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

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

33. Horizontal Bar Chart
Study Exploratory Imaging Agents Botanicals Combinations b
Single dose/DRF Yes Yes Yes or No Yes or No
Repeat dose Yes or No Yes Yes or No Yes or No
Genotoxicity No Yes Yes or No No
Safety Pharmacology
Yes – in Tox
studies Yes Yes or No No
Study Juvenile c
Orphan Cellular and Gene Therapeutics
Single 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 No
Safety Pharmacology Yes or No Yes Yes – in Tox studies
b
: 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. 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)