DRUG RESISTANCE TESTING NEW DRUG DEVELOPMENT (ANTI RETROVIRAL HIV) Baseline Genotype and Virologic Response

Baseline Genotype and Virologic Response
Analyses should be conducted to evaluate HIV RNA response according to the presence and absence of baseline mutations. These analyses can help assess the association between a specific mutation or mutational pattern and virologic response rates. For example, for a new nucleoside analogue, virologic response rates would be determined for patients with and without clinically relevant mutations associated with resistance to other nucleoside analogs. Table 1 shows one example of virologic response rates for a hypothetical nucleoside analog by the presence or absence of zidovudine-associated mutations at baseline.

Table 1 shows response rates according to the presence or absence of specific mutations. In clinical isolates, however, mutations often occur in patterns, some of which are considered primary and others compensatory or accessory. Exploratory analyses should be conducted to define sets of mutational patterns with the largest effect on subsequent response rates.
For some drugs, defining specific mutational patterns that best correlate with a reduction in treatment response can be difficult. In these cases, another approach can be to investigate the number of baseline mutations that affects overall response. We encourage sponsors to explore how the number of baseline mutations correlate with maximal, reduced, or minimal virologic responses. For example, the response rate (less than 400 copies/mL) in patients with 1 to 2 protease inhibitor- (PI) associated mutations at baseline may be 80 percent, 45 percent if 3 to 4 PI-associated baseline mutations are present, or 10 percent if 5 or more PI-associated baseline mutations are present. For some drugs, the number and types of mutations may be important for overall clinical response. Therefore, we recommend sponsors conduct analyses as suggested in Tables 2A and 2B. Sponsors should discuss in advance with the division the specific mutations to be included in the overall mutation score. Additional exploratory analyses may be recommended to further investigate the effect of certain mutations on virologic response.

Note the number of PI mutations (4) used in Table 2B is for illustrative purposes. The number of mutations that affect virologic response rates vary for each drug; therefore, the number and type of mutations used for analyses of HIV RNA response should be discussed with the division. We recognize the limitations of this type of analysis in that an interaction between two or more mutations may not be detected. However, this analysis may provide insight into baseline predicators of response and may provide useful information regarding relationships between number and type of mutations for further exploratory analyses.


Source:

Drug Resistance Assay and Antiretroviral drug development guidance--->
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071173.pdf

IV. NONCLINICAL STUDIES
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
V. CLINICAL STUDIES: USE OF RESISTANCE TESTING IN CLINICAL PHASES OF DRUG DEVELOPMENT
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

REGULATORY REQUIREMENTS FOR SUBMITTING HIV RESISTANCE DATA

SUMMARY



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Last updated :28-Oct-2010