Title of PowerPoint 32 pt Arial

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
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 –
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 –
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 –
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
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 –
• 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 –
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 –
• 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 –
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
• 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- anything other than GRAS requires additional
• Studies required will vary from no additional work required
(GRAS) to conducting all studies in the “Traditional” Approach
• Use in previously approved products or GRAS status?
• Indication - lifesaving therapies vs. low morbidity
• Novel - adequate prior human exposure has not been
• “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
• 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
• 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 –
• “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 –
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
• 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
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
• 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
• 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
• 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 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
• 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
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
• Common issues that arise
• No material available, insufficient material available
• Protocol approval
• Veterinary intervention
• Communication
• Background information on compound and possible toxicities
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
Horizontal Bar Chart
Single dose/DRF
Yes (1 or 2 species)
Yes (1 species)
Repeat dose
Safety Pharmacology
Yes (1 or 2 species)
Yes – in Tox studies
Yes (1 species)
Yes – in Tox studies
Single dose/DRF
Repeat dose
Safety Pharmacology
Animal Rule Excipients
Yes or No
Yes or No
Yes or No
Yes or No
- dependent on type of test article
Reformulated or
Yes or No
Yes or No
Yes or No
Yes or No
Yes (1 species)
Yes (1 species)
Horizontal Bar Chart
Single dose/DRF
Repeat dose
Safety Pharmacology
Yes or No
Yes or No
Yes or No
Yes or No
Yes or No
Yes or No
May or may not be needed on the combination. “Traditional” studies should be completed on individual entities.
Single dose/DRF
Repeat dose
Safety Pharmacology
Exploratory Imaging Agents
Yes or No
Yes – in Tox
Juvenile c
Yes or No
Yes or No
Yes or No
Yes or No
Cellular and Gene Therapeutics
Yes (1 or 2 species)
Yes (1 or 2 species)
Yes – in Tox studies
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)
Q3A (R2)
Q3B (R2)
Q3C (R4)
S1C (R2)
S2 (R1)
• S3A
• S3B
Impurities in New Drug Substances
Impurities in New Drug Products
Impurities Guidelines for Residual Solvents
Need for Carcinogenicity Studies for Pharmaceuticals
Testing for Carcinogenicity of Pharmaceuticals
Dose Selection for Carcinogenicity Studies of Pharmaceuticals
Guidance on Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use
Note for Guidance on Toxicokinetics: The Assessment of Systemic
Exposure in Toxicity Studies
Pharmacokinetics: Guidance for Repeat Dose Tissue Distribution
• ICH (Continued)
• S4
• S5 (R2)
• S6 (R1)
• S7A
• S7B
M3 (R2)
Duration of Chronic Toxicity Testing in Animals (Rodent and
Nonrodent Toxicity Testing)
Detection of Toxicity to Reproduction for medicinal Products &
Toxicity to Male Fertility
Preclinical Safety Evaluation of Biotechnology-Derived
Safety Pharmacology Studies for Human Pharmaceuticals
The Non-Clinical Evaluation of the Potential for Delayed
Ventricular Depolarization (QT interval prolongation) by
Human Pharmaceuticals
Immunotoxicology Studies for Human Pharmaceuticals
Nonclinical Evaluation of Anticancer Pharmaceuticals
Photosafety Evaluation
Guidance on Nonclinical Safety Studies for the Conduct of
Human Clinical Trials and Marketing Authorization for
• 3BS11A
• CHMP/SWP/302413/08
• EMEA/194898/2006
• CPMP/SWP/2592/02 Rev 1
Pharmacokinetics and metabolic studies in the
safety evaluation of new medicinal products in
Need for revision of the guideline single dose
toxicity (3BS1A)
Repeated dose toxicity
Repeated dose toxicity
Limits of genotoxic impurities
Reflection Paper on the assessment of the
Genotoxic Potential of Antisense
Carcinogenicity Evaluation of Medicinal Products
for the Treatment of HIV Infection
CHMP SWP Conclusions and recommendations
on the use of genetically modified animal models
for carcinogenicity assessment
• EMEA (Continued)
• CPMP/SWP/2877 /00
• CPMP/SWP/372/01
• EMEA/CHMP/203927/05
• CHMP/SWP/169215/05
• CPMP/SWP/2600/01
• CPMP/SWP/2145/00
• CHMP/SWP/150115/06
Carcinogenic potential
Points to consider on the Non-clinical
assessment of the carcinogenic potential of
human insulin analogues
Risk Assessment of Medicinal Products on
Human Reproduction and Lactation: From Data
to Labeling
Need for Non-Clinical Testing in Juvenile
Animals on Human Pharmaceuticals for
Pediatric Indications
Points to consider on the Need for assessment
of reproduction toxicity of human insulin
Non-clinical local tolerance testing of medicinal
Non-clinical guideline on drug-induced
• EMEA (Continued)
• CHMP/SWP/94227/04
• CPMP/SWP/398/01
• CPMP/SWP/728/95
• CHMP/SWP/28367/07
• CHMP/GTWP/125459/2006
• EMEA/CHMP/SWP/91850/06
• EMEA/CHMP/94526/05
Non-Clinical Investigation of the Dependence
Potential of Medicinal Products
Need for revision of the Note for Guidance on
photosafety testing
Replacement of animal studies by in vitro
Strategies to identify and mitigate risks for firstin-human clinical trials with investigational
medicinal products
Non-clinical studies required before first clinical
use of gene therapy medicinal products
Development of a CHMP Guideline on the NonClinical Requirements to Support Early Phase I
Clinical Trials with Pharmaceutical Compounds
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
• EMEA (Continued)
• EMEA/273974/05
• CPMP/SWP/799/95
• CHMP/SWP/258498/05
• CPMP/SWP/1094/04
• CPMP/SWP/2599/02
• CPMP /3097/02*
Quality, Preclinical and Clinical aspects of Gene
Transfer Medicinal Products - Annex on NonClinical testing for Inadvertent Germline
transmission of Gene Transfer Vectors
Non-Clinical Documentation for Mixed Marketing
Authorization Applications
Non-Clinical Development of Fixed
Combinations of Medicinal Products
Evaluation of Control Samples for Non - clinical
Safety Studies: Checking for Contamination with
the Test Substance
Position Paper on the non-clinical safety studies
to support clinical trials with a single micro dose
Comparability of medicinal products containing
biotechnology-derived proteins as active
substance -annex on non-clinical and clinical
• EMEA (Continued)
• CPMP/SWP/997/96
• CPMP/SWP/465/95
• EMEA/HMPC/107079/07
• EMEA/HMPC/32116/05
Pre-clinical evaluation of anti- cancer medicinal
Pre-clinical pharmacological and toxicological
testing of vaccines
Assessment of genotoxicity of herbal
Non-Clinical Documentation for Herbal Medicinal
Products in Applications for Marketing
Authorization (Bibliographical and Mixed
Applications) and in Applications for Simplified
• 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
• 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
• 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
Applications covered by Section 505(b)(2)

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