Risk Assessment Algorithms in Pharmacovigilance: A Review

INTRODUCTION. In the Russian Federation, risk-based approaches/methods to assess the safety of medicinal products have been used since 2016, but existing models based on them are few and applicable mainly to healthcare organizations. This underscores the need to systematise risk assessment procedures for medicinal products within pharmacovigilance frameworks by pharmacovigilance specialists using a risk-based approach in the risk management system.

AIM. This study aimed to analise of the key tools of the risk-based approach and optimise their application in medicinal product risk management systems.

RESULTS. A four-stage risk management framework for medicinal products was developed using a risk-based methodology: identification of risks associated with medicinal product use, determination of risk factors specific to individual medicinal products, correlation and evaluation of data for each risk factor with each of the identified risks and a conclusion on the benefit-risk ratio of medicinal products use. Key tools for implementing this approach include: 1) organization of work with information about adverse drug reactions; 2) active monitoring of drug safety; 3) development, implementation, and evaluation of risk mitigation measures; 4) targeted communication of safety issues to healthcare professionals, patients, and caregivers. Spontaneous reports, reports of adverse drug reactions received on request from the holder of the registration certificate, data from pharmacoepidemiological studies, information published in the scientific medical literature, as well as Internet resources are used as sources of information to identify the risks of adverse drug reactions at the post-registration stage of medicinal products circulation. Risk factors for the development of adverse drug reactions in the use of medicinal products are physiological changes in the patient's body, gender, age, presence of comorbidities, genetic predisposition, differences in pharmacokinetics and pharmacodynamics of medicinal products depending on the patient's age, use of off-label medicinal products. A five-step algorithm for medicinal product risk assessment was developed: parameters and objectives of risk evaluation, data sources, potential risks, severity and probability of risks, and benefit-risk ratio assessment. Additional risk minimisation measures are summarised.

CONCLUSIONS. The proposed variant of the risk-based approach using available tools can be used by pharmacovigilance specialists in drug risk management.

1. Kuzmina AV, Asetskaya IL, Zyryanov SK, Polivanov VA. Detecting medication errors associated with the use of beta-lactams in the Russian Pharmacovigilance database. BMC Pharmacol Toxicol. 2021;22(1):5. https://doi.org/10.1186/s40360-020-00470-x

2. Sienkiewicz K, Burzyńska M, Rydlewska-Liszkowska I, Sienkiewicz J, Gaszyńska E. The importance of direct patient reporting of adverse drug reactions in the safety monitoring process. Int J Environ Res Public Health. 2021;19(1):413. https://doi.org/10.3390/ijerph19010413

3. Shubnikova EV. Postmarketing surveillance: Review of open sources of drug safety data. Safety and Risk of Pharmacotherapy. 2024;12(3):309–30 (In Russ.). https://doi.org/10.30895/2312-7821-2024-12-3-309-330

4. Komissarova VA. Risk minimization measures in pharmacovigilance: Review of national and international experience. Good Clinical Practice. 2019;(3):33–43 (In Russ.). https://doi.org/10.24411/2588-0519-2019-10081

5. Kuznetsova EV, Zhuravleva MV, Mikhailov IA, Khabriev RU. Development of organizational technology for drug safety management in medical organizations based on a risk-based approach. Bulletin of Semashko National Research Institute of Public Health. 2024;(2):71–80 (In Russ.). https://doi.org/10.69541/NRIPH.2024.02.012

6. Ezaki A, Hirakawa A, Hanaoka H, Uyama Y. Factors influencing classifications of safety specifications in a risk management plan for antineoplastic agents approved in Japan: a review and descriptive analysis. Ther Innov Regul Sci. 2021;55(5):1075–81. https://doi.org/10.1007/s43441-021-00309-5

7. Zhuravleva MV, Romanov BK, Gorodetskaya GI, Muslimova OV, Krysanova VS, Demchenkova EYu. Topical issues of drug safety, possibilities of improving of pharmacovigilance. Safety and Risk of Pharmacotherapy. 2019;7(3):109–19 (In Russ.). https://doi.org/10.30895/2312-7821-2019-7-3-109-119

8. Kuznetsova EV, Zhuravleva MV, Mikhailov IA, Kurnosova TI. Development of methodological approaches to the formation of a risk-based model to minimize the prevalence of adverse reactions in drug application in medical organizations of Moscow. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2023;16(2):248–57 (In Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2023.184

9. Melnikova OA, Smirnov AV, Marchenko SD, Melnikov MYu. Model of a risk-based approach in the implementation of pharmaceutical activities. Farmatsiya.2022;71(2):41–8 (In Russ.). https://doi.org/10/29296/25419218-2022-02-07

10. Mayevskaya VA, Gorelov KV, Korozina NS, Stromova AS. Pharmacovigilance in Yaroslavl region on the example of antibacterial drugs. Journal of Volgograd State Medical University. 2021;(2):169–76 (In Russ.). https://doi.org/10.19163/1994-9480-2021-2(78)-169-176

11. Sabaté M, Montané E. Pharmacoepidemiology: An overview. J Clin Med. 2023;12(22):7033. https://doi.org/10.3390/jcm12227033

12. Alomar M, Tawfiq AM, Hassan N, Palaian S. Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: current status, challenges and the future. Ther Adv Drug Saf. 2020;11:2042098620938595. https://doi.org/10.1177/2042098620938595

