Authored By: B. V Waghmare

Thursday, October 28, 2010


Methods and Types of Analyses
Several types of resistance analyses can be used to characterize a drug’s resistance profile. Analyses for treatment-experienced patients are more complicated than for treatment-naïve patients. Some analyses are possible only when larger datasets are available. In phase 3, clinical trial datasets can be sufficiently large to study the effect that mutations confer upon drug susceptibility and outcome. Pooling data from several trials can be appropriate (provided the study populations, endpoints, and assays are similar), but should be discussed in advance with the division. To facilitate pooling data, sponsors should attempt to use similar, if not identical, assays during phase 3. Whenever possible, resistance analyses should be prospectively defined, with the caveat that prospectively defining key mutations or susceptibility breakpoints is not always possible. In some cases, retrospective analyses can provide important information in characterizing resistance and cross-resistance.
Because of a large number of potential comparisons, statistical testing can be problematic for analyses of resistance testing and outcome. Sponsors are encouraged to provide resistance analysis plans to the division in advance.
Analyses of virologic outcome by baseline genotype or phenotype should be based on a censored population to assess the effect of baseline resistance on outcome without confounding factors such as early discontinuation because of adverse events. Therefore, patients who discontinue study treatment while suppressed or who discontinue study treatment before confirmed suppression for adverse event, noncompliance, protocol violation, pregnancy, or withdrawal of consent should be censored. Rules for censoring patients who appear to have a virologic response before discontinuation should be discussed with the division. We encourage sponsors to analyze the baseline resistance data by the primary and secondary endpoints used in the trial. Virologic response parameters recommended for analyses include the following, but are not limited to: proportion of HIV RNA below the limit of quantification (e.g., less than 400 or less than 50 copies/mL), proportion less than 1 log10 decrease from baseline, and mean and/or median change from baseline or time average change from baseline at the protocol-specified time points. Sponsors are encouraged to discuss endpoints with the division in advance. All patients should be included in the dataset until the time of censoring. The datasets should include variables for reasons for censoring patients. Refer to Appendix A for further details.
In general, we recommend analyses of baseline genotype and phenotype for all treatment-experienced patients to evaluate baseline predictors of virologic response. In addition, genotypic and phenotypic analyses of samples obtained at baseline and at the time of virologic failure are recommended for all treatment-experienced patients to characterize resistance and cross-resistance.
The following examples reflect suggested analyses for studies in treatment-experienced patients. Sponsors are strongly encouraged to conduct additional analyses and should discuss these analyses with the division before submission of a new drug application (NDA). In most cases, we do not anticipate baseline genotype and phenotype and virologic outcome analyses, as described below, for all treatment-naïve patients. However, circumstances may arise in treatment-naïve patients where analyses of baseline resistance and virologic outcome data are warranted, particularly in the event of unexpected efficacy results. In addition, in select cases, sponsors can propose to collect samples at baseline and at the time of failure on a subset of treatment-naïve patients, for example, when cell culture data indicate that acquisition of a specific single mutation results in a high degree of phenotypic resistance.
We also acknowledge for various analyses the number of patients in certain subgroups may be limited and as a result definitive conclusions regarding specific baseline factors will not be possible.


Drug Resistance Assay and Antiretroviral drug development guidance--->

A. Mechanism of Action
B. Antiviral Activity in Cell Culture
C. Cytotoxicity and Therapeutic Indexes
D. Protein Binding
E. Selection of Drug-Resistant HIV-1 Variants in Cell Culture
1. Genotype
2. Phenotype
F. Cross-Resistance
G. Characterization of Genotypic and Phenotypic Assays
1. Genotypic Assays
2. Phenotypic Assays
A. General Considerations
B. Data Collection
C. Methods and Types of Analyses
1. Baseline Genotype and Virologic Response
2. Development of HIV Mutations
3. Baseline Phenotype and Virologic Response
4. Genotypic and Phenotypic Correlations: Changes in Susceptibility from Baseline
5. Cross-Resistance
6. Additional Analyses
D. Other Considerations
1. Role for Supporting Initial Activity and Dose-Finding Studies
2. Data Collection from Dose-Finding Trials
3. Use of Resistance Data to Establish an Indication
4. Use of Resistance Data for Study Enrollment Criteria, Background Regimen Selection, and Stratification Factors
5. Nonclade B Subtypes
E. Monitoring during Phase 4



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Last updated : 28-10-2010

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