A proposed approach to accelerate evidence generation for genomic-based technologies in the context of a learning health system.

Theranos Experience Exposes Weaknesses in FDA Regulatory Discretion.

There is a need for valid and reliable biomarkers in hidradenitis suppurativa (HS) for diagnosis and disease activity monitoring. Imaging-based biomarkers have the potential to fulfil this unmet need but no evaluation of analytical or clinical validity has yet been undertaken. To evaluate the analytical and clinical validity of sonographic epidermal thickness, Doppler ultrasound and dermal tunnel diameter in patients with HS. Twenty-two participants with HS were recruited and underwent a total of 65 matched ultrasound and skin biopsies of lesional, perilesional and unaffected tissue. Ultrasound measurements were performed in triplicate with mean values used. Skin biopsies underwent immunohistochemistry as per previously published methods. Analytical validity was assessed in individual ultrasound-biopsy pairs (n = 65) by comparisons of sonographic variables with histological correlates. Clinical validity was assessed in individual patients (n = 22) by comparing measures of overall disease activity with sonographic outcomes. Epidermal thickness, dermal tunnel diameter and power Doppler intensity were assessed. Sonographic epidermal thickness and dermal tunnel diameter have high analytical validity with corresponding histological measurements. Power Doppler intensity demonstrated high correlation with dermal CD3+ and CD11c+ cell counts but not neutrophil elastase-positive cells. Power Doppler ultrasound has significant correlation with pain scores, abscess and nodule count, International HS Severity Scoring System score and number of draining tunnels. Sonographic epidermal thickness and dermal tunnel diameter have acceptable levels of analytical validity in the assessment of HS lesions. Power Doppler intensity demonstrates acceptable clinical and analytical validity, suggesting it is a valid imaging-based biomarker in HS.

The use of anti–human epidermal growth factor receptor 2 (HER2) targeted agents in addition to cytotoxic chemotherapy has had a substantial and positive impact on the survival of patients with HER2-overexpressing or -amplified breast cancer. However, treatment is not effective for every patient. Therefore, over the last decade or more there has been a quest to identify biomarkers that predict benefit, or more importantly, lack of benefit, from anti-HER2 therapies. Unfortunately, this quest has been unsuccessful, and so we continue to treat all patients with HER2-positive breast cancer with costly, inconvenient, and occasionally toxic therapies to ensure that we include the roughly one third who will benefit with improved diseasefree and overall survival. Indeed, the most recent update of the American Society of Clinical Oncology/College of American Pathologists HER2 guidelines were admittedly directed toward sensitivity over specificity of the assays, given that these treatments have been so effective and are reasonably well tolerated. In the article that accompanies this editorial, Loibl et al from the German Breast Group have evaluated the association between presence of PIK3CA mutations and response to anti-HER2 therapy by analyzing specimens collected from patients who participated in three previously conducted, prospective neoadjuvant clinical trials. Their data indicate that the presence of PIK3CA mutations is associated with a poorer pathologic complete response (pCR) in patients who received trastuzumab, lapatinib, or a combination of the two. Although intriguing, the exact clinical application of these data requires a thoughtful discussion of their meaning. Substantial attention has been paid to the development and testing of new therapeutic agents, but less rigor has been applied when identifying and validating tumor biomarkers. However, recent efforts to generate the same sense of value for tumor biomarkers that we have for anticancer treatments have gained traction. It is important to understand that a tumor biomarker is an indication of cancer biology and behavior, but that there may be one or more tests for that biomarker, and that they may not provide identical, or even similar, results. In this regard, a tumor biomarker test should not be incorporated into routine clinical care until it has cleared a number of hurdles, best articulated by the Evaluation of Genomic Applications in Practice and Prevention Working Group of the Centers for Disease Control and Prevention. First, a tumor biomarker must be demonstrated to have analytic validity. In other words, the assay must accurately, reliably, and reproducibly measure what it is intended to measure. Second, the tumor biomarker test must have clinical (or biologic) validity, which implies that it separates one population into two or more groups with distinctly different outcomes. However, for a tumor biomarker test to be incorporated into standard of care, it must also be shown to have clinical utility. Establishment of clinical utility requires a high level of evidence from either prospective or prospective–retrospective studies demonstrating that application of the marker to direct therapy improves patient outcomes with sufficient magnitude to justify testing all eligible patients. How should these high levels of evidence be generated? Ideally, as with new therapeutics, one would perform a prospective trial in which the clinical utility of the tumor biomarker test is the primary objective. Several authors have published various trial designs to address this issue. However, unlike new therapeutics, it might be possible to generate high levels of evidence for a tumor biomarker test using archived specimens. Simon et al have proposed criteria for such studies. These criteria are rigorous, requiring that the archived specimens be collected from patients who participated in previously conducted clinical trials that addressed a use to which the tumor biomarker test might be applied, and that a prospectively written correlative science protocol be prepared with a set study design and analytic plan. These criteria raise several points. It does seem that the assay for PIK3CA mutations has high analytic validity. However, we must ask: what is the intended use of the tumor biomarker assay? In the accompanying article, Loibl et al investigated the apparent prediction of anti-HER2 therapy benefit or lack of benefit. However, their clinical trials were not designed to address this question. In other words, patients were not randomly assigned to receive or not receive antiHER2 therapy, nor were they given single-modality anti-HER2 therapy, without chemotherapy, to determine if response was a result of the anti-HER2 therapy or the chemotherapy. Just as importantly, we must ask: what is the study end point? Although response is a convenient surrogate end point to determine JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 29 OCTOBER 1

