Drug regulatory authorities havebeen trying to harmonize pharmacovigilance activities across major worldwideregions. In 1990, Europe, US and Japanmet for the first International Conference on Harmonization (ICH) of TechnicalRequirements for Registration of Pharmaceuticals for Human Use.
ICH is an international organizationestablished in 1990 to harmonize regulations for the registration and ongoingregulations of the pharmaceutical medicines worldwide. By harmonizing theguidelines, ICH aims to ensure that developed medicines are safe, effective andof good quality. Despite this international PVframework, pharmacovigilance activities across major worldwide regions remain unharmonised. In this essay, Iwill highlight the differences in PV activities between EU, US and Japan andwill discuss the reasons that could explain such differences.Concerning pre-marketing safety, expeditedreporting timeframes for investigational drugs in US, EU and Japan areconsistent with ICH E2A. In fact, fatal or life-threatening and unexpectedADRs have to be reported no later than 7calendar days after the sponsor is notified. While, other serious and expectedADRs have to be expedited ? as soon as possible, and no later than15 calendar days after the sponsor is notified. However, the requirements forexpedited reporting are different in EU from USA.
Indeed, in USA, sponsorreports to FDA any suspected adverse reaction that is both serious andunexpected only if there is evidence to suggest a causal relationship betweenthe drug and the adverse event . Causality usually requires aggregate data andunderstanding of background and sponsor (alone) is responsible for determiningcausality .In the other hand, in EU, thesponsor reports all SUSARs (Suspected Unexpected Serious Adverse Reactions) toCompetent Authorities, Eudravigilance and Ethics Committees. The investigator usually makes the causalityassessment. If the sponsor disagrees, the opinion of both the investigator andsponsor should be provided with the report. Concerning post-marketing safety, timeframes and requirements of expedited reporting for approved drugs aredifferent between EU, USA and Japan.
In USA, expedited ICSRs apply to serious andunexpected ADRs while they apply to only serious ADRs in EU and Japan. In USAand EU, expedited reporting should be transmitted in 15 days after receipt /awareness. In the other hand, in Japan, serious unexpected ADRs have to beexpedited in 15 days and serious expected ADRs have to be expedited in 15 days(death, ADR caused by new drug 2 years after its approval and ADR detected inEarly Phase Post-marketing Vigilance) or 30 days (for others). No timeframe isdefined for HCP reporting in Japan.ICSRs are submitted toEudravigilance in EU and FDA Adverse Event Reporting System (FAERS) in US. Eudravigilance is a databases dedicated forthe management and analysis of information related to suspected ADRs in bothpre and post-marketing phases, while FAERS is devoted to post-marketing ADRs.Furthermore, administrative content and technical requirements are divergingbetween FAERS and EudraVigilance. In Japan, ICSRs are submittedelectronically to the Pharmaceuticals and Medical Device Agency PMDA (E2B-Jstandard) and include Japan-specific requirements e.
g. Japanese language,specific reporting form, specific causality assessment rules… Furthermore,most companies use a J-specific system and global PV system. Periodic post-marketing reporting is coveredby PSURs (E2C R2 PBRER) in EU and Japan and Periodic Adverse Drug Experience Reports(PADERs) in U.
S. The format ofPADERs are different from PSURs (GVP Module VII format (PBRER)). Furthermore,PSURs include an analysis of the risk-benefit balance of the product, whilePADRs require data disclosure rather than analysis.
The periodicity of these reportsis not similar. PADER is required quarterly for three years from approval, thenannually for all products. PSURs in EUare required every 6 months in the first 2 years after product launch, thenannually for the following 2 years, every 3 years thereafter and anytime uponregulatory request. In Japan, the PSURs are required every 6 months in thefirst 2 years after approval of the Japanese new drug application (JNDA), thenannually during the defined “re-examination” period and every 5 yearsthereafter. (1)Post-marketing surveillance in Japaninclude PV activities that are specific to Japan, such as early post-marketingphase vigilance (EPPV), reexamination, reevaluation…Risk management guidelinesimplemented by regulatory agencies: FDA REMS (Risk Evaluation and MitigationStrategy) and EMA RMPs (Risk managemet plans) and J-RMP (Japan RMP) provide comparable guidance to reduce riskand minimize harms with some differences.
(2) The US Risk Management Plan (RMP) is theFDA-approved product label while the EU RMP is a formal document separate fromthe SmPC that is produced for all (new) products according to a template andGVP Module V. Differences in reporting time and actions for risk minimizationexist between FDA REMS and EMA RMP . (2)J-RMP Format differs from EU RMP, USREMS. It is short, includes bulleted information in boxes and tables and isless comprehensive document than FDA REMS and EMA RMPs. Burger 3 compared in her master thesis’comparaison of pharmacovigilance in Germany and Japan’ between the published J-RMP sections and the EMA-RMP sections of Kovaltry®and concluded that the European RMP was easier to read, and provides thehealthcare professionals and the patients with helpful overview of the risks ofKovaltry® and how they can be minimized . There are differences in Quality Management between USand EU. For example, unlike EU, FDA inspections can occur anywhere in theworld, without advance notice in USA, and with advance notice outside USterritories.In the previous paragraph, Idemonstrated that PV activities are still unharmonised across the majorworldwide regions.
Many reasons can explain these differences. The primary barrier is the lack of centralauthority. In fact, ICH documents are guidelines and cannot impose newregulatory requirements. Furthermore, these guidelines are constrained byexisting EU, US and Japanese regulations. Second, there are cultural anddemographic differences between the three ICH Regions. Citizens of Europe, USand Japan have different attitude toward medicines, risk, health… thesedifferences constitute an obstacle for the development of common standardguidelines (4). Third, the shortness and the old age of ICH guidelines relatedto pharmacovigilance (efficacy (E) and multidisciplinary (M) guidelines) is an additionalobstacle to achieve harmonization (3). Furthermore, not all nations are favorharmonization.
Some several observers found that the US is not supportingenough ICH : “By its own admission, the FDA is pursuing harmonization as asecondary effort while maintaining its primary effort of domestic drugcontrol.”(4)Finally, variations in PV activitiesbetween the three worldwide global regions are likely to continue. More effortsare needed to achieve harmonization.Reference:1 Biswas P.Pharmacovigilance in Asia. Journal of Pharmacology &Pharmacotherapeutics.
2013;4(Suppl1):S7-S19. doi:10.4103/0976-500X.120941.2 Lis Y,Roberts MH, Kamble S, J Guo J, Raisch DW. Comparisons of Food and DrugAdministration and European Medicines Agency risk management implementation forrecent pharmaceutical approvals: report of the International Society forPharmacoeconomics and outcomes research risk benefit management working group. Value Health.
2012 Dec;15(8):1108-18.3 AliceBurger. Comparaison of pharmacovigilance in Germany and Japan. master thesis.4 http://nrs.harvard.edu/urn-3:HUL.