Drug regulatory authorities have
been trying to harmonize pharmacovigilance activities across major worldwide
regions. In 1990, Europe, US and Japan
met for the first International Conference on Harmonization (ICH) of Technical
Requirements for Registration of Pharmaceuticals for Human Use.
ICH is an international organization
established in 1990 to harmonize regulations for the registration and ongoing
regulations of the pharmaceutical medicines worldwide. By harmonizing the
guidelines, ICH aims to ensure that developed medicines are safe, effective and
of good quality.
Despite this international PV
framework, pharmacovigilance activities across major worldwide regions remain unharmonised. In this essay, I
will highlight the differences in PV activities between EU, US and Japan and
will discuss the reasons that could explain such differences.
Concerning pre-marketing safety, expedited
reporting timeframes for investigational drugs in US, EU and Japan are
consistent with ICH E2A. In fact, fatal or life-threatening and unexpected
ADRs have to be reported no later than 7
calendar days after the sponsor is notified. While, other serious and expected
ADRs have to be expedited ? as soon as possible, and no later than
15 calendar days after the sponsor is notified.
However, the requirements for
expedited reporting are different in EU from USA. Indeed, in USA, sponsor
reports to FDA any suspected adverse reaction that is both serious and
unexpected only if there is evidence to suggest a causal relationship between
the drug and the adverse event . Causality usually requires aggregate data and
understanding of background and sponsor (alone) is responsible for determining
In the other hand, in EU, the
sponsor reports all SUSARs (Suspected Unexpected Serious Adverse Reactions) to
Competent Authorities, Eudravigilance and Ethics Committees. The investigator usually makes the causality
assessment. If the sponsor disagrees, the opinion of both the investigator and
sponsor should be provided with the report.
Concerning post-marketing safety, timeframes and requirements of expedited reporting for approved drugs are
different between EU, USA and Japan. In USA, expedited ICSRs apply to serious and
unexpected ADRs while they apply to only serious ADRs in EU and Japan. In USA
and EU, expedited reporting should be transmitted in 15 days after receipt /
awareness. In the other hand, in Japan, serious unexpected ADRs have to be
expedited 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 in
Early Phase Post-marketing Vigilance) or 30 days (for others). No timeframe is
defined for HCP reporting in Japan.
ICSRs are submitted to
Eudravigilance in EU and FDA Adverse Event Reporting System (FAERS) in US. Eudravigilance is a databases dedicated for
the management and analysis of information related to suspected ADRs in both
pre and post-marketing phases, while FAERS is devoted to post-marketing ADRs.
Furthermore, administrative content and technical requirements are diverging
between FAERS and EudraVigilance.
In Japan, ICSRs are submitted
electronically to the Pharmaceuticals and Medical Device Agency PMDA (E2B-J
standard) 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 covered
by PSURs (E2C R2 PBRER) in EU and Japan and Periodic Adverse Drug Experience Reports
(PADERs) in U.S. The format of
PADERs are different from PSURs (GVP Module VII format (PBRER)). Furthermore,
PSURs include an analysis of the risk-benefit balance of the product, while
PADRs require data disclosure rather than analysis. The periodicity of these reports
is not similar. PADER is required quarterly for three years from approval, then
annually for all products. PSURs in EU
are required every 6 months in the first 2 years after product launch, then
annually for the following 2 years, every 3 years thereafter and anytime upon
regulatory request. In Japan, the PSURs are required every 6 months in the
first 2 years after approval of the Japanese new drug application (JNDA), then
annually during the defined “re-examination” period and every 5 years
Post-marketing surveillance in Japan
include PV activities that are specific to Japan, such as early post-marketing
phase vigilance (EPPV), reexamination, reevaluation…
Risk management guidelines
implemented by regulatory agencies: FDA REMS (Risk Evaluation and Mitigation
Strategy) and EMA RMPs (Risk managemet plans) and J-RMP (Japan RMP) provide comparable guidance to reduce risk
and minimize harms with some differences. (2)
The US Risk Management Plan (RMP) is the
FDA-approved product label while the EU RMP is a formal document separate from
the SmPC that is produced for all (new) products according to a template and
GVP Module V. Differences in reporting time and actions for risk minimization
exist between FDA REMS and EMA RMP . (2)
J-RMP Format differs from EU RMP, US
REMS. It is short, includes bulleted information in boxes and tables and is
less 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 the
healthcare professionals and the patients with helpful overview of the risks of
Kovaltry® and how they can be minimized .
There are differences in Quality Management between US
and EU. For example, unlike EU, FDA inspections can occur anywhere in the
world, without advance notice in USA, and with advance notice outside US
In the previous paragraph, I
demonstrated that PV activities are still unharmonised across the major
worldwide regions. Many reasons can explain these differences.
The primary barrier is the lack of central
authority. In fact, ICH documents are guidelines and cannot impose new
regulatory requirements. Furthermore, these guidelines are constrained by
existing EU, US and Japanese regulations. Second, there are cultural and
demographic differences between the three ICH Regions. Citizens of Europe, US
and Japan have different attitude toward medicines, risk, health… these
differences constitute an obstacle for the development of common standard
guidelines (4). Third, the shortness and the old age of ICH guidelines related
to pharmacovigilance (efficacy (E) and multidisciplinary (M) guidelines) is an additional
obstacle to achieve harmonization (3). Furthermore, not all nations are favor
harmonization. Some several observers found that the US is not supporting
enough ICH : “By its own admission, the FDA is pursuing harmonization as a
secondary effort while maintaining its primary effort of domestic drug
Finally, variations in PV activities
between the three worldwide global regions are likely to continue. More efforts
are needed to achieve harmonization.
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 Drug
Administration and European Medicines Agency risk management implementation for
recent pharmaceutical approvals: report of the International Society for
Pharmacoeconomics and outcomes research risk benefit management working group. Value Health. 2012 Dec;15(8):1108-18.
Burger. Comparaison of pharmacovigilance in Germany and Japan. master thesis.