Application of Pharmacogenomics in Drug Development, Regulatory Review and Clinical Practice NIH Principles of Clinical Pharmacology, Bethesda, MD

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1 NIH -Principles of Clinical Pharmacology Course Bethesda, MD Application of Pharmacogenomics in Drug Development, Regulatory Review and Clinical Practice, PhD Deputy Director Office of Clinical Pharmacology Office of Translational Sciences CDER, FDA David A. Flockhart July 22, 1952-November 26, 2015 Cartoon courtesy: Carl Peck By Dave Klemm, Georgetown University Illustrator Ref: Flockhart and Huang, Clinical pharmacogenetics, Ch13,, Principles of Clinical Pharmacology. Eds Atkinson, Huang, Lertora, and Markey, Elsevier Pages S-M Huang The simple act of caring is just as important to the patient as the most complex medical science Interview with Sound Medicine Dr. Flockhart and friends celebrating Pi Day, From left: Pat Loehrer, Dave Flockhart, Eric Meslin and Barbara Lewis 3 S-M Huang 1

2 Emerging Market Outlook % USA 27% Europe 12% Japan 15% Africa, Asia & Australia 6% Latin America S-M Huang 4 S-M Huang 5 S-M Huang 5 S-M Huang 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: 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 6 S-M Huang 2

3 North America Asia Pacific Asia, South North Africa/ Middle East Sub-S Africa, Southern 7 S-M Huang Personalized Medicine in Drug Development 8 S-M Huang The 5R Framework Right Culture [Evaluation of Astra Zeneca s 142 projects between (surveys and questionnaires with 200 questions)] Cook D, et al Nat Rev Drug Discov June S-M Huang 3

4 Paradigm Change and the Progressive Reduction of Uncertainty Success Rate Approval Likelihood Root Cause for Suspended Program n=359 n=95 Ph 1 64% 10% Ph 2 32% 16% Ph 3 60% 50% NDA/BLA 83% 83% 835 drug developers >7300 projects in development Clinical trials targeting heterogeneous patient populations may have lower success rates than trials identifying responders within a population through the use of biomarkers. Hay M, et al. Nat Biotechnol Jan S-M Huang 10 The Next Generation of Medicine Is Upon Us The Gap Is Narrowing Slide courtesy: Mike Pacanowski 11 S-M Huang Genomics at FDA 2002 FDA commits to PGx Integrated IND/ NDA/ BLA drug review PDUFA V: industry invests in biomarkers and PGx FDA-DIA PGx Workshop Safe harbor concept Clinical PGx in early-phase trials guidance Companion Dx and enrichment guidances Inception of VGDS (later VXDS); PGDS guidance Biomarker Qualification Program Drug-diagnostic co-approvals Slide courtesy: Mike Pacanowski Present 12 S-M Huang 12 4

5 Clinical Utility December S-M Huang Predicting the Warfarin Stable Dose Age, Gender, Drugs, BW, Race, Diet Others Wadelius et al, Blood 2009, Gage et al, Clin Pharmacol Ther 2008, Caldwell et al, Clin Med Res 2007 Genotypes (CYP2C9, VKORC1) 14 S-M Huang 14 S-M Huang 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, S-M Huang 5

6 16 S-M Huang PD 17 S-M Huang 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 fda.gov/scripts/cder/drugsatfda/ 18 S-M Huang 6

7 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 19 S-M Huang 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 20 S-M Huang FDA Guidance Development - Early Phase Clinical Studies- 21 S-M Huang 7

8 Published in January mplianceregulatoryinformation/guidances/ucm pdf Included examples 22 S-M Huang Pharmacogenomic Information in the Labeling 23 S-M Huang 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 Azathioprine and 6- mercaptopurine hypersensitivity to abacavir. Genetic screening is recommended before starting abacavir. 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- Cetuximab/Panitumumab EGFR, KRAS 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. 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. New contraindication in children undergoing post-tonsillectomy 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 pp S-M Huang 8

9 Safety-Related 25 S-M Huang Abacavir Hypersensitivity & HLA Genotyping PREDICT-1: N=1956; 19 countries, 6-week study; other HIV therapy (efavirenz, Nevirapine, protease inhibitors) 26 S-M Huang < Mallal S, et al, NEJM Feb 2008; 358: > 26 S-M Huang 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 ) S-M Huang 9

