PGx in Clinical Medicine: What Is FDA Doing to Facilitate the Movement

Personalized Health Care National ConferenceThe Ohio State UniversityColumbus, OhioOctober 2, 2009

Lawrence J. Lesko, Ph.D., F.C.P.Office of Clinical PharmacologyCenter for Drug Evaluation and ResearchFood and Drug AdministrationSilver Spring, Maryland

One emerging opportunity is the area of personalized medicine in which the agency should work with scientific leaders on novel approaches to treating illness .

M.A. Hamburg and J.M. SharfsteinNEJM, June 11, 2009

FDA As A Public Health Agency Is Committed to Personalized Medicine

Number of Innovative Drugs Approved: Approvals in 2007 Lowest in 15 Years

Nature Reviews Drug Discovery, February 2008

Improving Drug Safety Will Continue to Be a Major Focus of Public Health Policy

Safety includes– Preventing or reducing the probability of

AEs– Includes inability to respond to a drug– Safety First and Sentinel Initiative

FDA Amendments Act (2007)– Post-marketing requirements (vs

commitments)– Post-marketing active surveillance systems– REMS requirements for higher risk drugs– Empowers requests to update labels

Dual Mission: To Promote and Protect Public Health

Develop and clearly articulate evidence standards for drugs and diagnostics

Foster innovation and promote new initiatives under critical path

Process: VGDS and Biomarker Qualification

PDUFA: Guidance on clinical PGx, adaptive designs, multiplicity and enrichment strategies

Research: Collaboration with Medco, Harvard Partners and Biovista

Trend Watching: Re-label older products to improve B/R with new evidence

FDAAA: Recommend PMC to obtain new data to improve drug safety

NDA review: GRP to look for genotype-phenotype associations

Life Cycle Approach to Evidence to Inform and Support Decisions

New drug development: high bar for approval of NDAsEncouraged companion tests premarketing, where appropriate, to improve the evidence on efficacy and safety of both test and drug performance: usually from RCTs

Previously approved drugs: incremental information to update of labelsAcademic and clinical studies independent of company designed to improve the value of a medicine by increasing benefit or decreasing risk using diagnostic tests: usually from non-RCTs

Growth in Reviews of Regulatory Submissions With Genomic Information

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Year

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Guidance Outlining the Quantity and Quality of Evidence to Support Various Effectiveness Claims

“In certain cases, effectiveness of a new product may be adequately demonstrated without additional adequate and well-controlled clinical efficacy trials. This is because other types of data provide a way to apply known effectiveness to a new population, a different dose or a different dosage form.”

http://www.fda.gov/ohrms/dockets/98fr/971oogdl.pdf

Examples of Difference in Evidence Standards: The Question and Prior Knowledge

1. More than 90% of generic drugs are approved on bioequivalence studies in healthy volunteers

2. 57% of all new pediatric label approvals are based on PK and safety studies

3. Virtually all dosing adjustments for patients with renal impairment are based on PK studies

4. Trileptal was approved for monotherapy of partial seizures in children 4 to 16 yr based on M/S

Hierarchy of Evidence to Support Efficacy and Safety Claims in PGx

To identify “responder” and select drug (efficacy PGx)

To identify “non-responder” and exclude

from treatment To identify “at-risk” patient for likelihood to have

serious AE (safety PGx)To improve precision of dose

selection To elucidate specific genetic sources of variability in PK

and/or PD

To explore hypothesis-free metabolism

and transporter

gene association

with PK

Highest quality and quantity of

evidence

Lowest quality and quantity of

evidence

Examples of Hierarchy Used in Regulatory Decisions

Tropism test for CCR5 virus for maraviroc (efficacy PGx)

