Virtual Drug Development in Southern California: A Pre-Clinical Focus -Presentation by MPI Research May 2013


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BIOCOM CRO event May 2013: Being an early stage virtual company is no easy task. Managing resources and timelines while minimizing costs are the new normal for successful virtual companies. This two hour event and panel discussion hosted by Explora Biolabs and MPI Research will explore successful preclinical drug development in a virtual setting. Explora BioLabs will discuss selecting a drug candidate using early biology/efficacy models as well as best practices for screening and partnering with a CRO to streamline your candidate selection in a resource constrained environment. Building on that discussion, MPI Research will describe how to advance a compound from early GLP tox and safety testing into phase 1 while utilizing successful partnerships.

Joining the presenters for a follow-on panel discussion will be:

David Johnson, Director of DMPK, MicroConstants, Inc.
Richard Lin, CEO, Explora Biolabs
Greg Ruppert, Sr. Study Director and Director of Sales, MPI Research
Jennifer Spinella, Vice President, Regulatory Affairs & Quality Assurance, Rare Disease Therapeutics

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Virtual Drug Development in Southern California: A Pre-Clinical Focus -Presentation by MPI Research May 2013

  1. 1. How Do I Get Into Phase 1Trials With My Compound?Greg RuppertDirector, North American SalesMay 9, 2013
  2. 2. Preface and DisclaimerThis presentation is in regard to nonclinical animal studies provided tosupport an investigational new drug (IND) application (21 CFR 312) forvarious scenarios and approaches. There are a number of otheraspects to the drug development process that are not covered.There isn’t a ‘one size fits all’ approach to designing a nonclinical INDpackage. Rather, nonclinical studies in support of an IND must betailored to the specific investigational agent and the proposed clinicaltrials.
  3. 3. Preface and Disclaimer“FDAs guidance documents, including this guidance, do not establishlegally enforceable responsibilities. Instead, guidances describe theAgencys current thinking on a topic and should be viewed only asrecommendations, unless specific regulatory or statutoryrequirements are cited. The use of the word should in Agencyguidances means that something is suggested or recommended,but not required.”“Before submitting the application, the applicant should submit a plan tothe appropriate new drug evaluation division identifying the types ofbridging studies that should be conducted. The applicant shouldalso identify those components of its application for which it expectsto rely on FDA’s finding of safety and effectiveness of a previouslyapproved drug product. The division will critique the plan andprovide guidance.”
  4. 4. What You Need To Do Before You StartAnimal Studies• Species selection• Metabolic profiles• Pharmacology• Vehicle• Solution vs. suspension• Concentration• Methods• Formulation• Bioanalytical• Immunological for biopharmaceuticals• Clinical plan
  5. 5. How Many Approaches To An IND –“Standard Approach”NCE Small Molecule or “Traditional” Approach• DRF and repeat toxicology in rodents & nonrodent with TK• Dosing regimen• Recovery?• Genotoxicity battery• Ames• Mammalian Cell Mutation (Chromosomal Aberration)• in vivo Micronucleus (optional)• Safety Pharmacology battery• CV nonrodent• in vitro hERG• CNS rodent• Respiratory rodentIn general, the differences from this “standard” approach ispresented for the following IND approaches.
  6. 6. How Many Approaches To An IND –BiopharmaceuticalsWhat is a biopharmaceutical?• Product derived from characterized cells (bacteria, yeast, insect,plant, mammalian).• Includes growth factors, recombinant proteins, antibodies,endogenous proteins, enzymes etc.• Does not include antibiotics, heparin, vitamins, vaccines, cellularand gene therapy etc.• Oligonucleotides
  7. 7. How Many Approaches To An IND –BiopharmaceuticalsSpecies selection – Needs to be the most relevant• Sequence homology• Cell based assays for binding affinities• Functional activity - in vivo or in vitro• If no orthologous target – consider homologous molecules,transgenic animals or animal models of disease.Monoclonal antibodies directed against foreign targets
  8. 8. How Many Approaches To An IND –BiopharmaceuticalsHow many species?• If pharmacologically active in two species, then 2 are needed forinitial studies.• Single species based on well understood pharmacology.• For novel antibody-drug conjugates (ADC) two species arerecommendedDose selection• High dose should be the highest of• Maximum pharmacological effect.• Up to 10-fold exposure over expected clinical levels..
