REGULATORY PERSPECTIVE - PowerPoint Presentation

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   Regulatory Perspective

                  “……no two individuals
                  are exactly alike
                  Garrod, A. 1902.

Brian C. Foster, Ph.D.            Agnes V. Klein, MD
TPD, Health Canada                BGTD, Health Canada
Ottawa, November 2009

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            Points to consider
Pharmacogenomics – Vogel 1959 – Happy 50th!
• Need for common language
• Limitations - Inter-relationships
• Evidence required
• Translational approach – need for education
• Final messages

                                                The Patient

                           The Scientist

PGx is a diagnostic tool to help identify right disease/drug at right
  dose for right patient at right time
New ways of generating & using information
• Drug disposition,
• Predisposition to diseases with genetic components,
• Surveillance of disease,
• Identification of target with greater or lesser response to drugs,
• Genetic basis of drug interactions, etc.
    – targeting therapies (Herceptin, Erbitux, in some respects Avastin,
      TNF-alpha antagonists, etc.)
    – defining subsets of populations
    – studying the presence of alternate metabolic pathways
    – safety profile of therapeutics (QTc interval for example)
    – other adverse reactions, etc.

        Canadian guidelines

• Objectives
  – Intended to provide guidance to sponsors on how
    and when to submit pharmacogenomic information
    to HC
• Scope
  – Applies to sponsors intending to submit
    pharmacogenomic information to HC either in
    support of a submission for a drug or biologic or a
    device, or part of ongoing post-market activities

    Regulatory Definitions/ Considerations
 Definitions: frame the subject and are the foundation of
  the topic; Based on ICH E-15
   Genomic Biomarker; Pharmacogenomics;
 Definitions of Endpoints:
 Generally used in the context of clinical trials that support
  market authorization for new therapeutic products
   Surrogate Endpoint(s): no regulatory definitions
   Common understanding: based on definitions from the
   Definitions from other organizations also used
     (CADTH, CDR)
                 ICH E-15
 Purpose to harmonize definition and reach a common
  understanding on terms
 Contains section on Categories for Genomic Data and
  Sample Coding
   Identified, single coded data and samples; double
    coded data and samples; anonymized data and
    samples; anonymous data and samples
   Consent for a study can depend on the type of coding
    used and the rationale for that use

                        ICH E-16
    Genomic Biomarkers Related to Drug Response: Context,
     Structure, and Format of Qualification Submissions:
 Key elements:
    Format harmonized with CTD and has sections linked to the
     sections in the CTD
    General Area; Specific Biomarker Use; Context Description;
    Biomarker can have more than one context including general and/or
     specific use
      Non-Clinical Safety; (toxicology; dose optimization);
      Critical Parameters of Context Description: Drug-specific use,
         disease prognosis, assay specifications, Tissue or
         physiological/pathological process addressed, Species,
         Demographics, Environmental factors, etc.

Biomarkers as Surrogate Endpoints: 1
The question remains how they relate to long-term
  clinical benefits; one of the objectives of the regulatory
The use of biomarkers followed by clinical validation
  underscores the iterative and dynamic nature of drug
Regulatory process likes certainty: without that certainty,
  labels for products cannot be constructed well
There is a need to better define the value of biomarkers
  and surrogates
• Health care system needs certainty when making
  decision on reimbursement of treatments

Biomarkers as Surrogate Endpoints: 2
Important to recognise and determine which rated
 parameters of disease would qualify as surrogates in the
 regulatory setting
   e.g. Cholesterol (HDL/LDL levels); ER/PR Status;
     CEA in Ovarian Cancer; PAS for prostate cancer;
     Her/neu; K-ras; respiratory assistance in Hurler’s
     syndrome; development of antibodies as evidence for
     immunity with Vaccines
Progress in science and medicine have forced the
 consideration of end-points that make sense, long before
 clinical benefit (that is long-term benefit) can be proven
Has the potential and purpose to shorten drug
 development; but ↑ risk for off-label or untested subjects
 Inter-relationships: PATIENT
 Intrinsic: Genetic: gender, race,
  polymorphisms. Physiological: age,
  target organ/tissue and function, clinical
  status – disease or comorbidity state,
  height, weight, body composition &
  index, pregnancy, ambulatory or not.
 Extrinsic: Environmental: climate,
  sunlight, culture (adherence, education –
  awareness), socio-economic (nutrition),
  pollution, diet, alcohol, smoking, stress,
  exposure - single or repeated dosing,
  interactions with other drugs, foods,
  NHPs &/or OTCs.
  Inter-individual Variations
- Past and current exposures to
  xenobiotics (environment may
  overcome some bad genes……)

