hepatitis C with new fixed dose combinations. Expert Opin Pharmacother. 2017;18(12):1235–42. https://doi.org/10.1080/14656566.2017.1346609

14. Bourliere M, Adhoute X, Ansaldi C, Oules V, Benali S, Portal I, et al Sofosbuvir plus ledipasvir in combination for the treatment of hepatitis C infection. Expert Rev Gastroenterol Hepatol. 2015;9(12):1483‒94. https://doi.org/10.1586/17474124.2015.1111757

15. Nehra V, Rizza SA, Temesgen Z. Sofosbuvir/velpatasvir fixed-dose combination for the treatment of chronic hepatitis C virus infection. Drugs Today (Barc). 2017;53(3):177–89. https://doi.org/10.1358/dot.2017.53.3.2604176

16. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ. 2001;79(1):61–8. PMID: 11217670

17. Svensson EM, Yngman G, Denti P, McIlleron H, Kjellsson MC, Karlsson MO. Evidence-based design of fixed-dose combinations: Principles and application to pediatric anti-tuberculosis therapy. Clin Pharmacokinet. 2018;57(5):591–9. https://doi.org/10.1007/s40262-017-0577-6

18. Joshi SR, Ramachandran A, Chadha M, Chatterjee S, Rathod R, Kalra S. Acarbose plus metformin fixed-dose combination in the management of type 2 diabetes. Expert Opin Pharmacother. 2014;15(11):1611–20. https://doi.org/10.1517/14656566.2014.932771

19. Pfutzner A, Wilhelm B, Forst T. Rosiglitazone and glimeperide: review of clinical results supporting a fixed dose combination. Vasc Health Risk Manag. 2007;3(2):211–20.

20. Blonde L, San Juan ZT. Fixed-dose combinations for treatment of type 2 diabetes mellitus. Adv Ther. 2012;29(1):1–13. https://doi.org/10.1007/s12325-011-0094-1

21. Derom E, Brusselle GG, Joos GF. Efficacy of tiotropium-olodaterol fixed-dose combination in COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:3163–77. https://doi.org/10.2147/COPD.S92840

22. Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14:49. https://doi.org/10.1186/1465-9921-14-49

23. Raffa RB, Pergolizzi JV Jr, Tallarida RJ. The determination and application of fixed-dose analgesic combinations for treating multimodal pain. J Pain. 2010;11(8):701–9. https://doi.org/10.1016/j.jpain.2009.12.010

24. Błaszczyk B, Miziak B, Czuczwar P, Wierzchowska-Cioch E, Pluta R, Czuczwar SJ. A viewpoint on rational and irrational fixed-drug combinations. Expert Rev Clin Pharmacol. 2018;11(8):1‒11. https://doi.org/10.1080/17512433.2018.1500895

25. Deardorff WJ, Grossberg GT. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease. Drug Des Devel Ther. 2016;10:3267‒79. https://doi.org/10.2147/DDDT.S86463

26. Shah N, Parikh R, Casabona G, Kolhapure S. A new combined vaccine against measles, mumps, rubella and varicella in India. Indian Pediatr. 2017;54(12):1041‒6. PMID: 29317560

27. Tan M, Jiang X. Recent advancements in combination subunit vaccine development. Hum Vaccin Immunother. 2017;13(1):180–5. https://doi.org/10.1080/21645515.2016.1229719

28. Nikityuk NF, Glushchenko VA, Panin IV. Scientific and methodical approaches to organizing and conducting immunization in patients with health disorders. BIOpreparaty. Profilaktika, diagnostika, lechenie = BIOpreparations. Prevention, Diagnosis, Treatment. 2016;16(1):35–42 (In Russ.) https://doi.org/10.30895/2221-996X-2016-16-1-35-42

29. De Leo V, Musacchio MC, Cappelli V, Piomboni P, Morgante G. Hormonal contraceptives: pharmacology tailored to women's health. Hum Reprod Update. 2016;22(5):634–46. https://doi.org/10.1093/humupd/dmw016

30. Galzote RM, Rafie S, Teal R, Mody SK. Transdermal delivery of combined hormonal contraception: a review of the current literature. Int J Womens Health. 2017;9:315–21. https://doi.org/10.2147/IJWH.S102306

31. Alyautdina O.S. Combined oral contraceptives: evolution of the relationship benefit/risk. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2016;(4):17–21 (In Russ.).

