Trends in risk assessment by lzv41816

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									                                   Trends in risk assessment

                        PRESENT                                                    FUTURE
             Major emphasis on hazard identification               Increasing emphasis on hazard
                                                                     characterization
             Apical tests for detection of toxicity
                                                                    Exploration of mechanisms at cellular and
             Empirical cross species extrapolation                  molecular level
             Dose metrics often unrelated to                       Rational mechanism-based risk
              assessment of biological response                      assessment
             Methods for hazard identification in                  Selection of dose metrics based on
              animals often different from man                       integration with assessment of biological
             Predictive value of animal data                        response
              questioned                                            Methods for assessment of safety in
                                                                     human more in line with those used in
                                                                     animals
                                                                    Better correlation between observations
                                                                     in animals and humans




SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
              Potential utility of biomarkers to discovery and
                  development of new pharmaceuticals


             selection of superior leads for development
             reduced failure rate in development
             enhanced understanding of potential hazard(s) to patients
             improved risk communication at all stages of development
              process
             exclusion of patients at risk of serious adverse effects
             improved risk management pre- and post- marketing
             more cost effective delivery of medicines to patients in need




SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
             Potential utility of biomarkers to risk assessment




             improved hazard identification and hazard characterization
             mechanistic understanding of toxic process(es)
             enhanced study designs
             identification of appropriate dose metrics (PK/TK/PD)
             risk assessment based on rational cross species extrapolation
             continuous refinement of predictive value of animal data
             continuous refinement of predictive value of human data




SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                             A conceptual view of biomarkers

     A biomarker is an indicator of response by a biological system to the specific and/or non-specific
     activity resulting from exposure to an exogenously applied substance at a given dose or
     concentration over a prescribed period of time.


             Biomarkers of hazard
               –   conventional tests, e.g., ALT, CBC
                      •   distal indicators of toxicity
               –   novel assays, e.g., cytokines, mRNA, cDNA
                      •   proximal indicators of biological activity

             Biomarkers of efficacy
               –   primary pharmacology (MOA)
                      •   intrinsic potency
                      •   species sensitivity
               –   secondary pharmacology (NSA)
                      •   specificity/selectivity
                      •   unique species differences

             Biomarkers of exposure
               –   products of endogenous metabolism
               –   unique products of biotransformation

SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                      Source of materials and methodologies
                          for assessment of biomarkers

                     MATERIAL                                            METHODOLOGY

             Biofluids                                             Biofluid MRS
               –   urine, serum, saliva
               –   bronchoalveolar lavage                           RT-PCR/Taq Man

             Cells                                                 In situ hybridization
               –   peripheral blood cells
               –   cell culture                                     MRI/MRS of tissue

             Tissue                                                Microarrays
               –   necropsy
               –   biopsy                                           2-D gel electrophoresis

                                                                    Flow cytometry

SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                    Biomarkers of hazard: specific examples


                     HAZARD                                                   BIOMARKER

             testicular toxicity                            serum testosterone
             thyroid tumors                                 serum TSH, T3, T4
             carcinoid tumors                               serum gastrin
             phospholipidosis                               cytoplasmic inclusions in PBLs
             reduced fertility                              serum estrogen/progesterone
             bone marrow toxicity                           reticulocyte counts
             arterial toxicity                              von Willebrand factor
             fluid retention                                hematocrit
             cardiac hypertrophy                            brain natriuretic peptide




SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
             Products of altered gene and protein expression




                                                                   mRNA
                                                                                              Therapeutic
                                                                                              Biomarker
              Pharmacophore                       DNA         mRNA Protein
                                                                                                        Molecular
                                                                                                       Therapeutic
                                          Proteins                                                       Index

               Toxicophore                                          mRNA
                                                                                                        Toxicologic
                                                                                                        Biomarker
                                                                         Protein



SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
        Biomarkers: extrapolation between animals and man


                                                                                               Toxicity
                                                                                               Biomarker