The use of modern genomic technologies, along with the benefits to the man and society, can lead to negative consequences. Such risks exist both in the process and after the production, isolation, modification, storage of DNA. Prior to detailed legislative regulation of relations regarding the use of genomic technologies for medicinal purposes and not for medical reasons, legal principles become vital.The paper formulates the following basic legal principles of genomic technologies application: the principle of preventive actions of the state to protect citizens from the risks of using genomic technologies; the principle of preserving the human genome as a special species; the principle of guaranteeing the inviolability of the individual of every citizen when using genomic technologies; the principle of priority of life and health of citizens over the interests of science and society; the principle of equality of citizens regardless of genetic characteristics; the principle of protection of genetic information of every citizen as part of personal data; the principle of guaranteeing access to the citizen’s own genetic information. Legal principles can be used to resolve a dispute by analogy of law.

IntroductionThe last decade has witnessed a steady adoption of personalized medicine. However, the evaluation of genetic and genomic tests is not straightforward. The purpose of this systematic review was to identify health technology assessment (HTA) reports assessing genetic and genomic tests to summarize the methodologies used, the maturity level of the evidence included, and the highlighted research gaps.Methods The PubMed, Scopus, and Web of Science databases were searched for HTA reports of genetic or genomic tests. The main national and international HTA report repositories (e.g., the international HTA database) were also searched. HTA reports that were specifically created to assess genetic or genomic technologies and included at least three core evaluation components (analytic validity, clinical validity, clinical utility, economic evaluation, organizational aspects, or ethical, legal, and social implications) were included. This study was supported by the European Commission and the Ministry for Universities and Research under the National Recovery and Resilience Plan (M4C2-I1.3 Project PE_00000019 “HEAL ITALIA”).ResultsOverall, 27,331 unique records were retrieved, 55 of which were included in the systematic review. The reports were mainly from Australia (29%), Canada (27%), and the UK (25%); focused on pharmacogenomics (36%) and oncology (35%); and investigated test use for treatment guidance (42%) or diagnosis (29%). The most reported evaluation components were economic evaluation (87%), clinical utility (76%), and clinical validity (67%). On the other hand, personal utility (7%), patients’ perspectives (27%), and ethical (15%), legal (11%), and social (24%) implications were poorly represented. Analytical validity, safety, and organizational aspects were included in about half of the reports.Conclusions Although these are only preliminary results, the substantial lack of a shared standard in the evaluation of genetic and genomic applications is clear given the heterogeneity of the dimensions addressed among the reports. Theres is a need to strengthen evaluation of the neglected dimensions, which are often of primary importance in defining the value and risks of personalized medicine.