• Pharmacogenetic and toxicogenetic
  factors rarely act alone; they produce a
  phenotype in concert with other variant
  factors - often polygenic which can
  change expression and catalytic
Inter-relationships: dose, drug/disease
 • DOSE: PK response; ADME - disposition
 • 30+ Phase I & multiple Phase II enzymes
    – 2D6, 60+ polymorphisms, rate can vary 1000-
      fold between phenotypes
 • Phase 0 and III (efflux & influx) transporters (~10K)
 • Heterogeneity, haplotypes

 • DRUG/DISEASE: PD response; receptors
    – very little known, many are polymorphic
    – may be most important PGx target

    The Equivocal Genotype - Problems
               Nebert DW, Tox Appl Pharmacol. 207:S34-42, 2007

•   Genocopy – same SNP, different trait (outcome)
•   Phenocopy – different SNPs, same trait
•   Penetrance – proportion with same SNP and trait if <100%
•   Non-penetrance – failure of trait when SNP present
•   Expressivity – variability in expression, degree, severity of trait
•   Epistasis – interaction ≥2 genes, locus dominance function of other
•   Epigenetics – not controlled by classical Mendelian genetics
•   Dynamic genome
•   Gene-gene interactions
•   Molecular or meiotic drive
•   Gene conversion or silencing
•   etc. and each can override the importance of any one SNP and its
    association with a trait

The Equivocal Phenotype - Problems
        Nebert DW, Tox Appl Pharmacol. 207:S34-42, 2007

• Overlapping specificities of enzymes,
  receptors, transporters chaperones, ion
  channels, transcription factors, signal
  transduction pathways, etc.
• Heterogeneity of the genes and unknown
• Complexity of metabolic pathways

May need an integrated (systems biology)
 approach in real time - metabonomics

     The Promiscuity Factor
         Ma & Lu Curr Drug Metab. 9:374-383, 2008

Xenobiotic enzymes, receptors, &
  transporters: unlike their classical
  forms, these may all exhibit:
• substrate recognition and catalysis with
  broad substrate specificity,
• low turnover rates,
• atypical kinetics (substrate specific),
• multi-product formation; and
• other unusual properties.
    PGx Stringency Criteria
To be useful for everyone:
• Individuals with “factor/marker/haplotype”,

    •     should show same response 100% of the time (p < 10-6 or 10-7),
                       • those without - should not,

         requiring multiple markers required to demonstrate biologic
           plausibility rather than spurious association in multi-allelic
                                 disease or therapy.

•       Large, statistically valid, multi-centered, multi-ethnic, multi-
        factorial studies are required, not sanitized PGx studies.

    If product will be used off label, safety studies are still required and
                    this will NOT lead to shorten clinical trials.

                  Codeine - prodrug
• Activation by O-demethylation to morphine by 2D6
  (mother risk haplotype: 2D6 UM with UGT2B7*2/*2;
  ~1.4% W. European ancestry)

• Limitations
   –   Large inter-individual differences
   –   Transporter(s) not considered
   –   Difficult to distinguish UM from EMs without phenotyping
   –   Dose-response temporal relationships
   –   UGT expression and functional levels in neonate are low
• Options: Genotype (who, what?); titrate upwards from
  low initial dose; use another drug
           And the future…
 Need programme to qualify genomic biomarkers;
 Up to date literature and interaction with other regulatory
  agencies to weigh the value of each biomarker used in
  submissions happens from time to time
 Considerations and Needs:
    Should Canada adopt the list of biomarkers developed in the
    Interface with Progressive Licensing and the Regulatory
     amendment to come
    Need "inventory" of what is being done in the regulatory area

                   Critical Issues
- More intrinsic and extrinsic heterogeneity than expected:
  one size does not fit all in therapy or diagnostics
- Locus heterogeneity: except for mono-allelic disease, 1
  SNP ≠ 1 disease/response
- Single [gene-based] testing: cannot identify global
  signalling, pathways or networks
- Alternative pathways: lack of specificity as a substrate
  may bind with more than one enzyme/protein
- Substrate specificity: not all substrates are affected by a
  given polymorphism in the same way……………….
- Magnitude of issue: will there be PGx testing for all?
  clinical trial orphans: off label use, product pipeline

              Final messages……….
• Disease and drug disposition: complex & multi-factorial,
  multiple markers required to demonstrate biologic
  plausibility rather than spurious association, few valid
  biomarkers (p < 10-6 or 10-7)
   - requires pluralistic approach of genomic, epigenic, transcriptomic,
     proteomic and metabonomic (expression & function)
• Genetics (potential) may ≠ trait (response)
   – neonatal response may differ from adult response
   – genotype ≠ phenotype
• “Future risk”: science not 100% – there will be
  uncertainty, misdiagnosis & legal liability
• Translational activity: education - ethics, social, technical

• PGx - application of the science is still early
• Clinical validation of biomarkers will require
  extensive clinical trials
• May be virtually impossible to assign
  unequivocal genotype or phenotype
• Regulatory system is the critical component
  for the future of personalized medicine