Principles for Codevelopment of an 1 In Vitro Companion Diagnostic


  Preanalytic Procedures and Testing Protocols



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6.  Preanalytic Procedures and Testing Protocols 

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Many IVD companion diagnostics require a number of preanalytic steps to prepare the 

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analyte(s) for measurement (e.g., tissue fixation, DNA and RNA extraction, melanin 

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removal, whole genome amplification, bisulfite modification).  Preanalytic reagents and 

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instrumentation are typically considered to be part of the test system and should be validated 

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with the IVD.   

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Variations in preanalytical steps at different testing sites may make it difficult to interpret 

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analytical performance studies.  Thus, for all steps of preanalytical specimen handling and 



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preparation, sponsors should have a detailed standard operating procedure (SOP) or protocol 

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that is followed at each site that performs any of the preanalytical steps.  The sponsor should 



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ensure that all sites handling the specimens are trained to use the specific method, follow the 

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SOPs, and record any deviations from the SOP.   



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FDA bioresearch monitoring (BIMO) personnel may, and in some cases (e.g., when a PMA 

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for an IVD is under review) generally do, examine laboratory records to determine whether 

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protocols have been followed (see also Section III. F.1.iii. of this guidance).  In cases where 

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there is significant and/or uncontrolled deviation from the specimen testing protocol , FDA 

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may be unable to approve the regulatory submission because it  may deem the data derived 

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from poorly controlled testing to be unreliable and non-representative of the IVD companion 

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diagnostic’s performance under its proposed instructions for use. 

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7.  Planning Ahead for Analytical Validation Studies 

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The IVD sponsor should consider the types of studies needed for analytical validation to 

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Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

20 



support marketing authorization of an IVD companion diagnostic and plan accordingly.

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For example, if the analyte is labile, a plan to collect several specimens from a small 

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number of subjects to assess lability to inform appropriate limitations on storage and 



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transport durations may be appropriate.  Note that some analytical validation studies may 

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not require use of samples from therapeutic product clinical trial subjects, although the 



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studies should be conducted with samples from the same target population to ensure that 

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the variability parameters defined are relevant to the population to be tested.  



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It is important to ensure that appropriate specimens are collected and banked (where 

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analyte stability allows) in sufficient quantities and maintained adequately to support the 

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full range of analytical studies.  Collecting the appropriate pathologic-based annotation 

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(e.g., tumor content, necrosis, adiposity, presence of large amounts of stroma, and other 

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characteristics) for the samples may help to support conclusions about the performance of 

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the assay.  Appendix 2 provides additional detail on specimen handling considerations.  

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In cases where multiple markers will be detected/measured by the test, analytical validation 

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of each reported marker may be required regardless of each marker’s prevalence.  When it is 



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not possible for sponsors to obtain specimens containing a particular marker, validation 

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studies with contrived samples may be permitted.



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  Analytical validation studies may also be 

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complicated for IVDs that have the potential to detect a very large number of markers, in 



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which case it may be necessary for the study to use a representative sampling of markers.  

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For example, for next generation sequencing panels, the ability of the IVD to detect single-



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nucleotide polymorphisms, copy-number variations, inversions or deletions, and other 

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relevant variant classes should be studied.  Sponsors who are concerned about the feasibility 



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of conducting analytical validation studies for all markers detected by an investigational IVD 

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should consult with FDA before beginning sample collection and analytical validation 



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studies. 

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D. Therapeutic Product Clinical Trial Design Considerations  

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When planning therapeutic product clinical trials designed to rely on information 

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provided by an IVD, whether for enrollment, stratification, dose, or other uses, sponsors 

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should consider clinical trial designs that can be used to support the claims for both the 

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therapeutic product and IVD companion diagnostic, and consider whether the IVD 

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companion diagnostic development strategy is aligned with the approval goals for the 

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therapeutic product.   

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Understanding the population of subjects enrolled in a clinical trial is critical.  It is 

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conceivable, for example, that assessment of preclinical or early clinical studies indicates a 



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 Sponsors may find it helpful to consider resources on analytical validation studies, e.g., Mansfield, E., et al. 