BackgroundThe revolution in DNA sequencing technologies over the past decade has made it feasible to sequence an individual’s whole genome at a relatively low cost. The potential value of the information generated by genomic technologies for medicine and society is enormous. However, in order for exome sequencing, and eventually whole genome sequencing, to be implemented clinically, a number of major challenges need to be overcome. For instance, obtaining meaningful informed-consent, managing incidental findings and the great volume of data generated (including multiple findings with uncertain clinical significance), re-interpreting the genomic data and providing additional counselling to patients as genetic knowledge evolves are issues that need to be addressed. It appears that medical genetics is shifting from the present “phenotype-first” medical model to a “data-first” model which leads to multiple complexities.DiscussionThis manuscript discusses the different challenges associated with integrating genomic technologies into clinical practice and describes a “phenotype-first” approach, namely, “Individualized Mutation-weighed Phenotype Search”, and its benefits. The proposed approach allows for a more efficient prioritization of the genes to be tested in a clinical lab based on both the patient’s phenotype and his/her entire genomic data. It simplifies “informed-consent” for clinical use of genomic technologies and helps to protect the patient’s autonomy and privacy. Overall, this approach could potentially render widespread use of genomic technologies, in the immediate future, practical, ethical and clinically useful.SummaryThe “Individualized Mutation-weighed Phenotype Search” approach allows for an incremental integration of genomic technologies into clinical practice. It ensures that we do not over-medicalize genomic data but, rather, continue our current medical model which is based on serving the patient’s concerns. Service should not be solely driven by technology but rather by the medical needs and the extent to which a technology can be safely and effectively utilized.

Background: Omics technologies, enabling the measurements of genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics), are valuable tools for personalized decision-making. We aimed to identify the existing value assessment frameworks used by health technology assessment (HTA) doers for the evaluation of omics technologies through a systematic review. Methods: PubMed, Scopus, Embase and Web of Science databases were searched to retrieve potential eligible articles published until 31 May 2020 in English. Additionally, through a desk research in HTA agencies’ repositories, we retrieved the published reports on the practical use of these frameworks. Results: Twenty-three articles were included in the systematic review. Twenty-two frameworks, which addressed genetic and/or genomic technologies, were described. Most of them derived from the ACCE framework and evaluated the domains of analytical validity, clinical validity and clinical utility. We retrieved forty-five reports, which mainly addressed the commercial transcriptomic prognostics and next generation sequencing, and evaluated clinical effectiveness, economic aspects, and description and technical characteristics. Conclusions: A value assessment framework for the HTA evaluation of omics technologies is not standardized and accepted, yet. Our work reports that the most evaluated domains are analytical validity, clinical validity and clinical utility and economic aspects.

BackgroundIn the last decade, the research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers (Pepe et al., 2001) to AD, with the aim to accelerate their development and implementation in clinical practice (Frisoni et al., 2017). With this work we assess the maturity of tau biomarkers and we define the research priorities.MethodsIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity for first and second generation tau PET tracers, CSF, and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshop.ResultsTau PET biomarkers showed partial evidence of analytical and clinical validity, particularly in their efficiency to distinguish AD dementia patients from healthy controls. First‐generation and second‐generation tracers showed different properties in terms of specific binding and accuracy in distinguishing AD from other neurodegenerative diseases. Plasma biomarkers showed promising achievements in analytical validity for p‐tau and Aβ42, while total tau was judged as unsuccessful by the experts. Compared to the recent introduction of tau PET and plasma, cerebrospinal fluid (CSF) biomarkers have been explored for decades in AD, and consistently they showed the highest level of maturity according to the strategic roadmap, with significant improvements compared to 2017, the development of fully automated assays being the most valuable. Research priorities consequently mainly concern analytical and clinical validity aims, with a main focus on covering assay definition and validation versus post‐mortem specimens. In view of studies on clinical utility, the definition of appropriate patient‐ and clinically‐relevant outcomes emerged as an urgent priority.ConclusionsDespite the recent development of PET‐ and plasma‐based tau biomarkers, both so far provide partial evidence for clinical validity. However, completion of studies on analytical validity is a key step required to properly investigate their clinical utility.

Contribution of biomarkers to personalized medicine

A plethora of genetic tests for susceptibility to common complex disorders have made their way onto the market. Groceries, clothing, hardware equipment, plane tickets and, now, even genetic tests can be ordered directly over the internet, from the comfort of your own home, without ever seeing a physician. Is this simply a natural progression, following in the footsteps of home pregnancy tests and blood-pressure monitors, which many people would admit do fulfill a certain niche and accomplish a lot of good for health-conscious consumers? After all, genetic testing is at the root of personalized medicine within the context of specific drug responses (pharmacogenetics). There are examples of genetic variants that do have a significant and clinically relevant effect on drug response; therefore, testing for them can lead to more efficient and cost–effective treatments [1]. However, there are many more examples with questionable validity and usefulness, so this begs the question: do direct-to-consumer (DTC) genetic services, which allow consumers to completely bypass the traditional healthcare system, do more harm than good? Direct-to-consumer genetic testing can be understood as including two related aspects: first, the advertising of genetic tests directly to consumers; and second, the direct access or ordering of genetic tests without the intermediate of a healthcare professional [2]. Although both aspects are equally important and do raise important ethical issues, they differ sufficiently to warrant separate analyses. This editorial will focus solely on DTC access to genetic testing. Other publications have tackled the issue of advertising [3,4]. Over 1100 genetic tests are available clinically and several hundreds are available in research settings. Although most genetic tests are still only available through a healthcare provider, a growing number of tests