  9. 9. How Many Approaches To An IND –BiopharmaceuticalsImmunogenicity• Assessment of anti-drug antibodies (ADAs) not needed ifevidence of sustained pharmacology, no unexpected changes isPK/TK, no evidence of immune-mediated reactions.• Take blood samples for analysis of ADAs, analyze if needed.• If ADAs detected – characterize impact on exposure,pharmacology, toxicity.• Neutralizing antibody assays – generally not needed if there isadequate understanding of PK/PD relationship.
  10. 10. How Many Approaches To An IND –BiopharmaceuticalsDifferences in nonclinical approach for IND• Species selection• Pharmacology not metabolism• Number of species• One or two• Safety pharmacology• Separate or incorporated• Genetic toxicology• Not needed except for special situations• Toxicology• Dose selection
  11. 11. How Many Approaches To An IND –Vaccines• Single species - generally rabbit• Single dose toxicity• Adjuvant toxicity study – if novel adjuvant is used• Repeat dose toxicity• Include local tolerance and evaluation of immunogenicityin repeat-dose study• Biodistribution and Integration study may be required• Safety Pharmacology and genotoxicity batterygenerally not required
  12. 12. How Many Approaches To An IND –OncologyCancer – advanced vs. palliative care• “The investigation does not … significantly increases the risks (ordecreases the acceptability of the risks) associated with the useof the drug product.”• Pharmacology (mechanism of action, resistance, scheduledependencies, and anti-tumor activity).• Safety Pharmacology battery generally included in generaltoxicology studies.• Reversibility (in at least one of the repeat-dose studies).• Genotoxicity battery generally not required.
  13. 13. How Many Approaches To An IND –Animal Rule• Compounds where conducting a clinical trial in humansis not feasible – radiation sickness, neurotoxic gasexposure• For an IND a standard approach is used along with aPhase 1 in humans, but the clinical trials for efficacyare carried out in animals not humans.
  14. 14. How Many Approaches To An IND –ExcipientsExcipients- anything other than GRAS requires additionalwork• Studies required will vary from no additional work required(GRAS) to conducting all studies in the “Traditional” Approach(Novel).• Use in previously approved products or GRAS status?• Indication - lifesaving therapies vs. low morbidityindications.• Novel - adequate prior human exposure has not beendocumented.• “The sponsor is encouraged to contact the appropriate reviewdivision to receive specific guidance when necessary.”
  15. 15. How Many Approaches To An IND –Reformulated/Repurposed Drugs505(b)(2)• Bridging studies may substitute Safety Pharmacology battery andGeneral Toxicology studies if they are found to provide anadequate basis for reliance upon FDA’s finding of safety andeffectiveness.• Particular toxicities associated with the new route ofadministration should be considered/evaluated.• May require additional nonclinical work based on thecomposition of the formulation and known toxicities.• May be required in two species (ocular, intrathecal, orepidural) or one species (all other routes).• Additional nonclinical work may be required depending onthe alternate route being utilized (i.e. hypersensitivity andphototox for dermal, blood compatibility for IV, etc.).
  16. 16. How Many Approaches To An IND –Biosimilar• “Generic” form of a biopharmaceutical.• Not as straightforward as for small molecules where yousynthesize the exact same structure.• For biopharmaceuticals, the process by which they arecreated does not lend itself to duplication – manyprocesses are proprietary.• Need to establish the biosimilar is equivalent to theinnovator compound.
  17. 17. How Many Approaches To An IND –BiosimilarProving equivalency.•First step is characterizing the product for structure and activity, typicallydone in vitro.•Guidance documents• Nothing much from the FDA yet.• Guidance form Canada, WHO, as well as multiple documents fromEMEA.•Could involve animal studies prior to IND.• Typically single species.• Goal is comparison of biosimilar to innovator – are there anydifferences in the tox profile?
