EXPERT APPROACHES TO EQUIVALENCE EVALUATION OF DRUGS — ANALOGUES OF ENDOGENOUS COMPOUNDS AS CONSISTENT WITH THE RUSSIAN LEGISLATION AND INTERNATIONAL LAW

The article demonstrates that bioequivalence studies of generic drugs whose active substances are analogues of endogenous compounds found in the human body in natural concentrations present a major challenge as compared to other products and call for a specific regulatory approach. In the absence of available scientific data demonstrating that the product intake can increase the general concentration of the endogenous compound, conducting bioequivalence studies can be economically impractical in contrast to a standard comparative clinical trial, because first it would be necessary to demonstrate a significant increase in the compound concentration in blood plasma. The article analyses Russian legislation and international law with respect to evaluation of medicinal products that are analogues of endogenous compounds, i.e. vitamins, hormones, enzymes, amino acids and salts. It was demonstrated that correction for endogenous compound concentration in blood plasma and control of its dietary intake are required in order to obtain accurate bioequivalence results. The article summarises the experience gained at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation with respect to evaluation of medicines that are analogues of endogenous compounds, and outlines the most frequent mistakes in testing protocols. It substantiates the need for an individual approach tailored for each particular product, since there is no single solution to the problem of background concentration of endogenous compounds. The authors of the article developed some key solutions that can help minimize the impact of background concentrations of test samples on the results of bioequivalence assessment. Based on the results of the analysis performed and accumulated experience the authors of the article suggested some ways to resolve the problem.

1. Federal Law of the Russian Federation of 12.04.2010, No. 61-FZ «On Circulation of Medicines» (In Russ.) Available from: http://www.consultant.ru/document/cons_doc_LAW_99350

2. Development of scientific and technical guidelines harmonized with international norms and approaches in the field of medicinal products circulation, including the development and research of medicinal products. Research report (intermediate). FSBI «SCEEMP» of the Ministry of Health of Russia; advisors: Olefir YuV, Merkulov VA; prepared by: Bondarev VP, Vasiliev AN. Moscow; 2015. 341 p. No. SR 115111740006. Deposited in CITIS on 16.02.2016, No. IKRBS 216021650026 (In Russ.)

3. Development and improvement of methodological criteria for the expert assessment, standardization and principles of planning, conducting and documenting the research results of individual groups of medicinal products. Research report (intermediate). FSBI «SCEEMP» of the Ministry of Health of Russia; advisors: Bunyatyan ND, Bondarev VP, Vasiliev AN; prepared by: Volgin AR, Kuznetsov AL. Moscow; 2015. 758 p. No. SR 115111740005. Deposited in CITIS on 16.02.2016, No. IKRBS 216021650030 (In Russ.)

4. Soldatov AA, Avdeeva ZhI, Alpatova NA, Medunitsyn NV, Kiselevsky MV, Lysikova SL, et al. Problems of registration of biological non-original drugs. BIOpreparations. Prevention, Diagnosis, Treatment 2014; (4): 24-36 (In Russ.)

5. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. United States Food and Drug Administration. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465.pdf

6. Draft Guidance on Progesterone. United States Food and Drug Administration. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM209294.pdf

7. Draft Guidance on Ethinyl Estradiol; Norethindrone. United States Food and Drug Administration. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM199639.pdf

8. Draft Guidance on Prednisolone Sodium Phosphate. United States Food and Drug Administration. Available from: https://www.fda.gov/downloads/Drugs/.../Guidances/ucm089506.pdf

9. Guidance on Testosterone. United States Food and Drug Administration. Available from: https://www.fda.gov/downloads Drugs/.../Guidances/ucm090592.pdf

10. Draft Guidance on Levothyroxine Sodium. United States Food and Drug Administration. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM428208.pdf

11. Potassium Chloride Modified-Release Tablets and Capsules: In Vivo Bioequivalence and In Vitro Dissolution Testing. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Available from: https://www.fda.gov/ohrms/dockets/98fr/02d-0307-gdl0002.pdf

12. Merkulov VA, Bunyatyan ND, Pereverzev AP. Good Pharmacovigilance Practice in the United States and the European Union. Safety and Risk of Pharmacotherapy 2014; (4): 23-8 (In Russ.)

13. Investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1). European Medicines Agency. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01WC500070039.pdf

14. Rules for bioequivalence studies of drugs of the Eurasian Economic Union (In Russ.) Available from: http://www.eurasiancommission.org/ru/act/texnreg/deptexreg/konsultComitet/Documents/%D0%9F%D1%80%D0%B0%D0%B2%D0%B8%D0%BB%D0%B0%20%D0%91%D0%AD%D0%98%20%D0%B8%D1%82%D0%BE%D0%B3%2020.02.2015%20%D0%BD%D0%B0%20%D1%81%D0%B0%D0%B9%D1%82.pdf

15. Dissanayake S. Assessing the bioequivalence of analogues of endogenous substances («endogenous drugs»): considerations to optimize study design. Br J Clin Pharmacol. 2010; 69(3): 238-44.

16. Khokhlov AL, Lileeva EG, Sinitsina OA, Speshilova SA, Demarin SM, Shitov LN. Problems of bioanalytical research of bioequivalence of drugs in Russia. Pharmacokinetics and Pharmacodynamics 2014; (1): 37-43 (In Russ.)

17. Ewerth S, Angelin B, Einarsson K, Nilsell K, Bjorkhem I. Serum concentrations of ursodeoxycholic acid in portal venous and systemic venous blood of fasting humans as determined by isotope dilutionmass spectrometry. Gastroenterology 1985; 88: 126-33.

18. Zherdev VP, Kolyvanov GB, Litvin AA, Sariev AK. Harmonization of research on bioequivalence of drugs: questions and their possible solution. Experimental and Clinical Pharmacology 2003; 66(2): 60-4 (In Russ.)

19. Romanov BK, Olefir YuV, Merkulov VA, Pegova YuO. Revision of restrictive lists of medicines. Safety and risk of pharmacotherapy 2016; (1): 5-9 (In Russ.)