KRAS-testing to exclude non-responders to panitumamab

HLA-B*1502 and SJS with CBZ (safety PGx)CYP2D6-guided

dosing of tetrabenazine Association of

irinotecan PK variability with

common variants of ABCs, CYP3A4,

CYP3A5 and UGT1A9

DMET chip with 1936 genetic

variations in 225 genes

Relabeling of Previously Approved Drugs

Drug Test New Approval

New Label

Imatinib KIT+ GIST X

Dasatinib PH+ ALL X

Maraviroc CCR5 Tropism X

Tetrabenazine CYP2D6 X

Abacavir HLA-B*5701 X

Panitumamab KRAS Mutation X

Warfarin CYP2C9/VKORC1 X

Clopidegrel CYP2C19 X

Regulatory Decision on Retrospective Analyses of Banked Samples

Cetuximab and panitumamab approved in 2004 and 2006 for patients with colorectal cancer

Sponsor presented retrospective data on genetic testing for somatic mutations in the KRAS gene

Tumors from patients with colorectal cancer enrolled in 7 clinical trials of the two drugs

Retrospective subgroup analyses showed patients with mutated KRAS genes failed to respond

FDA updated indication and usage sections of labels of both drugs

ODAC, December 16, 2008

Critical Evidence to Support the KRAS Biomarker Hypothesis for EGFRI

1. Biological plausibility: downstream effects of blocking EGFR signaling not efficient with mutant KRAS activation

2. Consistent differences in objective response between WT and MT KRAS in 6 pooled single arm studies (replication)

3. High ascertainment rate of ~90% tumor samples from AWC studies (bias)

4. Prespecified statistical plan for data collection and retrospective analysis

5. Practical PCR test for KRAS mutations was analytically valid – sensitivity (95%) and specificity (100%)

Class Labeling Change

Indication and Usage (Colorectal Cancer)

Retrospective subset analysis of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13. The use of these drugs are not recommended for the treatment of colorectal cancer patients with these mutations [See Clinical Studies and Clinical Pharmacology]

PGx of Clopidegrel and CV Events in 1477 Patients with ACS

esterases

CYP1A2CYP2C19CYP2B6

CYP3A4/5CYP2C9CYP2C19CYP2B6

esterases

CYP1A2CYP2C19CYP2B6

CYP3A4/5CYP2C9CYP2C19CYP2B6

esterases

CYP1A2CYP2C19CYP2B6

CYP3A4/5CYP2C9CYP2C19CYP2B6

esterases

CYP1A2CYP2C19CYP2B6

CYP3A4/5CYP2C9CYP2C19CYP2B6

esterases CYP1A2, 2C19, 2B6

CYP3A4/5, 2C19, 2C9, 2B6

(inactive)

(active)

Mega, NEJM, 2009

Re-Labeling of Clopidegrel: Reduce Risk of Ineffectiveness (Improve Safety)

Additions to Clopidegrel Label: May 21, 2009

• Large section of label on CYP 2C19 PGx• Phenotype and genotype distribution in

populations• Effect of genotype on active metabolite exposure• Antiplatelet response between IMs and PMs• Genotype-linked CV event rates or stent

thrombosis l• PGx testing can identify genotypes• Omits recommendation of optimal doses for PMs• New advice on PPI inhibition of CYP2C19http://www.genomeweb.com/dxpgx/fda-updates-plavix-label-pgx-data-does-not-provide-dosing-recommendations

Summary: PGx Is Not Qualitatively Different Than Current Clinical Practice

Observations

Actions:

Select DrugSelect Dose

Predictable

Response

Molecular Tests

Clinical Decisions Current Practice PGx Practice Examples

Disease subsets Lipid profiles KIF6 Dose of Statin

Drug choice HIV resistance tests

CCR5 Selection of Maraviroc

Drug dose Clcr CYP2C9 Adjust Warfarin Dose

Lack of response Platelet aggregation

CYP2C19 Picking Clopidegrel

Monitor safety Culture tests for HSR

HLA-B*5701 Abacavir Toxicity

What Else Needs to Be Done?

Ways to consensus on evidence needed to support new drug approvals and relabeling of older drug

Develop more unambiguous drug product labels to enable actionable medical decisions

Improve communication between CDER and CDRH on co-development and companion diagnostics