  18. 18. How Many Approaches To An IND –Exploratory IND• Obtain human data on exposure and distribution, no efficacyor safety.• Should only be considered when planning limited, earlyexploratory IND studies in man.• Early Phase I studies, limited human exposure, no therapeutic ordiagnostic intent.• Conducted prior to the “traditional” dose escalation, safety, andtolerance studies generally conducted in Phase I trials.• Generally are used to determine if MOA can be achieved inman, provide PK information in man, select most promisinglead, and/or explore biodistribution characteristics.
  19. 19. How Many Approaches To An IND –Exploratory INDReduced scope of the Exploratory IND results in reducednonclinical need:• Expanded acute toxicology studies may suffice if supporting amicrodose study (less than 1/100thof the dose that producespharmacologic effect).• Single species may be used if supported by in vitrometabolism and in vivo PD effects.• Safety Pharmacology and genotoxicity battery generally notrequired.
  20. 20. How Many Approaches To An IND –Exploratory IND• 14-Day Repeat-Dose toxicology studies may suffice ifsupporting a study designed to evaluate pharmacologic effectof up to 14 days.• Two species with standard designs.• Dose selection based on anticipated clinical exposures.• Safety Pharmacology evaluations can be evaluated in thetoxicology studies.• Genotoxocity limited to Ames assay in specific scenarios*
  21. 21. How Many Approaches To An IND –Imaging AgentsFDA encourages meeting due to uniqueness of each agent• Biological products should be evaluated similar tobiopharmaceuticals described previously• Generally single lifetime exposure, or only a few exposures usedto diagnose or monitor diseases or conditions, therefore results inreduced nonclinical need.• Need to consider dose (e.g. mass dose), route, frequency ofexposure, and kinetics.• Studies should be conducted to evaluate effects of a large massdose (or maximum feasible dose).• NOAEL in acute toxicology and safety pharmacology studiesshould be at least 100X and NOAEL in repeat-dose toxicology beat least 25X the maximal mass dose in man.
  22. 22. How Many Approaches To An IND –Botanical Products• Definition - products that contain vegetable matter as ingredients,may be a food (including dietary supplement), drug (includingbiopharmaceuticals), device, or cosmetic.• For the guidance, botanical includes plant materials, algae,macroscopic fungi and combinations thereof – does not includematerials from genetically engineered species, fermentationproducts (even if already approved for other uses in US), or highlypurified/chemically modified substances derived from botanicalsubstances.• Unique situation in that many of the products in development havebeen taken/sold for many years with no nonclinical support.
  23. 23. How Many Approaches To An IND –Botanical ProductsNonclinical approach• If legally available already and there are no known safety issues(serious or life threatening), additional toxicology may not beneeded.• If contains multiple components from different plant, algae, orfungal species it would be subject to the requirements of acombination drug product, although this may be changing.• For compounds marketed outside the US, dependent on route ofadministration• For compounds that have never been marketed such as traditionalherbal medicines – dependent on preparation and dosing
  24. 24. How Many Approaches To An IND –Drug CombinationsCombinations – 3 scenarios• New + new- Nonclinical combination studies recommended.• Marketed + new• If no cause of concern, additional nonclinical studies generallynot required to support POC studies up to 1 month.• Marketed + marketed• If clinical experience with co-administration available, additionalnonclinical studies generally not required unless there is asignificant toxicological concern.• If no clinical experience with co-administration available, but nocause of concern based on available data, nonclinical studiesgenerally not required to support short duration clinical trials (upto 3 months), however are recommended for longer durations.
  25. 25. How Many Approaches To An IND –Drug Combinations• Nonclinical development programs should be conducted on theindividual entities.• Duration of combination studies should be equivalent to duration ofclinical trial (not to exceed 90 days) and take into account thecharacteristics of the combination.• Should be limited to single relevant species, unless unexpected toxicityis identified.• If complete nonclinical development programs are not available for theindividual entities, a complete program with the combination will sufficeas long as the individual agents are only planned to be used incombination.• Combination Safety Pharmacology and genotoxicity battery generallynot recommended.
