Omics Project in PMDAYasuto OtsuboReviewerOffice of New Drug IIPharmaceuticals and Medical
Devices Agency
• Overview of Omics team in PMDA• Consultation on
Pharmacogenomics/Biomarkers• Current PGx implementations for
approved drugs• Future tasks in PGx and POP team
Outline
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• Member: 26 representatives from various offices (as of April 2011)
• Mission– Share data, information and knowledge– Discuss regulatory issues relating to Omics– Keep decision consistency among
offices/reviewers in PMDA– Evaluate and interpret data which are not directly
related to individual drug/diagnostic development
PMDA Omics Project (POP) team
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Consultation on Pharmacogenomics/
Biomarkers
Notifications related to pharmacogenomics issued by MHLW
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Notification Issued date NotifierGuidance on Clinical Pharmacokinetics Studies ofPharmaceuticals Jun 2001 PFSB/ELD
Guidance on Methods of Drug Interaction Studies Jun 2001 PFSB/ELDSubmission of information to Regulatory Authorities forPreparation of Guidance on the Use of Pharmacogenomics inClinical Studies
Mar 2005 PFSB/ELD
Request to cooperate in research regarding severe cutaneousadverse reactions Jun 2006 PFSB/SD
Terminology in Pharmacogenomics (ICH-E15 guideline) Jan 2008 PFSB/ELDand PFSB/SD
Points to Consider for Evaluating Genotyping Platforms Basedon DNA Chips Apr 2008 PFSB/ELD
and PFSB/SD
Guidance on Clinical Studies using Pharmacogenomics Sep 2008 PFSB/ELD
Request to cooperate in research regarding severe adversereactions (skin disorder and rhabdomyolysis) Jul 2009 PFSB/SD
Biomarkers Related to Drug or Biotechnology ProductDevelopment: Context, Structure and Format of Qualifications(ICH-E16)
Jan 2011 PFSB/ELDand PFSB/SD
PFSB/ELD: Pharmaceutical and Food Safety Bureau/Evaluation and Licensing DivisionPFSB/SD: Pharmaceutical and Food Safety Bureau/Safety Division
• PDMA scientific consultation regarding Pharmacogenomics/Biomarker qualification
• Fee:3,030,000 Yen = 30,000 $ (100 Yen=1 $)• Focus on general strategy for using PGx in
drug development or Biomarker Qualification– Individual issues related to an individual drug are
covered in the traditional consultation
• Provide a report for this consultation
Consultation on Pharmacogenomics/Biomarkers
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http://www.pmda.go.jp/operations/shonin/info/consult/file/0928001-betten03.pdf(Japanese only)
Standard Timeline of Consultation on PGx/Biomarker Qualification
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PMDA’saction
Pre‐meeting (informal)
Schedule Arrangement
Sponsor’saction
1st Inquiry 2nd Inquiry(If necessary)
DraftReport
FinalReport
0 2W 6W 9W 12W 14W 16W 22W 24W
Application
DocumentSubmission
Response
F2F
Comments to draft report
• Submitted document should contain following information and data (ICH E16)– Scientific rationale and impacts of pharmacogenomic test
and biomarker use– Context for a biomarker– Methodology and Results– Study Reports– Other Supportive Documents and References
• It is recommended that qualification submissions be submitted simultaneously to pertinent regulatory authorities
Information/data for Consultation on PGx/Biomarker Qualification
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• Context:Use for a (genomic) biomarker – General area; pre-clinical/clinical,
pharmacology/toxicology, efficacy/safety– Specific biomarker use; patients selection,
dose adjustment, toxicity/adverse event – Critical parameters which define when and
how the biomarker should be used; species, race, region
Information/data for Consultation on PGx/Biomarker qualification
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Examples of Context
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Biomarker(Drug)
CYP2C9(Warfarin)
HLA-B*1502(Carbamazepine)
General area
・Clinical pharmacology・Drug metabolism・Safety
・Clinical・Safety
Specific biomarker use
・Patient selection (inclusion/exclusion, enrichment, subgroup analysis)
・Dose adjustment and risk reduction
・Patient selection (inclusion/exclusion)
・Safety predictor and mechanism of adverse events
Critical parameters
・Specific drug・Human・Allele frequency
・Specific drug・Human・Race (Han-Chinese)
Example of Biomarker Qualification-Renal Biomarker-
Consultation on PGx/Biomarkers:Biomarker for Nephrotoxicity
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Podocin RPA1 TFF3 Timp1 Total Urinary Protein Uromodulin (Tamm-Horsfall) VEGF Macrophage Migration Inhibitory
Factor Monokine Induced by Interferon
Gamma Interferon Gamma Induced 10 KDa
Protein
Predictive Safety Testing Consortium (PSTC) 23 proposed exploratory biomarkers of kidney
toxicity 7 Priorities for JVXDS Albumin β2-microglobulin Calbindin d28 Clusterin Cystatin C EGF GSTα GSTμ Kim-1 Lipocalin2 (NGAL) NAG Osteoactivin Osteopontin
Testing facility Merck Novartis Pharma FDAStrain of rats Sprague-Dawley Han Wistar Sprague-Dawley
Sex Male Male MaleNo. of animals
per group 4-6 6 3-6
No. of nephrotoxicants 11 8 4
No. of non-nephrotoxicants 9 2 0
BMs measured Kim-1, albumin, TFF3, sCr, BUN
Kim-1, clusterin, cystatinC, β2-microglobulin, total
protein, sCr, BUNKim-1, sCr, BUN
Consultation on PGx/Biomarkers:Biomarker for Nephrotoxicity
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Nephrotoxicants:gentamicin, vancomycin, doxorubicin, furosemide, lithium carbonate, cisplatin, puromycin, tacrolimus, carbapenem, cyclosporine, thioacetamide, hexachlorobutadiene, allopurinol, phenylanthranilic acid, D-serine, propyleneimine, mercuric chloride, sodium dichromateNon-nephrotoxicants: α-naphtyl-isothiocyanate, methapyrilene, isoproterenol, furan, genipin, cerivastatin, carbon tetrachloride, trichlorobromomethane, water, 2% sodium chloride aqueous solution, 4% sucrose aqueous solution
