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

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

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Larry Lesko, director of the Office of Clinical Pharmacology at the Center for Drug Evaluation and Research with the Federal Drug Administration, begins his talk by making the FDA’s commitment to ...

Larry Lesko, director of the Office of Clinical Pharmacology at the Center for Drug Evaluation and Research with the Federal Drug Administration, begins his talk by making the FDA’s commitment to personalized medicine as a public health agency. He touched on the future focus of improving drug safety and its role in future healthcare policy, citing the FDA Amendments Act of 2007.

Lesko explained that the dual mission at hand is to foster innovation and promote new initiatives under a critical path while developing and clearly articulating the standards for drugs and diagnostics. The organization takes a lifecycle approach to evidence to inform and support decisions—this goes for previous drugs and new drug development.

Moving forward, what else needs to be done? Lesko explained that ways to consensus on evidence are needed to support new drug approvals and relabeling of older drugs. He also believes that the FDA needs to develop more unambiguous drug product labels to enable actionable medical decisions and improve communication between CDER and CDRH on co-development and companion diagnostics.

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    Pharmacogenomics in Clinical Medicine:  What Is FDA Doing to Facilitate the Movement Pharmacogenomics in Clinical Medicine: What Is FDA Doing to Facilitate the Movement Presentation Transcript

    • 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 Pharmacology
      Center for Drug Evaluation and Research
      Food and Drug Administration
      Silver 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
      Trend Watching: Re-label older products to improve B/R with new evidence
      FDAAA: Recommend PMC to obtain new data to improve drug safetyNDA review: GRP to look for genotype-phenotype associations
      • 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
      • Develop and clearly articulate evidence standards for drugs and diagnostics
    • 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
    • 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 monotherapyof partial seizures in children 4 to 16 yr based on M/S
    • Hierarchy of Evidence to Support Efficacy and Safety Claims in PGx
      Highest quality and quantity of evidence
      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
      Lowest quality and quantity of evidence
    • Examples of Hierarchy Used in Regulatory Decisions
      KRAS-testing to exclude non-responders to panitumamab
      Tropism test for CCR5 virus for maraviroc (efficacy PGx)
      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
    • 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
      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 CYP2C19
      http://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
      Actions:Select DrugSelect Dose
      PredictableResponse
      Observations
      Molecular Tests
    • 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