To be published with LET-00549-12.
Letter to the Editors
Are there any differences in the regulations of personalized medicine among the USA, EU and Japan?
Article first published online: 8 APR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 5, pages 1365–1367, May 2013
How to Cite
Shimazawa, R. and Ikeda, M. (2013), Are there any differences in the regulations of personalized medicine among the USA, EU and Japan?. British Journal of Clinical Pharmacology, 75: 1365–1367. doi: 10.1111/j.1365-2125.2012.04462.x
- Issue published online: 8 APR 2013
- Article first published online: 8 APR 2013
- Accepted manuscript online: 14 SEP 2012 05:40AM EST
- Manuscript Accepted: 29 AUG 2012
- Manuscript Received: 24 AUG 2012
In their cautious review, Shah and Shah  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  drugs whose pharmacogenomic biomaker is required on the label. We also studied ivacaftor and pertuzumab, which were omitted in the list  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 (http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/), European public assessment reports (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125) and the PMDA website (http://www.info.pmda.go.jp/approvalSrch/PharmacySrchInit?), 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.
|Generic name||US trade name||Indication||Biomarker||Submission date||Approval date||Submission delay (months)||Approval delay (months)|
|Arsenic trioxide||Trisenox||APL||PML/RARα||March 2000||December 2000||June 2003||September 2000||March2002||October2004||8||38||17||49|
|Cetuximab||Erbitux||Colon cancer||EGFR, KRAS||August 2003||July 2003||January 2007||February 2004||June 2004||July 2008||–1||42||5||53|
|Crizotinib||Xalkori||Lung cancer||ALK||March 2011||NA||March 2011||August 2011||Unapproved||March 2012||—||0||—||7|
|Dasatinib||Sprycel||CML/Ph1+ ALL||Ph1/BCR-ABL||December 2005||January 2006||August 2007||June 2006||November 2006||January 2009||0||20||5||31|
|Denileukin diftitox||Ontak||Lymphoma||CD25||December 1997||NA||NA||February 1999||Unapproved||Unapproved||—||—||—||—|
|Imatinib (1)||Gleevec||CML||Ph1/BCR-ABL||February 2001||March 2001||April 2001||May 2001||November 2001||November 2001||0||2||6||6|
|Imatinib (2)||Gleevec||MDS/MPD||PDGFR||December 2005||NA||NA||October 2006||November 2006||Unapproved||—||—||1||—|
|Ivacaftor||Kalydeco||Cystic fibrosis||CFTR (G551D)||October 2011||October 2011||NA||January 2012||July 2012||Unapproved||0||—||6||—|
|Lapatinib||Tykerb||Breast cancer||Her2/neu||September 2006||October 2006||March 2007||March 2007||June 2008||April 2009||1||7||15||25|
|Lenalidomide||Revlimnid||Multiple myeloma||Chromosome 5q||April 2005||February 2006||June 2009||December 2005||June 2007||August 2010||11||51||18||56|
|Maraviroc||Selzentry||HIV||CCR5||December 2006||December 2006||October 2008||August 2007||September 2007||December 2008||0||22||1||17|
|Nilotinib||Tasigna||CML/Ph1+ ALL||Ph1/BCR-ABL||September 2006||October 2006||June 2007||October 2007||November 2007||January 2009||0||9||1||15|
|Panitumumab||Vectibix||Colon cancer||EGFR, KRAS||December 2005||April 2006||June 2008||September 2006||December 2007||April 2010||4||30||14||43|
|Pertuzumab||Perjeta||Breast cancer||Her2/neu||December 2011||NA||NA||June 2012||Unapproved||Unapproved||—||—||—||—|
|Tositumomab||Bexxar||Lymphoma||CD20 antigen||June 1999||NA||NA||June 2003||Unapproved||Unapproved||—||—||—||—|
|Trastuzumab||Herceptin||Breast cancer||Her2/neu||May 1998||February 1999||January 2000||September 1998||August 2000||April 2001||9||21||23||30|
|Tretinoin||Vesanoid||APL||PML/RARα||NA||NA||NA||November 1995||December 1996||January 1995||—||—||13||–10|
|Vemurafenib||Zelboraf||Melanoma||BRAF||April 2011||May 2011||NA||August 2011||February 2012||Unapproved||0||—||6||—|
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  and melanoma  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 . 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.
There are no competing interests to declare.
- 2The Personalized Medicine Coalition. The case for personalized medicine. Washington, DC, 2011. Available at http://www.personalizedmedicinecoalition.org/about/about-personalized-medicine/the-case-for-personalized-medicine (last accessed 17 August 2012).