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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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.

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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

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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

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Similarity or Equivalence
Investigational Drug
No Difference
10 Better
10 Worse
Similar
Similar
Not Similar
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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

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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

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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)

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MDRTB

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

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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.

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Other Issues

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