Application of Pharmacogenomics in Drug Development ... Huang 6 Application of Pharmacogenomics in Drug Development, Regulatory Review and Clinical Practice NIH Principles of Clinical

Shiew-Mei Huang

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Application of Pharmacogenomics in Drug Development, Regulatory Review and Clinical Practice

NIH Principles of Clinical Pharmacology, Bethesda, MD

December 3, 2015

Application of Pharmacogenomics in Drug

Development, Regulatory Review and

Clinical Practice

NIH

-Principles of Clinical Pharmacology Course

Bethesda, MD

December 3, 2015

Shiew-Mei Huang, PhD

Deputy Director

Office of Clinical Pharmacology

Office of Translational Sciences

CDER, FDA

Cartoon courtesy: Carl Peck By Dave Klemm, Georgetown University Illustrator 2 S-M Huang

Ref: Flockhart and Huang, Clinical pharmacogenetics, Ch13, “, Principles of Clinical Pharmacology”. Eds Atkinson, Huang, Lertora, and Markey, Elsevier. 2012. Pages 195-215

David A. Flockhart July 22, 1952-November 26, 2015

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December 3, 2015

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“The simple act of caring is just as important to the patient as the most complex medical science”

http://sideeffectspublicmedia.org/post/pioneering-medical-researcher-kept-learning-even-through-his-own-fight-cancer

Interview with Sound Medicine

Dr. Flockhart and friends celebrating Pi Day, 2015. From left: Pat Loehrer, Dave Flockhart, Eric Meslin and Barbara Lewis

http://www.efpia.eu/uploads/Figures_Key_Data_2013.pdf

http://www.imap.com/imap/media/resources/IMAP_PharmaReport_8_272B8752E0FB3.pdf

Emerging Market Outlook

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2007-2011

2012

41% USA 12% Japan 27% Europe 15%

Africa, Asia

& Australia

6% Latin

America

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December 3, 2015

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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for

IFNL3 (IL28B) Genotype and PEG Interferon-α–Based Regimens

Muir AJ et al. Clin Pharmacol Ther. February 2014

FDA guidance 10/13: http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf

FDA: Because race (e.g., Black, Asian) and ethnicity (e.g., Latino) affect response

rates to anti-HCV treatment, the ability to ensure sufficient diversity in clinical trial

demographics to conduct meaningful analyses of such groups is important

http://www.fda.gov/downloads/Drugs/



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December 3, 2015

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North

America

Asia

Pacific

Asia,

South

North Africa/

Middle East Sub-S Africa,

Southern

Personalized Medicine

in Drug Development

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December 3, 2015

The 5R Framework

Cook D, et al Nat Rev Drug Discov June 2014

[Evaluation of Astra Zeneca’s 142 projects between 2005-2010 (surveys and questionnaires with 200 questions)]

Right Culture

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Paradigm Change and the

‘Progressive Reduction of Uncertainty’

10 Hay M, et al. Nat Biotechnol Jan 2014

Success

Rate Approval

Likelihood

Ph 1 64% 10%

Ph 2 32% 16%

Ph 3 60% 50%

NDA/BLA 83% 83%

Root Cause for Suspended Program

• Clinical trials targeting heterogeneous patient populations

may have lower success rates than trials identifying

responders within a population through the use of

biomarkers.

n=95

n=359

835 drug developers

>7300 projects in development 2003-2011

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December 3, 2015

The Next Generation of

Medicine Is Upon Us

“The Gap” Is Narrowing

Slide courtesy: Mike Pacanowski 11 S-M Huang

Genomics at FDA

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FDA commits to PGx

FDA-DIA PGx Workshop

“Safe harbor” concept

Inception of VGDS (later VXDS);

PGDS guidance

Biomarker

Qualification

Program

Clinical PGx in early-phase trials

guidance

Integrated IND/ NDA/ BLA drug

review

PDUFA V: industry invests in

biomarkers and PGx

Companion Dx and enrichment guidances

Drug-diagnostic co-approvals

2002

Present Slide courtesy: Mike Pacanowski 12 S-M Huang

https://www.cfservicespharmacy.com/ProductsandPrices/KalydecoFAQs/

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December 3, 2015

Clinical Utility

December 2010

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Predicting the Warfarin

Stable Dose

Age, Gender, Drugs,

BW, Race, Diet

Others

Genotypes (CYP2C9,

VKORC1) Wadelius et al, Blood 2009, Gage et al, Clin Pharmacol

Ther 2008, Caldwell et al, Clin Med Res 2007

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http://www.nature.com/clpt/journal/v88/n6/