                    Animal                                                             Human
                                                                                                             Molecular/
                                                                                              Efficacy       Metabolic
Response                                                                                      Biomarker      Therapeutic
                                                                                                             Index




                                                                                         Pharmacology
                                                                                         Biomarker




                                                      Dose
                             Gene expression pattern                                           Biofluid MRS pattern
SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                     Biomarkers: cross species extrapolation




                          Rat     Dog Man Monkey
                                                      Toxicity
                                                                           Congruent pattern of response
                                                                            across species

                                                                           Significant difference in animal
                                                                            species sensitivity
    R                                        Pharmacology
                                                                           Therapeutic ratio similar across
                                                                            species

                                                                           Dose-response relationships
                                          Biology
                                                                            unknown in man

                      D/E

SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
    Biomarkers: milestones on the exposure-response curve



                        Rat               Man         Monkey
                               BM IV                          BM VI
                                                                                    Species diversity in
                                                                                     biological and
                                                                                     toxicological response
                      BM III


                                        BM V          BM V                          Congruent and
R                                                                                    non-congruent effect
                                                                                     on biomarkers across
                     BM II             BM II
                                                                                     species

              BM I


                     D/E


SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                     Biomarkers: cross species extrapolation
                              for risk assessment



                                                                                Toxicity




                         Dog             Rat             Mouse
                         (0.4)           (5)             (10)                                 Therapeutic
                                                                                              ratio same
                 R                                                        Pharmacology        in all
                                                                                              species




                                                                      Biology



                                     D/E
                        ( ) AUC at no toxic effect dose in animal species relative
                        to AUC at therapeutic dose in human.


SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                 Biomarkers: application to risk assessment




                                                              CNS toxicity
                                                              teratogenicity


                                              Uremia/nephrotoxicity             I

                                                                                       II
                  R                                                                          III
                                            Prolactin/mammary hyperplasia




                                     Pharmacologic activity



                                     D/E


SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                 Biomarkers: application to risk assessment




                                                             CNS toxicity
                                                             teratogenicity


                                             Uremia/nephrotoxicity


                 R                                                                          III
                                           Prolactin/mammary hyperplasia
                                                                                      II
                                                                                I
                                    Pharmacologic activity



                                    D/E


SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
        Biomarkers of effects induced by Thiazolidinediones


                                          Biomarker of                  Biomarker of                 Biomarker of
                                      Pharmacologic Effect            Physiologic Effect           Toxicologic Effect




                  R       FFA        Insulin                 Plasma                    Cardiac
                                                             Volume   Hct            hypertrophy
                                                                                        (MRI)




                                      D/E


SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                                                         Plasma von Willebrand factor
                                                        rats given 60 mg/kg SKF-82526

                                                      200
               % of Normal Rat Pool [mean + S.E.M.]




                                                      190      Control
                                                               60 mg/kg
                                                      180

                                                      170

                                                      160

                                                      150

                                                      140

                                                      130

                                                      120

                                                      110

                                                      100
                                                                0             2              6       24
                                                                               Hours Post-Dose
                                                                          n = 6-10/group/timepoint

SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                                                  Heart weight in different models
                                                      of cardiac hypertrophy


                                                     control
                                            0.6      treated
                 Relative heart weight, %



                                                                                        *
                                                       *              *
                                            0.4




                                            0.2




                                            0.0
                                                    Volume        Trophic          Pressure
           % increase                                 20              25               16
                                                               Duration: 4 weeks

SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999
                                   LV-cTnT concentration in difference
                                     models of cardiac hypertrophy



                                       Control
                                       Treated
                                                                                                          *
                             750
                                                                      *
             LV cTnT, ug/g




                             600
                                       *
                             450


                 300
           Duration (wks) 1                         4                 1                 4             15 -19
                                           Volume                         Trophic                    Pressure
SmithKline Beecham Pharmaceuticals, Dr. D. Gwyn Morgan
Advisory Committee for Pharmaceutical Science Nonclinical Studies Subcommittee, FDA, Gaithersburg, MD, Dec. 14, 1999

								
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