Wolf Rogowski

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

What is personalized medicine: sharpening a vague term based on a systematic literature review

BackgroundRecently, individualized or personalized medicine (PM) has become a buzz word in the academic as well as public debate surrounding health care. However, PM lacks a clear definition and is open to interpretation. This conceptual vagueness complicates public discourse on chances, risks and limits of PM. Furthermore, stakeholders might use it to further their respective interests and preferences. For these reasons it is important to have a shared understanding of PM. In this paper, we present a sufficiently precise as well as adequate definition of PM with the potential of wide acceptance.MethodsFor this purpose, in a first step a systematic literature review was conducted to understand how PM is actually used in scientific practice. PubMed was searched using the keywords “individualized medicine”, “individualised medicine”, “personalized medicine” and “personalised medicine” connected by the Boolean operator OR. A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing the search terms in title or abstract were screened for definitions. Definitions were extracted; according to the means/ends distinction their elements were assigned to the corresponding category. To reduce complexity of the resulting list, summary categories were developed inductively from the data using thematic analysis. In a second step, six well-known criteria for adequate definitions were applied to these categories to derive a so-called precising definition.ResultsWe identified 2457 articles containing the terms PM in title or abstract. Of those 683 contained a definition of PM and were thus included in our review. 1459 ends and 1025 means were found in the definitions. From these we derived the precising definition: PM seeks to improve stratification and timing of health care by utilizing biological information and biomarkers on the level of molecular disease pathways, genetics, proteomics as well as metabolomics.ConclusionsOur definition includes the aspects that are specific for developments labeled as PM while, on the other hand, recognizing the limits of these developments. Furthermore, it is supported by the quantitative analysis of PM definitions in the literature, which suggests that it it is widely acceptable and thus has the potential to avoid the above mentioned issues.

Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers.

BackgroundTissue engineering is an emerging field. Novel bioengineered skin substitutes and genetically derived growth factors offer innovative approaches to reduce the burden of diabetic foot and venous leg ulcers for both patients and health care systems. However, they frequently are very costly. Based on a systematic review of the literature, this study assesses the cost-effectiveness of these growth factors and tissue-engineered artificial skin for treating chronic wounds.MethodsOn the basis of an extensive explorative search, an appropriate algorithm for a systematic database search was developed. The following databases were searched: BIOSIS Previews, CRD databases, Cochrane Library, EconLit, Embase, Medline, and Web of Science. Only completed and published trial- or model-based studies which contained a full economic evaluation of growth factors and bioengineered skin substitutes for the treatment of chronic wounds were included. Two reviewers independently undertook the assessment of study quality. The relevant studies were assessed by a modified version of the Consensus on Health Economic Criteria (CHEC) list and a published checklist for evaluating model-based economic evaluations.ResultsEleven health economic evaluations were included. Three biotechnology products were identified for which topical growth factors or bioengineered skin substitutes for the treatment of chronic leg ulceration were economically assessed: (1) Apligraf®, a bilayered living human skin equivalent indicated for the treatment of diabetic foot and venous leg ulcers (five studies); (2) Dermagraft®, a human fibroblast-derived dermal substitute, which is indicated only for use in the treatment of full-thickness diabetic foot ulcers (one study); (3) REGRANEX® Gel, a human platelet-derived growth factor for the treatment of deep neuropathic diabetic foot ulcers (five studies). The studies considered in this review were of varying and partly low methodological quality. They calculated that due to shorter treatment periods, fewer complications and fewer inpatient episodes the initial cost of the novel biotechnology products may be offset, making the treatment cost-effective or even cost-saving. The results of most studies were sensitive to initial costs of the products and the evidence of effectiveness.ConclusionThe study results suggest that some growth factors and tissue-engineered artificial skin products feature favourable cost-effectiveness ratios in selected patient groups with chronic wounds. Despite the limitations of the studies considered, it is evident that health care providers and coverage decision makers should take not only the high cost of the biotechnology product but the total cost of care into account when deciding about the appropriate allocation of their financial resources. However, not only the cost-effectiveness but first of all the effectiveness of these novel biotechnology products deserve further research.

Challenges of translating genetic tests into clinical and public health practice

Research in genetics and genomics has led to an expanding list of molecular genetic tests, which are increasingly entering health care systems. However, the evidence surrounding the benefits and harms of these tests is frequently weak. Here we present the main challenges to the successful translation of new research findings about genotype–phenotype associations into clinical practice. We discuss the means to achieve an accelerated translation research agenda that is conducted in a reasonable, fair and efficient manner.

Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.

Background: Proposals for population screening for genetic diseases require careful scrutiny by decision makers because of the potential for harms and the need to demonstrate benefits commensurate with the opportunity cost of resources expended. Methods: We review current evidence-based processes used in the United States, the United Kingdom, and the Netherlands to assess genetic screening programs, including newborn screening programs, carrier screening, and organized cascade testing of relatives of patients with genetic syndromes. In particular, we address critical evidentiary, economic, and ethical issues that arise in the appraisal of screening tests offered to the population. Specific case studies include newborn screening for congenital adrenal hyperplasia and cystic fibrosis and adult screening for hereditary hemochromatosis. Results: Organizations and countries often reach different conclusions about the suitability of screening tests for implementation on a population basis. Deciding when and how to introduce pilot screening programs is challenging. In certain cases, e.g., hereditary hemochromatosis, a consensus does not support general screening although cascade screening may be cost-effective. Conclusion: Genetic screening policies have often been determined by technological capability, advocacy, and medical opinion rather than through a rigorous evidence-based review process. Decision making should take into account principles of ethics and opportunity costs.

Genetic screening by DNA technology: A systematic review of health economic evidence

OBJECTIVES The Human Genome Project has led to a multitude of new potential screening targets on the level of human DNA. The aim of this systematic review is to critically summarize the evidence from health economic evaluations of genetic screening in the literature. METHODS Based on an extensive explorative search, an appropriate algorithm for a systematic database search was developed. Twenty-one health economic evaluations were identified and appraised using published quality criteria. RESULTS Genetic screening for eight conditions has been found to be investigated by health economic evaluation: hereditary breast and ovarian cancer, familial adenomatous polyposis (FAP) colorectal cancer, hereditary nonpolyposis colorectal carcinoma (HNPCC), retinoblastoma, familial hypercholesterolemia, hereditary hemochromatosis, insulin-dependent diabetes mellitus, and cystic fibrosis. Results range from dominated to cost-saving. Population-wide genetic screening may be considered cost-effective with limited quality of evidence only for three conditions. The methodology of the studies was of varying quality. Cost-effectiveness was primarily influenced by mutation prevalence, genetic test costs, mortality risk, effectiveness of treatment, age at screening, and discount rate. CONCLUSIONS Health economic evidence on genetic screening is limited: Only few conditions have properly been evaluated. Based on the existing evidence, healthcare decision makers should consider the introduction of selective genetic screening for FAP and HNPCC. As genetic test costs are declining, the existing evaluations may warrant updating. Especially in the case of hereditary hemochromatosis, genetic population screening may be about to turn from a dominated to a cost-effective or even cost-saving intervention.

Clearing up the hazy road from bench to bedside: A framework for integrating the fourth hurdle into translational medicine

BackgroundNew products evolving from research and development can only be translated to medical practice on a large scale if they are reimbursed by third-party payers. Yet the decision processes regarding reimbursement are highly complex and internationally heterogeneous. This study develops a process-oriented framework for monitoring these so-called fourth hurdle procedures in the context of product development from bench to bedside. The framework is suitable both for new drugs and other medical technologies.MethodsThe study is based on expert interviews and literature searches, as well as an analysis of 47 websites of coverage decision-makers in England, Germany and the USA.ResultsEight key steps for monitoring fourth hurdle procedures from a company perspective were determined: entering the scope of a healthcare payer; trigger of decision process; assessment; appraisal; setting level of reimbursement; establishing rules for service provision; formal and informal participation; and publication of the decision and supplementary information. Details are given for the English National Institute for Health and Clinical Excellence, the German Federal Joint Committee, Medicares National and Local Coverage Determinations, and for Blue Cross Blue Shield companies.ConclusionCoverage determination decisions for new procedures tend to be less formalized than for novel drugs. The analysis of coverage procedures and requirements shows that the proof of patient benefit is essential. Cost-effectiveness is likely to gain importance in future.

