Assessment of Preclinical Data for Safety - PDF by jfn37636


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									      Elizabeth M. Sutkowski, Ph.D.
Office of Vaccines Research and Review

   4th Meeting on Novel Adjuvants
  23 - 25 June 2003, Annecy, France
• Key components in non-clinical safety
• Challenges in toxicity assessments for
• Initiatives to address non-clinical safety
  evaluation programs
• Current CBER approach to toxicity
  assessments for adjuvants and adjuvanted
• How is the regulatory process evolving ?
• Preclinical safety assessment
  – Includes product characterization, animal safety testing
  – Prerequisite to the initiation of clinical trials

• Non-clinical safety assessment
  – Preclinical safety assessment plus safety assessments
    during various stages of clinical/ product development
     • If significant changes to the product manufacturing
       and/or formulation are made
     • To evaluate potential safety concerns from Phase 1
       and Phase 2 clinical trials
• Novel products - those that belong to a new
  product class for which there is little or no prior
  clinical experience

• New products - those which have undergone
  significant changes in the production process;
  previously licensed products administered by a
  novel route and/or for a new indication;
  previously licensed products formulated with
  novel adjuvants or excipients

  *OVRR regulates preventive vaccines and
  therapeutic vaccines for infectious
  disease indications
• Adjuvant – an agent that augments specific
  immune responses to antigens
  – Numerous investigational studies with novel adjuvants
  – Alum, cytokines, IFA, MPL, liposomes, toxins, QS-21

• Use in licensed vaccines
  – Limited to aluminum-derived adjuvants (in US)
  – A specific antigen/adjuvant formulation is licensed
  – Adjuvants alone are not licensed; are regulated as
    constituent materials
• 21 CFR 610 - General Biological Product
  –   Lot Release/Certificate of Analysis
  –   Potency
  –   General Safety/Abnormal Toxicity
  –   Sterility/Bioburden
  –   Purity - moisture, pyrogenicity
  –   Identity
  –   Constituent Materials (Adjuvants):
       • All ingredients shall meet accepted
         standards of purity and quality: Certificate of
         Analysis provided to IND (or a X-referenced
         Drug Master File)
       • Adjuvant may be included if no adverse
         affect on safety or potency (21 CFR 610.15)
• Product characterization          • In vitro studies
• Manufacturing process             • Animal safety studies
                                       – Immunogenicity
   – Starting materials
                                       – Challenge/Protection Studies
   – In-process controls for
                                          (If animal models exist)
                                       – Pyrogenicity testing
   – Validated process
                                       – Neurovirulence testing
                                       – Reversion to virulence
   – Consistency in manufacture
   – Lot release
      • Adequate specifications        – GLP Toxicity Study To Support
      • Purity, potency, identity        Phase 1 (certain products)
                                       – Devel Tox for Pregnant Women
   – Stability
– Immunization of pregnant women
– Novel adjuvants
– Novel route of administration
– Adverse effects observed in clinical trials
  • Potential toxicity of vaccine assessed in non-
    clinical trials designed to replicate specific
    clinical events
• Historically, toxicity testing has not always been
  part of vaccine development
• Vaccines administered to healthy individuals
  including pediatric population
• Progress in biotechnology has resulted in broad
  range of vaccine products
• Increased focus on non-clinical safety
  assessment including toxicity testing
• ICH S5a Detection of Toxicity to Reproduction for
  Medicinal Products, 1994
• ICH S6 Preclinical Safety Evaluation of
  Biotechnology-derived Pharmaceutical, 7/1997
• CPMP Note for guidance on preclinical
  pharmacological and toxicological testing of
  vaccines, 6/1998
• US FDA Guidance for Industry: Considerations
  for Reproductive Toxicity Studies for Preventive
  Vaccines for Infectious Disease Indications,
• K. L. Goldenthal, J.A. Cavagnaro,
  C.R. Alving, and F.R. Vogel; Safety
  Evaluation of Vaccine Adjuvants:
  National Cooperative Vaccine
  Development Meeting Working
  Group; AIDS Res. Hum. Retroviruses,
  Vol. 9: S47-51, Suppl. 1, 1993
• Uncertainty regarding applicability of currently
  available documents for preventive vaccines
• Uncertainty whether toxicity testing should
  always be part of product development?
• Uncertainty regarding timing of toxicity studies,
  if needed
• Uncertainty whether toxicity testing standards
  developed for conventional drugs applicable for
• Vaccines - complex, diverse class of
  biological products

