Principles for Codevelopment of an 1 In Vitro Companion Diagnostic


  Prospective-Retrospective Approaches



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4.  Prospective-Retrospective Approaches  

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A prospective-retrospective study with respect to an IVD companion diagnostic is one in 

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which there is a pre-specified plan to prospectively collect specimens and retrospectively 

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analyze outcomes based on the IVD result (which result may be obtained at the time of 

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specimen collection or at a later point) after the clinical trial is completed.  The statistical 

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analysis plan should pre-specify a marker-based study objective that identifies the 

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samples that will be collected, the testing that will be conducted based on the samples 

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collected, and how outcomes will be analyzed based on the IVD results.  

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By definition, in a prospective-retrospective study, the random assignment of subjects to 

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treatment arms cannot have been stratified by marker status.  However, subjects within 



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the marker-based subpopulation were randomly assigned to treatment arms, preserving 

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the validity of treatment comparisons within that marker-based subpopulation. 



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Therapeutic product indications are usually based on prospective clinical trials.  

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Therapeutic product claims based on prospective-retrospective studies will generally be 

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accepted only in defined circumstances, and will likely need to be substantiated in more 

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than one adequate, well-controlled study.  A prospectively-defined retrospective analysis 

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might be considered acceptable if the following recommendations are followed:

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·  Pre-specification of the primary analysis endpoint(s) occurs prior to study 

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unblinding or any unblinded interim analysis. 



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·  The banked samples are from an adequate, well-conducted, well-controlled study. 

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·  The study is of adequate size such that treatment effects in one or more marker-



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defined subgroups of interest can be determined. 

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·  The test result can be ascertained in a very large proportion of the study subjects. 



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·  The IVD has acceptable analytical performance. 

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·  The pre-specified retrospective analysis plan is considered acceptable by FDA. 



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·  Users of the assay are blinded to the study’s clinical outcomes.  

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To use a prospective-retrospective design, knowledge of the prevalence of the marker of 

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interest in the population to be treated is critical to enable a valid analysis, both to assure 

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that enough marker-positive subjects will be enrolled and to assure sufficient 

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 For further discussion, see transcripts from the December 16, 2008, meeting of FDA’s Oncologic Drugs 



Advisory Committee discussing KRAS testing (

http://www.fda.gov/ohrms/dockets/ac/cder08.html

). 

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

26 



randomization of marker-positive and -negative subjects to the various treatment arms. 

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The statistical analysis plan should include a plan to address robustness (sensitivity) of 

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study conclusions to missing test results.  Subjects with and without test results should be 



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compared on the distribution of variables that could affect the assay result, especially 

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variables concerning the characteristics of the sample, its handling, and its processing.  



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Subjects with and without test results may also need to be compared on the distribution of 

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individual characteristics, disease characteristics, and outcome.  The impact of missing 



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data on clinical performance (e.g., hazard ratio in marker-defined subset) should be 

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analyzed.  To evaluate the sensitivity of clinical performance to missing data, a model 



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may be used to impute missing test results based on the variables described above.  

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Analyses should consider that data may be missing not at random but may 



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disproportionately include subjects with assay results near the cutoff, for example.  

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Analysis based on an incomplete sample of marker data may yield biased results. 



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For trials in which subject samples are taken prior to treatment assignment, the 

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probability of having a test result for a subject is independent of treatment assignment.  

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However, for various reasons the distribution of available test results on archived samples 

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may be distorted relative to the distribution in fresh samples (e.g., tumors with larger 

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volume may be overrepresented), which may limit the generalizability of treatment 

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effects observed in retrospective studies of archived samples.   

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5.  Considerations for Identifying Intended Populations 

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In codevelopment programs, the goal is usually to identify a population expected to benefit 

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from the therapeutic product (or a particular dose) or to avoid serious toxicities caused by the 

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therapeutic product.  Therefore, sponsors should pay close attention to the range of analytes 

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and establishing the appropriate assay cutoffs to adequately define this population. 

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i.  Adequate Representation of Markers in Study Population 

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Selection of appropriate study populations or doses/dosing interval, etc. of the therapeutic 

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product in codevelopment programs may rely on results from an IVD that detects or 

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measures a single marker or detects or measures multiple genetic variants or other markers.

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In general, sample size depends on the primary outcome of interest, the magnitude of the 

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treatment effect in the population to be analyzed and the prevalence of the marker in the 

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population to be analyzed.  When designing a clinical trial, the most straightforward option is 

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to ensure adequate representation of each marker of potential importance to enable 

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characterization of the efficacy and/or safety across all of the markers within a population.  