The Cost-Effectiveness of Screening for Hereditary Hemochromatosis in Germany: A Remodeling Study

Objective . Genetic tests for hereditary hemochromatosis (HH) are currently included in the German ambulatory care reimbursement scheme but only for symptomatic individuals and the offspring of HH patients. This study synthesizes the most current evidence to examine whether screening in the broader population is cost-effective and to identify the best choice of initial and follow-up screening tests. Methods . A probabilistic decision-analytic model was constructed to calculate cost per life year gained (LYG) for HH screening among male Caucasians aged 30. Three strategies were considered in both the general population and male offspring of HH patients: phenotypic (transferrin saturation, TS), genotypic (C282Y mutation), and sequential (genotype if TS is elevated) screening. Results . The incremental cost-effectiveness of sequential screening among male offspring, sequential population-wide screening, and genotypic screening is 41 000, 124 000, and 161 000 /LYG, respectively. All other strategies were subject to simple or extended dominance. The results are subject to high uncertainty. The most influential parameters in the deterministic one-way sensitivity analysis are discounting of life years gained and the adherence of patients to preventive phlebotomy. Discussion . The current German policy of only screening at-risk individuals is consistent with health economic decision making based on typically accepted thresholds. However, conducting the DNA test after the first elevated TS result is more cost-effective than waiting for a second TS result as recommended by the German guidelines. Further empirical work regarding adherence to long-term prevention recommendations and explicit and well-justified guidance for the choice of discount rates in German economic evaluation are needed.

Genetic Testing and Common Disorders: How to Assess Relevance and Possibilities

In recent years, the attention of the genomics and genetics research community has shifted toward understanding the basis of common disorders. The spectacular growth of genome-wide association studies has shed new light on the variants influencing risk factors. Understanding pathogenesis and etiology, and finding new ways to prevent and treat those diseases are major challenges. In the era of genomics, a promise of personalized prevention and drug treatment is presented, which many people meet with enthusiasm but which others call into question. The Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG), EuroGentest and the Institute for Prospective Technological Studies (IPTS) convened to discuss the relevance and possibilities of genetic testing for common disorders. Currently (in 2010), the genetics research community is skeptical about the possibilities of genetic susceptibility testing and screening contributing significantly to the improvement of the quality of health care. Meanwhile, some applications of very limited clinical utility have become available directly to consumers. Recently, the PPPC published critical recommendations on policy concerning DTC genetic testing (EJHG, 25 August 2010). When considering the potential of new genomic developments for a public health perspective, this Background Document takes the spectrum ranging from monogenic disorders on the one hand to common complex disorders on the other hand into account. It is argued that associations between genetic variants and disease risks of clinical relevance have been established, for instance for hereditary breast and ovarian cancer, colon cancer, diabetes mellitus (MODY subtypes), thrombosis, cardiovascular disorders, celiac disease and Alzheimers disease. Although these examples relate to the monogenic subforms of common disease, they can nevertheless be used to reflect on the possibilities and relevant obstacles in using the new genetics in public health. The deliberations, reflected in the final Background Document, have led to the below recommendations from the PPPC concerning the pitfalls and possibilities of genetic testing in common disorders. A draft of both the Background Document and Recommendations has been distributed and posted on the web during the summer of 2009 to elicit further comments. The PPPC and the Board of the ESHG approved the final version. This final text is considered to reflect the views of the European human genetics scientific and professional community.

Eliciting preferences for priority setting in genetic testing: a pilot study comparing best-worst scaling and discrete-choice experiments

Given the increasing number of genetic tests available, decisions have to be made on how to allocate limited health-care resources to them. Different criteria have been proposed to guide priority setting. However, their relative importance is unclear. Discrete-choice experiments (DCEs) and best-worst scaling experiments (BWSs) are methods used to identify and weight various criteria that influence orders of priority. This study tests whether these preference eliciting techniques can be used for prioritising genetic tests and compares the empirical findings resulting from these two approaches. Pilot DCE and BWS questionnaires were developed for the same criteria: prevalence, severity, clinical utility, alternatives to genetic testing available, infrastructure for testing and care established, and urgency of care. Interview-style experiments were carried out among different genetics professionals (mainly clinical geneticists, researchers and biologists). A total of 31 respondents completed the DCE and 26 completed the BWS experiment. Weights for the levels of the six attributes were estimated by conditional logit models. Although the results derived from the DCE and BWS experiments differed in detail, we found similar valuation patterns in the DCE and BWS experiments. The respondents attached greatest value to tests with high clinical utility (defined by the availability of treatments that reduce mortality and morbidity) and to testing for highly prevalent conditions. The findings from this study exemplify how decision makers can use quantitative preference eliciting methods to measure aggregated preferences in order to prioritise alternative clinical interventions. Further research is necessary to confirm the survey results.