32. Inui K, Koike T. Combination therapy with biologic agents in rheumatic diseases: current and future prospects. Ther Adv Musculoskelet Dis. 2016;8(5):192–202. https://doi.org/10.1177/1759720X16665330

33. Day D, Siu LL. Approaches to modernize the combination drug development paradigm. Genome Med. 2016;8(1):115. https://doi.org/10.1186/s13073-016-0369-x

34. Lidzhiyeva AA, Smolyarchuk EA, Eltsova EA. Biosimilars – advantages and prospects. BIOpreparaty. Profilaktika, diagnostika, lechenie = BIOpreparations. Prevention, Diagnosis, Treatment. 2015;(3):21‒4 (In Russ.) https://doi.org/10.30895/2221-996X-2015--3-21-24

35. Pelfrene E, Pinheiro MH, Cavaleri M. Artemisinin-based combination therapy in the treatment of uncomplicated malaria: review of recent regulatory experience at the European Medicines Agency. Int Health. 2015;7(4):239–46. https://doi.org/10.1093/inthealth/ihv017

36. Goloenko NG, Yagudina RI, Serpik VG, Kulikov AYu. Methodological approaches to the assessment of orphan medicinal products when making decisions about their inclusion in the program of medicinal maintenance: international experience and possible ways of its adaptation to the conditions of the health care system of the Russian Federation. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2017;5(2):53‒60 (In Russ.) https://doi.org/10.30895/2312-7821-2017-5-2-53-60

37. Kavanagh ON, Albadarin AB, Croker DM, Healy AM, Walker GM. Maximising success in multidrug formulation development: A review. J Control Release. 2018;283:1‒19. https://doi.org/10.1016/j.jconrel.2018.05.024

38. Jayasheel BG. Regulatory requirements for marketing fixed dose combinations. Perspect Clin Res. 2010;1(4):120‒3. https://doi.org/10.4103/2229-3485.71768

39. Poudel A, Mohamed Ibrahim MI, Mishra P, Palaian S. Assessment of the availability and rationality of unregistered fixed dose drug combinations in Nepal: a multicenter cross-sectional study. Glob Health Res Policy. 2017;2:14. https://doi.org/10.1186/s41256-017-0033-z

40. Prajapati K, Shah S, Desai M. Critical analysis of cardiovascular and central nervous system fixed dose combinations available in indian market. J Clin Diagn Res. 2016;10(12):FC36-FC39. https://doi.org/10.7860/JCDR/2016/21515.9049

41. Shafiq N, Kumar G, Gautam V, Ray P, Malhotra S. Fixed-dose combinations of antimicrobials: A need for special attention. Indian J Med Microbiol. 2016;34(2):208‒9. https://doi.org/10.4103/0255-0857.180305

42. Gidal BE. Seeking the rational (or at least avoiding the irrational). Epilepsy Curr. 2015;15(5):260‒2. https://doi.org/10.5698/1535-7511-15.5.260

43. Gautam CS, Saha L. Fixed dose drug combinations (FDCs): rational or irrational: a view point. Br J Clin Pharmacol. 2008;65(5):795‒6. https://doi.org/10.1111/j.1365-2125.2007.03089.x

44. Duconge J, Ruaño G. Fixed-dose combination products and unintended drug interactions: urgent need for pharmacogenetic evaluation. Pharmacogenomics. 2015;16(15):1685‒8. https://doi.org/10.2217/pgs.15.123