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The prevalence of the markers may differ substantially relative to one another, such that it 

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may not always be appropriate to enroll all subjects with a given marker.  To assure 

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enrollment of an adequate number of subjects with a low-prevalence marker of interest, a 

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pre-specified enrichment strategy is appropriate.  When determining the appropriate study 

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 Note that multiple markers that are combined to generate a single composite result are generally treated as a 



single marker, and thus prevalence of individual markers would not be a concern. 

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

27 



population and breadth of marker capture, sponsors may consult with the lead therapeutic 

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product review center for feedback on whether and to what extent marker-negative and rarer-

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marker subjects should be included.  It is also important to include, where applicable, 

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subjects with a range of positivity on the marker to assess the relation of the degree of 

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marker-positivity to outcome and to establish a marker cutoff.  If there is insufficient 

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evidence to support the use of certain markers detected by the IVD, the therapeutic product 

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review center will determine whether or how such markers should be included in the 

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therapeutic product labeling.  Sponsors should be aware that, regardless of each marker’s 

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prevalence, analytical validation of the IVD for each reported marker may be necessary (see 

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Section III.C.7.).   

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ii.  Establishing Cutoffs for IVD Companion Diagnostics 

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The cutoff for an IVD companion diagnostic is the test value above (or below) which the 

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clinical decision changes (for example, subjects with test results above the cutoff value are 

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eligible for treatment, whereas those with test results below the cutoff value are not given the 

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treatment).  Pre-specified cutoff values are essential for the analysis of use of the IVD in a 

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clinical trial.  These may be chosen based on prior data but validating the cutoff is often an 

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important objective of the clinical trial.  The cutoff value is intended to represent a point 

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where the sponsor can reliably identify the subjects who are suitable for randomization, 

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choose the appropriate dose, or make other clinical trial decisions.  Although the analysis will 

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often be based on the population above the cutoff, results from subjects below the cutoff will 

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also be of interest (e.g., assessment of the appropriateness of the cutoff).   

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An IVD companion diagnostic’s cutoff value should represent a point above (or below) 

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which patients are considered to be positive or negative for the marker(s) of interest.  Cutoff 

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values that distinguish relevant trial populations usually should be established for the 

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investigational IVD prior to use in clinical trials intended to be submitted to support a 

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therapeutic product’s approval.

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To date, most IVD companion diagnostics have yielded a qualitative result that classifies 

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subjects into two or more groups (e.g., mutation present or absent).  Qualitative results often 

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have an underlying quantitative variable that is important for establishing the cutoff between 

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the qualitative classifications.  This cutoff may be the limit of detection, the limit of 

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quantitation, or a value that corresponds to a clinically-significant decision point.   

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When a test result is quantitative (i.e., yields a continuum of values), consideration should be 

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given to whether additional studies evaluating the dose-response relationship between the 



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marker of interest and the therapeutic product are necessary to refine the cutoff to include a 

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range of marker-positive subjects in the clinical trial, either as distinct randomized groups or 



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as subsets that can be analyzed later, perhaps leading to a formal baseline-response study.  If 

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the marker is both prognostic and predictive, it may also be necessary to stratify subjects to 



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treatment arms based on a pre-specified cutoff value.   

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 See note 51.



 

Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

28 



For ordinal values (e.g., immunohistochemistry (IHC) tests scored as 0, 1+, 2+, 3+), pre-

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specification of categories considered above and below the cutoff is strongly recommended.  

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Although the statistical plan will include a cutoff (e.g., ≥ 2+), results in all categories will be 

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informative. 

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If indeterminate (or equivocal) values will be produced, the sponsor should discuss how 

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subjects with such values will be classified for purposes of the clinical trial, and how the 



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indeterminate zone will be used clinically if the therapeutic product and its IVD companion 

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diagnostic receive marketing authorization.



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  The sponsor should also consider other data 

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that would be needed to classify such patients.  In light of these complexities, IVD 



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companion diagnostics that provide clear cutoff values are strongly recommended, where 

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available. 



 

 

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For IVD companion diagnostics, the validity of the test is determined by the ability of the test 

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result to support conclusions made about the treated group when the specified cutoff is used.  



