Principles for Codevelopment of an 1 In Vitro Companion Diagnostic


  Preanalytic Procedures and Testing Protocols



Yüklə 0,62 Mb.
Pdf görüntüsü
səhifə4/6
tarix26.02.2017
ölçüsü0,62 Mb.
#9737
1   2   3   4   5   6

6.  Preanalytic Procedures and Testing Protocols 

646


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

647


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

648


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

649


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

650


with the IVD.   

651


652

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

653

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



654

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

655

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



656

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

657

SOPs, and record any deviations from the SOP.   



658

659


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

660


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

661


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

662


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

663


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

664


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

665


diagnostic’s performance under its proposed instructions for use. 

666


667

7.  Planning Ahead for Analytical Validation Studies 

668


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

669


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

20 



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

56

  



670

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

671

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



672

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

673

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



674

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

675

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



676

677


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

678


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

679


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

680


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

681


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

682


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

683


684

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

685

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



686

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

687

studies with contrived samples may be permitted.



57

  Analytical validation studies may also be 

688

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



689

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

690

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



691

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

692

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



693

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

694

should consult with FDA before beginning sample collection and analytical validation 



695

studies. 

696

D. Therapeutic Product Clinical Trial Design Considerations  

697


When planning therapeutic product clinical trials designed to rely on information 

698


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

699


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

700


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

701


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

702


therapeutic product.   

703


704

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

705

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



706

                                                 

56

 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.

 

57



 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

58

 and harmful in a test-



707

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

708

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



709

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

710

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



711

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

712

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



713

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

714

negatives that would result in misclassification),



59

 sponsors should ensure that the 

715

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



716

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

717

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



718

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

719

guidance).  



720

721


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

722


associated with IVD development such as prescreening, preanalytical processing 

723


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

724


Section III.E of this guidance).   

725


726

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

727

therapeutic product for use with a developmental IVD companion diagnostic. 



728

729


1.  General Considerations for Early Therapeutic Product 

730


Development  

731


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

732


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

733


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

734


analytically validated or is validated with inappropriate analysis methods may produce 

735


spurious associations.

60

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



736

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

737

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



738

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

739

                                                 



58

 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. 

59

 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.  

 

60

 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 

740


likely to be informative. 

741


742

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

743

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



744

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

745

pathway for continued development of selected therapeutic products with accompanying 



746

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

747

diagnostic. 



748

749


2.  General Considerations for Late Therapeutic Product 

750


Development 

751


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

752


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

753


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

754


companion diagnostic.

61

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



755

study a developmental IVD companion diagnostic in combination with a therapeutic 

756

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



757

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

758

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



759

of the marker.

62

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



760

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

761

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



762

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

763

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



764

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

765

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



766

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

767

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



768

subjects).   

769

770


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

771


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

772


appropriate therapeutic product review center.

63

 



773

774


                                                 

61

 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. 

62

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



 

63

 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 

775


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

776


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

777


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

778


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

779


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

780


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

781


782

783


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

784


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

785


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

786


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

787


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

788


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

789


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

790


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

791


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

64

  The clinical trial design depicted in 



792

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

793

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



794

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

795

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



796

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

797

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



798

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

799

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



800

                                                 

64

 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

 



801

802


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

803


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

804


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

805


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

806


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

807


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

808


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

809


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

810


811

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

812

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



813

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

814

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



815

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

816

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



817

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

818

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



819

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

820

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



821

identify patients who are to be treated.   

822

823


3.  Prognostic and Predictive Markers  

824


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

825


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

826


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

827


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

828


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

829


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

830


discussed elsewhere.

66

   



831

832


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

833


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

834


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

835


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

836


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

837


                                                 

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 

838


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

839


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

840


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

841


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

842


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

843


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

844


recommended.   

845


846

Yüklə 0,62 Mb.

Dostları ilə paylaş:
1   2   3   4   5   6




Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©www.azkurs.org 2022
rəhbərliyinə müraciət

    Ana səhifə