The International Society for Pharmacoeconomics & Outcomes Research Group has issued an 11-page review of the state of the art of health technology assessments and molecular diagnostics:
The authors conclude that "HTA organizations should provider greater transparency" including "explicit recognition and rationale for differential approaches." In overview, the authors summarize a wide range of case studies of genomic test technology assessments by different bodies. Then, the authors summarize ten points, essentially a mix of problems-seen and recommendations for moving forward.
The article Garfield et al. is online here. It isn't open access; it's $35, or a journal subscription is $332, or a membership in ISPOR including the journal is $150. There are also three supplemental pages online, however. A one page summary is open access, here. A Q&A interview with Garfield is online, here. The home page for the committee (ISPOR's diagnostics assessment committee) is online, here.
The first author, Susan Garfield, is Principal at the global consultancy EY (formerly Ernst & Young), here. I also cited her work on pharma strategy a few months ago on this blog (here). Thanks to Prof. Kathryn Phillips of UCSF for pointing the new ISPOR article out. Philips heads the Center for Translational and Policy Research on Personalized Medicine.
Also this fall, Deverka and colleagues
produced a position paper on genomics clinical utility, based on interviews and analysis with a large group of consensus-driven stakeholders, here
. Deverka and colleagues provide ten action points to guide better production of clinical utility evaluations.
And also this fall, another recent consensus review article on "clinical utilities in molecular pathology testing procedures" by a collective group of authors at AMP, see Loren Joseph et al
., J Molec Dx, here
. Joseph, who is at Harvard/Beth Israel, also
published a single-author article on clinical utility of cancer profiling in Exp Rev Molec Dx, here
Abstracts posted below, after the break.
See also a 2016 review of these topics by Sey et al. in Exp Rev Drug Met & Toxicol, here
. For a 2015 open-access review in EPMA journal by Akhmetov & Bubnov, here
. For an earlier, 2014 review by Parkinson et al. in Clinical Cancer Research, see here
2016 Jul-Aug;19(5):577-87. doi: 10.1016/j.jval.2016.02.012. Epub 2016 May 11.
Health Technology Assessment for Molecular Diagnostics: Practices, Challenges, and Recommendations from the Medical Devices and Diagnostics Special Interest Group.
Health technology assessments (HTAs) are increasingly used to inform coverage, access, and utilization of medical technologies including molecular diagnostics (MDx). Although MDx are used to screen patients and inform disease management and treatment decisions, there is no uniform approach to their evaluation by HTA organizations.
The International Society for Pharmacoeconomics and Outcomes Research Devices and Diagnostics Special Interest Group reviewed diagnostic-specific HTA programs and identified elements representing common and best practices.
MDx-specific HTA programs in Europe, Australia, and North America were characterized by methodology, evaluation framework, and impact. Published MDx HTAs were reviewed, and five representative case studies of test evaluations were developed: United Kingdom (National Institute for Health and Care Excellence's Diagnostics Assessment Programme, epidermal growth factor receptor tyrosine kinase mutation), United States (Palmetto's Molecular Diagnostic Services Program, OncotypeDx prostate cancer test), Germany (Institute for Quality and Efficiency in Healthcare, human papillomavirus testing), Australia (Medical Services Advisory Committee, anaplastic lymphoma kinase testing for non-small cell lung cancer), and Canada (Canadian Agency for Drugs and Technologies in Health, Rapid Response: Non-invasive Prenatal Testing).
Overall, the few HTA programs that have MDx-specific methods do not provide clear parameters of acceptability related to clinical and analytic performance, clinical utility, and economic impact. The case studies highlight similarities and differences in evaluation approaches across HTAs in the performance metrics used (analytic and clinical validity, clinical utility), evidence requirements, and how value is measured. Not all HTAs are directly linked to reimbursement outcomes.
To improve MDx HTAs, organizations should provide greater transparency, better communication and collaboration between industry and HTA stakeholders, clearer links between HTA and funding decisions, explicit recognition of and rationale for differential approaches to laboratory-developed versus regulatory-approved test, and clear evidence requirements.
Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
diagnostics; health technology assessment
2016 Aug;18(8):780-7. doi: 10.1038/gim.2015.162. Epub 2015 Dec 3.
Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology.
