In their cautious review, Shah and Shah [1] emphasized differences in regulations of personalized medicine (PM) among the three major authorities, the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Specific points regarding the differences, however, were not raised for the drugs they selected for discussion in their review. Given that the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industries of the USA, Europe and Japan, scientific and technical aspects of drug registration should be harmonized. To identify differences, if any, in regulations of PM, we investigated approvals of PM drugs in the three regions.

As a typical example of PM, we focused on PM [2] drugs whose pharmacogenomic biomaker is required on the label. We also studied ivacaftor and pertuzumab, which were omitted in the list [2] simply because they were approved after publication of the list. The US, European and Japanese approval data on these drugs were obtained from Drugs@FDA (, European public assessment reports ( and the PMDA website (, respectively. We defined submission/approval delay as the difference between the date of submission/approval in the USA and that in the EU or in Japan.

Of 17 FDA-approved drugs and 18 indications whose biomarker is labelled as required, 13 drugs and 14 indications were approved in the EU, whereas 12 drugs and 12 indications were approved in Japan (Table 1). The median submission delay from the submission in the USA was 0 months in the EU and 21 months in Japan. The median approval delay from the approval in the USA was 6 months in the EU and 28 months in Japan.

Table 1. US, EU and Japanese data on the approval of personalized medicine drugs whose pharmacogenomic biomarker is required on the label
Generic nameUS trade nameIndicationBiomarkerSubmission dateApproval dateSubmission delay (months)Approval delay (months)
  1. Abbreviations are as follows: ALK, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukaemia; APL, acute promyelocytic leukaemia; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CCR5, chemokine receptor type 5; CD, cluster of differentiation; CEL, chronic eosinophilic leukaemia; CFTR, cystic fibrosis transmembrane conductance regulator; CML, chronic myelogenous leukaemia; EGFR, epidermal growth factor receptor; GIST, malignant gastrointestinal stromal tumours; Her2/neu, human epidermal growth factor receptor 2; HES, hypereosinophilic syndrome; KRAS, Kirsten rat sarcoma 2 viral oncogene homolog; MDS/MPD, myelodysplastic syndrome/myeloproliferative diseases; NA, not available; PDGFR, platelet-derived growth factor receptor; Ph1/BCR-ABL, Philadelphia chromosome/breakpoint cluster region-Abelson tyrosine kinase; PML/RARα, promyelocytic leukemia/retinoic acid receptor alpha.

Arsenic trioxideTrisenoxAPLPML/RARαMarch 2000December 2000June 2003September 2000March2002October20048381749
CetuximabErbituxColon cancerEGFR, KRASAugust 2003July 2003January 2007February 2004June 2004July 2008–142553
CrizotinibXalkoriLung cancerALKMarch 2011NAMarch 2011August 2011UnapprovedMarch 201207
DasatinibSprycelCML/Ph1+ ALLPh1/BCR-ABLDecember 2005January 2006August 2007June 2006November 2006January 2009020531
Denileukin diftitoxOntakLymphomaCD25December 1997NANAFebruary 1999UnapprovedUnapproved
Imatinib (1)GleevecCMLPh1/BCR-ABLFebruary 2001March 2001April 2001May 2001November 2001November 20010266
Imatinib (2)GleevecMDS/MPDPDGFRDecember 2005NANAOctober 2006November 2006Unapproved1
IvacaftorKalydecoCystic fibrosisCFTR (G551D)October 2011October 2011NAJanuary 2012July 2012Unapproved06
LapatinibTykerbBreast cancerHer2/neuSeptember 2006October 2006March 2007March 2007June 2008April 2009171525
LenalidomideRevlimnidMultiple myelomaChromosome 5qApril 2005February 2006June 2009December 2005June 2007August 201011511856
MaravirocSelzentryHIVCCR5December 2006December 2006October 2008August 2007September 2007December 2008022117
NilotinibTasignaCML/Ph1+ ALLPh1/BCR-ABLSeptember 2006October 2006June 2007October 2007November 2007January 200909115
PanitumumabVectibixColon cancerEGFR, KRASDecember 2005April 2006June 2008September 2006December 2007April 20104301443
PertuzumabPerjetaBreast cancerHer2/neuDecember 2011NANAJune 2012UnapprovedUnapproved
TositumomabBexxarLymphomaCD20 antigenJune 1999NANAJune 2003UnapprovedUnapproved
TrastuzumabHerceptinBreast cancerHer2/neuMay 1998February 1999January 2000September 1998August 2000April 20019212330
TretinoinVesanoidAPLPML/RARαNANANANovember 1995December 1996January 199513–10
VemurafenibZelborafMelanomaBRAFApril 2011May 2011NAAugust 2011February 2012Unapproved06

One would expect that labels would not differ significantly among countries, given that regulatory authorities evaluate the same scientific data. Both biological and nonbiological factors, however, can affect regulatory decisions. For example, a much lower incidence of cystic fibrosis [3] and melanoma [4] in Japan compared with the West could discourage the makers of ivacaftor and vemurafenib to file an application to the PMDA. Denileukin diftitox and tositumomab, which were approved for lymphoma by the FDA in 1999 and 2003, respectively, remain unavailable in both the EU and Japan, probably because better treatment modalities are available now.

The approval delay in Japan was observed in other therapeutic areas [5]. The present study shows that three-quarters of the approval delay consisted of delays in submission. The approval delay without submission delay in the EU indicates that the reviews took longer for the EMA than for the FDA. The cross-sectional design of our study makes causal inference of these delays difficult.

Our results show some similarities and differences in the approvals of PM drugs among the three regions of the ICH. Further studies are needed to investigate differences in postmarketing regulations of PM drugs, because such regulations are important for risk–benefit assessment of PM and are greatly affected by local factors, such as health polices, culture and financial settings.

Competing Interests

There are no competing interests to declare.


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