“Biomarkers for pharmacogenetic and pharmacogenomic studies: Locking down analytical performance.”  

Drug Discovery Today: Technologies. 2007, Vol. 4, No. I, pp. 17-01.

 

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 For example, see FDA guidance “Guidance on Pharmacogenetic Tests and Genetic Tests for Heritable 

Markers” 

(

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm077862.htm



). 

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

21 



therapeutic product may be beneficial in the test-positive subgroup

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 and harmful in a test-



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negative subgroup.  In such cases, subjects with false-positive results may be harmed by the 

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therapy, and subjects with false-negative results may be deprived of beneficial therapy.  



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Additionally, false-positive results could lead to underestimation of effect size, whereas 

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false-negative results could lead to underestimation of the proportion of subjects who are 



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more likely to respond.  Therefore, the therapeutic product and IVD sponsors should work 

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closely to understand how the IVD’s analytical performance affects the selection of subjects 



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in the trial.  To minimize the proportion of incorrect test results (i.e., false positives and false 

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negatives that would result in misclassification),



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 sponsors should ensure that the 

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appropriate analytical validation studies are carried out and that the level of analytical 



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validation of the proposed IVD(s), in relation to its specific role in the clinical trial, has been 

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adequately assessed.  This is especially important when progressing from the versions of the 



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test used in a trial to the candidate IVD companion diagnostic (see Section III.E.3. of this 

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guidance).  



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Sponsors should also be aware of, and plan to address, potential sources of bias or error 

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associated with IVD development such as prescreening, preanalytical processing 

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(discussed in Section III.C of this guidance), and bridging studies when necessary (see 

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Section III.E of this guidance).   

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The following sections discuss considerations for the design of clinical trials for a 

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therapeutic product for use with a developmental IVD companion diagnostic. 



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1.  General Considerations for Early Therapeutic Product 

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Development  

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Performing tests for exploratory purposes (referred to as exploratory testing) to identify 

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potential biomarkers in early therapeutic product development may lead to a codevelopment 

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program.  Sponsors should be aware that using exploratory testing that is not sufficiently 

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analytically validated or is validated with inappropriate analysis methods may produce 

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spurious associations.

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  This could result in the failure of a codevelopment program if, for 



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example, a late-phase clinical trial enrolls only “marker-positive” subjects, when positivity is 

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based on flawed exploratory programs.  When using exploratory testing, it is advisable for 



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sponsors to establish procedures that specify the process for sample acquisition and handling 

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 Note that the terms “test-positive” and “test-negative” are often used interchangeably with the term “marker-

positive” and “marker-negative;” however, it is important to be aware that tests for the same marker that have 

different performance characteristics may identify different subpopulations of “marker-positive” patients. 

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 For example, molecular tests that are intended to select for one target but have undetected cross-reactivity 



with other targets may result in selection of a substantial number of patients with the cross-reactive target but 

not the target of interest.  

 

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 Sponsors should consider principles laid out in the National Cancer Institute publication, “Criteria for the use 



of omics-based predictors in clinical trials,” McShane, et al., Nature. 2013, Vol 502, pp. 317-320; and FDA 

guidance for industry “Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and 

Recommendations for Labeling” 

(

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pd



f

). 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

22 



and the testing and analysis plans so that the preliminary evidence that is generated is most 

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likely to be informative. 

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Some early therapeutic product clinical trial designs employ testing for multiple markers to 

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assign subjects to one of multiple different therapeutic arms with the goal of testing multiple 



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hypotheses under one study protocol.  Sponsors of these clinical trials should consider the 

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pathway for continued development of selected therapeutic products with accompanying 



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IVDs in the event that such trials support further development of a candidate IVD companion 

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diagnostic. 



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2.  General Considerations for Late Therapeutic Product 

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Development 

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When a clinical trial is properly designed to establish the safety and effectiveness of a 

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therapeutic product in a population based on measurement or detection of a marker, the 

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results of the clinical trial can also be used to establish the clinical validity of the IVD 

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companion diagnostic.

