Pharmacology/Toxicology in the Investigator Brochure - PowerPoint Presentation

1. Pharmacology/Toxicology in the Investigator BrochureBrenda J. Gehrke, Ph.D.Office of New Drugs/CDER/FDANovember 2016

2. AbbreviationsADME: absorption, distribution, metabolism, excretionHU: hydroxyureaIB: Investigator BrochureICH: International Council for HarmonisationIGFR: insulin-like growth factor receptorIND: Investigational New Drug applicationMOA: mechanism of actionmTOR: mammalian target of rapamycinPNH: paroxysmal nocturnal hemoglobinuria

3. ObjectivesAn overview of Pharmacology/Toxicology (nonclinical) informationPharmacologySafety PharmacologyToxicologyGeneral toxicologyGenetic toxicologyOther toxicology studies: reproductive toxicityExamples of toxicity data

4. Nonclinical information included in the Investigator Brochure (IB)PharmacologySafety PharmacologyToxicologyGeneral toxicologyGenetic toxicologyOther toxicology studiesPharmacokinetics

5. Pharmacology

6. PharmacologyUsed to define intended and unintended targets/ effectsAmount of information variesType of molecule (e.g. small molecule vs biologic)Stage of drug developmentIndication

7. How much attention to pay to the pharmacology?Drug not the first in class? Better idea of toxicitiesFor biologics (e.g. an antibody): which species best predicts toxicities in humansCan explain some toxicities seen in animals: exaggerated pharmacologic effects

8. Safety Pharmacology

9. Safety PharmacologyCardiovascularIn vitroIn animals (dogs or monkeys)CNS (usually rodents)Pulmonary (usually rodents)

10. General Toxicology

11. General toxicologyToxicology studies with the same route and schedule of administration as proposed in subjects:Duration of nonclinical studies relative to clinical development described in ICH guidance M3R2Anticancer pharmaceuticals follow ICH S9

12. Purpose of these studiesDetermine whether it is safe to put drug candidate into humansDetermine an initial safe dose for human clinical trialsHelp determine a safe stopping dose (if necessary)Identify dose limiting toxicities (what should be monitored in clinical trials)Assess potential toxicities that cannot be identified in clinical trials

13. Which Species to TestRegulatory guidelines accept data from a variety of species In practice, only a small number of rodent and nonrodent species are consistently chosenSpecies are chosen because they have been used before, and studied extensively

14. Species Commonly UsedRodentsRatsMice Non RodentsBeagle dogsCynomolgus and Rhesus monkeysRabbits

15. Species in toxicology studiesFor biotech derived products, e.g. an antibody, the species should be pharmacologically relevant. Toxicology studies in a second species may be waived if no other relevant species has been identified.

16. Toxicity information in the IB: Real examplesIndication: Treatment of systemic amyloidosisTarget: amyloid fibrilsDrug: Humanized IgG1 monoclonal antibodyTarget not present in healthy animals (pivotal tox studies are conducted in healthy animals)How is toxicity assessed in the absence of a relevant species? What to monitor in patients?

17. Toxicity information in the IB: Real examplesDrug/Indication: Microtubule inhibitor being developed for treatment of advanced solid tumorsProduced irreversible optic nerve degeneration at mid and high doses in rat repeat-dose toxicology studyBased on concerns monitoring was increased (optic exams and imaging), and information was added to the protocol and informed consent

18. Toxicity information in the IB: Real examplesAb-drug conjugate (indication: cancer)Cynomolgus monkey was the relevant speciesFindings in monkeys: mainly myelosuppresionFindings in rats: myelosuppression, also severe hepatotoxicity (necrosis, increased liver enzymes) How much to worry about hepatotoxicity?

19. 100% homology to human sequences100% homology to human sequencesToxicity information in the IB: Real examplesFusion protein to inhibit the complement pathway (immune system)Indication: PNH

20. 60% homology to protein sequences in rat90% homology to protein sequences in CynoDeaths in rats and monkeys, due toImmunogenicity Is immunogenicity relevant to humans? Continued

21. General toxicology used to define the starting dose in humansShould I worry about the starting dose?The review team reviewed the IND package and agreed on the starting dose.Be aware of toxicitiesUnderstand what the nonclinical data mean and how relevant they are

22. … and how relevant are they?ADME differences between test animals and humans (e.g., N-acetylation)Species differences in anatomy (gall bladder) and physiology (folate levels)Species differences in pharmacodynamic responses (binding affinities)

23. Other limitationsAdverse reactions that can only be communicated verbally by the patient are not normally recognized in animals (e.g. pain)Concomitant drugs in humans may exacerbate toxicity

24. In general, animals are good predictors of toxicities in humansSignal transduction pathways, e.g. IGFR/mTOR inhibition and hyperglycemiaInfusion reaction in monkeys to antisense oligonucleotideCmax-related: slower infusion reduces infusion reactionHematologic toxicities of cytotoxic drugs predicted by animal studies

25. Genetic Toxicology

26. GenotoxicityData from genotoxicity studies are used as a surrogate for carcinogenicity during clinical trials.Results from carcinogenicity studies are generally not available until the time of product approval. Many people, including healthy volunteers, will have been exposed to pharmacologically active doses before carcinogenicity data are available.