• Act through complex mechanism
  whereby the product itself is not the
  final triggering component; elements
  of the immune system are the
• Potential inherent toxicity of the
• Potential toxicity of impurities or
• Potential toxicity due to interaction
  of components
• Potential toxicity linked to the
  immune response to the vaccine
• Framework needed for non-clinical safety
  testing of preventive vaccines
  – Use existing documents as a base to develop
• Goals
  – Make regulatory recommendations and/or
    requirements more transparent
  – Facilitate discussions between regulatory
    agencies & sponsors
  – Promote relevant and consistent non-clinical
    testing and reviews

• Formation of a Working Group:
  – “Preclinical Safety Testing of Preventive

• Develop written guidance:
  – CBER Reviewer Document: “Preclinical
    Toxicity Studies for Vaccines to Support
    Initiation of Clinical Studies”
  – “Guidance for Industry Document: Non-
    clinical Safety Evaluation of Preventive

• CBER Reviewer Document
 – Clarify for what product types preclinical
   toxicity assessment is needed
 – Clarify timing, extent, and approaches to
   design of preclinical safety studies to support
   initiation of clinical trials
 – Describe the extent of preclinical study
   documentation required prior to initiation of
   clinical trials
CBER Reviewer Document
– Need for preclinical toxicity study
  depends on risk/benefit consideration,
  target population, ROA, available
  clinical data from the use of related
  products, product features (novelty),
  availability of animal models
– Scientific judgment should be the basis
  for decision
      When to Conduct Toxicity
   Assessments to Support Phase 1
          Clinical Trials ?

• “Likely Yes”       • “Likely NO”

  – Novel adjuvant     – Product category
  – Toxic adjuvant       (well characterized)
  – Novel product        with extensive
    class                clinical experience,
                         usually already
  – Novel ROA            licensed
       Considerations for Toxicity
             Study Design

• Adequate to identify/characterize toxic
• No one study design for all product
• Parameters to be considered:
  – Animal species/strain; clinical plan - dosage
    form, dose, routes of exposure, frequency of
    exposure, devices; product features, previous
• Evaluation of potential toxic effects:
  – Target organs, reversibility of observed toxic
• Dedicated stand alone toxicity study or in
  combination with safety/immunogenicity
• Use route of administration and dose
  intended for human use
• Episodic dosing, total number of doses
  exceeds number for human use
• Use intended delivery device, if possible
• Mimick but also maximize exposure
  – Multiple dose toxicity studies for adjuvant
    alone and antigen/adjuvant combination
     • Dose per injection equal or exceed human
     • Total number of doses (episodic) equal or
       exceed number intended in humans
     • Cumulative dose in animals>intended
       human dose
• Immunogenicity
• Clinical assessments (general health, body weight,
  food consumption, injection site observation, limb
  use impairment)
• Serum chemistries including liver and renal function
  tests (ALT, AST, creatine kinase, BUN)
• Hematologic analyses (CBC and differential)
• Injection Site Histopathology (Inflammatory reactions)
• Terminal procedures (necropsy-organ description,
  weights, select histopathology) at 2-3 days and 2
  weeks after last injection (allowing for a recovery
• Good Laboratory Practice (GLP, 21 CFR 58.1)
CBER Reviewer Document
– Prior to initiating Phase 1 clinical trials
– Discuss with CBER/reach agreement prior to
  or during pre-IND meeting
   • Provide adequate information on clinical
– Submit toxicity protocols for CBER review
  prior to initiation of animal studies
– Submit toxicity study report in original
  submission to the IND
   • Full tabulation of data, line listings, well
     organized tables
– Additional toxicity studies may be necessary
  as product/clinical development continues
  Workshop on Non-clinical Safety Evaluation
   of Preventive Vaccines - December 2002