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

BackgroundWith the emergence of disease-modifying therapies for Alzheimer’s disease (AD), there is an urgent need for scalable, accurate, and well-validated blood test alternatives to positron emission topography (PET) and lumbar punctures for identifying amyloid pathology to facilitate identification of candidates for therapy. Plasma p-Tau 217 has emerged as a plasma-based biomarker with sufficient sensitivity and specificity to both rule out and rule in amyloid pathology with high confidence, potentially serving as a readily scalable non-invasive test to aid AD diagnosis. In this report, we describe robust analytical and clinical validation of a lab developed test for plasma p-Tau 217 suitable for clinical diagnostic use.MethodsA high sensitivity digital immunoassay using single molecule array (Simoa) technology was developed for plasma p-Tau 217 utilizing a 2-cutoff approach. The assay was analytically validated with industry standard protocols and clinically validated across 873 symptomatic individuals from two independent clinical cohorts using PET or cerebrospinal fluid (CSF) biomarkers as comparators.ResultsThe assay exhibited acceptable analytical characteristics with an analytical sensitivity enabling measurement of plasma p-Tau 217 in all clinical samples. Excluding results between the two cutoffs, clinical sensitivity, specificity, and agreement with comparator methods (accuracy) were >90%, with 30.9% of the samples falling in the intermediate zone between the two cutoffs.DiscussionThe performance characteristics of the Simoa p-Tau 217 assay align with current accuracy recommendations for blood-based biomarker test performance for diagnostic use, making the test suitable for clinical use under the Clinical Laboratory Improvement Act (CLIA) as a diagnostic plasma test to aid in Alzheimer’s diagnosis.

Javitt et al. [1]propose a blueprint for a mandated genetic test registry to support informed health care decision making. According to the authors, the core aim of the registry is ‘to promote transparency, which includes disclosure of both what is known and what is not known.’ They propose that for each test, the registry should include not only a description of the test and its intended use, but also information about its analytic and clinical validity, clinical utility, and proficiency testing. We agree that reporting data on validity and utility is an essential element of quality assurance in genetic testing. Nevertheless, whether reporting to a genetic test registry is mandated or not, there is a fundamental challenge in implementation of such a registry, particularly with regard to the sources, standards and quality of submitted data and their systematic evaluation. As acknowledged by the authors, laboratories performing genetic tests may have only some of the data needed to evaluate validity and utility of tests. In particular, information on clinical validity and utility will have to be brought together from multiple sources, including basic research, clinical trials, and epidemiological and clinical studies. The available information is frequently fragmented, sometimes contradictory, or simply not available. Thus, a comprehensive assessment of clinical validity and utility requires knowledge synthesis in the form of systematic evidence reviews from multiple sources. Most laboratories are currently not equipped to conduct such analyses. We believe that a remedy for this problem is a process of systematic knowledge synthesis followed by evidence-based recommendations by an independent group. The Centers for Disease Control and Prevention (CDC) has explored the feasibility and methods for such a process by 2 synergistic initiatives. The first initiative, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) project was launched in 2004 [2]. The main goal of EGAPP is to establish a rigorous, systematic, evidence-based process for evaluating genetic tests that are in transition from research to clinical and public health practice. An independent, non-federal EGAPP working group developed methods for reviewing evidence on emerging complex genetic tests by modifying existing approaches used by professional organizations, advisory committees, independent task forces (e.g., U.S. Preventive Services Task Force and CDC's Task Force on Community Preventive Services) and international health technology assessment groups. The EGAPP working group also developed processes for identifying, prioritizing and selecting topics, performing evidence reviews, and developing recommendations for practice based on the evidence. As of July 2009, EGAPP has published their methods [3], 5 evidence reports and 4 recommendations, with others still in the pipeline [4]. The second initiative is the Genomic Applications in Practice and Prevention Network (GAPPNet), launched in 2009 [5]. GAPPNet is a stakeholder-driven enterprise with representation from academia, government, health care, public health, industry, and the community. The network aims to promote systematic review of research findings, support for translation research, and diffusion of high quality information on genomic applications in practice and prevention. One of GAPPNet's goals is the development of an online knowledge base on the clinical validity and utility of genomic applications [6]. When systematic reviews have been conducted by EGAPP or other health technology assessment groups, the knowledge base will provide links to these reviews. For selected genomic applications lacking comprehensive reviews, brief systematic summaries of available evidence will be provided. When no information is available, this will also be noted, which will stimulate research to fill these knowledge gaps. The GAPPNet knowledge base is expected to provide an initial point of reference for what we know and what we don't know, as well as a source for updated information as it is compiled by GAPPNet members from published and unpublished applied research. Clearly, establishing a genetic test registry is a worthwhile goal; however, the blueprint by Javitt et al. describes a structure without the necessary utilities: that is, the connections to a growing grid of translational research and evidence-based knowledge syntheses that will provide the essential multifaceted data on validity and utility. Creating a registry with credible information requires more than mandating submission of data by laboratories. The methods and products of EGAPP, together with the goals and upcoming activities of GAPPNet, could easily be integrated into the implementation of the genetic test registry to enhance the utility of the registry to providers, consumers, researchers, and policy makers.