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December 3, 2015

Public Debates

LJ Lesko, Clin Pharmacol & Ther, September 2008

DA Garcia, Clin Pharmacol & Ther, September 2008

AACC warfarin Debate: Hallworth, Huang, Eby, Linder, Jaffer, July 28, 2008

http://www.aacc.org/publications/cln/2008/July/dailies/Pages/mon_daily1.aspx 15 S-M Huang

•

•

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December 3, 2015

PD

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If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these

ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and

*3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR

effect for a given dosage regimen than patients without these CYP variants.

------------------------DOSAGE AND ADMINISTRATION----------------------

• Knowledge of genotype can inform initial dose selection. (2.3)

Warfarin & CYP2C9 & VKORC1

Drugs at the FDA (COUMADIN,“ Initial Dosage”) – initial approval 1954; current Oct 2011 version http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdfhttp://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ 18 S-M Huang

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December 3, 2015

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Debates on Warfarin Continued

Access to data opens door for the transformation of research, clinical care and patient engagement

Utility of genomic information for drug prescribing must be documented with rigorous evidence

FDA has worked to respond to,

anticipate and help drive scientific developments

in personalized therapeutics and diagnostics

The concept of

personalized medicine is

not new…What is new is

that advances in a wide

range of fields from

genomics to medical

imaging…are allowing

patients to be treated and

monitored more precisely

and effectively…

http://www.fda.gov/ScienceResearch/SpecialTopics/PersonalizedMedicine/ucm20041021.htm 20 S-M Huang

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December 3, 2015

FDA

Guidance Development - Early Phase Clinical Studies-

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Published in January 2013

Included examples

http://www.fda.gov/downloads/Drugs/GuidanceCo

mplianceRegulatoryInformation/Guidances/UCM33

7169.pdf

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December 3, 2015

Pharmacogenomic

Information in the Labeling

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pdf

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Examples of FDA Labeling with

Pharmacogenetics-Related Information Drug Gene Context

Abacavir HLA-B Boxed warning that patients with the HLA-B*5701 allele are at increased risk for

hypersensitivity to abacavir. Genetic screening is recommended before starting

abacavir.

Azathioprine and 6-

mercaptopurine

TPMT Description of increased risk for myelotoxicity with conventional azathioprine or 6-

mercaptopurine doses in patients with a nonfunctional TPMT allele in the clinical

pharmacology section. Consideration of TPMT genetic testing is recommended.

Atomoxetine CYP2D6 Warning that dose adjustment may be necessary in CYP2D6 poor metabolizers to

avoid adverse drug effects.

Capecitabine DPD Warning about an increased risk for severe toxicity (e.g. diarrhea, stomatitis,

neutropenia, and neurotoxicity) in patients with dihydropyrimidine dehydrogenase

deficiency.

Carbamazepine HLA-B Boxed warning of increased risk for serious dermatologic reactions (e.g. toxic

epidermal necrolysis, Stevens-Johnson syndrome) in patients with the HLA-

B*1502 variant. Patients from genetically at-risk regions (e.g. Southeast Asia)

should be screened for the HLA-B*1502 allele prior to starting carbamazepine.

Cetuximab/Panitumumab EGFR,

KRAS

These drugs are indicated for EGRF-expressing colorectal cancer and may be

ineffective in patients whose tumors have a KRAS mutation in codon 12 or 13.

Codeine CYP2D6 Warning about greater conversion to morphine in patients who are ultra-rapid

metabolizers secondary to the CYP2D6*2x*2 genotype.

Clopidogrel CYP2C19 Boxed warning of possible reduced drug effectiveness in CYP2C19 poor

metabolizers with 2 loss-of-function alleles.

Crizotinib ALK Confirmation of the lymphoma kinase (ALK)-positive mutation is required prior to

drug use. Postmarketing trial in ALK-negative patients is ongoing

Cavallari LH, Klein TE, Huang SM. Ch. 7, In Lam YWF, Cavallari LH (eds). Pharmacogenomics: Challenges

and Opportunities in Therapeutic Implementation. Elsevier Inc: Maryland Heights, MO. 2013. pp.63-88. 24 S-M Huang

New contraindication in children undergoing post-tonsillectomy- 2015

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December 3, 2015

Safety-Related

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Abacavir Hypersensitivity

& HLA Genotyping

< Mallal S, et al, NEJM Feb 2008; 358: 568-579 >

PREDICT-1: N=1956; 19 countries, 6-week study; other HIV therapy (efavirenz,

Nevirapine, protease inhibitors) 26 S-M Huang

http://content.nejm.org/content/vol358/issue6/images/large/05t2.jpeg

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December 3, 2015

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir.

Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction.

Boxed Warning

Drugs at the FDA (Ziagen, July 2008, “Highlights” and “Boxed Warning”) http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020977s019,020978s022lbl.pdf http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/

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28 S-M Huang https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/7/hla-b--5701-

screening

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December 3, 2015

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Carbamazepine and HLA

(Stevens-Johnson Syndrome)

FDA Labeling Boxed Warning

Drugs at the FDA (Tegretol, February 2013) http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016608s105,018281s053,018927s046,020234s038lbl.pdf http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ 30 S-M Huang

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December 3, 2015

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Efficacy-Related

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December 3, 2015

Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms

<Simon et al. N Engl J Med;360:363-375, January 2009 >

<Mega J et al. N Engl J Med; 360: 354-362, January 2009> 33 S-M Huang

<Mega J et al. N Engl J Med 2008;10.1056/NEJMoa0809171 >

CYP2C19 and Clopidogrel

Carriers

Non-Carriers

Carriers: with at least one variant alleles,

*2, 3, 4, 5, 8 (IM+PM);

*Outcome: a composite of death from

cardiovascular causes, myocardial infarction,

or stroke

PM: with two reduced function alleles;

IM: one reduced function allele

EM: no variant alleles;

UM: one or two *17

Active Metabolite AUC Composite Clinical Outcome*

Another study also examined MDR1

<Simon T et al. N Engl J Med 2008; http://content.nejm.org/cgi/content/full/360/4/363> 34 S-M Huang

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December 3, 2015

Mega JL, et al, JAMA 2010

Trenk D, et al, Clin Pharmacol Ther October 2012

CYP2C19 Loss-of-Function Genotype &

Risk of MACE and Risk of Stent Thrombosis

CYP2C19 loss-of-function genotype and risk of MACE (left panel) and risk of stent

thrombosis (right panel) in a meta-analysis of nine studies of patients undergoing

percutaneous coronary interventions. MACE, major adverse cardiovascular events

(combined end point of cardiovascular death, myocardial infarction, or ischemic stroke)

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Clopidogrel and CYP2C19

Drugs at the FDA (Plavix,“HIGHLIGHTS”) July 2015 labeling

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020839s061lbl.pdf 36 S-M Huang

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December 3, 2015

Clinical Pharmacogenetics

Implementation Consortium (CPIC)

Recommendation- Clopidogrel and CYP2C19 -

SA Scott, et al, Clin Pharmacol Ther 2013

Algorithm for suggested clinical actions based on CYP2C19 genotype when considering treatment with clopidogrel for ACS patients undergoing PCI (ACS/PCI). ACS: acute coronary syndrome; PCI: percutaneous coronary intervention; UM: ultrarapid metabolizer; EM: extensive metabolizer; IM: intermediate metabolizer; PM: poor metabolizer

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(*1/*2, *1/*3, *2/*17)

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Adapted from http://www.onclive.com/publications/oncology-live/2012/september-

2012/evolving-biologic-diversity-generates-new-challenges/3

Histology Driven

Chemotherapy Targeted Therapy

Targeting Oncogenic Drivers

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Squamous Cell Lung Cancer Master Protocol; November 2013

http://www.focr.org/master-protocol

Umbrella trial

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December 3, 2015

KRAS Mutations & Overall Survival

< Karapetis CS et al, NEJM 359:1757-1765, 2008 >

Cetuximab

Mutated K-ras

Wild K-ras

(colorectal cancer)

n=394 (70% of n=572)

had tumor samples;

OS: 9.5 vs. 4.8 months

(wild vs. mutated)

n=198 on cetuximab

n=196 on supportive care 39 S-M Huang

Youssoufian H, presentation at the

Oncology Advisory committee

meeting, December 2008

Drugs at the FDA (Erbitux, April 2015 labeling; initial approval 2004)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125084s167lbl.pdf

http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ 40 S-M Huang

Cetuximab and KRAS

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December 3, 2015

Crizotinib and ALK

XALKORI labeling: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202570s013lbl.pdf (2015 labeling)

FDA Approval letter 2011: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202570s000ltr.pdf

PMC to

evaluate

marker-

negative

patients

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Genetics and Drug-Drug Interactions

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http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202570s013lbl.pdf (2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202570s013lbl.pdf (2015

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December 3, 2015

CERDELGA labeling: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205494Orig1s000lbl.pdf

Eliglustat and CYP2D6

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44 Clin Pharmacol Ther, 2011

Apply

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December 3, 2015

Janet Woodcock, “Precision” Drug Development?” Clin Pharmacol Ther Feb 2016

“Future drug development will increasingly need to

rely on powerful computational techniques that have

the ability to integrate laboratory data, information

from animal studies, and human data into models of

health, disease, and outcomes of interventions.”

“Precision medicine will need to be supported by

very accurate, reliable diagnostics and the

development of these may well be the rate-

‐limiting step for advancement of the field.”

http://onlinelibrary.wiley.com/doi/10.1002/cpt.255/pdf

“Precision” Drug Development?

(online Aug 2015)

Approaches to

Drug-Diagnostic Codevelopment

Fridlyand, et al. NRDD 2013 46 S-M Huang

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December 3, 2015

The Evolving Regulatory

Framework for Personalized Medicines

Clinical

Pharmacogenomics

Collect DNA to facilitate biomarker

development (sometimes it is needed)

Enrichment

Use enrichment strategies (via trial design

or patient selection) to decrease noise,

increase event rates, or enhance treatment

effect

Companion

Diagnostics

IVD needed if essential for safe and

effective use; need for pre-market review,

risk-based regulation

Co-development

(in preparation)

Process-oriented guidance on use and

development of companion IVDs in a

therapeutic trial context

For more information on other related guidance documents, visit

http://www.fda.gov/ScienceResearch/SpecialTopics/PersonalizedMedicine/ucm372544.htm

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The Precision

Medicine Initiative &

Next Generation

Sequencing (NGS)

• Most diagnostic tests follow a “one test-one disease”

paradigm

• NGS – a single test identifies thousands (or millions) of

genetic variants by a single individual- integral to the future

of personalized or precision medicine

• First market approval Illumina’s MiSeqDx in 2013

• Beta test of PrecisionFDA in December 2015

http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM427869.pdf

PrecisionFDA: http://blogs.fda.gov/fdavoice/index.php/tag/precision-medicine-initiative/

Reference materials- http://biorxiv.org/content/early/2015/09/15/026468

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January 2015

Analytical performance evaluation standards and clinical validation: November 12-13, 2015.

http://blogs.fda.gov/fdavoice/index.php/2015/09/fda-taking-genomic-testing-to-the-next-level/

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December 3, 2015

A Hresko, SB Haga, J Pers Med 2012

Varied Insurance Coverage Policies

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A Hresko, SB Haga, J Pers Med 2012

Insurance Coverage Policies in US

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December 3, 2015

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December 3, 2015

Summary

• Individual patient doses may need to be

adjusted based on patient-specific factors

(genetics, race, organ functions, concomitant

medications)

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• Complex computational tools can aid in the

determination of the “right” dose for patients

(including those with rare diseases) with

multiple patient factors in drug development

• The FDA has provided (via guidances)

regulatory framework for personalized medicine

Summary (2) • Challenges need to be continued to be

addressed in the translation of genetic/genomic

information to product labeling and

clinical practice

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• Collaborations

is key to future

success-

emerging efforts

to modernize

drug development

A Parekh, S Buckman-

Garner, S McCune et al,

Clin Pharmacol Ther

March 2015

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December 3, 2015

References

FDA Drug Development and Drug Interactions;

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Develop

mentResources/DrugInteractionsLabeling/ucm080499.htm

Drugs@FDA:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Genomics at the FDA:

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharm

acogenetics/default.htm

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Clinical Pharmacology Guidance for industry:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma

tion/Guidances/ucm064982.htm

CDER Personalized Medicine;

http://www.fda.gov/ScienceResearch/SpecialTopics/Personalized

Medicine/ucm372544.htm

Office of Clinical Pharmacology (OCP)/OTS

FDA White Oak

Bldg 51& bldg 64 —Where OCP resides

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Documents

Application of Pharmacogenomics in Drug Development ... Huang 6 Application of Pharmacogenomics in Drug Development, Regulatory Review and Clinical Practice NIH Principles of Clinical