• To reach a consensus on the most appropriate non-
  clinical methods for safety assessment of
  investigational new vaccine products
   – Animal models
   – Applicability of acute and repeat dose toxicity study
     designs for vaccines?
   – Criteria for selecting the appropriate ROA, doses,
   – Endpoints
   – Necropsy timepoints
   – Toxicity studies for adjuvants
   – Alternative methods
 Questions Regarding Animal Models
• What are the considerations for choosing
  a relevant animal model beyond the ability
  to elicit an immune response?
  – In general, one species is adequate; non-
    human primates not generally necessary
  – Choose species in which antigen is
    immunogenic and adjuvant augments immune
  – Evaluate quality of immune response, if
  – Ideally, evaluate in animal model that allows
  – Additional Considerations (e.g., use of naïve
    versus partially immune or immune animals)
    Questions Regarding Animal Models

• If a relevant animal model does not exist,
  should a vaccine toxicity study still be
  conducted (to look for intrinsic toxicity of
  antigen/adjuvant, contaminant, or

  – Yes
• Should the safety evaluation of adjuvants
  be considered separately and in the
  context of the final vaccine?

• If so, are "drug" evaluation guidelines
  more appropriate for the adjuvant stand
  alone study?
  When novel adjuvant + antigen
  combination proposed:
• Evaluate relevant vaccine/adjuvant formulations
  in preclinical GLP safety studies:
   – Vaccine product with and without adjuvant in
     preclinical studies (demonstrate immunologic
     benefit of adjuvant)
   – Antigen/adjuvant formulation intended for
     clinical use
• Develop safety profile for new adjuvant alone if
  no existing Master File equivalent
   – These studies may be more “drug-like”
• Toxin adjuvants (mutants and derivatives)
  need to be evaluated alone in humans
  prior to evaluating antigen/toxin adjuvant
• Ideally should assess antigen/adjuvant
  combination vs. saline placebo and vs.
  adjuvant alone
• Should demonstrate immunologic benefit
  of adjuvant early in clinical development

• “Guidance for Industry: Non-clinical
  safety evaluation of preventive vaccines”
  –   Live, attenuated vaccines
  –   Vector vaccines
  –   Inactivated vaccines
  –   Subunit vaccines
  –   Nucleic acid vaccines
  –   Combination vaccines

  – Adjuvanted vaccines
  – Products given by novel route(s)
• Toxicity testing as part of non-
  clinical safety evaluation program for


• CBER to continue using science-
  based, case-by-case approach
• Non-clinical safety assessment is a key
  component in vaccine development

• Toxicity testing is requested as part of non-
  clinical safety evaluation program for certain
  products, e.g., novel adjuvants

• Approaches to toxicity assessments that are
  specific for vaccines will need to be optimized
   – Prevent generation of non-interpretable data
   – Prevent unnecessary use of animals
   – Prevent delay of product development

• Vaccine-specific guidance for non-clinical safety
  assessment of vaccines is being developed
• Web:
• Fax: 1-888-CBER-FAX

• Division of Vaccines Applications (OVRR)
          Phone: 301-827-3070
• 21 CFR 312 - IND Regulations
  – 312.23(a)(7) - Chemistry/Composition, Manufacturing and
    Control Information
     • Assure proper identification, quality, purity, and
       strength of investigational drug
     • Stability for the planned duration of the trial

  – 312.23(a)(8) - Pharmacologic and Toxicologic Studies
     • In vivo or in vitro studies to conclude that proposed
       clinical studies are reasonably safe (GLP)

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