The safety of medicines is a critical public health concern that requires continuous monitoring and evaluation throughout a drug’s lifecycle, including post-authorization. Over the past decade, Portugal has undergone significant changes in its pharmaceutical sector, driven by regulatory actions from the National Authority of Medicines and Health Products (INFARMED, I.P.), which ensures the safety, effectiveness, and quality of medicines.
Objective
This study aimed to analyze the regulatory actions taken due to safety concerns in Portugal from 2013 to 2023.
Methods
A retrospective analysis was conducted using safety alerts published by INFARMED, I.P. between January 2013 and December 2023. The analysis focused on changes in marketing status, drugs involved, causes of regulatory actions, and yearly patterns.
Results
During the study period, 602 safety and quality alerts were issued, being 41 from safety and 561 from quality. The highest number of regulatory actions occurred in 2018, with 172 cases (28.57%). Generic drugs accounted for the majority, with 432 cases (72.19%). Batch recalls (76.65%) corresponded to the main regulatory action related to quality. Quality alerts were often related to impurities or stability (65.42%), non-conformity with GMP standards (11.76%), and labeling or packaging problems (10.70%). Unfavorable risk-benefit ratios were the cause of 100% of safety-related alerts.
Conclusions
The findings highlight the importance of robust surveillance systems and continuous evaluation of manufacturing and regulatory processes to enhance drug safety. Collaboration between regulators, the pharmaceutical industry, and healthcare professionals is essential to ensure that the benefits of medicines consistently outweigh the risks associated with their use.
OnakpoyaIJHeneghanCJAronsonJK. Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Med2016; 14: 1.
KostisJBDobrzynskiJM. Limitations of randomized clinical trials. Am J Cardiol2020; 129: 109–115.
4.
AlomarMTawfiqAMHassanN, et al.Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: current status, challenges and the future. Ther Adv Drug Saf2020; 11: 2042098620938595.
5.
ChabalengeBJereENanyangweN, et al.Substandard and falsified medical product recalls in Zambia from 2018 to 2021 and implications on the quality surveillance systems. J Med access2022; 6: 27550834221141770.
FelixTJordanJBAkersC, et al.Current state of biologic pharmacovigilance in the European Union: improvements are needed. Expet Opin Drug Saf2019; 18(3): 231–240. DOI: 10.1080/14740338.2019.1577818.
8.
SullivanJW. A pharmaceutical manufacturer’s perspective on reporting adverse drug experiences. Am J Hosp Pharm1990; 47(6): 1342–1345.
9.
MontanéESantesmasesJ. Characteristics of drug safety alerts issued by the Spanish medicines agency. Front Pharmacol2023; 14: 1090707. DOI: 10.3389/fphar.2023.1090707.
10.
FurbergCD. Understanding drug safety and how to maximize it for patients. J Am Acad Physician Assistants2011; 24(11): 16–17.
GouveiaBGRijoPGonçaloTS, et al.Good manufacturing practices for medicinal products for human use. J Pharm BioAllied Sci2015; 7(2): 87–96.
15.
BranchSK. Guidelines from the International Conference on Harmonisation (ICH). J Pharm Biomed Anal2005; 38(5): 798–805.
16.
World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products. Geneva: WHO, 2002, pp. 1–48.
17.
CorreiaIArmadaLVeigaP. Generics competition in the Portuguese pharmaceutical market. J Gene Med2020; 17(1): 17–28. DOI: 10.1177/1741134320953875.
18.
HerdeiroMTFigueirasAPoloniaJ, et al.Influence of pharmacists’ attitudes on adverse drug reaction reporting : a case-control study in Portugal. Drug Saf2006; 29(4): 331–340.
19.
HerdeiroMTFigueirasAPoloniaJ, et al.Physicians’ attitudes and adverse drug reaction reporting: a case-control study in Portugal. Drug Saf2005; 28(9): 825–833.
20.
MatosCRodriguesLJoaquimJ, et al.Attitudes of community pharmacy professionals towards consumers reporting in Portugal. Pharmacoepidemiol Drug Saf2016; 25: 428–429.
21.
MatosCvan HunselFJoaquimJ. Are consumers ready to take part in the pharmacovigilance system? - a Portuguese preliminary study concerning ADR reporting. Eur J Clin Pharmacol2015; 71: 883–890.
22.