, Messner DA1
, McCormack R2
, Lyman GH3
, Piper M4
, Bradley L5
, Parkinson D6
, Nelson D7
, Smith ML8
, Jacques L9
, Dutta T1
, Tunis SR1
Enthusiasm for molecular diagnostic (MDx) testing in oncology is constrained by the gaps in required evidence regarding its impact on patient outcomes (clinical utility (CU)). This effectiveness guidance document proposes recommendations for the design and evaluation of studies intended to reflect the evidence expectations of payers, while also reflecting information needs of patients and clinicians.
Our process included literature reviews and key informant interviews followed by iterative virtual and in-person consultation with an expert technical working group and an advisory group comprising life-sciences industry experts, public and private payers, patients, clinicians, regulators, researchers, and other stakeholders.
Treatment decisions in oncology represent high-risk clinical decision making, and therefore the recommendations give preference to randomized controlled trials (RCTs) for demonstrating CU. The guidance also describes circumstances under which alternatives to RCTs could be considered, specifying conditions under which test developers could use prospective-retrospective studies with banked biospecimens, single-arm studies, prospective observational studies, or decision-analytic modeling techniques that make a reasonable case for CU.
Using a process driven by multiple stakeholders, we developed a common framework for designing and evaluating studies of the clinical validity and CU of MDx tests, achieving a balance between internal validity of the studies and the relevance, feasibility, and timeliness of generating the desired evidence.Genet Med 18 8, 780-787.
_____ JOSEPH (GROUP)
_____ JOSEPH (SOLO)
J Mol Diagn.
2016 Sep;18(5):605-19. doi: 10.1016/j.jmoldx.2016.05.007. Epub 2016 Aug 16.
The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer: A Report of the Association for Molecular Pathology.
, Cankovic M2
, Caughron S3
, Chandra P4
, Emmadi R5
, Hagenkord J6
, Hallam S7
, Jewell KE8
, Klein RD9
, Pratt VM10
, Rothberg PG11
, Temple-Smolkin RL12
, Lyon E13
Clinical utility describes the benefits of each laboratory test for that patient. Many stakeholders have adopted narrow definitions for the clinical utility of molecular testing as applied to targeted pharmacotherapy in oncology, regardless of the population tested or the purpose of the testing. This definition does not address all of the important applications of molecular diagnostic testing. Definitions consistent with a patient-centered approach emphasize and recognize that a clinical test result's utility depends on the context in which it is used and are particularly relevant to molecular diagnostic testing because of the nature of the information they provide. Debates surrounding levels and types of evidence needed to properly evaluate the clinical value of molecular diagnostics are increasingly important because the growing body of knowledge, stemming from the increase of genomic medicine, provides many new opportunities for molecular testing to improve health care. We address the challenges in defining the clinical utility of molecular diagnostics for inherited diseases or cancer and provide assessment recommendations. Starting with a modified analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications model for addressing clinical utility of molecular diagnostics with a variety of testing purposes, we recommend promotion of patient-centered definitions of clinical utility that appropriately recognize the valuable contribution of molecular diagnostic testing to improve patient care.
Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
The clinical utility of molecular genetic cancer profiling.
Next-Generation-Sequencing (NGS) has enabled gene mutation profiling - cataloguing sequence variants and modifications in clinical assays encompassing tens to thousands of genes in tumors and in germlines. The clinical benefit of applying multi-gene NGS to diverse applications in various malignancies remains to be demonstrated.
Applications of gene mutation profiling in oncology include screening cancer-prone families, classification of malignancies, treatment selection, and monitoring the response to treatment of solid tumors (the 'liquid biopsy'). Google Scholar was used to search PubMed for the period 2011-2016 using combinations of the following search terms: 'clinical utility', NGS, 'molecular diagnostics'. Expert commentary: Clinical studies are in progress pairing mutation profiling with streamlined new trial designs to speed identification of promising drug-target combinations and to see if genotype-informed treatment selection will improve outcome across a spectrum of histologies. The analytical advantages and falling cost of NGS make focused gene panels likely to become the dominant modality in molecular diagnostic testing even if trials eventually discourage use of large panels to test all malignancies.
