# Presentation: 271032

## PhRMA Commentary

- An Industry Perspective
- Alan Goldhammer, PhD
- Deputy Vice President, Regulatory Affairs, PhRMA

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## General

- PhRMA welcomes discussions on use of NI* trials
- These are often required in antibiotic development
- A well-developed guidance will be helpful to sponsors
- However, PhRMA has concerns with the FDA proposal in two broad areas
- Lack of detail on practical designs for NI studies using available assessment criteria for antibiotic indications
- Decision that agreed SPAs may no longer be valid
- Concerns outlined in detail in our 8 Feb 08 letter regarding the draft NI guidance
- Today’s comments focus on CAP study design
- CAP highlights all key issues regarding NI studies

**non-inferiority*

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## The big picture

- Collaboration among industry, regulatory agencies, & clinicians is key to bringing new drugs to patients
- Trials in CAP play an important role in this contribution
- CAP trial design challenges have been identified
- Data supporting efficacy must be credible
- Path forward must offer feasible approach to CAP
- Demonstrating efficacy in CAP has been, and will be, fundamental  to the development of new antibacterials
- Clarity is needed urgently

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Two kinds of NI-based approaches in CAP are required

- Routes to study of more severe (inpatient, IV) & less severe (outpatient, oral) CAP are required
- Oral agents are important for overall cost reduction
- Not all agents can be developed both IV and PO
- Existing data and known endpoints must be used
- At least for now, we must use existing tools
- New tools may be possible but should be viewed as an extension of current approaches, not a replacement
- Feasible trial sizes & study durations are required

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Superiority-based approaches are not feasible for CAP

- Superiority designs based on withholding active therapy are not feasible because of ethical and safety concerns for patients
**Placebo-controlled studies are not possible**
- Delayed therapy approaches are also not acceptable
- Dose-ranging studies offer only limited help
- Requiring clinical superiority is also wrong
- New drugs are needed to address resistance
- But, comparative efficacy can only be tested versus isolates that are not resistant to the comparator: The new drug is effectively handicapped relative to old

**See appendix for more on why placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Acceptable approaches can be defined using current data

- Although imperfect, two broad routes do exist
- More severe: Clinical response, including mortality
- Less severe: Clinical response alone must be used
- Clinical response is a valid endpoint
- Approach used to date1 detects drug differences
- Exposure-response analyses also show differences
- A consensus effect size estimate is possible
- Most modern agents could be the comparator
- Historical data are limited to old agents at low doses
- Properly dosed modern agents have similar efficacy

*1**Test of cure at ~7 days after the end of therapy*

**See appendix for additional exposure-response data**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Severity categories should be approached carefully

- Analyses of data based on PORT1 (or CURB-652) categories may be misleading
- These tools focus on predicting need for hospitalization
- They are heavily driven by age
- They may underestimate severity in younger patients
- More useful approaches include
- Clinical: More severe vs. less severe – ATS guidelines3 offer a plausible approach
- Microbiological: Untreated *S. pneumoniae* has a high risk of poor outcome, even if initial clinical picture is good

*1**Fine, N Engl J Med 336:243-50, 1997; **2**Lim, Thorax 2003 58:377-82, 2003; **3**Mandell, Clin Infect Dis 44:S27-72, 2007*

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Updated statistical approaches may also prove helpful

- Traditional non-inferiority statistical approaches
- Employ arbitrary targets (e.g., 50% effect retention) and are very conservative
- Do not focus on the real goal of demonstrating efficacy relative to placebo
- Alternative ideas now understood, such as
- “Effect retention likelihood” discussed in Oncology
- Flexibility is needed in the guidance to permit use of such techniques where appropriate

**See appendix for a further discussion of statistical approaches**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Making progress depends on...Making progress!

- Lancet 8:209, 2008 (Anonymous editorial)
- “The practicalities of running trials and encouraging industry participation in antibiotic development should not be forgotten in the desire for theoretical perfection.”
- Routes to non-inferiority CAP studies would
- Maintain industry momentum in antibiotic discovery
- Provide convincing support for registration
- Provide convincing support for validation of new tools such as patient-report outcome tools
- We can’t advance unless we create such a path

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Failure is not an option

- Drug discovery & development takes years
- Once the epidemic of drug resistance is fully upon us
- There will be no time left
- To have drugs in 10 years
- We must start now
- No choice but to study future drugs in today’s context
- CAP is a key indication for anti-infectives
- Lack of feasible development paths will drive further removal of resources from antibiotic development

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Much is at stake

- It is critical that we get this right
- We should not
- Decide from a single viewpoint
- Make the road forward too narrow
- Voltaire: *The perfect is the enemy of the good*
- Sound, well-supported options do exist
- We must not replace a working, albeit imperfect, process with an unproven approach that also discourages future drug development
- Clarity is needed urgently
- Regulatory uncertainty discourages drug development

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Thank you

- Alan Goldhammer, PhD
- Deputy Vice President, Regulatory Affairs, PhRMA

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Appendix

- Supplemental notes on
- The problem of placebo-controlled studies
- Exposure-response relationships
- Alternative statistical approaches

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Placebo-control is not possible (1)

- Reality check: Active therapy is expected!
*“... **all patients with (name of non-fatal disease) do not seek care; hence it is ethical to withhold therapy in a clinical trial ...”*
- But, patients approached regarding a study _did_ seek care
- Attempts to gain IRB approval for placebo in diseases milder than CAP (e.g., sinusitis) have failed
- And for CAP in particular?
- Evidence for an antibiotic effect in CAP is very strong
- Low mortalities in mild & moderate CAP are in era of use of antibiotics
- In short, placebo-controlled CAP studies are not possible
- Whether implied or explicit, any argument or requirement for placebo-controlled studies must be supported by empirical proof of feasibility based on surveys of IRBs, advisory boards, or similar

**Placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Placebo-control is not possible (2)

- Argument that clinical trials inherently include risk of inactive therapy is true but misses a key point
- This is not 3rd-line salvage therapy for a malignancy
- Modern antimicrobials come to Phase 2 having shown
- Ability to kill bacteria in test tube
- Ability to cure infections in animal models
- A dose regimen that is likely to yield these results in man
- Phase 3 then begins with very strong proof of activity
- Risk of failure of selected dose is minimized
- Patients, physicians, and IRBs will demand this

**Placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## What about delayed therapy?

- Delays in initiation of active therapy are sometimes proposed as a route to showing effect
- Concept is that of “rescue therapy”
- This has the same problem as placebo
- Disease can progress rapidly
- Antibiotic therapy known to offer prompt improvement
- This will be unacceptable to patients & IRBs
- As with placebo, arguments or requirements for this must be supported by empirical proof of feasibility based on surveys of IRBs, advisory boards, or similar

**Placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## What about dose-ranging?

- Dose-ranging can show instructive activity trends
- But, showing size of margin versus placebo requires broad outcome range that goes from success to failure
- Such a range of outcomes might occur, but we hope not
- IRBs, patients, and physicians expect that all regimens are predicted reasonably likely to be active
- Some uncertainty will be tolerated, but not too much
- Deliberately inadequate regimens will be rejected
- Response variation of slightly inadequate regimens is not the same as a placebo & does not settle the question at hand
- We should, however, collect PK data and correlate exposure to response (see strong results later from this technique)
- In contrast, broad dose-ranging is used in other diseases
- E.g, find dose inhibiting target enzyme thought driving a cancer

**Placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Why not just study resistant bugs?

- Why not study only resistant isolates & show superiority?
*“**If current drugs work, then we don’t need new drugs”*
*“**If resistance is a big issue, new drugs will easily show their value”*
- It’s not that simple
- Must remove subject from study if infecting isolate found resistant
- Leaving in the study creates bias in effect of the control drug1
- Many isolates are still susceptible to some drug – but which?
- Serious illness  no time for error
- New drug with little resistance will offer value even today
- New drugs offer even more future value
- Current drugs don’t always fail ... yet
- If don’t start until they do fail, we will face a long delivery gap
- No choice but to study future drugs in today’s context

*1**Fleming TR. Controversies in non-inferiority trials. Stat Med 27:317-322, 2008.*

**Placebo-controlled studies are not possible**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Telithromycin exposure & response

- Lodise et al. DMID 52:45-52, 2005
- Telithromycin 800 mg/day for CAP
- Pooled data from two randomized double-blind studies plus two non-comparative studies
- N = 115 treated with telithromycin, organism isolated, and PK data
- S. pneumoniae: 51 (44%), H. influenzae: 30 (26%)
- By CART, probability of success (presumed or proven organism eradication) changed with AUC/MIC
- AUC/MIC > 3.375: 89/97 (92%)
- AUC/MIC < 3.375: 13/17 (76%)

**Exposure-Response relationships**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Exposure vs. time to afebrile:Tigecycline in pneumococcal CAP

**When *****f*****AUC****0-24****:MIC, dichotomized based on this threshold (12.8), was evaluated as a stratification variable in a Kaplan-Meier time-to-event analysis, patients with *****f*****AUC****0-24****:MIC values > and ≤ this threshold showed significant differences in time to defervescence (p = 0.050). **
**As an aside, it is interesting to note how time to resolution in this 2007 study compares to time to resolution in the 1938-39 studies**

- Rubino CM et al. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 17-20, 2007.

- Exposure vs. time to afebrile:Tigecycline in pneumococcal CAP

**Exposure-Response relationships**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Non-inferiority design challenges

- The first objective of an active-control, non-inferiority trial is not non-inferiority
- The true goal is to establish indirectly that a new therapy would have beaten placebo had a placebo-controlled trial been possible
- For effect retention
- A 50% M1/M2 (or any fraction) approach is totally arbitrary
- Application of an non-zero effect retention requirement introduces a different standard for effectiveness
- The standard is therefore determined by trial design, which fundamentally cannot be right
- Further work in this area is needed
- Effect retention is used to adjust for uncertainty
- Other approaches are possible: See next slide for an example

**Statistical design**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt

## Effect retention likelihoodAn updated statistical approach

- Carroll K. Pharmaceut Statist 5:283, 2006: A step-wise approach
- Step 1: Size trial to show indirectly that the new drug would have beaten placebo had a direct comparison been possible
- Step 2: After study done, estimate probability that new drug is superior to placebo
- Step 3: If step 2 confirms superiority to placebo, relative efficacy of new drug vs. control drug is assessed using an effect retention likelihood plot
- Simpler than it perhaps sounds – the paper makes it very clear
- Key point: Analysis is not bounded by desire to retain an arbitrary percentage of the control effect.
- Why 50%? Why not 49%? Doesn’t it depend on the quality of the comparator?
- Instead, you start by knowing that new drug would have beaten placebo
- You then analyze how this looks relative to the actual comparator

**Statistical design**

- PhRMA comments, 1-2 Apr 08 AIDAC.ppt