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  There are a variety of clinical trial designs that may be used to 



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study a developmental IVD companion diagnostic in combination with a therapeutic 

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product in premarket codevelopment programs.  The appropriate clinical trial design to 



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support the diagnostic strategy depends on the proposed claim(s) for the IVD and what 

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has already been established about the predictive, prognostic, or other critical properties 



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of the marker.

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  The success of a clinical trial design strategy depends on many factors, 



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including but not limited to the following: a) the characteristics of the marker as applied 

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to the target population for whom the therapeutic product will be indicated, specifically 



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the mechanistic rationale for selecting the marker, its predictive/prognostic/other utility 

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and its intrinsic properties (e.g., variability and specificity with respect to the disease); b) 



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the nature of the disease; and c) the need to fully characterize the therapeutic product’s 

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benefits and risks, such as the safety profile (e.g., taking into account a possible lack of 



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benefit in the test-negative population), and the degree of observed benefit, if any, in the 

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population for whom the therapeutic product may not be indicated (e.g., test-negative 



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subjects).   

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Two marker-based clinical trial designs that are commonly used are illustrated in Figure 

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1; however, other designs could be appropriate and should be discussed with the 

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appropriate therapeutic product review center.

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 For IVDs, clinical validity typically refers to the accuracy with which the test identifies, measures, or predicts 



the presence or absence of a clinical condition or predisposition in a patient.  In the case of an IVD companion 

diagnostic, clinical validity typically refers to the accuracy with which the test identifies the patients for whom 

use of the therapeutic product is safe, effective, or both. 

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 See Section III.D.3. and Section III.G.1 for additional discussion of predictive and prognostic markers.



 

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 For additional trial designs and further discussion, please also refer to FDA draft guidance “Enrichment 



Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products” 

(

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332181.pdf



). 

FDA draft guidance represents FDA’s proposed approach on this topic.  When final, this guidance will 

represent the FDA’s current thinking on this topic.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

23 



Figure 1.  Clinical Trials Involving Markers.  Trial design A, called an interaction or 

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biomarker-stratified design, is designed to evaluate treatment and marker effects, and 

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their interaction, by stratifying randomization based on marker status, as determined by 

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an IVD.  Trial design B, called a targeted or selection design, is designed to evaluate 

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treatment effects in a targeted population by selecting only those who are test-positive.  

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Key: test-positive, +; test-negative, -; randomize, R.  Treatment A is typically the 

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experimental arm and Treatment B is typically standard-of-care or placebo. 

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In many efficacy trials, it is generally desirable to obtain information about the safety and 

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effectiveness of the therapeutic product for all subjects (rather than for only those 

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subjects with a particular marker status), to ascertain the appropriateness of restricting the 

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therapy to a patient population on the basis of a marker.  However, this does not mean all 

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subjects, regardless of marker status, should be randomized.  The study could enroll 

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marker-positive subjects and include only a sample of marker-negative subjects, e.g., 

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when marker-positive subjects are only a small percentage.  Testing for the presence of 

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particular markers may provide information on prognosis, prediction of response (i.e., 

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response, non-response, or toxicity), or both.

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  The clinical trial design depicted in 



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Figure 1A, in which both test-positive and at least some test-negative subjects are 

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enrolled and randomized, is the most informative design because treatment by marker 



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interaction, as well as the prognostic versus predictive value of the marker, can be 

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assessed.  This approach may be particularly valuable when the biological plausibility or 



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medical relevance of the biomarker is not well understood (e.g., based on findings from 

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exploratory studies or post-hoc analyses in other trials).  Other variations on this design 



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exist, such as those including interim futility analysis where, for example, further 

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enrollment could be limited to test-positive subjects if harm or lack of efficacy is 



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 A purely predictive marker will predict that patients, given a particular marker status, will have better or 



worse outcomes than patients without the marker, solely as a result of having received the investigational 

therapeutic product; that is, there is a clear therapy-marker interaction.  A prognostic marker would suggest that 

patients with the marker would, as a consequence of the natural history of the disease, have better or worse 

outcomes even absent treatment with the investigational therapeutic product; that is, the marker has little or no 

interaction with the therapy.  Some markers may have both predictive and prognostic properties in a given 

disease/therapy setting.  For example, the presence of HER-2 protein overexpression indicates a poorer 

prognosis in patients with breast cancer than in patients who do not overexpress HER-2, but the same marker 

also predicts greater likelihood of response to the drug trastuzumab (Herceptin).  Thus, it is important to 

understand the role the marker is expected to play in the therapeutic product trial.  The prognostic value of the 

marker, if unknown at the time of the therapeutic product trial, should be assessed in clinical trials that are 

stratified by marker status.  