  26. 26. How Many Approaches To An IND –Juvenile IndicationsIf starting in humans and expanding into juveniles• Review of the data from standard toxicology studies to determine ifadditional studies are neededIf Juvenile is the target population• Design of juvenile animal toxicology studies:• Consider intended use in children, timing of dosing relativeto growth and development phases in intended population,differences in pharmacological and toxicological profilesbetween mature and immature systems.• Should be designed to evaluate effects on organ systemsthat develop postnatally ( nervous, reproductive, pulmonary,renal, skeletal, and immune) and measurements of growth.
  27. 27. How Many Approaches To An IND –Cellular and Gene Therapies• Design of nonclinical study package should take into consideration thepopulation of cells to be administered or the class of vector; the animalspecies and physiologic state most relevant for clinical indication andproduct class; and the intended doses, route of administration, andtreatment regimens.• Follow same rules as for biopharmaceuticals.• Species specificity, permissiveness for infection by viral vectors,comparative physiology, etc. should be considered in study design.• Single species (most appropriate, pharmacologically relevant) should beemployed.• Other “non-standard” endpoints may be required such as cell fate,functional, product-dependent, or disease-dependent endpoints.• Generally difference lies in stricter manufacturing regulations andcontrols.
  28. 28. Which Path Do I TakeDepends on test article type, indication, route, clinical plan• Review the guidelines (FDA/EMEA/ICH)• Pre-IND Meeting• Propose what makes scientific sense, along with the data tosupport your approach• Ask if the Agency agrees with this approach
  29. 29. Where Do I Go To Get The Work Done• What to look for in a CRO• Inspections – how often, any 483s, if so what were they for (not all 483sindicate issues)• Experience – SD and technical• Capacity – are they overbooked• Historical data – needed to discern background from test article-related• Communication – if they are hard to contact during proposal process, willthat carry through to the study• Reporting history – can they follow through on commitments• What the CRO needs from you• Test article• Understanding of project scope• Communication
  30. 30. Where Do I Go To Get The Work Done(Continued)• Common issues that arise• No material available, insufficient material available• Protocol approval• Veterinary intervention• Communication• Background information on compound and possible toxicities
  31. 31. SummaryHow do I get an IND for my compound depends on• Indication• Compound class• Clinical planNumerous guidance documents to helpHire a consultant as neededWork with your CRO as appropriateTake advantage of a pre-IND meeting with the Agency
  32. 32. Horizontal Bar ChartStudy Traditional Biopharmaceuticals Vaccines CancerSingle dose/DRF Yes Yes (1 or 2 species) Yes (1 species) YesRepeat dose Yes Yes (1 or 2 species) Yes (1 species) YesGenotoxicity Yes No No NoSafety Pharmacology Yes Yes – in Tox studies No Yes – in Tox studiesStudy Animal Rule ExcipientsReformulated orRepurposed BiosimilarSingle dose/DRF Yes Yes or No Yes or No Yes (1 species)Repeat dose Yes Yes or No Yes or No Yes (1 species)Genotoxicity YesaYes or No Yes or No NoSafety Pharmacology YesaYes or No Yes or No Noa- dependent on type of test article
  33. 33. Horizontal Bar ChartStudy Exploratory Imaging Agents Botanicals Combinations bSingle dose/DRF Yes Yes Yes or No Yes or NoRepeat dose Yes or No Yes Yes or No Yes or NoGenotoxicity No Yes Yes or No NoSafety PharmacologyYes – in Toxstudies Yes Yes or No NoStudy Juvenile cOrphan Cellular and Gene TherapeuticsSingle dose/DRF Yes or No Yes Yes (1 or 2 species)Repeat dose Yes or No Yes Yes (1 or 2 species)Genotoxicity Yes or No Yes NoSafety Pharmacology Yes or No Yes Yes – in Tox studiesb: May or may not be needed on the combination. “Traditional” studies should be completed on individual entities.c: May or may not be needed in the juvenile animal. “Traditional” studies should be completed in the adult animals.