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As with any IVD, changing the cutoff(s) can change the way patients are classified (e.g., 

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marker-negative or marker-positive).  Therefore, it is very important that the cutoff be 



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specified prior to using the test in a clinical trial.  In most cases, inclusion of some subjects 

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below the cutoff can be useful to refine the cutoff (e.g., when subjects with values below the 



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cutoff have some likelihood of achieving the treatment effect of the therapeutic product), 

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even if the primary analysis includes only subjects above the cutoff.  It is recognized that the 



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optimal cutoff may be unknown before clinical data are available in a reasonable number of 

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subjects.  In such cases, another clinical trial confirming the results with the new cutoff, or an 



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adaptive design that allows intra-trial cutoff alterations, would be necessary to ensure that 

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positive results are not due to bias or chance.  



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E. Considerations for IVD Development in Late Therapeutic 

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Product Development 

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For the majority of IVD companion diagnostics for novel therapeutic products, FDA 

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expects that clinical evidence to support use of the IVD companion diagnostic will be 

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generated in the major efficacy trial(s) intended to support approval of the therapeutic 

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product.  Therefore, it is important that the investigational IVD(s) used in these trials is 

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completely specified and that analytical validation is complete and meets the therapeutic 

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product sponsor’s expectations for performance.

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  To assure that the analytical validation 



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is well-established and that the IVD can be relied on to supply the correct results, the 

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70

 An example of use of an indeterminate cutoff is the 2+ result of the IHC tests for HER-2 overexpression.  

Reproducibility studies revealed that readers had a difficult time separating 2+ from 1+ and 3+ results.  The 

clinical trial confirmed that fewer persons with 2+ results were having positive treatment outcomes than persons 

with clear 3+ results, and, as a result, 2+ results were re-categorized as representing indeterminate rather than 

positive results.  To address the uncertainty of values in this gray zone, a recommendation in the clinical 

practice was introduced to have all 2+ results evaluated by re-assay with another type of test. (See Herceptin 

(trastuzumab) package insert, available at: 

http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/trasgen020900LB.htm

). 


 

71

 Note that there may be some circumstances where an alternative approach may be appropriate, such as 



prospective adaptive designs or prospective-retrospective trials.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

29 



elements discussed in the following sections should be considered for relevance to the 

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investigational IVD, and applicable elements should be addressed appropriately in the 

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validation study design. 

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1.  Training Samples Sets versus Validation Samples Sets 

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The set of clinical samples used to design an IVD and establish the clinical decision 

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point(s) and assay cutoff(s) is referred to as the “training set.”  Testing should be 

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conducted with a second set of independent clinical samples (i.e., the “validation set”) 

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and with the final IVD design to validate the IVD and determine whether the assay 

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cutoffs correlate with clinical outcome.  For IVD companion diagnostics, the validation 

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sample set is generally made up of samples from subjects screened for enrollment into the 

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major efficacy clinical trial(s) that is intended to support efficacy claims for the 

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therapeutic product.  For this reason, IVD design and assay cutoffs should be established 

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before the IVD is applied to these samples.   

1010


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If changes are made to the IVD based on results obtained with the clinical samples from 

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the major efficacy trial(s) (e.g., changing the cutoff to include all those who responded in 



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the trial), then what would otherwise have been the validation set effectively becomes a 

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new training set for the modified IVD.  The modified IVD likely could not receive 



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marketing authorization as an IVD companion diagnostic without further studies, as it 

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will likely not select the same population represented in the major efficacy trial(s).  For 



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this reason, the analytical development of the new IVD should not be conducted with the 

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specimens needed to clinically validate the assay.  While it may seem logical to use the 



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trial specimens to assure concordance between the two versions of the test, there is no 

1020

assurance as to whether the same concordance would be obtained with a different set of 



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samples.  The new IVD design may be established with a set of procured clinical samples 

1022

similar to the subjects in the trial or samples from earlier investigational trials. 



1023

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2.  Effect of Changes to the Test Design  

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In codevelopment programs, the target population for a therapeutic product is selected on 

1026


the basis of test results.  It is important to ensure that this same population can be 

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identified after approval of the therapeutic product.  When the use of an IVD companion 

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diagnostic is essential for the safe and effective use of the therapeutic product and its use 

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is part of the instructions for use of the therapeutic product, FDA recommends that, 

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whenever possible, the candidate IVD companion diagnostic be validated as part of the 

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major efficacy trial(s).   

1032


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Whenever an IVD is changed (e.g., changes in reagent configurations, instruments, 

1034

platforms, methods, calibration), the change may generate questions as to whether the 



1035

new test would result in the same clinical trial actions as the original test.  If a revised 

1036

IVD is implemented, generally a bridging study (see Section III.E.3.) would be needed to 



1037

demonstrate high concordance between the two IVDs.  Note that discordance between the 

1038

IVDs with respect to patient enrollment may make interpretation of clinical trial results 



1039

difficult or impossible.   