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

24 



identified in the test-negative population.

65

 



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In the approach depicted in Figure 1B, only a subgroup identified by the marker status is 

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enrolled (e.g., only subjects deemed positive by the test are enrolled into the clinical 

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trial).  With this design, the predictive value of the test cannot be determined because 

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there is no information on the treatment effect in the test-negative population.  Likewise, 

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there is no information about whether the assigned assay cutoff adequately distinguishes 

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those who will respond from those who will not.  FDA does not object to this approach 

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categorically because it may be appropriate in some situations (see also Section III.D.3 of 

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this guidance).  A modification of the design, however, could stratify by assay cutoff.   

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Sponsors planning to evaluate the safety and effectiveness of a therapeutic product only 

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in a subset of subjects identified by an IVD should consider whether there is persuasive 



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evidence (e.g., evidence from strong preclinical data, preliminary clinical data, or from 

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clinical trials with similar therapeutics) for the marker as a predictive measure of 



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response or non-response.  Although the sponsor may select any cutoff , FDA 

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recommends that sponsors choosing a marker-positive only approach assure that the 



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chosen marker and assigned assay cutoff are relevant to the disease under study (i.e., 

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known prevalence of marker positivity in the general patient population) within the 



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context of likelihood of a subpopulation’s response (e.g., biologic plausibility, 

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mechanism of action), and that sponsors make a persuasive case for use of the IVD to 



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identify patients who are to be treated.   

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3.  Prognostic and Predictive Markers  

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In clinical trial designs, prognostic markers can be used either to identify the population 

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to be enrolled or to stratify treatment randomization.  For putative prognostic markers, no 

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difference in the effect size is expected in marker-negative versus marker-positive 

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subjects.  Effect size may be measured in different ways, depending on the clinical trial.  

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In oncology trials with time to death as an endpoint, a hazard ratio may be used.  

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Potential study designs for markers expected to be predictive of therapeutic response are 

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discussed elsewhere.

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With respect to a predictive marker, the clinical trial can stratify by the marker test result 

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and randomly assign subjects with the same marker status to the experimental treatment 

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and control (Figure 1A).  If there is little possibility of any effect in marker-negative 

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subjects, however, only marker-positive subjects might be randomly assigned to 

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treatment (Figure 1B), but this provides no formal test of whether the marker predicts 

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65

 See note 63.  Sponsors may also find it helpful to consider resources on this topic, e.g., Wang SJ, O’Neill RT, 



Hung HMJ.  “Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset.” 

Pharmaceutical Statistics  Vol. 6, pp.227-244. 

 

66



 See note 63.  Additionally, sponsors may find it helpful to consider resources on clinical trial designs, e.g., 

Fridlyand, J. et al. “Considerations for the successful co-development of targeted cancer therapies and 

companion diagnostics.” Nat Rev Drug Discov. 2013. Vol. 10, pp. 743-55; Temple, R. “Enrichment of clinical 

study populations.” Clin Pharmacol Ther. 2010. 88(6), pp. 774-8. 



Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

25 



treatment benefits only in such marker-positive subjects.  In clinical trial designs depicted 

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in Figure 1 above, for a continuous marker for which a firm cutoff has not been 

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determined, there could be randomization at varying degrees of marker positivity, or less 

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formally, there could be a post-hoc analysis of the treatment effect at a range of cutoff 

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values.  As noted, if the marker is both prognostic and predictive, then post-hoc analyses 

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of response by marker positivity in the clinical trial designs depicted in Figure 1A or 1B 

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are likely to be confounded, and stratification by degree of marker positivity is strongly 

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recommended.   

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