Nonclinical Perspective on Initiating Phase 1 Studies for Biological Oncology Products

1
Nonclinical Perspective on Initiating Phase 1
Studies for Biological Oncology Products

• Martin D. Green, Ph.D.
• Supervisory Pharmacologist
• DBOP/OODP/CDER

2
Outline and Purpose of Presentation

• Discuss the review of nonclinical safety data for
  an initial IND
• Present results from an internal review of
  initial INDs for nonclinical information and
  clinical hold decisions
• Currently developing new guidance for nonclinical
  standards for biological oncology
• New molecular structures
• New approaches to treatment of patients with
  cancer
• Presentation today
• Assist in gaining comment on revisions to
  nonclinical recommendations for safety testing
  for biological oncology products and in
  particular on the question of the duration of
  nonclinical studies relative to clinical studies

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Sources for Information to Guide Reviewers and
Assist Sponsors

• ICH S6 Preclinical Safety Evaluation of
  Biotechnology-Derived Pharmaceuticals
• Relevant animal model
• Typically relying on a single species
• ICH M3 Nonclinical Safety Studies for the Conduct
  of Human Clinical Trials for Pharmaceuticals
• Timing and duration
• Early stages should be 1 for 1 in terms of
  duration
• CBER Points to Consider in the Manufacture and
  Testing of Monoclonal Antibody Products for Human
  Use
• Tissue cross-reactivity studies
• In some exceptional cases this information may be
  the sole source of nonclinical safety data
• Pre-INDs
• Outline of nonclinical toxicity studies or
  summary results often discussed and include
  comments on duration and frequency of dosing
• Provides a broad and flexible system

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Process of Evaluating Nonclinical Data for
Scientific and Regulatory Decisions

• Consider selectivity and specificity of
  biological product
• Molecular targeting (site and affinity of binding
  sites)
• Non-specific effects (restricted or unrestricted
  access to tissue sites)
• Evaluate nonclinical data in terms of the
  proposed clinical study. Capability of
  addressing the safety concerns
• Numbers of animals (often varies with species,
  e.g., non-human primates)
• Quantitative and quality of aspects of endpoints
  (during dosing and recovery)
• Range of doses (clinical relevant safe dose vs.
  one that avoids toxicity)
• Duration frequency of dosing (relative to
  proposed clinical study)
• Unique aspects of the clinical situation relative
  to nonclinical testing
• Special conditions, e.g., wound healing model for
  anti-angiogenesis biologicals

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Process of Evaluating Nonclinical Data for
Scientific and Regulatory Decisions

• Analysis and extrapolation
• Was data adequate in terms of route of
  administration, dosing regimen and clinical
  population?
• What concerns remained unaddressed?
• What are the consequences of failing to obtain
  the additional data?
• Means of bridging the gap
• Altering the starting dose
• Modifying the dose escalation scheme
• Increasing monitoring
• Changing the inclusion and exclusion criteria
• Primary objective is to determine whether the
  clinical study can go forward safely with the
  available data

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Toxicology Study

• Primary means of assessing safety prior to
  clinical experience
• Widely understood industrial standards
• Comprehensive approach examining various levels
  of effect
• Inter-relationship between frequency of dosing,
  dose (systemic exposure) and expression of
  toxicity
• Monitoring
• Reversibility
• Represents a resource issue for some development
  plans often in terms of time
• Limitations
• Development of anti-product antibodies in test
  animals
• Neutralization, carrier formation, blocking
• Changes in pharmacokinetics and access to various
  organs
• In rare instances human unique no available
  animal model
• Differences in disposition based on receptor
  expression and extrapolation of pharmacokinetics
  (allometric principles)

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Factors Considered in Adequacy of Nonclinical
Studies to Support Clinical Trials

• Dose
• Sufficiently high to reveal potential adverse
  effect or
• Provide sufficient multiples of the intended
  clinical dose
• Adequate number and timing of doses
• Pharmacokinetics long half-life, accumulation,
  steady-state, access to deep compartments
• Clinical dosing regimens are typically
  accumulative and require long periods of time to
  achieve steady-state conditions
• Receptor modulation up- or down-regulation,
  e.g. IL12
• Adequate duration to express toxicities
• Immediate acting (direct cell lysis or death,
  e.g. ricin conjugates)
• Longer acting
• Effects on cellular pools with slow turnover
  (e.g. skin) or
• Physiological reserves (e.g. immune ablation and
  susceptibility to infection)

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IND Database

• Time period of July 2001 through Nov 2005
• Continuous series of 51 INDs
• INDs were included if
• NME
• Proposed as anti-tumor agents
• INDs were excluded if
• Single patient INDs, Emergency INDs
• Radiolabeled therapeutic
• Approved products
• Diagnostic or supportive use only

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Mechanisms of Action

• Represented in the database
• Blockade ligand binding
• Complement dependent cytotoxicity
• Antibody dependent cell-mediated cytotoxicity
• Apoptosis induction
• Disruption of signaling
• Inhibition of angiogenesis
• Toxin-mediated killing
• Antagonist receptor activity
• Agonist receptor activity
• Not used as a classification for the database
• Multiple potential actions
• Evolving understanding

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Sources of Data Analyzed in the data base

• Pharmacology and Medical Reviews
• Official correspondence
• Divisional files
• Biological Information Management System (BIMS)
• Original Submissions
• As available at the time the original IND was
  submitted or within the 30 day period of review
  prior to a final decision