  34. 34. The FDA And Their DivisionsCenter for Drug Evaluation and Research (CDER)• Conventional synthetic chemicals• Antibiotics, natural and recombinant hormones• Novel drugs such as antisense oligonucleotides and syntheticpeptides (< 40 AA)
  35. 35. The FDA And Their DivisionsCenter for Biologic Evaluation and Research (CBER)• Blood and blood products• Vaccines and allergenics• Conventional biotechnology-derived products• Recombinant proteins, monoclonal antibodies, antigenic peptides• Novel biotechnology-derived productsCenter for Devices and Radiological Health (CDRH)Center for Veterinary Medicine (CVM)
  36. 36. Guidelines• ICH• Q3A (R2) Impurities in New Drug Substances• Q3B (R2) Impurities in New Drug Products• Q3C (R4) Impurities Guidelines for Residual Solvents• S1A Need for Carcinogenicity Studies for Pharmaceuticals• S1B Testing for Carcinogenicity of Pharmaceuticals• S1C (R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals• S2 (R1) Guidance on Genotoxicity Testing and Data Interpretation forPharmaceuticals Intended for Human Use• S3A Note for Guidance on Toxicokinetics: The Assessment of SystemicExposure in Toxicity Studies• S3B Pharmacokinetics: Guidance for Repeat Dose Tissue DistributionStudies
  37. 37. Guidelines• ICH (Continued)• S4 Duration of Chronic Toxicity Testing in Animals (Rodent andNonrodent Toxicity Testing)• S5 (R2) Detection of Toxicity to Reproduction for medicinal Products &Toxicity to Male Fertility• S6 (R1) Preclinical Safety Evaluation of Biotechnology-DerivedPharmaceuticals• S7A Safety Pharmacology Studies for Human Pharmaceuticals• S7B The Non-Clinical Evaluation of the Potential for DelayedVentricular Depolarization (QT interval prolongation) byHuman Pharmaceuticals• S8 Immunotoxicology Studies for Human Pharmaceuticals• S9 Nonclinical Evaluation of Anticancer Pharmaceuticals• S10 Photosafety Evaluation• M3 (R2) Guidance on Nonclinical Safety Studies for the Conduct ofHuman Clinical Trials and Marketing Authorization forPharmaceuticals
  38. 38. Guidelines• EMEA• 3BS11A Pharmacokinetics and metabolic studies in thesafety evaluation of new medicinal products inanimals• CHMP/SWP/302413/08 Need for revision of the guideline single dosetoxicity (3BS1A)• CHMP/SWP/488313/07 Repeated dose toxicity• CPMP/SWP/1042/99 Repeated dose toxicity• CPMP/SWP/5199/02 Limits of genotoxic impurities• CHMP/QWP/251344/2006• CHMP/SWP/199726/04 Reflection Paper on the assessment of theGenotoxic Potential of AntisenseOligodeoxynucleotides• EMEA/194898/2006 Carcinogenicity Evaluation of Medicinal Productsfor the Treatment of HIV Infection• CPMP/SWP/2592/02 Rev 1 CHMP SWP Conclusions and recommendationson the use of genetically modified animal modelsfor carcinogenicity assessment
  39. 39. Guidelines• EMEA (Continued)• CPMP/SWP/2877 /00 Carcinogenic potential• CPMP/SWP/372/01 Points to consider on the Non-clinicalassessment of the carcinogenic potential ofhuman insulin analogues• EMEA/CHMP/203927/05 Risk Assessment of Medicinal Products onHuman Reproduction and Lactation: From Datato Labeling• CHMP/SWP/169215/05 Need for Non-Clinical Testing in JuvenileAnimals on Human Pharmaceuticals forPediatric Indications• CPMP/SWP/2600/01 Points to consider on the Need for assessmentof reproduction toxicity of human insulinanalogues• CPMP/SWP/2145/00 Non-clinical local tolerance testing of medicinalproducts• CHMP/SWP/150115/06 Non-clinical guideline on drug-inducedhepatotoxicity
