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Issues in TB Drug Development: A Regulatory Perspective

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Issues in TB Drug Development: A Regulatory Perspective Mark J Goldberger MD MPH Center for Drug Evaluation and Research US Food and Drug Administration – PowerPoint PPT presentation

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Title: Issues in TB Drug Development: A Regulatory Perspective


1
Issues in TB Drug Development A Regulatory
Perspective
  • Mark J Goldberger MD MPH
  • Center for Drug Evaluation and Research
  • US Food and Drug Administration

2
Safe and effective
  • Substantial evidence from adequate and well
    controlled studies so that a physician qualified
    on the basis of training and experience could
    reasonably conclude that the drug has the effect
    claimed in labeling

3
No added value
  • There is no requirement that a drug be better
    than what is already available either by safety
    or efficacy. Ultimately it must be efficacious
    and appropriately safe.

4
The Need for New Therapies
  • Drug susceptible disease
  • Shorten duration of therapy
  • Decrease total number of doses
  • These goals will impact design and analysis of
    the trials
  • Drug resistant disease
  • Improve outcome of therapy

5
Drug Class
  • Existing class used in TB Rx
  • Design of experimental regimen should be easier
  • Dose size, frequency and treatment duration still
    an issue
  • New class not used previously for TB Rx
  • Pre-clinical info on activity more important re
    design issues
  • Dose size, frequency and treatment duration still
    an issue

6
How Do We Decide What to Do?
  • Rationale
  • Resources Required
  • Public Health Implications
  • Pre-Clinical Data
  • In vitro Testing
  • Cellular Models
  • In vivo Testing
  • What properties of potential therapies should we
    try to assess in these models?
  • Early Killing
  • Sterilizing Activity
  • Usefulness in Combination

7
Design of Pre-Clinical Experiments
  • Appropriate model
  • Dose range to focus on achievable and tolerable
    human exposure
  • Combinations studied to reflect likely regimens
    in people

8
What is the Role/Requirement for Early Human Data?
  • Pharmacokinetics
  • Identify candidate drugs for less frequent
    dosing i.e new rifamycins
  • Explore drug interactions assess Q-T
    prolongation
  • Early Bactericidal Activity - EBA (and related
    approaches)
  • Initial evidence of activity in humans
  • Safety Tolerability
  • Multiple Dosing
  • Use in HIV Patients

9
Pilot Studies
  • EBA and related trials
  • Advantages Evaluate as single agent, opportunity
    for dose escalation, quick
  • Disadvantages Doesnt assess sterilizing
    activity, pk issues, reproducibility
  • Short term Rx trials
  • Advantages Opportunity to assess sterilizing
    activity, effect in multi-drug regimens, at what
    point can we predict clinical activity?
  • Disadvantages Multi-drug regimens, more resource
    intensive, requires sufficient data to support
    rationale

10
Safety Considerations
  • Is the product previously approved?
  • If so will dose and duration be substantially
    different?
  • If not additional preclinical and clinical safety
    data needed
  • Diversity of population
  • Sex, race, age, underlying medical conditions
    including HIV
  • Adequate duration of exposure at proposed dose
  • Sufficient number of subjects in safety database

11
Drug Susceptible Disease
  • Standard Regimen INH, RIF, PZA, frequently SM
    or EMB
  • Highly successful but with limitations
  • Prolonged therapy (6 mo.)
  • Many doses required
  • Each drug contributes to the regimen
  • Early activity
  • Sterilizing ability
  • Prevention of resistance

12
Phase III Trials
  • Design developed from earlier data
  • Add or substitute new drug
  • Dose size, frequency of dosing, duration
  • In all situations good follow-up of patients
    essential
  • Demonstrate contribution of new drug
  • Outcome
  • Treatment duration
  • of doses
  • Alternative endpoints
  • Validation
  • Timing 2 mo, 6 mo, 6 mo after Rx, 2 yrs after Rx
  • Goal
  • A label that describes safe and effective use of
    the drug

13
Susceptible Disease Current Approaches
  • Intensive Phase of Rx (8 weeks)
  • INH, RIF, PZA, SM/EMB, daily or daily then BIW
  • Continuation Phase (16 weeks)
  • INH, RIF administered BIW
  • We can Substitute or Add a new therapy to the
    above whichever we do, we must be able to show
    the contribution of that therapy to the regimen.

14
Substitution
  • INH, RIF, PZA, (SM/EMB) vs. X, RIF, PZA
    (SM/EMB)
  • This could test superiority or equivalence.
    Different amounts of prior data would be required
    depending upon the proposed change
  • We might substitute for any of the components
    interpretation may be difficult when substituting
    for SM/EMB.
  • In the above example, establishing the
    contribution (usefulness) of X might be
    (surprisingly) difficult.

15
Addition
  • INH, RIF, PZA, (SM/EMB) vs. INH, RIF, PZA,
    (SM/EMB) X
  • The investigational arm needs to be superior in
    some way. This need not mean a higher cure rate
    (which would be difficult), but a similar success
    rate with a shorter overall duration of treatment
    or with less frequent dosing.
  • Whether SM/EMB should be used in this type of
    trial should have prior discussion.

16
Can Multiple Unapproved Agents Be Used Together?
  • No fundamental regulatory prohibition (FDA)
  • Many practical issues
  • How to determine that each product contributes to
    efficacy
  • How to sort out safety profiles
  • Would need to be labeled for use in combination
  • If one or some products already approved for TB
    or other indication the path forward may be easier

17
Endpoints (I)
  • In an equivalence trial what is our level of
    comfort regarding acceptable differences in
    efficacy of the investigational and standard Rx?
  • This is calculated by computing the 95
    confidence interval around the difference between
    treatment arms.
  • Factors which influence the results of this
    calculation include
  • Observed responses
  • Number of patients studied
  • Number of patients lost to follow

18
Similarity or Equivalence
Investigational Drug
No Difference
10 Better
10 Worse
Similar
Similar
Not Similar
19
Endpoints (II)
  • Standard Relapse rate (microbiologic) two years
    after completion of Rx.
  • Advantage This is what we want to know
  • Disadvantage Long delay in getting results
  • Alternative An endpoint collected during or soon
    after the completion of therapy - surrogate
    endpoint
  • Advantage Information available sooner
  • Disadvantage Uncertainty about correlation with
    long-term result

20
Alternative (Surrogate) Endpoints (I)
  • Sputum conversion rate at two months
  • Advantage Data available very early
  • Disadvantage Not influenced by therapy
    administered after measurement
  • Sputum status at end of therapy
  • Advantage Data available early
  • Disadvantage Doesnt work

21
Alternative (Surrogate) Endpoints (II)
  • Sputum Status Six Months After Completion of Rx
  • Advantage Some data to suggest many relapses in
    short course chemoRx occur early
  • Disadvantage Data available somewhat later (but
    still earlier than two years)

22
MDRTB
  • Previous info
  • Pre-clinical data
  • Drug susceptible patients
  • Design
  • Randomized trial
  • Historically controlled trial
  • Endpoints
  • Time of sputum conversion
  • Ultimate success

23
Clinical Trials in Drug Resistant Disease
  • Standard Design X plus best available therapy
    vs. best available therapy
  • Issue Probably cant be done given outcome with
    current Rx
  • Alternate Design X plus best available therapy
    vs. historical controls
  • Issue Applicability of historical controls
  • HIV Status, Overall level of care etc.
  • A powerful drug might fare well under the
    alternate design but detecting the contribution
    of a drug of more modest activity may be
    difficult.

24
Other Issues
  • Need for Data in Women, Children, HIV Patient
    Groups.
  • Usefulness of Foreign Study Data
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