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NMEs

• 51 NME products
• Products comprising the data base
• Monoclonal antibodies, N 37 (73)
• Fusion proteins, N 8 (16)
• Cytokines, N 2 (4)
• Other, N 4 (8)
• Data elements
• Nonclinical study duration (estimate of exposure)
• Frequency of nonclinical dosing (most often to
  match clinical dosing regimen but in some few
  cases to make-up for duration)
• Issues related to clinical holds
• Safety concerns based on pharmacology and
  toxicology data
• Proposed and actual clinical holds

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Nonclinical Toxicology Studies by Study Duration
Submitted in Initial INDs

• Nonclinical studies of 1 week to 4 weeks
• 41 of initial INDs
• Most commonly performed nonclinical study
• Nonclinical studies gt4 weeks to 3 months
• 27 of initial INDs
• Nonclinical studies lt1 week
• 25 of initial INDs
• Nonclinical studies gt3 months
• 4 of initial INDs
• No toxicity studies performed
• 4 of initial INDs

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Duration Nonclinical -Toxicology Study vs.
Clinical Study

• Duration ratio
• Defined as the days of the nonclinical dosing
  divided by the proposed days of clinical dosing
• Calendar days
• Does not consider number of doses administered in
  the period to time
• Mean 4.5
• 95 Confidence Interval of 8.64 - 0.42
• Average initial INDs contained 4 to 5 times more
  nonclinical days of exposure to biological
  product compared to proposed clinical dosing
• Wide range often reflects intended duration of
  clinical study

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Number of Doses - Nonclinical Toxicology Study
vs. Clinical Study

• Number of doses ratio
• Defined as the number of nonclinical doses
  divided by number of proposed clinical doses
• Nonclinical dosing regimen tended to match
  proposed clinical dosing regimen
• Mean of 1.6
• Range 0.27 to 7
• Nonclinical studies on averaged closely
  approximated the frequency of dosing in the
  proposed clinical study
• Higher dosing ratios were not problematic
• Lower dosing ratios were often regarded as under
  dosed relative to the clinical dosing regimen
• Animals often have increased rates of clearance
• Production of anti-product antibodies was not a
  confounding variable in this series
• Formulations in nonclinical studies were similar
  to those proposed clinically

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Clinical Hold Decisions

• A majority of potential hold concerns involved
  chemistry (CMC), clinical and/or
  pharmacology/toxicology were resolved prior to 30
  day date
• Additional information provided by sponsor
• Modification of clinical protocol
• Increased monitoring
• Staggering of dose cohorts
• Inclusion and exclusion criteria
• Dose escalation scheme

16
Continuation of Clinical Dosing Beyond
Nonclinical Testing

• Continuation allowed based on
• Acceptability of toxicities
• Reversible
• Degree of potential harm clinically manageable
• Ability to monitor
• Occurred in approximately 90 of IND when
  requested

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Proposed Clinical Holds and Pharmacology and
Toxicology Concerns

• Involved 9 INDs
• Less than half of the holds were resolved in
  discussions and modifications with the sponsor
  during review cycle
• Four involved adequacy of duration
• Often pharmacology and toxicology concerns
  accompanied concerns of other disciplines, e.g.
  clinical aspects of study or issues related to
  chemistry (CMC)

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Examples of Safety Concerns Related to
Pharmacology and Toxicology in Proposed Clinical
Holds

• Lack of stability of investigational biological
  product used in the toxicity study
• Failure to demonstrate anticipated binding
  pattern in the human tissue cross-reactivity
  study
• Potential clinical risk revealed by animal
  findings and inability to provide adequate
  monitoring and provide emergency care in the
  clinical study
• Preclinical data suggesting tumor stimulation

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Actual Divisional Holds

• Of 13 of the actual clinical holds, 6 involved
  pharmacology and toxicology issues
• Four were primarily based on concerns related to
  pharmacology and toxicology
• Three of these involved duration
• Their average duration ratio was 0.3
• These INDs used frequency of dosing in the
  nonclinical studies approximated the proposed
  clinical dosing
• Involved clinical proposals for continuous dosing

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Examples of Safety Concerns Related to
Pharmacology and Toxicology - Actual Clinical
Holds

• Example A 3 month toxicology study
• Failure to use a relevant animal species
• Toxicity study considered invalid
• Human tissue cross-reactivity study failed to
  demonstrate anticipated binding pattern
• Technically unacceptable
• Example B 2 month concern based on member of
  class exhibiting toxicity at times gt2 mo product
  contamination issue
• Concerns based on the relationship of toxicity
  and duration are subject of the subsequent
  presentation

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Conclusion and Summary

• Assessing clinical risk from nonclinical studies
• Evolving over time
• Increasingly complex
• Current approach to assessing of safety from
  nonclinical studies
• Flexible and broad standards
• Based on general guidances for biotechnology
  products
• In the future there will be a nonclinical
  guidance on biological oncology products

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Conclusion and Summary

• Review of recently submitted biologic INDs
• Regarding clinical holds for initial INDs,
  toxicity testing was a component in approximately
  50 of the holds and a major component in
  approximately 30 of the holds
• In approximately 90 of clinical studies allowing
  continuous dosing was contingent on
• Clinical population
• Actual and perceived risks
• Acquisition of additional nonclinical data
  concurrent with the clinical study