How Do I Get Into Phase 1 Trials With My Compound? Greg Ruppert Director, North American Sales May 9, 2013

Preface and Disclaimer This presentation is in regard to nonclinical animal studies provided to support an investigational new drug (IND) application (21 CFR 312) for various scenarios and approaches. There are a number of other aspects to the drug development process that are not covered. There isn’t a ‘one size fits all’ approach to designing a nonclinical IND package. Rather, nonclinical studies in support of an IND must be tailored to the specific investigational agent and the proposed clinical trials.

Preface and Disclaimer “FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.” “Before submitting the application, the applicant should submit a plan to the appropriate new drug evaluation division identifying the types of bridging studies that should be conducted. The applicant should also identify those components of its application for which it expects to rely on FDA’s finding of safety and effectiveness of a previously approved drug product. The division will critique the plan and provide guidance.”

What You Need To Do Before You Start Animal Studies Species selection Metabolic profiles Pharmacology Vehicle Solution vs. suspension Concentration Methods Formulation Bioanalytical Immunological for biopharmaceuticals Clinical plan

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 rodent In general, the differences from this “standard” approach is presented for the following IND approaches.

How Many Approaches To An IND – Biopharmaceuticals What 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, cellular and gene therapy etc. Oligonucleotides

How Many Approaches To An IND – Biopharmaceuticals Species 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

How Many Approaches To An IND – Biopharmaceuticals How many species? If pharmacologically active in two species, then 2 are needed for initial studies. Single species based on well understood pharmacology. For novel antibody-drug conjugates (ADC) two species are recommended Dose selection High dose should be the highest of Maximum pharmacological effect. Up to 10-fold exposure over expected clinical levels. .

How Many Approaches To An IND – Biopharmaceuticals Immunogenicity Assessment of anti-drug antibodies (ADAs) not needed if evidence of sustained pharmacology, no unexpected changes is PK/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 is adequate understanding of PK/PD relationship.

How Many Approaches To An IND – Biopharmaceuticals Differences 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

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 immunogenicity in repeat-dose study Biodistribution and Integration study may be required Safety Pharmacology and genotoxicity battery generally not required

How Many Approaches To An IND – Oncology Cancer – advanced vs. palliative care “The investigation does not … significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.” Pharmacology (mechanism of action, resistance, schedule dependencies, and anti-tumor activity). Safety Pharmacology battery generally included in general toxicology studies. Reversibility (in at least one of the repeat-dose studies). Genotoxicity battery generally not required.

How Many Approaches To An IND – Animal Rule Compounds where conducting a clinical trial in humans is not feasible – radiation sickness, neurotoxic gas exposure For an IND a standard approach is used along with a Phase 1 in humans, but the clinical trials for efficacy are carried out in animals not humans.

How Many Approaches To An IND – Excipients Excipients- anything other than GRAS requires additional work 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 morbidity indications. Novel - adequate prior human exposure has not been documented. “The sponsor is encouraged to contact the appropriate review division to receive specific guidance when necessary.”

How Many Approaches To An IND – Reformulated/Repurposed Drugs 505(b)(2) Bridging studies may substitute Safety Pharmacology battery and General Toxicology studies if they are found to provide an adequate basis for reliance upon FDA’s finding of safety and effectiveness. Particular toxicities associated with the new route of administration should be considered/evaluated. May require additional nonclinical work based on the composition of the formulation and known toxicities. May be required in two species (ocular, intrathecal, or epidural) or one species (all other routes). Additional nonclinical work may be required depending on the alternate route being utilized (i.e. hypersensitivity and phototox for dermal, blood compatibility for IV, etc.).

How Many Approaches To An IND – Biosimilar “Generic” form of a biopharmaceutical. Not as straightforward as for small molecules where you synthesize the exact same structure. For biopharmaceuticals, the process by which they are created does not lend itself to duplication – many processes are proprietary. Need to establish the biosimilar is equivalent to the innovator compound.

How Many Approaches To An IND – Biosimilar Proving equivalency. First step is characterizing the product for structure and activity, typically done in vitro. Guidance documents Nothing much from the FDA yet. Guidance form Canada, WHO, as well as multiple documents from EMEA. Could involve animal studies prior to IND. Typically single species. Goal is comparison of biosimilar to innovator – are there any differences in the tox profile?

How Many Approaches To An IND – Exploratory IND Obtain human data on exposure and distribution, no efficacy or safety. Should only be considered when planning limited, early exploratory IND studies in man. Early Phase I studies, limited human exposure, no therapeutic or diagnostic intent. Conducted prior to the “traditional” dose escalation, safety, and tolerance studies generally conducted in Phase I trials. Generally are used to determine if MOA can be achieved in man, provide PK information in man, select most promising lead, and/or explore biodistribution characteristics.

How Many Approaches To An IND – Exploratory IND Reduced scope of the Exploratory IND results in reduced nonclinical need: Expanded acute toxicology studies may suffice if supporting a microdose study (less than 1/100th of the dose that produces pharmacologic effect). Single species may be used if supported by in vitro metabolism and in vivo PD effects. Safety Pharmacology and genotoxicity battery generally not required.

