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

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 Short term Rx trials
Advantages: Evaluate as single agent, opportunity for dose escalation, quick
Disadvantages: Doesn’t 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
10% Worse
No Difference
10% Better
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: Doesn’t 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 Design Endpoints 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 can’t 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