How Do I Get Into Phase 1 Trials With My Compound?

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 isnt 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 FDAs finding of safety and effectiveness of a
  previously approved drug product. The division
  will critique the plan and provide guidance.

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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

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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.

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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

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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

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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.
• .

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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.

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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

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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

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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.

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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.

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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.

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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 FDAs 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.).

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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.

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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?

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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.

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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.

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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

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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

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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

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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

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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

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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
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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
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 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
c May or may not be needed in the juvenile
animal. Traditional studies should be
completed in the adult animals.
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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 (lt 40 AA)

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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)

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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

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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

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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)