MatosCvan HunselFTavares RibeiroR, et al.Diabetes patient’s pharmacovigilance knowledge and risk perception: the influence of being part of a patient organisation. Ther Adv Drug Saf2020; 11: 2042098620953935.
23.
AdvinhaAM. Farmacovigilância--A caminho do Futuro. Rev Port Farmac2023; 15(1–2): 19–22.
24.
INFARMED. National authority of medicines and health products I.P. (Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.). Lisbon: INFARMED, 2023. https://www.infarmed.pt/web/infarmed/circulares
25.
RozenbergSRevercezPFastrezM, et al.Suspension of ulipristal acetate for uterine fibroids during ongoing EMA’s review of liver injury risk: unfortunate timing during the Covid-19 pandemic. Eur J Obstet Gynecol Reprod Biol2020; 252: 300–302.
26.
OvermanRABorseMGourlayML. Salmon calcitonin use and associated cancer risk. Ann Pharmacother2013; 47(12): 1675–1684.
EbbersHCMantel-TeeuwisseAKMoorsEH, et al.A cohort study exploring determinants of safety-related regulatory actions for biopharmaceuticals. Drug Saf2012; 35: 417–427.
ThomasSKHodsonJMcIlroyG, et al.The impact of direct healthcare professional communication on prescribing practice in the UK hospital setting: an interrupted time series analysis. Drug Saf2013; 36: 557–564.
McNaughtonRHuetGShakirS. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open2014; 4(1): e004221. DOI: 10.1136/bmjopen-2013-00422.
35.
CraveiroNSSilvaSReisAM, et al.Drug withdrawal due to safety: a review of the data supporting withdrawal decision. Curr Drug Saf2020; 15(1): 4–12.
36.
AlvesCMarquesFBMacedoAF. Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier. Eur J Clin Pharmacol2014; 70: 745–756.
37.
SoaresSRoqueFRodriguesAT, et al.Safety alerts: an observational study in Portugal. Clin Therapeut2015; 37(9): 2122–2128.
38.
MontanéESantesmasesJ. Characteristics of drug safety alerts issued by the Spanish Medicines Agency. Front Pharmacol2023; 14: 1090707.
39.
SenguptaPChatterjeeBTekadeRK. Current regulatory requirements and practical approaches for stability analysis of pharmaceutical products: a comprehensive review. Int J Pharm2018; 547(1-2): 1–8. DOI: 10.1016/j.ijpharm.2018.04.007.
40.
IzutsuKIAndoDMoritaT, et al.Generic drug shortage in Japan: GMP noncompliance and associated quality issues. J Pharmaceut Sci2023; 112(7): 1763–1771.
41.
AlvarengaBCarneiroR. Chemometrics approaches in forced degradation studies of pharmaceutical drugs. Molecules2019; 24(20): 3804. DOI: 10.3390/molecules24203804.
42.
ChauhanYNexRSevakG, et al.Stability testing of pharmaceutical products. Res J Pharm Dosage Forms Technol2021; 2: 317–328. DOI: 10.52711/0975-4377.2021.00052.
43.
SörgelFKinzigMAbdel-TawabM, et al.The contamination of valsartan and other sartans, part 1: new findings. J Pharm Biomed Anal2019; 172: 395–405.
44.
SilvaASousaJMarquesC. Supply chain resiliency in the pharmaceutical industry – a simulation-based approach. Proceedings of the international conference on industrial engineering and operations management, Rome, Italy, July 26-28, 2022. IEOM Society International, 2022.
45.
INFARMED. Circular Informativa N.° 101/CD/8.1.7: Recolha de lotes dos medicamentos Aceclofenac Germed e Aceclofenac Mylan. Lisboa: INFARMED - Autoridade Nacional do Medicamento e Produtos de Saúde, I.P, 2013.
46.
OnakpoyaIJHeneghanCJAronsonJK. Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis. Crit Rev Toxicol2016; 46(6): 477–489.
47.
HuangBBarberSFoerg-WimmerC. Lessons learnt from providing technical assistance to Chinese generic medicines manufactures to achieve the WHO prequalification standards. J Generic Med2019; 15(3): 133.
48.
RavinettoRTintoHDiroE, et al.It is time to revise the international good clinical practices guidelines: recommendations from non-commercial north–south collaborative trials. BMJ Glob Health2016; 1(3): e000122.
