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

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…

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.

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

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

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

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

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

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

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

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

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

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.

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.

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.

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

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

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

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

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

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)

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

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.

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