Evolution of Translational Omics Lessons Learned and the Path Forward (2012) / Chapter Skim
Currently Skimming:
4 Evaluation of Omics-Based Tests for Clinical Utility and Use
4 Evaluation of Omics-Based Tests for Clinical Utility and Use
Pages 79-104
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 79... ...
As described in Chapter 1, omics-based tests can be considered a complex form of a biomarker, using a defined set of measurements combined with fully defined computational procedures as a clinical test. In parallel to the recommendations presented in Chapters 2 and 3, Figure 4-1 highlights the recommended steps in the evaluation for clinical utility and use of tests that are intended to guide patient management in a clinical care setting, the third component of the committee's recommended development and evaluation process for omics-based test.
|
From page 80... ...
L FDA Approval/Clearance or LDT Process for Clinical Test I Additional High-Quality Evidence to Evaluate Clinical Utility of the Test N E See Chapter 2 See Chapter 3 Practice Guidelines and Reimbursement Clinical Use FIGURE 4-1 Omics-based test development process, highlighting the evaluation for clinical utility and use stage. The bright line signifies the point in test development where a fully defined, validated, and locked-down clinical test is necessary.
|
From page 81... ...
Just as it is important to fully standardize and understand the components, dose, and schedule of a new therapeutic before taking it into clinical trials to assess clinical efficacy, it is essential that analytical validity for an omics-based test be demonstrated (Chapters 2 and 3)
|
From page 82... ...
. The purpose of this chapter is to briefly outline the types of clinical studies and clinical trials used to gather evidence prior to introducing tests into clinical practice and for assessing the clinical utility of tests, but only inasmuch as needed to explain the committee's recommendations related to the Evaluation for Clinical Utility and Use Stage of omics-based test development.
|
From page 83... ...
if the test is to be used in a prospective clinical trial. Following the clinical studies or clinical trials, the test either must achieve FDA clearance or approval or must follow the LDT process for introducing a test into clinical practice, with subsequent evaluation and perhaps incorporation of the test into clinical practice guidelines and reimbursement by payers.
|
From page 84... ...
Nonetheless, to address the fundamental charge of this Committee (determining when an omics-based test is fit for use as a basis for a clinical trial design) , it is important to ensure that a test used to direct care in a prospective clinical trial is vetted very carefully.
|
From page 85... ...
To continue the comparison between the regulatory processes for approval of a new therapeutic and the regulatory process for clearance of a new omics-based test, a new therapeutic must undergo rigorous definitive testing in one or more properly designed and conducted prospective clinical trials before it is accepted for routine clinical use. The same is true for omics-based tests that might be used to direct clinical management.
|
From page 86... ...
As illustrated in Figure 4-1, there are three pathways to generate such evidence: • Prospective–retrospective studies using archived specimens from previously conducted clinical trials that address the intended use of the omics-based test, or • Prospective clinical trials that directly address the utility of the omics-based test, where either -- The test does not direct patient management, or -- The test does direct patient management. Each of these pathways will be discussed in the next sections of the chapter, and examples of trial designs are summarized in Table 4-1.
|
From page 87... ...
. However, given the difficulty of conducting prospective trials, it has been proposed that high-quality5 evidence to assess the clinical utility of a new omics-based test may be obtained by conducting prospective– retrospective studies using archived specimens from previously conducted prospective clinical trials or cohort studies that addressed the intended clinical use of the test (Pepe et al., 2008; Simon et al., 2009)
|
From page 88... ...
• s test-directed treatment better I • his design requires a T than standard of care in the prospective written protocol overall study population? describing study objectives, (indirect assessment only)
|
From page 89... ...
• ess resource- and time L • tandard of care may have evolved from the time S intensive than a prospective of the clinical trial. clinical trial because specimens • t least two prospective–retrospective studies A have already been collected and showing consistent promising results are required.
|
From page 90... ...
• tatistical analyses are S • s the test prognostic? I stratified by the test result.
|
From page 91... ...
• tatistical power to detect prognostic factors or S treatment effect modifiers, or treatment effect in the test-positive subset, may be limited unless effects are strong. • f the number of patients accrued to the trial is I small or if the size of certain test-defined subgroups is very small, then treatment assignments might not be well-balanced within the test result categories, resulting in a loss of efficiency.
|
From page 92... ...
• n alternate rule must be A pre-specified to handle cases for which a test result is unavailable for a patient assigned to the test-guided arm. • atients randomized to the P non-guided arm receive standard of care.
|
From page 93... ...
re-evaluated, while other • rovides insufficient information about the utility P categories require prospective of the test if uncertainties exist about the new evaluation in a clinical trial. therapy's effect in test-negative patients; if the new • fficient design for assessing E therapy is beneficial in test-negative patients, then a efficacy of treatment in promising therapy may be missed for these test-positive patients.
|
From page 94... ...
However, if a retrospective study is designed to use archived specimens from a previously conducted prospective trial, and if certain conditions are prospectively delineated in a written protocol before the marker study is performed, we argue that it might be considered a prospective–retrospective study. Such a study should carry considerably more weight toward determination of clinical utility of the marker than a simple study of convenience, in which specimens and an assay happen to be available.
|
From page 95... ...
3) If appropriate archived specimens from previously conducted clinical trials are not available, then investigators need to assess the clinical utility of an omics-based test in prospective clinical trials, as illustrated in the right side of Figure 4-1.
|
From page 96... ...
Prospective Clinical Trials Where the Omics-Based Test Is Not Used for Patient Management To establish clinical utility, the study must be properly designed and powered to address the intended clinical use of the omics-based test. One approach is to perform clinical trials in which the test is not used to direct therapy, but the primary objective of the clinical trial is to assess the clinical usefulness of the test for its intended use.
|
From page 97... ...
Hence, the two designs in Figure 4-2 are equally well suited to assess whether the biomarker is an effect modifier of treatment. Prospective Clinical Trials Where the Omics-Based Test Is Used for Patient Management The design that most directly assesses the clinical utility of a new omicsbased test is a prospective clinical trial in which the omics-based test under study is used to guide patient management decisions.
|
From page 98... ...
. Because a control group is needed to determine whether a test is a prognostic factor and whether it is a treatment effect modifier, designs of randomized trials rather than single-arm trials are discussed.6 Enrichment design In some cases, investigators might assume that the utility of one of the test-designated categories is established, or likely to be, while the others are uncertain and require prospective evaluation in a clinical trial.
|
From page 99... ...
. Preclinical data strongly suggested that trastuzumab would only be effective against cancers that greatly overexpress HER2, and nearly all subsequent clinical trials have only enrolled patients with very high levels of HER2 protein and/or with HER2 gene amplification (Wolff et al., 2007)
|
From page 100... ...
versus an arm in which patients are randomly assigned to investigational therapy versus control standard of care management without knowledge of the test results. For example, this was the design used in the prospective Duke trial of preoperative chemotherapy for breast cancer included in the committee's statement of task (NCT00636441; see Appendix B)
|
From page 101... ...
Regardless of choice, however, the committee strongly recommends consulting with FDA prior to initiation of clinical trials. For a trial in which patient management will be influenced by the omics-based test findings, obtaining an IDE from FDA is a legal requirement.
|
From page 102... ...
2011. Discussion with the IOM Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC, August 19.
|
From page 103... ...
2010. A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program.
|
From page 104... ...
2007. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.