Molecular genetic diagnostics as a triage mechanism in cardiology using the example of familial hypercholesterolemia: Organisational and ethical implications (part 1) and economic effects (part 2)

Research areas: Prevention and screening, Health economics

Project lead: Melanie Walter (part 1), Christoph Strohmaier (part 2)
Duration: May 2020 – October 2020
Language: English (with German summary)

Publication: HTA Project report No. 130: http://eprints.aihta.at/1281/

 

Background:

The so-called personalised medicine or precision health care (PM/PHC) are domains that gradually take roots in the medical field influencing the decisions and behaviour of clinicians, the pharmaceutical industry, patients, payers, decision makers, and the functioning of the health system in general. These fields are strongly driven by new diagnostics and therapeutics, which - based on biomarkers, genetic, phenotypic or psychosocial characteristics - distinguish an individual patient from other patients with similar clinical conditions and thus form risk-based strata [1]. Molecular genetic tests are an increasingly important instrument of diagnostics, on the one hand for the definitive diagnosis of a disease and on the other hand as a prerequisite (companion diagnostics) for therapy with specifically effective drugs (prognostics). Often, however, the focus is not only on the genetic constitution of the affected patients themselves, but also on the resulting consequences for their offspring and relatives (prediction). In oncology and neurology, molecular genetic diagnostic, prognostic as well as predictive tests have been established for years and are widely used.

Due to the discovery of functional gene sequences related to familial hypercholesterolemia (FH) (LDLR, APO-B, PCSK9), molecular genetic testing is becoming increasingly important in cardiology, particularly as a triage mechanism for risk stratification in the prevention of (arteriosclerotic) cardiovascular diseases. FH is a widespread inheritable disorder of the lipid metabolism that increases the risk of (arteriosclerotic) cardiovascular events, even at a young age [2]. In Austria, a molecular genetic confirmation of the presence of a mutation on the FH-associated genes is not mandatory for diagnosis. In addition to a definitive diagnosis, an expansion of molecular genetic testing may help to more effective cascade tests of relatives at risk, the initiation of therapies in earlier years as well as to improved and more efficient therapeutic decisions in general (e.g. a decision on the use of PCSK9 inhibitors) [2]. Against this background, organisational-logistical questions as well as ethical aspects of the implementation of a systematic test, but also far-reaching economic effects, have to be considered.

Project objectives and research questions:

The aim of the project is to provide a decision document for the implementation of (predictive) molecular genetic diagnostics as a triage mechanism in cardiology using the example of the FH.  The following research questions are to be answered:

• Q1: Which test strategies to diagnose FH exist and which are recommended by (inter-) national associations?
• Q2: What are the organisational/logistical requirements and necessities for the different test strategies?
• Q3: Which ethical and regulatory aspects have to be considered in (predictive) molecular genetic diagnostics?
• Q4: Which test strategy is currently used in Austria?
• Q5: What are the economic implications of the different test strategies?

Methods:

The following methods are used to answer the research questions:

• Q1: Systematic synthesis of test strategies in a country comparison (without evaluating the effectiveness and the benefit of the respective test strategy): Overview of guidelines, algorithms, and recommendations from expert societies on how to proceed in dealing with the diagnosis of FH as well as the prescription and response control of PCSK9 inhibitors in the presence of a FH-diagnosis.
• Q2: Extraction of the organisational processes, description of the actors involved and their interactions as well as the qualitative deduction of the logistic requirements and necessities of the respective test strategy.
• Q3: Systematic synthesis of ethical and regulatory aspects: Overview of recommendations for dealing with (predictive) genetic information and extraction of relevant arguments and aspects (based on the Hofmann question catalogue [3]) in form of a perspective-sensitive matrix.
• Q4: Analysis of the current processes in Austria and contrasting them to other test strategies, including contacting experts from the field of cardiology and human genetics as well as patient organisations.
• Q5: Economic extrapolation of the cost implications of different test strategies, organisational models and follow-up costs in form of a scenario analysis respectively a budget impact analysis; if accessible, Austria-specific costs based on tariff catalogues and administrative data are used.

For Q1, Q3 and Q5, systematic searches supplemented by iterative manual searches (in German and English) will be conducted in several databases (Medline, Embase, G-I-N guidelines, Trip Database, EconLit, RePec etc.).

In addition, for Q1

• official public health institutions (e.g. NHS, G-BA, KBV, KV, social insurances)
• expert societies (e.g. AWMF, AHA, NLA)
• HTA, EbM institutions (e.g. NICE, NIH, ethics councils)

for Q3

• ethics-related databases (e.g. Belit, CINAHL, EthxWeb, ETHICSWEB, PsycINFO, Scopus)
• guidelines from national genetics networks
• stakeholder websites

and for Q4

• sources of Austria-specific guidelines, national expert societies, policy documents, etc.

will be searched for relevant literature.

For Q5, additional administrative data (tariff regulations, claims data, etc.) and the unit cost database of the Department for Health Economics at the Med-Uni Vienna will be used as data sources for cost calculations and exploration of the budget consequences.

PICO framework/scope:

Population	·    Patients with clinically and/or genetically diagnosed familial hypercholesterolemia ·    Patients with -     primary hypercholesterolemia -     primary hypercholesterolemia and diagnostically confirmed coronary artery disease and/or peripheral arterial disease and/or cerebral arterial disease -     suspected FH ·    Family/relatives of the above patient groups
Intervention	(Predictive) Molecular genetic diagnosis of FH (mutations in FH-associated genes (LDLR, APO-B, PCSK9))
Comparators	Standard clinical diagnosis of FH
Outcomes	·    Q1 und Q4: organisational and logistical aspects of different test strategies: -     Timing of testing -     Data documentation -     Involved stakeholders -     Quality standards -     Etc. ·    Q3: ethical and regulatory aspects of (predictive) molecular genetic diagnostics: -     Benefit-harm balance -     Autonomy -     Respect for persons -     Fair access to technology -     Etc. ·    Q5: cost implications and differences of the test strategies, organisational models, and their follow-up costs
Setting	Ambulatory/outpatient setting (extramural)
Study design	No restrictions
Publication period	No restrictions
Language	English, German

All work steps are carried out according to the 4-eyes principle (MW, CS); the results are subjected to an internal and external review.

Time schedule:

Period	Activity
May 2020	Scoping, preparation of the project protocol
May to June 2020	Literature search, selection of literature, hand search, contact with experts
June to August 2020	Data extraction, economic scenario analysis/budget impact analysis, conducting the experts interviews
July to September 2020	Writing/drafting the report
October 2020	Internal and external review, finalisation

References:
[1]        Jameson J. L. and Longo D. L. Precision medicine--personalized, problematic, and promising. N Engl J Med. 2015;372(23):2229-2234. Epub 2015/05/28. DOI: 10.1056/NEJMsb1503104.
[2]        Sturm A. C., Knowles J. W., Gidding S. S., Ahmad Z. S., Ahmed C. D., Ballantyne C. M., et al. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680. Epub 2018/08/04. DOI: 10.1016/j.jacc.2018.05.044.
[3]        Hofmann B., Droste S., Oortwijn W., Cleemput I. and Sacchini D. Harmonization of ethics in health technology assessment: a revision of the Socratic approach. Int J Technol Assess Health Care. 2014;30(1):3-9. Epub 2014/02/07. DOI: 10.1017/S0266462313000688.