Outline of the studies
Consultation on PGx/Biomarkers:Biomarker for Nephrotoxicity
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Sensitivity
1-Specificity 1-Specificity
Assessment of renal tubular injury
Sensitivity
Assessment of glomerular injury
Opinion of PMDA (1)• It is an important process to qualify novel BMs for the
objective and context of use and so on at the stage before wide use of novel BMs in development of medicines
• Use of the 7 novel BMs is acceptable as BMs that provide additional information, given that these BMs are used for the purpose to detect drug-induced acute urinary tubular changes or acute glomerularalterations/damage in rat GLP studies, and they are used in combination with existent BMs (sCr and BUN)
• These 7 novel BMs has not been sufficiently qualified for general wide use in early clinical studies (phase I study, etc.) . Examination of these renal BMs in clinical trials is expected in future clinical development of drugs or a future BM qualification in Japan and other countries in order to gather further data
Consultation on PGx/Biomarkers:Biomarker for Nephrotoxicity
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Opinion of PMDA (2)• It is desirable to proactively perform further
evaluation in future for at least the following non-clinical issues
① Changes of BMs over time during long term treatment (changes or consistency over time) and its reversibility (whether the BMs correlate with regression of lesions)
② Evaluation for sex difference③ Information on organ-specificity and site-
specificity of the test substances to urinary tubules or glomerulus
Consultation on PGx/Biomarkers:Biomarker for Nephrotoxicity
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Report for the Consultation
17http://www.pmda.go.jp/operations/shonin/info/consult/m03_pharma_kekka.html
• The same qualification data set for the BMs was previously submitted by C-Path to the FDA and the EMA, with a favorable decision announced in 2008 from both agencies
• 7 novel BMs are qualified among ICH agencies
• Facilitate the use of BMs in global drug developments
Global Qualification
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http://www.pmda.go.jp/operations/shonin/info/consult/m03_pharma_kekka.htmlhttp://www.emea.europa.eu/htms/human/mes/biomarkers.htm
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Example of PGx implementations for approved drugs
Relationships between HLA-B*1502 and SJS/TEN
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HLA-B*1502
CBZ-SJS 100%(44/44)
CBZ-tolerant 3%(3/101)
Normal 8.6%(8/93)
Chung WH et al, Nature, 2004
Allele Frequencies of HLA-B*1502
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• Differences exist even among Asian populations
Database, Allele frequencies in Worldwide Populations(http://www.allele frequencies.net/ )
Ethnic group Prevalence
Han-Chinese 1.9 – 11.6 %Thailand 6.1 – 8.5 %Singapore Chinese 5.7 %Korean 0.2 %Japanese 0.1 %Caucasian 0 – 1 %
• HLA-B*1502 screening could provide a benefit in counties, in which HLA-B*1502 is relatively prevalent
Usability of HLA-B*1502 Screening
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Chen P et al, N Engl J Med, 2011
HLA‐B*1502–Positivewith Alternative Medication(N = 215)
HLA‐B*1502–Negative with CBZ
(N = 4120)
Estimated historical incidence
CBZ‐SJS/TEN 0(0%) 0(0%) 0.23%
• CBZ-induced SJS/TEN patients carrying HLA-B*1502 have not been found in Japan (Ozeki T et al, Hum Mol Genet, 2011, Kashiwagi M et al, J Dermatol, 2008, Kaniwa N et al, Epilepsia, 2010)
• HLA-A*3101 is associated with CBZ-induced SJS/TEN in Japanese and European
Relationships between HLA-A*3101 and SJS/TEN
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Takeshi Ozeki et al, Hum Mol Genet, 2011McCormack M et al, N Engl J Med, 2011
HLA-A*3101
Japanese European
CBZ-SJS 83%(5/6)
42%(5/12)
CBZ-tolerant 13%(54/420)
4%(10/257)
Label Information of CBZ in Japan and US
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Japan USOther attentionRetrospective studies have found that in patients of Han-Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. HLA-B*1502 is present greater than 15% in Philippines, Thailand, Hong Kong, Malaysia, compared to about 10% in Taiwan and <1% in Japan and Korea.The relationships of HLA-B*1502 with carbamazepineinduced SJS/TEN are not clear in Japanese.
(Information about relationships between HLA-A*3101 and SJS/TEN is under consideration)
WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS).
Drug Development Using PGx
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h
o co ogy
Synthesis, Preparation, Pharmacology,Toxicology
Research/Select Candidates of BM,
Mechanism
Prioritize BMs, Usage in non‐clinical
Usage of BM: patients selection, dose adjustment, monitoring, etc
Personalized medicine,
Efficacy/Safety monitoring
Diagnostic Development Confirm practicality
NDASurvey
PhaseⅣ
Drug development
Diagnosis
PhaseⅠ
Basic study Clinical Post Market Review
Consultation on Pharmacogenomics/Biomarkers
Pre clinical
PGx/BMs
Clinical trial consultationPMDA
PhaseⅡ
PhaseⅢ
Application
Effective Use of PGx/Biomarker Information for Drug Therapy
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PGx/BM consultation・New PGx/BM qualification・Expand BM use
Evidence accumulation from ・Pre-clinical・Clinical・Post market
Conduct of continuous pre-clinical/clinical evaluations for further qualification
PGx‐based MedicineEfficient drug development