Introduction: the paper deals with the problem of civil rights protection when using genomic technologies in the field of artificial human reproduction. Breakthrough advances in medical and biological science set the state an important task of developing an effective system of legal guarantees aimed at ensuring a fair balance of interests of the parties to the relevant relationship and third parties, protecting the rights and interests of an individual, preventing human biotechnological engineering for the purposes of eugenic practice, etc. According to the author, special attention should be paid to the problem of protecting the rights of the child when using genomic technologies, including preimplantation genetic testing. Purpose: to solve the problem of developing the conceptual foundations of civil rights protection under civil law when using genomic technologies in the field of artificial human reproduction, which involves researching the grounds and peculiarities of applying methods of civil rights protection when using genomic technologies, in particular the technology of preimplantation genetic testing, which will make it possible to productively use these constructions; to create a uniform law enforcement practice in this area. Methods: general scientific, interdisciplinary methods common to the science of civil law and biomedicine (e.g. mathematical method, logical method) and methods specific to each of these sciences; logical, comparative legal, formal legal methods. Results: the author has studied the following: the available Russian and foreign regulatory framework and doctrinal sources on the protection of civil rights, especially the rights of the child, in the field of genomic technologies application; the implementation of the methods of protecting civil rights when using genomic technologies and, in particular, protecting the rights of the child, with attention focused on the specific features of the parties involved in legal relations in this area; the peculiarities of the legal nature of civil liability in the considered category of disputes. Conclusions: the paper provides conclusions reflecting the author's conceptual view of the problem of civil rights protection under civil law when using genomic technologies, in particular, the technology of preimplantation genetic testing. There were determined the directions for improving legislation in relation to persons born as a result of artificial reproduction with the use of genomic technologies; the limits of genomic technologies application in the field of reprogenetics and the conditions of liability in case of their violation were justified.

The purpose of the paper is to determine the main international standards and positions of international intergovernmental and non-governmental organizations regarding the use of genomic technologies in medicine, which are reflected in their documents. At the universal level, there is no international treaty containing uniform rules in this area, but there are many documents of international organizations (such as WHO, UNESCO) that set out the relevant standards. At the regional level, the experience of the Council of Europe in the field of legal regulation of genomic medicine plays a significant role. National approaches to the legal regulation of genomic medicine vary. In such conditions, the practice of international non-governmental organizations in the field of biomedicine and genetic technologies plays a significant role. They set standards and represent the positions of the biomedical community.Based on the analysis of international acts, it can be concluded that the general position of the international biomedical community is that genome editing technologies can be widely used for therapeutic and scientific purposes, provided that there is no criterion for transmitting genes to descendants. Genome editing should be carried out in accordance with international professional and ethical standards, including the principles of benefit over harm and informed consent. Discussions about the admissibility of hereditary genome editing continue. The prevailing approach of international organizations is that there are currently no reasonable standards for the safety and effectiveness of this technology, while research itself is encouraged.