1. Methods to Adjust Doses Based on Exposure-Response Information Points to Consider Richard Lalonde Clinical Pharmacokinetics and Pharmacodynamics Pfizer Global Research and Development Ann Arbor Richard Lalonde Clinical Pharmacokinetics and Pharmacodynamics Pfizer Global Research and Development Ann Arbor

2. Richard Lalonde, CPS Meeting 10-20022  Generally very supportive of the Agency’s attempt to standardize methods for dose adjustments based on E-R data  More consistency across sponsors and across therapeutic groups at FDA  Once a consensus is reached on some key details, sharing this information as part of a guidance or other means should help sponsors/FDA implement the approach  Studies have demonstrated that labels are not very effective at preventing drug interactions (terfenadine, cisapride, mibefradil)  What other measures should we (FDA, industry,etc.) consider to increase the effectiveness of the dose adjustments recommended in the label Overall Comment

3. Richard Lalonde, CPS Meeting 10-20023 Proposed Decision Tree for Dosing Adjustment Recommendations (Peter Lee et al) Is PK/PD available ? Default goal post for AUC and Cmax Can “no effect boundaries” be defined based on E-R ? If the 90% CI of test/ref is within the boundaries y n No dose adjustment Dosing adjustment, precaution, or warning yn y n ?

4. Richard Lalonde, CPS Meeting 10-20024  Without adequate PK-PD data, then default to 80 – 125%  With PK-PD data, possibly define another boundary  The former is typically based on a mean change and the 90% confidence for this estimate  The latter is based on the distribution of exposure and E-R relationship in the population Proportion of patients with response above a critical level Includes components of variability that are not included in the usual criterion based on the mean  Approach based on distribution of response in the population seems logical  Would like to see more examples that include PK variability and E-R variability in setting the no-effect boundary Proposed Decision Tree and No-Effect Boundaries

5. Richard Lalonde, CPS Meeting 10-20025 Proposed Standard Outputs of E-R Results (Peter Lee et al) Exposure Response Variable Frequency reftest E+  Response Frequency reftest Probability of clinical significant response = Exposure

6. Richard Lalonde, CPS Meeting 10-20026  Questions about some practical aspects of the proposed method How to select the critical fraction of patient, while taking into account the selected critical level of response and the risk/benefit for particular drug/therapeutic indication Estimates of tails of distributions less precise than means  Balance between greater risk and greater efficacy Utility or cost function  When a consensus is reached on the above, it would seem reasonable to share the guidelines with industry to foster greater use in regulatory submissions  Promote modeling of E-R relationship for key responses in Phase 2/3 trials (clinical outcomes, desired and adverse effects) Recent gabapentin example and its impact on regulatory decision Points to Consider

7. Richard Lalonde, CPS Meeting 10-20027  Current labels generally report effects of intrinsic/extrinsic factors without necessarily making a recommendation about dose adjustments  Are we looking to make a change and offer a dose recommendation for all studied factors?  Default 80 – 125% goalpost is quite conservative and maybe that is fine to claim that a dose adjustment is not needed Mean change generally < 10% for the 90% CI to be within 80 – 125%  What would be the dose adjustment, if any, for the following situations based on the default goalpost of 80 – 125%? Mean test/reference ratio90% CI 10365 – 160 119107 – 133  Should the dose adjustment take into account the patient’s current dose (i.e. low dose versus maximum recommended dose) Points to Consider for Dosing Adjustments

8. Richard Lalonde, CPS Meeting 10-20028  Trials performed under the current pediatric regulations  Propose that sponsors be allowed to provide pediatric clinical PK information in an appropriate section of the label even if a pediatric indication is not approved With appropriate wording about the lack of demonstrated benefit in children for a particular indication PK information could provide information to clinicians who chose to use the drug off label  Similar to other intrinsic/extrinsic factors in the label for which we provide PK information without specific evidence of safety/efficacy Renal impairment, drug interactions  Off label use is very common in pediatrics (EJCP 2002;58:292-7)  Consistent with the spirit of the pediatric regulations aimed at generating data to guide clinical use of drugs in children Pediatric Dosing Recommendations and “Negative” Efficacy Trials

9. Richard Lalonde, CPS Meeting 10-20029  Generally very supportive of the Agency’s attempt to standardize methods for dose adjustments based on E-R data  More examples to better understand the properties of the proposed method to define no-effect boundaries  What other measures should we consider to increase the effectiveness of the dose adjustments recommended in the label Summary