How Many Approaches To An IND – Exploratory IND 14-Day Repeat-Dose toxicology studies may suffice if supporting a study designed to evaluate pharmacologic effect of up to 14 days. Two species with standard designs. Dose selection based on anticipated clinical exposures. Safety Pharmacology evaluations can be evaluated in the toxicology studies. Genotoxocity limited to Ames assay in specific scenarios*

How Many Approaches To An IND – Imaging Agents FDA encourages meeting due to uniqueness of each agent Biological products should be evaluated similar to biopharmaceuticals described previously Generally single lifetime exposure, or only a few exposures used to diagnose or monitor diseases or conditions, therefore results in reduced nonclinical need. Need to consider dose (e.g. mass dose), route, frequency of exposure, and kinetics. Studies should be conducted to evaluate effects of a large mass dose (or maximum feasible dose). NOAEL in acute toxicology and safety pharmacology studies should be at least 100X and NOAEL in repeat-dose toxicology be at least 25X the maximal mass dose in man.

How Many Approaches To An IND – Botanical Products Definition - products that contain vegetable matter as ingredients, may be a food (including dietary supplement), drug (including biopharmaceuticals), device, or cosmetic. For the guidance, botanical includes plant materials, algae, macroscopic fungi and combinations thereof – does not include materials from genetically engineered species, fermentation products (even if already approved for other uses in US), or highly purified/chemically modified substances derived from botanical substances. Unique situation in that many of the products in development have been taken/sold for many years with no nonclinical support.

How Many Approaches To An IND – Botanical Products Nonclinical approach If legally available already and there are no known safety issues (serious or life threatening), additional toxicology may not be needed. If contains multiple components from different plant, algae, or fungal species it would be subject to the requirements of a combination drug product, although this may be changing. For compounds marketed outside the US, dependent on route of administration For compounds that have never been marketed such as traditional herbal medicines – dependent on preparation and dosing

How Many Approaches To An IND – Drug Combinations Combinations – 3 scenarios New + new- Nonclinical combination studies recommended. Marketed + new If no cause of concern, additional nonclinical studies generally not required to support POC studies up to 1 month. Marketed + marketed If clinical experience with co-administration available, additional nonclinical studies generally not required unless there is a significant toxicological concern. If no clinical experience with co-administration available, but no cause of concern based on available data, nonclinical studies generally not required to support short duration clinical trials (up to 3 months), however are recommended for longer durations.

How Many Approaches To An IND – Drug Combinations Nonclinical development programs should be conducted on the individual entities. Duration of combination studies should be equivalent to duration of clinical trial (not to exceed 90 days) and take into account the characteristics of the combination. Should be limited to single relevant species, unless unexpected toxicity is identified. If complete nonclinical development programs are not available for the individual entities, a complete program with the combination will suffice as long as the individual agents are only planned to be used in combination. Combination Safety Pharmacology and genotoxicity battery generally not recommended.

How Many Approaches To An IND – Juvenile Indications If starting in humans and expanding into juveniles Review of the data from standard toxicology studies to determine if additional studies are needed If Juvenile is the target population Design of juvenile animal toxicology studies: Consider intended use in children, timing of dosing relative to growth and development phases in intended population, differences in pharmacological and toxicological profiles between mature and immature systems. Should be designed to evaluate effects on organ systems that develop postnatally ( nervous, reproductive, pulmonary, renal, skeletal, and immune) and measurements of growth.

How Many Approaches To An IND – Cellular and Gene Therapies Design of nonclinical study package should take into consideration the population of cells to be administered or the class of vector; the animal species and physiologic state most relevant for clinical indication and product class; and the intended doses, route of administration, and treatment 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 be employed. 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 and controls.

Which Path Do I Take Depends 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 to support your approach Ask if the Agency agrees with this approach

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 483s indicate 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, will that 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

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

Summary How do I get an IND for my compound depends on Indication Compound class Clinical plan Numerous guidance documents to help Hire a consultant as needed Work with your CRO as appropriate Take advantage of a pre-IND meeting with the Agency

Reformulated or Repurposed Horizontal Bar Chart Study Traditional Biopharmaceuticals Vaccines Cancer Single dose/DRF Yes Yes (1 or 2 species) Yes (1 species) Repeat dose Genotoxicity No Safety Pharmacology Yes – in Tox studies Study Animal Rule Excipients Reformulated or Repurposed Biosimilar Single dose/DRF Yes Yes or No Yes (1 species) Repeat dose Genotoxicity Yesa No Safety Pharmacology a - dependent on type of test article

Cellular and Gene Therapeutics Horizontal Bar Chart Study Exploratory Imaging Agents Botanicals Combinations b Single dose/DRF Yes Yes or No Repeat dose Genotoxicity No Safety Pharmacology Yes – in Tox studies b: May or may not be needed on the combination. “Traditional” studies should be completed on individual entities. Study Juvenile c Orphan Cellular and Gene Therapeutics Single dose/DRF Yes or No Yes Yes (1 or 2 species) Repeat dose Genotoxicity No Safety Pharmacology Yes – in Tox studies c: May or may not be needed in the juvenile animal. “Traditional” studies should be completed in the adult animals.

