Day 2 of FDA Hearing on Use of HIV Drug Resistance Testing 
Nov 3, Gaithersburg, MD, Holiday Inn

The discussion today took a focus onto the use of resistance testing in the drug development process, FDA approval and in clinical studies. Speakers agreed that testing should be part of all studies, and that all populations should be looked at to detect differences. Testing in studies could be stratified b population such as naive, experience with 1 PI, and highly exerienced (3 PIs). It was suggested that resistance profile at baseline compared to after drug failure can identify resistance profile associated with failure to drug and that this information should be supplied for FDA approval. After characterizing a person' resistance profile this info may help to identify which individuals may be most responsive to a drug. The potential large expense to conducting these studies was mentioned. The committee discussed the importance of other parameters in assessing failure besides resistance. They agreed the effects of PK are important and should be researched, analyzed and correlated with resistance profile. Emphasis was placed in discussions on the need to study new drugs in highly experienced patients prior to approval. Its important to collect resistance and PK data on effects of new drugs in this patient population prior to FDA approval. A hope is that certain resistance profiles may be identified for which certain drugs may be effective or not effective. Again, this information ought to be made available for submission to FDA upon application for approval. The quality of work at lab in performing testing and in interpretation is very important because quality and consistency when comparing vaious labs appears variable. Getting different results from different labs can be disconcerting and confusing. It appears obvious to me that we are in infancy stages in developing this area. But as said yesterday resistance testing is available and is being used.

The purpose of hearing is to address issues related to resistance testing and drug approval, product labels, clinical studies, adequacy and type of data needed, etc. The FDA will have to make policy on these issues.

Following is free flowing of comments made at hearing many of which reflect summary above. This is not a full report of all the day's proceedings as I had to leave at about 12 noon. Public testimony was scheduled for later this afternoon.

Richard D'Aquila--
Fitness between different mutants is another consideration but clinical effect of fitness is not easily characterized. 

Fitness in presence of drug may not be same against wild-type virus or when other drug is used. Other variables can effect the effect of fitness.

Should the EC50 or EC90 be used to measure resistance. Not resolved. EC50 is easier to perform.

Merging PK and resistance data is important.

Drug Development & Resistance Testing-
Doug Mayers raised issue that drugs are initially tested in patients naive or with little experience. They need to be tested initially in highly resistant patients. Others agreed data should be presented for aproval application on all populations particularly in highly experienced patients. Baseline resistance data should be performed for future comparisons but possibly not necessary in all populations such as truely naive populations. Resistance testing at baseline may not be necessary in all trials for all populations.

Scott Hammer said prospective resistance testing at baseline for stratifcation in studies is important for studies in certain populations. 

PK may overcome resistance so resistance data alone may not be enough to predict outcome. It was suggested these studies be conducted in smaller sub-populations of study groups rather than entailing expense of doing it in all study participations.

Hammer said we need to stratify by experience and other factors to better understand effects of resistance and various circumstances (different resistance profiles) in which may or may not be effective.

Trip Gulick suggested expanded access might be good opportunity to conduct these studies. Hammer raised concern this might be very expensive.

Plasma storage is likely going on in all phase I/II/III studies. So not all patients in studies need prospective baseline testing. Selected groups should be tested. 

Hammer said all populations should be tested but not all individuals in studies need baseline testing.

Comparing baseline profiles to profile at failure on new drugs ought to yield resistance profile associated with failure of drug(s) in study.

It was suggested that information on PK, drug exposure, and resistance, and other parameters should be made available by drug company when seeking FDA approval. As well, since reliability of some labs is questionable drug company has to furnish which lab did testing and their record of reliability.

It was suggested that testing ought to also be conducted at say 16 weeks if person is not undetectable yet. Mayers and Hammer suggested drug levels and resistance testing may be used together to evaluate therapy and its failure, and the logistics of doing this will have to be addressed such as timing of dosing and samples.

Hammer reminded that since the interpretation of testing is an issue this needs to be considered when designing trials. Utility of testing is "as good as person interpreting results".

The FDA reviewed regulatory framework and the product labeling for using susceptibility testing for other organisms for which interpretive criteria have been established. Clinically relevant breakpoints are included. Well controlled clinical and in vitro data is included. Possibly 100 isolates should be tested, geographically representative, recent clinical isolates. Description of test methods should be included. Should be data on in vitro activity against susceptible and resistant strains. Are resistant strains more or less virulent or respond differently to therapy? This should be addressed in label. Is there a relationship between in vitro and in vivo data? Are pathogenetic viruses less susceptible? 

Wong said antifungal resistance testing has been standardized but its relationship to clinical outcome is in early development and not established. So it may be a while before we're able to establish this relationship in resistance testing for HIV.

Mazur asked who will take responsibility for establishing breakpoints?

In current situations breakpoints are researched and studied in multiple labs to better establish credibility. IC50 levels can be different in different labs. Its important to develop some standardization in establishing breakpoints. 

It was suggested that CNS and other compartments should be considered in evaluating resistance.

Jeff Murray of the FDA said testing can improve surveillance and help doctors imprve treatment strategies. But FDA doesn't feel testing can be used a measure of clinical benefit. Need breakpoints for each new drug as the drug becomes available. Is real time testing in clinical studies important yet? As a goal, label should identify levels of resistance leading to cross-resistance. How much data and what type of data is needed to claim activity against resistance virus, support an application for approval?

The committee just broke for lunch and I have to go.