1040


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

30 



1041

3.  IVD Bridging Studies 

1042


If a test other than the candidate IVD companion diagnostic is used for the major efficacy 

1043


trial(s), the IVD sponsor should demonstrate that the candidate IVD companion 

1044


diagnostic has performance characteristics that are very similar to those of the test that 

1045


was used in the trial (sometimes referred to as the clinical trial assay or CTA).  This is 

1046


generally demonstrated through a bridging study between the two tests, using the original 

1047


clinical trial samples and a pre-specified statistical analysis plan, to show that results with 

1048


the candidate IVD companion diagnostic are very similar to those with the CTA.  A 

1049


bridging study evaluates efficacy of the therapeutic product in subjects whose marker 

1050


status is determined by the candidate IVD companion diagnostic by assessing both 

1051


concordance and discordance between the two tests using the same specimens from 

1052


subjects who were tested for trial eligibility.  The analysis needs to consider any potential 

1053


impact of missing samples not available for the concordance study.  The ability of the 

1054


candidate IVD companion diagnostic to predict the efficacy of the therapeutic product 

1055


can be supported indirectly by high analytical concordance with the CTA on a large 

1056


number of representative samples, including samples from subjects excluded from the 

1057


trial because they were marker-negative by the CTA.  Thus, FDA's assessment of the 

1058


clinical validity of the candidate IVD companion diagnostic will rely on extrapolating the 

1059


clinical performance characteristics of the CTA to the clinical performance characteristics 

1060


of the candidate IVD companion diagnostic.   

1061


1062

The ideal bridging study is one in which all samples tested with the trial test are retested 

1063

with the candidate IVD companion diagnostic and valid test results are obtained and used 



1064

to assess comparative performance.

72

  A bridging study with specimens from an all-



1065

comers trial also allows an analysis of efficacy using the results of the candidate IVD 

1066

companion diagnostic.  Note, however, that care should be taken in understanding the 



1067

analytical performance of the IVD prior to the bridging study because adjustments to the 

1068

IVD should not be made from results obtained with the clinical trial samples (see Section 



1069

III.E.1). 

1070

1071


Whether a clinical trial enrolls subjects irrespective of the test result or enrolls only the 

1072


subset of subjects identified by the test result, both the test-negative and test-positive 

1073


clinical trial samples should be included in bridging studies to avoid bias due to 

1074


prescreening (see Section III.C.5.).  FDA recognizes, however, that there are many 

1075


reasons why all the samples tested with the CTA may not be available for retesting, 

1076


including that samples are missing, not accessible, or insufficient in quantity to retest, and 

1077


it may not be possible to retest all samples.  If only a subset of samples is retested, the 

1078


sponsor should ensure that the characteristics of the subset adequately reflect the 

1079


characteristics that affect test performance (e.g., tumor size, histology, melanin content, 

1080


necrotic tissue, resected tissue versus core needle biopsy) and that the characteristics of 

1081


the subjects that may affect therapeutic product efficacy (e.g., patient demographics, 

1082


                                                 

72

 See Appendix 2 for a discussion of appropriate specimen handling, which can affect the validity of bridging 



studies.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

31 



stage of disease, stratification factors) are proportionally preserved in the retest sample 

1083


set when compared to the samples in the original set.  In addressing baseline imbalance 

1084


between the retested and non-retested analysis sets, FDA recommends that sponsors 

1085


identify any covariates that can affect the test result and then check for baseline 

1086


imbalance between the retested and non-retested analysis sets using the set of covariates 

1087


identified. 

1088


1089

A re-analysis of the primary outcome data should be made according to the final test 

1090

results with the retest sample set in order to assure that any reclassification that occurs 



1091

does not alter conclusions about the safety and efficacy of the therapeutic product in the 

1092

selected population.  When all samples are not retested, a second re-analysis can be 



1093

conducted in which missing data for the final test are imputed.  The nature of the re-

1094

analysis will be product-specific and may be discussed with the appropriate IVD review 



1095

center.   

1096

1097


Finally, additional analytical validation may be requested to support satisfactory 

1098


concordance across methods where discordance may arise, e.g., precision, limit of 

1099


detection, and accuracy.  In the event there is discordance in a marker-positive-only trial, 

1100


it is possible that the candidate IVD companion diagnostic will more accurately predict 

1101


responders, a difference that would represent an advantage for optimal use of the 

1102


therapeutic product.  

1103


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