Gene profiling; NGS; cancer; clinical trials; clinical utility; liquid biopsy; molecular diagnostics
Evolving landscape of tumor molecular profiling for personalized cancer therapy: a comprehensive review.
Tumour molecular profiling has been at the crossroads of large-scale integrative genomic studies and major clinical trials over the past 5 years and has provided roadmaps for better disease stratification and therapeutic management.
We review the landscape of precision oncology trials in Asia, Europe and the United States, and emerging insights gained from recently reported studies such as the SHIVA and CUSTOM trials. Changes in the molecular portraits of human cancers and the immune contexture of the tumor microenvironment during treatment may predict the course of tumor progression, including the development of treatment resistance. 'Liquid biopsy' approaches that harness circulating tumor cells, cell-free DNA and exosomes may provide a non-invasive means of monitoring the parent tumor in real-time. Several molecular signatures are being evaluated as biomarkers for emerging immunologic approaches, such as the mismatch-repair deficiency status and nonsynonymous mutation burden in anti-PD-1 immune checkpoint blockade. Finally, we review the current actionability and future clinical impact of multigene panel and next-generation sequencing (NGS)-based profiling.
In the future, molecular profiling may help to fulfill unmet needs for predictive biomarkers in novel immunotherapeutic approaches, while ongoing precision trials are laying the foundations for clinical uptake of NGS testing.
Whole-genome sequencing; cancer genomics; cancer immunology; exosomes; immunotherapy; liquid biopsy; next-generation sequencing; precision oncology; tumour microenvironment; whole-exome sequencing
2015 Sep 30;6:19. doi: 10.1186/s13167-015-0041-3. eCollection 2015.
Assessing value of innovative molecular diagnostic tests in the concept of predictive, preventive, and personalized medicine.
Molecular diagnostic tests drive the scientific and technological uplift in the field of predictive, preventive, and personalized medicine offering invaluable clinical and socioeconomic benefits to the key stakeholders. Although the results of diagnostic tests are immensely influential, molecular diagnostic tests (MDx) are still grudgingly reimbursed by payers and amount for less than 5 % of the overall healthcare costs. This paper aims at defining the value of molecular diagnostic test and outlining the most important components of "value" from miscellaneous assessment frameworks, which go beyond accuracy and feasibility and impact the clinical adoption, informing healthcare resource allocation decisions. The authors suggest that the industry should facilitate discussions with various stakeholders throughout the entire assessment process in order to arrive at a consensus about the depth of evidence required for positive marketing authorization or reimbursement decisions. In light of the evolving "value-based healthcare" delivery practices, it is also recommended to account for social and ethical parameters of value, since these are anticipated to become as critical for reimbursement decisions and test acceptance as economic and clinical criteria.
Companion diagnostics; Cost-effectiveness; Economic models; Health technology assessment; Market access; Predictive Preventive Personalized Medicine; Reimbursement; Strategy; Value
Evidence of clinical utility: an unmet need in molecular diagnostics for patients with cancer.
, McCormack RT
, Keating SM
, Gutman SI
, Hamilton SR
, Mansfield EA
, Piper MA
, Deverka P
, Frueh FW
, Jessup JM
, McShane LM
, Tunis SR
, Kelloff GJ
This article defines and describes best practices for the academic and business community to generate evidence of clinical utility for cancer molecular diagnostic assays. Beyond analytical and clinical validation, successful demonstration of clinical utility involves developing sufficient evidence to demonstrate that a diagnostic test results in an improvement in patient outcomes. This discussion is complementary to theoretical frameworks described in previously published guidance and literature reports by the U.S. Food and Drug Administration, Centers for Disease Control and Prevention, Institute of Medicine, and Center for Medical Technology Policy, among others. These reports are comprehensive and specifically clarify appropriate clinical use, adoption, and payer reimbursement for assay manufacturers, as well asClinical Laboratory Improvement Amendments-certified laboratories, including those that develop assays (laboratory developed tests). Practical criteria and steps for establishing clinical utility are crucial to subsequent decisions for reimbursement without which high-performing molecular diagnostics will have limited availability to patients with cancer and fail to translate scientific advances into high-quality and cost-effective cancer care. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development."