27. Types of genotoxicity assaysin vitroAn assay in bacteria to detect mutations in a target geneAmes Test - Salmonella and E.ColiAn assay in mammalian cells to detect chromosomal damageChinese Hamster Ovary (CHO) cellsMouse lymphoma cellsin vivoAn assay in a rodent species to detect chromosomal damage to hematopoietic cellsOther genotoxicity assays are available and may be conducted

28. TimingTiming of genetic toxicology studies relative to clinical developmentGene mutation assay for single dose clinical studiesAdd chromosomal damage study for multiple dose clinical studiesComplete battery conducted prior to phase 2Submit with marketing application for anticancer drugs

29. Worried about results of genetic toxicity studies?Review team made a decision that the trial is reasonably safe to proceedNegative results in genotoxic assaysPositive or likely/possibly to be positive (based on MOA, other drugs in the same class, equivocal results)Life-threatening indication/ cancer? Genotox studies not needed until marketing application; short life-expectancySerious condition and no other therapy? HU in sickle cellA single, small/sub-therapeutic dose in humans?

30. A few typical daily exposures to carcinogensSource of carcinogenCarcinogenAverage daily human exposureIndoor airFormaldehydeBenzene598 µg155 µgTap waterBromodichloro-methanechloroform13 µg17 µgCelery8-methoxy psoralen4.9 µgCoffeeCatecholHydroquinoneCaffeic acid1.3 mg333 µg23.9 mgLettuceCaffeic acid7.9 mgBrown mustardAllyl isothiocyanate62.9 µg

31. Other toxicity studies:Reproductive toxicology

32. Teratogenicity Thalidomide is a well-known examplePrescribed to pregnant women for nausea and insomnia.Resulted in over 10,000 births with severe limb malformations. Link between exposure and adverse effects was possible because of the potency of the drug and relatively short time period between exposure and manifestation of effects.

33. Thalidomide-induced birth defects

34. Reproduction Toxicity TestingFor small moleculesProtocols are standardCovers fertility, embryo-fetal, and pre- and post- natal periodsFollow ICH S5R2For biotechnology derived pharmaceuticalsMore case-by-caseStudy designs evolving based on revisions to ICH S6

35. In general, animals are good predictors of toxicities in humansThalidomide-like limb abnormalities in monkeys are induced by thalidomide analogs.Hormonal agents (e.g. estrogen receptor agonists) and loss of pregnancy

36. Reproduction Toxicity TestingWomen of child bearing potentialGenerally, where appropriate preliminary reproduction toxicity data are available from two species, and where precautions to prevent pregnancy in clinical trials are used, inclusion of WOCBP (up to 150) receiving investigational treatment for a relatively short duration (up to 3 months) can occur before conduct of definitive reproduction toxicity testing.Pregnant womenBefore the inclusion of pregnant women in clinical trials, all female reproduction toxicity studies and the standard battery of genotoxicity tests should be conducted. In addition, safety data from previous human exposure should be evaluated.

37. Reproduction Toxicity TestingFollow ICH M3R2Malescan be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies. A male fertility study should be completed before the initiation of large scale or long duration clinical trials (e.g., Phase III trials).Women not of childbearing potentialWomen not of childbearing potential (i.e., permanently sterilized, postmenopausal) can be included in clinical trials without reproduction toxicity studies if the relevant repeated-dose toxicity studies (which include an evaluation of the female reproductive organs) have been conducted. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.

38. References

39. ICH Guidances and Guidelinesfda.gov/cder/guidance or ich.orgS1 Carcinogenicity S2 Genetic toxicity S3 ToxicokineticsS4 Duration of Chronic Toxicity Testing S5 Reproductive toxicity S6 BiotechnologyS7 Safety PharmacologyS8 ImmunotoxicologyS9 Nonclinical studies for development anticancer drugs and biologics M3 Nonclinical Safety Studies for the conduct of Human Clinical TrialsOther guidances available from fda.gov

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