The FDA And Their Divisions Center for Drug Evaluation and Research (CDER) Conventional synthetic chemicals Antibiotics, natural and recombinant hormones Novel drugs such as antisense oligonucleotides and synthetic peptides (< 40 AA)

The FDA And Their Divisions Center 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 products Center for Devices and Radiological Health (CDRH) Center for Veterinary Medicine (CVM)

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 for Pharmaceuticals Intended for Human Use S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies S3B Pharmacokinetics: Guidance for Repeat Dose Tissue Distribution Studies

Guidelines ICH (Continued) S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing) S5 (R2) Detection of Toxicity to Reproduction for medicinal Products & Toxicity to Male Fertility S6 (R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S7A Safety Pharmacology Studies for Human Pharmaceuticals S7B The Non-Clinical Evaluation of the Potential for Delayed Ventricular Depolarization (QT interval prolongation) by Human 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 of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

Guidelines EMEA 3BS11A Pharmacokinetics and metabolic studies in the safety evaluation of new medicinal products in animals CHMP/SWP/302413/08 Need for revision of the guideline single dose toxicity (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 the Genotoxic Potential of Antisense Oligodeoxynucleotides EMEA/194898/2006 Carcinogenicity Evaluation of Medicinal Products for the Treatment of HIV Infection CPMP/SWP/2592/02 Rev 1 CHMP SWP Conclusions and recommendations on the use of genetically modified animal models for carcinogenicity assessment

Guidelines EMEA (Continued) CPMP/SWP/2877 /00 Carcinogenic potential CPMP/SWP/372/01 Points to consider on the Non-clinical assessment of the carcinogenic potential of human insulin analogues EMEA/CHMP/203927/05 Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labeling CHMP/SWP/169215/05 Need for Non-Clinical Testing in Juvenile Animals on Human Pharmaceuticals for Pediatric Indications CPMP/SWP/2600/01 Points to consider on the Need for assessment of reproduction toxicity of human insulin analogues CPMP/SWP/2145/00 Non-clinical local tolerance testing of medicinal products CHMP/SWP/150115/06 Non-clinical guideline on drug-induced hepatotoxicity

Guidelines EMEA (Continued) CHMP/SWP/94227/04 Non-Clinical Investigation of the Dependence Potential of Medicinal Products CPMP/SWP/398/01 Need for revision of the Note for Guidance on photosafety testing CPMP/SWP/728/95 Replacement of animal studies by in vitro models CHMP/SWP/28367/07 Strategies to identify and mitigate risks for first- in-human clinical trials with investigational medicinal products CHMP/GTWP/125459/2006 Non-clinical studies required before first clinical use of gene therapy medicinal products EMEA/CHMP/SWP/91850/06 Development of a CHMP Guideline on the Non- Clinical Requirements to Support Early Phase I Clinical Trials with Pharmaceutical Compounds EMEA/CHMP/94526/05 Annex Guideline on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues - Guidance on Similar Medicinal Products containing Recombinant Erythropoietins

Guidelines EMEA (Continued) EMEA/273974/05 Quality, Preclinical and Clinical aspects of Gene Transfer Medicinal Products - Annex on Non- Clinical testing for Inadvertent Germline transmission of Gene Transfer Vectors CPMP/SWP/799/95 Non-Clinical Documentation for Mixed Marketing Authorization Applications CHMP/SWP/258498/05 Non-Clinical Development of Fixed Combinations of Medicinal Products CPMP/SWP/1094/04 Evaluation of Control Samples for Non - clinical Safety Studies: Checking for Contamination with the Test Substance CPMP/SWP/2599/02 Position Paper on the non-clinical safety studies to support clinical trials with a single micro dose CPMP /3097/02* Comparability of medicinal products containing biotechnology-derived proteins as active substance -annex on non-clinical and clinical issues

Guidelines EMEA (Continued) CPMP/SWP/997/96 Pre-clinical evaluation of anti- cancer medicinal products CPMP/SWP/465/95 Pre-clinical pharmacological and toxicological testing of vaccines EMEA/HMPC/107079/07 Assessment of genotoxicity of herbal substances/preparations EMEA/HMPC/32116/05 Non-Clinical Documentation for Herbal Medicinal Products in Applications for Marketing Authorization (Bibliographical and Mixed Applications) and in Applications for Simplified Registration

Guidelines CDER Animal Models - Essential elements to Address Efficacy under the Animal Rule Developing Medical Imaging Drugs and Biological Products - Part 1: Conducting Safety Assessments Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 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 Therapeutic Radiopharmaceuticals   Nonclinical Safety Evaluation of Drug or Biologic Combinations   Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route Nonclinical Safety Evaluation of Pediatric Drug Products

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 for the Treatment of N/A Non-Life Threatening Disease Evaluation of Drug Toxicity Prior 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 Rodent Carcinogenicity Studies of Pharmaceuticals   Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs  Exploratory IND Studies Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination Applications covered by Section 505(b)(2)