13. Etminan M, Gill S, Fitzgerald M, Samii A. Challenges and opportunities for pharmacoepidemiology in drug-therapy decision making. J Clin Pharmacol. 2006;46(1):6–9. https://doi.org/10.1177/0091270005283285

14. Sandberg L, Taavola H, Aoki Y, Chandler R, Norén GN. Risk factor considerations in statistical signal detection: Using subgroup disproportionality to uncover risk groups for adverse drug reactions in VigiBase. Drug Saf. 2020;43(10):999–1009. https://doi.org/10.1007/s40264-020-00957-w

15. Zazzara MB, Palmer K, Vetrano DL, Carfì A, Onder G. Adverse drug reactions in older adults: a narrative review of the literature. Eur Geriatr Med. 2021;12(3):463–73. https://doi.org/10.1007/s41999-021-00481-9

16. Sychev DA, Ostroumova OD, Pereverzev AP, Kochetkov AI, Ostroumova TM, Klepikova MV, Ebzeeva E.Yu. Advanced age as a risk factor of drug-induced diseases. Safety and Risk of Pharmacotherapy. 2021;9(1):15–24 (In Russ.). https://doi.org/10.30895/2312-7821-2021-9-1-15-24

17. Bűdi T, Tóth K, Nagy A, Szever Z, Kiss Á, Temesvari M, et al. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia. 2015;56(6):849–55. https://doi.org/10.1111/epi.13011

18. Aurich B, Apele-Freimane D, Banaschewski T, Chouchana L, Day S, Kaguelidou F, et al. c4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children — A c4c expert group white paper. Br J Clin Pharmacol. 2022;88(12):4997–5016. https://doi.org/10.1111/bcp.15119

19. Akhlaghi F, Matson KL, Mohammadpour AH, Kelly M, Karimani A. Clinical pharmacokinetics and pharmacodynamics of antihyperglycemic medications in children and adolescents with type 2 diabetes mellitus. Clin Pharmacokinet. 2017;56(6):561–71. https://doi.org/10.1007/s40262-016-0472-6

20. Sutherland A, Ashcroft DM, Phipps DL. Exploring the human factors of prescribing errors in paediatric intensive care units. Arch Dis Child. 2019;104(6):588–95. https://doi.org/10.1136/archdischild-2018-315981

21. Martsevich SYu, Navasardjan AR, Komkova NA. Off-label prescribing possible causes, types and consequences. Legal regulation in the Russian Federation. Rational Pharmacotherapy in Cardiology. 2017;13(5):667–74 (In Russ.). https://doi.org/10.20996/1819-6446-2017-13-5-667-674

22. Russkikh SV, Tarasenko EA, Moskvicheva LI, Orlov SA, Tryakin AA, Vorobeva AV, et al. “Off-label” drugs: legal problems and socio-economic aspects of application practice. Pharmacy & Pharmacology. 2023;11(2):149–60 (In Russ.). https://doi.org/10.19163/2307-9266-2023-11-2-149-160

23. Belayneh A, Tadese E, Molla F. Safety and biopharmaceutical challenges of excipients in off-label pediatric formulations. Int J Gen Med. 2020;13:1051–66. https://doi.org/10.2147/IJGM.S280330

24. Mouchantaf R, Auth D, Moride Y, Raine J, Han SY, Smith MY. Risk management for the 21st century: Current status and future needs. Drug Saf. 2021;44(4):409–19. https://doi.org/10.1007/s40264-020-01033-z

25. Esslinger S, Quinn L, Sampat S, Otero-Lobato M, Noël W, Geldhof A, et al. Risk management plans: Reassessment of safety concerns based on Good Pharmacovigilance Practices Module V (Revision 2)-a company experience. J Pharm Health Care Sci. 2022;8(1):14. https://doi.org/10.1186/s40780-022-00244-z

26. Renske JG, Thomas G, Helga G. Limitations reported in evaluating effectiveness of risk minimization measures in the EU during 2018–2021: A qualitative analysis of industry-sponsored post-authorization safety studies. Clinical Pharmacology & Therapeutics. 2024;116(5):1252–8. https://doi.org/10.1002/cpt.3369

27. Essink SCM, Zomerdijk IM, Goedecke T, Straus SMJM, Gardarsdottir H, De Bruin ML. Duration of time intervals for risk minimization measure effectiveness studies. Clin Pharmacol Ther. 2025;117(4):1106–14. https://doi.org/10.1002/cpt.3569

28. Francisca RDC, Baba E, Hoeve CE, Zomerdijk IM, Sturkenboom MCJM, Straus SMJM. Introduction or discontinuation of additional risk minimisation measures during the life cycle of medicines in Europe. Drug Saf. 2021;44(1):63–72. https://doi.org/10.1007/s40264-020-00993-6

29. Bukatina TM, Shubnikova EV. Risk management plan: expert review of applications for marketing authorisation in the EAEU depending on the type of medicinal product (review). Safety and Risk of Pharmacotherapy. 2024;12(2):201–13 (In Russ.). https://doi.org/10.30895/2312-7821-2024-12-2-201-213

30. Essink SCM, Zomerdijk IM, Straus SMJM, Gardarsdottir H, DeBruin ML. Duration of effectiveness evaluation of additional risk minimisation measures for centrally authorised medicinal products in the EU Between 2012 and 2021. Drug Saf. 2023;46(10):1007–20. https://doi.org/10.1007/s40264-023-01341-0