10 S-M Huang screening Carbamazepine and HLA (Stevens-Johnson Syndrome) 29 S-M Huang FDA Labeling Boxed Warning Drugs at the FDA (Tegretol, February 2013) 34s038lbl.pdf 30 S-M Huang 10

11 31 S-M Huang Efficacy-Related 32 S-M Huang Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms <Simon et al. N Engl J Med;360: , January 2009 > <Mega J et al. N Engl J Med; 360: , January 2009> 33 S-M Huang 11

12 CYP2C19 and Clopidogrel Composite Clinical Outcome* Active Metabolite AUC Carriers Non-Carriers Carriers: with at least one variant alleles, PM: with two reduced function alleles; *2, 3, 4, 5, 8 (IM+PM); IM: one reduced function allele *Outcome: a composite of death from EM: no variant alleles; cardiovascular causes, myocardial infarction, or stroke UM: one or two *17 <Mega J et al. N Engl J Med 2008; /NEJMoa > Another study also examined MDR1 <Simon T et al. N Engl J Med 2008; 34 S-M Huang 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) Trenk D, et al, Clin Pharmacol Ther October 2012 Mega JL, et al, JAMA S-M Huang Clopidogrel and CYP2C19 Drugs at the FDA (Plavix, HIGHLIGHTS ) July 2015 labeling 36 S-M Huang 12

13 Clinical Pharmacogenetics Implementation Consortium (CPIC) Recommendation- Clopidogrel and CYP2C19 - (*1/*2, *1/*3, *2/*17) 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 SA Scott, et al, Clin Pharmacol Ther S-M Huang Histology Driven Chemotherapy Targeting Oncogenic Drivers Targeted Therapy Adapted from /evolving-biologic-diversity-generates-new-challenges/3 Squamous Cell Lung Cancer Master Protocol; November Umbrella trial 38 S-M Huang 38 S-M Huang KRAS Mutations & Overall Survival (colorectal cancer) Mutated K-ras Cetuximab Wild K-ras Youssoufian H, presentation at the Oncology Advisory committee meeting, December 2008 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 < Karapetis CS et al, NEJM 359: , 2008 > 39 S-M Huang 13

14 Cetuximab and KRAS Drugs at the FDA (Erbitux, April 2015 labeling; initial approval 2004) S-M Huang Crizotinib and ALK PMC to evaluate markernegative patients XALKORI labeling: (2015 labeling) FDA Approval letter 2011: 41 S-M Huang Genetics and Drug-Drug Interactions 42 S-M Huang 14

15 Eliglustat and CYP2D6 CERDELGA labeling: 43 S-M Huang Apply Clin Pharmacol Ther, S-M Huang 44 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 (online Aug 2015) 15

16 Approaches to Drug-Diagnostic Codevelopment Fridlyand, et al. NRDD S-M Huang The Evolving Regulatory Framework for Personalized Medicines Clinical Pharmacogenomics Enrichment Companion Diagnostics Collect DNA to facilitate biomarker development (sometimes it is needed) Use enrichment strategies (via trial design or patient selection) to decrease noise, increase event rates, or enhance treatment effect 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 47 S-M Huang January 2015 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: Reference materials- Analytical performance evaluation standards and clinical validation: November 12-13, S-M Huang 16

17 Varied Insurance Coverage Policies A Hresko, SB Haga, J Pers Med S-M Huang Insurance Coverage Policies in US A Hresko, SB Haga, J Pers Med S-M Huang 51 S-M Huang 17

18 52 S-M Huang 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 53 S-M Huang 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 A Parekh, S Buckman- Garner, S McCune et al, Clin Pharmacol Ther March S-M Huang 18

19 References Clinical Pharmacology Guidance for industry: tion/guidances/ucm htm Genomics at the FDA: acogenetics/default.htm FDA Drug Development and Drug Interactions; mentresources/druginteractionslabeling/ucm htm CDER Personalized Medicine; Medicine/ucm htm 55 S-M Huang Office of Clinical Pharmacology (OCP)/OTS FDA White Oak Bldg 51& bldg 64 Where OCP resides 56 S-M Huang 19