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

Transcription

1 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

2 Photo of Dr. David Flockart Cartoon courtesy: Carl Peck By Dave Klemm, Georgetown University Illustrator Image of Principles of Clinical Pharmacology textbook Taken from Chapter 13 Clinical Pharmacogenetics Ref: Flockhart and Huang, Clinical pharmacogenetics, Ch13,, Principles of Clinical Pharmacology. Eds Atkinson, Huang, Lertora, and Markey, Elsevier Pages

3 The simple act of caring is just as important to the patient as the most complex medical science Interview with Sound Medicine Photo of Dr. Flockhart and friends celebrating Pi Day, From left: Pat Loehrer, Dave Flockhart, Eric Meslin and Barbara Lewis Photo of Dr. Flockhart

4 Emerging Market Outlook % USA 18% Europe 9% Japan 9% Rest of the World 2% Pharmerging % USA 27% Europe 12% Japan 15% Africa, Asia and Australia 6% Latin America _8_272B8752E0FB3.pdf

5 Is this the drug or dose for you? Impact and consideration of ethnic factors in global drug development, regulatory review, and clinical practice S-M Huang and R Temple Chart Clinical Pharmacology & Therapeutics, vol. 84 number 3, September 2008

6 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for IFNL3 (IL28B) Genotype and PEG Interferon-α Based Regimens Table Muir AJ et al. Clin Pharmacol Ther. February 2014 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 FDA guidance 10/13: GuidanceComplianceRegulatoryInformation/Guidances/UCM pdf

7 Direct-Acting Antiviral Drugs for the Treatment of Chronic Hepatitis C Virus Infection: Interferon Free Is Now Map Clinical Pharmacology & Therapeutics, vol. 98 number 4, September 2015

8 Personalized Medicine in Drug Development

9 The 5R Framework Right target Strong link between target and disease Differentiated efficacy Available end predictive biomarkers Right tissue Adequate bioavailability and tissue exposure Definition of PD biomarkers Clear understanding of preclinical and clinical PK/PD Understanding of drug-drug interactions Right safety Differentiated and clear safety margins Understanding of secondary pharmacology risk Understanding of reactive metabolites, genotoxicity, drugdrug interactions Understanding of target liability Right patients Right commercial potential

10 Paradigm Change and the Progressive Reduction of Uncertainty Graph Clinical trials targeting heterogeneous patient populations may have lower success rates than trials identifying responders within a population through the use of biomarkers.

11 The Next Generation of Medicine Is Upon Us The Gap Is Narrowing Image of types of drugs

12 Genomics at FDA 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

13 Clinical Utility

14 Predicting the Warfarin Stable Dose Wadelius et al, Blood 2009, Gage et al, Clin Pharmacol Ther 2008, Caldwell et al, Clin Med Res 2007

15 Public Debates Articles LJ Lesko, Clin Pharmacol & Ther, September 2008 DA Garcia, Clin Pharmacol & Ther, September 2008 AACC warfarin Debate: Hallworth, Huang, Eby, Linder, Jaffer, July 28, _daily1.aspx

16 Warfarin Dosing

17 A Regulatory Science Perspective on Warfarin Therapy: A Pharmacogenetic Opportunity

18 Warfarin & CYP2C9 & VKORC DOSAGE AND ADMINISTRATION Knowledge of genotype can inform initial dose selection. (2.3) 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. Drugs at the FDA (COUMADIN, Initial Dosage ) initial approval 1954; current Oct 2011 version 8s107lbl.pdfhttp:// DA/

19 Debates on Warfarin Continued

20 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

21 FDA Guidance Development - Early Phase Clinical Studies-

22 Guidance for Industry Published in January toryinformation/guidances/ucm pdf

23 Pharmacogenomic Information in the Labeling toryinformation/guidances/ucm pdf

24 Examples of FDA Labeling with Pharmacogenetics-Related Information

25 Safety-Related

26 Abacavir Hypersensitivity & HLA Genotyping

27 Boxed Warning 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. Drugs at the FDA (Ziagen, July 2008, Highlights and Boxed Warning ) 7s019,020978s022lbl.pdf

28 Clinical Guidelines Portal

29 Carbamazepine and HLA (Stevens-Johnson Syndrome)

30 FDA Labeling Boxed Warning Drugs at the FDA (Tegretol, February 2013) 8s105,018281s053,018927s046,020234s038lbl.pdf

31 Article from The New England Journal of Medicine

32 Efficacy-Related

33 Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms

34 CYP2C19 and Clopidogrel

35 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)

36 Clopidogrel and CYP2C19

37 Clinical Pharmacogenetics Implementation Consortium (CPIC) Recommendation- Clopidogrel and CYP2C19 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

38 Adapted from

39 KRAS Mutations & Overall Survival 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

40 Cetuximab and KRAS Drugs at the FDA (Erbitux, April 2015 labeling; initial approval 2004) 4s167lbl.pdf

41 Crizotinib and ALK

42 Genetics and Drug-Drug Interactions

43 Eliglustat and CYP2D6

44 Applications of Physiologically Based Pharmacokinetics (PBPK) Modeling and Simulation During Regulatory Review

45 Precision Drug Development? 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. Janet Woodcock, Precision Drug Development? Clin Pharmacol Ther Feb

46 Approaches to Drug-Diagnostic Codevelopment

47 The Evolving Regulatory Framework for Personalized Medicines For more information on other related guidance documents, visit nalizedmedicine/ucm htm

48 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 PrecisionFDA: psconferences/ucm pdf Reference materialshttp://biorxiv.org/content/early/2015/09/15/ Analytical performance evaluation standards and clinical validation: November 12-13,

49 Varied Insurance Coverage Policies

50 Insurance Coverage Policies in US

51 Drug response

52 Statin Response

53 Summary Individual patient doses may need to be adjusted based on patient-specific factors (genetics, race, organ functions, concomitant medications) 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

54 Summary (2) Challenges need to be continued to be addressed in the translation of genetic/genomic information to product labeling and clinical practice Collaborations is key to future successemerging efforts to modernize drug development

55 References Clinical Pharmacology Guidance for industry: /Guidances/ucm htm Genomics at the FDA: genetics/default.htm FDA Drug Development and Drug Interactions; pmentresources/druginteractionslabeling/ucm htm CDER Personalized Medicine; ine/ucm htm

56 Office of Clinical Pharmacology (OCP)/OTS FDA White Oak Bldg 51& bldg 64 Where OCP resides

57 Questions: