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

2. 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.

3. 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.”

4. 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

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

6. 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

7. 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

8. 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. .

9. 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.

10. 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

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

12. 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.

13. 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.

14. 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.”

15. 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.).

16. 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.

17. 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?

18. 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.

19. 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.

20. 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*

21. 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.

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 (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.

23. 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

24. 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.

25. 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.

26. 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.

27. 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.

28. 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

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 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

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. 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

32. 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

33. 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.

34. 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)

35. 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)

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 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

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 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)