Authored By: B. V Waghmare

Thursday, October 28, 2010


Before advances in resistance testing technologies, resistance and cross-resistance data were often obtained late in drug development or during postmarketing. However, given the current availability of resistance testing in clinical practice and the need to give health care providers information about an antiretroviral drug’s resistance profile, comprehensive resistance testing should be undertaken in all phases of drug development. Crucial decisions in protocol design and drug development hinge on resistance and cross-resistance data.
Cell culture resistance and cross-resistance studies of an investigational drug can focus the scope of drug development. For example, drugs that exhibit extensive cross-resistance with approved drugs of the same class are unlikely to be suitable for studies in treatment-experienced patients harboring resistant isolates to that class. Conversely, for drugs that demonstrate a nonoverlapping or unique resistance profile, the division strongly encourages sponsors to develop clinical protocols studying treatment-experienced individuals. Although we encourage development of new antiretroviral drugs with unique resistance profiles in treatment-experienced patients, we also encourage concurrent clinical development in antiretroviral-naïve patients as appropriate.
Epidemiological data suggest that transmission of drug-resistant HIV is on the rise, meaning one cannot assume treatment-naïve patients harbor WT virus (Little et al. 2002). In this regard, the division strongly recommends the collection and storage of samples for baseline resistance testing (preferably for both genotype and phenotype) from all HIV-infected, multiple-dose study patients, regardless of treatment history.
Methods and Types of Analyses, for further information regarding settings where analyses on baseline and follow-up samples are recommended. Knowledge of the genotype and phenotype at baseline can aid in the interpretation of unexpected antiviral responses, particularly in smaller dose-ranging studies.

A. General Considerations
The goals of resistance testing are to:
• Determine the effect of an antiviral drug on the evolution of the virus
• Identify the baseline genotypic and phenotypic determinants of virologic success or failure (or clinical success or failure) in the study

We strongly recommend resistance testing in all phases of development and, in most cases, as soon as the drug is introduced into HIV-infected patients. Data from nonclinical studies and phase 1 and phase 2 clinical trials should provide a preliminary idea of the genotypic mutations that confer reduced drug susceptibility and a lack or loss of virologic response. Phase 3 trial designs should incorporate this information and expand on it, thereby aiming to further characterize drug resistance.
In general, the type of information collected and the types of analyses conducted should be the same for all phases of development. However, the amount of data collected and the types of analyses performed may differ for treatment-naïve versus treatment-experienced patients as described below. Whenever possible, resistance analyses should be prospectively defined. However, since it is not possible to define a priori key mutations or susceptibility breakpoints, retrospective analyses can provide important information in characterizing resistance and cross-resistance. The following sections provide recommendations on the type of resistance data that should be collected during drug development and the types of analyses that should be conducted. Appendix A provides guidance for submitting HIV resistance data. Information about the specific assays and mutational algorithms used in protocols also should be provided to the division.

B. Data Collection
To characterize drug resistance during development, sponsors are strongly encouraged to collect samples from both treatment-naïve and treatment-experienced patients. Overall, the extent and type of resistance testing should be discussed and agreed upon with the division throughout drug development. Discussions with the division are particularly important for new classes of antiretroviral agents as the data and technologies are evolving. The following data should be collected and analyzed:
• Baseline phenotype and genotype samples on all study patients. Samples can be analyzed at a later date as appropriate.
The reasons for obtaining baseline samples for phenotype and genotype on all clinical trial patients are twofold. First, the prevalence and rate of transmission of drug-resistant virus is increasing (Little et al. 2002), and may continue to increase, as the HIV population becomes more treatment experienced. Second, collection of baseline data provides an opportunity to examine the relationship between genotype and phenotype and virologic response to drug, particularly in treatment-experienced patient populations. Use of resistance testing in study protocols may help in choosing appropriate combination regimens for treatment-experienced patients (see section V.C.4, Genotypic and Phenotypic Correlations: Changes in Susceptibility from Baseline, for further details).
• Post-baseline phenotype and genotype samples on all study patients, regardless of treatment history who demonstrate a lack or loss of virologic response during the trial to determine mutations that may contribute to reduced drug susceptibility.
Collecting samples for resistance testing when patients are still on study drug, or as soon as possible if study drugs are discontinued, is important. Studies have shown WT virus may outgrow resistant HIV viral strains in the absence of selective drug pressure (Devereux et al. 1999; Halfon et al. 2003). In addition, continuation of resistance monitoring on subsequent regimens can provide useful information regarding cross-resistance and sequencing of therapy. We recognize collection of resistance data on subsequent regimens is not feasible for all clinical trials or patients; however, sponsors are encouraged to consider such studies in their development plans as appropriate (see Cross-Resistance, for details) and are encouraged to discuss continuation studies with the division.


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-Oct-2010 

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