  40. 40. Guidelines• EMEA (Continued)• CHMP/SWP/94227/04 Non-Clinical Investigation of the DependencePotential of Medicinal Products• CPMP/SWP/398/01 Need for revision of the Note for Guidance onphotosafety testing• CPMP/SWP/728/95 Replacement of animal studies by in vitromodels• CHMP/SWP/28367/07 Strategies to identify and mitigate risks for first-in-human clinical trials with investigationalmedicinal products• CHMP/GTWP/125459/2006 Non-clinical studies required before first clinicaluse of gene therapy medicinal products• EMEA/CHMP/SWP/91850/06 Development of a CHMP Guideline on the Non-Clinical Requirements to Support Early Phase IClinical Trials with Pharmaceutical Compounds• EMEA/CHMP/94526/05 Annex Guideline on Similar Biological MedicinalProducts containing Biotechnology-DerivedProteins as Active Substance: Non-Clinical andClinical Issues - Guidance on Similar MedicinalProducts containing Recombinant Erythropoietins
  41. 41. Guidelines• EMEA (Continued)• EMEA/273974/05 Quality, Preclinical and Clinical aspects of GeneTransfer Medicinal Products - Annex on Non-Clinical testing for Inadvertent Germlinetransmission of Gene Transfer Vectors• CPMP/SWP/799/95 Non-Clinical Documentation for Mixed MarketingAuthorization Applications• CHMP/SWP/258498/05 Non-Clinical Development of FixedCombinations of Medicinal Products• CPMP/SWP/1094/04 Evaluation of Control Samples for Non - clinicalSafety Studies: Checking for Contamination withthe Test Substance• CPMP/SWP/2599/02 Position Paper on the non-clinical safety studiesto support clinical trials with a single micro dose• CPMP /3097/02* Comparability of medicinal products containingbiotechnology-derived proteins as activesubstance -annex on non-clinical and clinicalissues
  42. 42. Guidelines• EMEA (Continued)• CPMP/SWP/997/96 Pre-clinical evaluation of anti- cancer medicinalproducts• CPMP/SWP/465/95 Pre-clinical pharmacological and toxicologicaltesting of vaccines• EMEA/HMPC/107079/07 Assessment of genotoxicity of herbalsubstances/preparations• EMEA/HMPC/32116/05 Non-Clinical Documentation for Herbal MedicinalProducts in Applications for MarketingAuthorization (Bibliographical and MixedApplications) and in Applications for SimplifiedRegistration
  43. 43. Guidelines• CDER• Animal Models - Essential elements to Address Efficacy under the Animal Rule• Developing Medical Imaging Drugs and Biological Products - Part 1: ConductingSafety Assessments• Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeuticsin Adult Healthy Volunteers• Genotoxic and Carcinogenic Impurities in Drug Substances and Products:Recommended Approaches• Immunotoxicology Evaluation of Investigational New Drugs• Nonclinical Evaluation of Late Radiation Toxicity of TherapeuticRadiopharmaceuticals• Nonclinical Safety Evaluation of Drug or Biologic Combinations• Nonclinical Safety Evaluation of Reformulated Drug Products and ProductsIntended for Administration by an Alternate Route• Nonclinical Safety Evaluation of Pediatric Drug Products
  44. 44. Guidelines• CDER (Continued)• Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients• Photosafety Testing• Recommended Approaches to Integration of Genetic Toxicology Study Results• Reference Guide for the Nonclinical Toxicity Studies of Antiviral Drugs Indicated forthe Treatment of N/A Non-Life Threatening Disease Evaluation of Drug ToxicityPrior to Phase I Clinical Studies• Safety Testing of Drug Metabolites• Single Dose Acute Toxicity Testing for Pharmaceuticals• Statistical Aspects of the Design, Analysis, and Interpretation of Chronic RodentCarcinogenicity Studies of Pharmaceuticals• Content and Format of Investigational New Drug Applications (INDs) for Phase 1Studies of Drugs• Exploratory IND Studies• Codevelopment of Two or More Unmarketed Investigational Drugs for Use inCombination• Applications covered by Section 505(b)(2)