Questions for the Panel
I. Performance Standards
The Agency plans to adopt the Performance Standards developed by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) as a means of communicating the basis by which each of three validated in vitro test methods, Corrositex®, EPISKIN/EpiDerm, and Transcutaneous Electrical Resistance (TER), are deemed acceptable for providing dermal corrosivity data. Performance Standards consist of descriptions of (1) essential test method components, which are the essential structural, functional, and procedural elements of a validated test method that should be included in the protocol of a proposed mechanistically and functionally similar test method; (2) a minimum list of Reference Chemicals, which is used to assess the accuracy and reliability of the similar test method; and (3) comparable accuracy and reliability values that should be achieved by the proposed test method when evaluated using the minimum set of Reference Chemicals.
- Question 1. Please comment on the provisions in the Performance Standards
for each of the three methods to demonstrate mechanistic similarity
of "me-too" methods. Do the essential test method components
for each method adequately describe the unique characteristics of the
method necessary to determine whether a test is mechanistically and
- Question 2. In its evaluation of any mechanistically similar test
system, the Agency plans to use the generic criteria used by ICCVAM
for selecting subsets of the Reference Chemicals for all three ICCVAM
Performance Standards documents. The criteria specify that chemicals
should be selected in such a way that the subset: includes representatives
of applicable chemical classes, measures a range of corrosive strengths,
includes well-defined chemicals that are currently available commercially,
and has unequivocal animal or other in vivo evidence. Please comment
on the strengths or weaknesses of this approach and identify and discuss
any modifications to the criteria that should be considered.
Question 3. The ICCVAM approach for demonstrating functional similarity of "me-too" test methods to validated methods includes the use of well-characterized Reference Chemicals and specifies the accuracy and reliability that should be achieved by "me-too" test systems when tested in intra- and inter-laboratory studies. Please comment on whether "me-too" test systems should be demonstrated to be effective for evaluating the testing endpoint for all of the chemicals in the Performance Standard. Please comment on the value of including chemicals with range of potencies in the Performance Standard. Under what circumstances might testing of "me-too" systems within one laboratory ever be sufficient to demonstrate functional equivalence?
II. Quality Control
The Agency is proposing quality control measures that should be considered when evaluating the reliability of test kits for regulatory purposes. Please address the following specific issues.
- Question 4. Subsets of the Reference Chemicals used in test method
validation may be used as training or calibration sets by testing laboratories
using in vitro systems. Please discuss the utility of and necessity
for training or calibration sets in assuring data quality. Please comment
on the chemicals selected by ICCVAM for use as a calibration set for
TER for this purpose. Please comment on the ranges of chemical classes
and potencies of these chemicals. How might other chemicals be selected
for possible use in the calibration sets? Please comment on the value
of identifying chemicals that might be used by laboratories as training
sets to demonstrate proficiency in performing the test.
- Question 5. Anticipating the use of systems using tissue constructs,
ex vivo systems, microarrays or genetically modified cells, please discuss
aspects of the quality control criteria that are necessary for assuring
the integrity of such systems over time and from lot-to-lot. Please
comment on whether and how the type of system - tissue constructs, ex
vivo systems, or genetically modified cells or animals - should affect
the criteria for quality control for assuring the integrity of such
systems, both over time and from lot-to-lot.
- Question 6. Please comment on the advantages and disadvantages of
including concurrent positive and negative controls with in vitro assays
when used as alternatives to animal testing. What are the important
characteristics of positive and negative controls for in vitro studies?
What aspects of positive control characteristics allow them to be used
as part of the quality control process? When might confirmation that
positive controls are performing within expected or historical limits
be sufficient to demonstrate that the Proprietary Test Method or non-proprietary
assay system is functioning properly? When might additional quality
control measures be needed?
- Question 7. Does the Panel agree that the benchmark controls serve a useful purpose to demonstrate the level of response that can be expected for each chemical class for each lot of Proprietary Test Method assays? Can the Panel suggest criteria for choice of appropriate benchmark controls?