Omics Project in PMDAPMDA Omics Project (POP) team 3 4 Consultation on Pharmacogenomics/ Biomarkers Notifications related to pharmacogenomics issued by MHLW 5 Notification Issued date

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

2

• 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

3

4

Consultation on Pharmacogenomics/

Biomarkers

Notifications related to pharmacogenomics issued by MHLW

5

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

6

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

8

• 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

9

Examples of Context

10

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


13

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


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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


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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


16

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

19

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

23

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

24

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

25

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

26

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