PONE-D-21-24987

Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries

PLOS ONE

Dear Dr. Samwald,

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János G. Pitter, MD, PhD

Academic Editor

PLOS ONE

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“DS has developed concepts of genetic information management (GIM) that are realized by the company bio.logis digital health GmbH. For the company, she is CEO. She is also medical director of diagnosticum Center of Human Genetics, a diagnostic institution that is applying and testing the GIM-systems in the context of medical care. GPP is Full Member and National representative of the European Medicines Agency, Committee for Human Medicinal Products (CHMP) - Pharmacogenomics Working Party, Amsterdam, the Netherlands. The other authors have no competing interests to declare.”

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Please include the name of the clinical trial registry and registration number in the Abstract. 

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: From a randomized crossover study design, the authors report results of clinical decision support systems (CDS) implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites. Personalized pharmacogenomics (PGx) reports were generated from 6884 genotyped samples. Participating healthcare providers expressed overall satisfactory adoption and acceptance of the CDS tools.

Minor revisions:

1- In addition to stating counts, provide corresponding percentages on the following pages: 11, 15-16, 17.

2- Line 343 indicates that averages were reported in table 3 but the column is labelled medians. Clarify.

3- Cite the statistical software used for the analysis.

4- Figure 5: Include the percentage of respondents in each country.

5- Figures 6-11: Include percentages which correspond to the counts.

Reviewer #2: Clinical Decision Support is a potentially crucial tool for widespread adoption of pharmacogenomics in clinical practice. In this manuscript, the authors analyze the rollout of a PGx CDS implementation project that spans multiple sites and countries in Europe. Strengths of the study include its multi-site, international nature and its mixed-methods approach for data collection. This is a potentially valuable study and the data collection, analysis, and results are generally well done. However, there are a number of issues with the paper's overall organization and flow, which should be corrected. Additionally, the Discussion section does not address some of the more interesting results that I expect readers could learn the most from. Feedback follows, organized by section:

Abstract

• The methods section references analysis of "workflow bottlenecks," but this terminology isn't used in the methods and results section, so it's not clear to me what this is specifically referring to.

• The majority of the Results section of the abstract reflects commentary from the Discussion section, not the results of the systematic analysis. I suggest reorganizing to make this clear to the reader and instead emphasizing the reported results.

Background

• Context should be expanded. A number of other PGx CDS programs have reported outcomes of their projects, so what are the specific literature gaps/unknowns this study addresses? U-PGx's international, multi-site nature is unique, so several can be inferred, but the authors should more explicitly state what they set out to learn with this study that's different from other PGx CDS implementation retrospectives.

Methods

• The Methods section contains editorial-type statements that are better suited to the Background or Discussion sections, including:

o A statement starting on line 129 providing a definition for "pre-emptive PGx testing"

o A statement starting on line 143 providing commentary on the necessity of PGx CDS

o A statement starting on line 217 regarding the value of risk matrices

• The Evaluation framework section lists four methods for data collection in this study. The following sub-sections explicitly define methods 2-4, but the first method, "tracking of general process indicators" is not explicitly defined. It's not clear to me what this means, what is being measured, or how the data was collected. (Additionally, the "Statistics on report retrievals" heading appears to be incorrectly formatted as a higher-level heading, but that could be an artifact of my reader – I suggest double checking the formatting to be sure.)

Results

• The "General implementation process indicators" section begins with several statements on methodology that are more appropriate for a Methods section. Reorganizing this would also help address my comment above.

• The Demographics section under "Decision support infrastructure evaluation survey" reports the demographics of those who responded to the survey, but it's not clear how representative these respondents are of overall U-PGx users. Are any statistics available on basic user demographics to put these numbers into context? For example, does a 30.8% proportion accurately reflect the number of Pharmacist users, or are they over/under-represented?

Discussion

• The statement starting on line 596 mis-characterizes the FDA's stance on PGx testing. The FDA has not banned PGx testing or CDS for gene-drug pairs that are not on their list. Rather, they have warned sellers of PGx tests and PGx CDS against making predictive statements about drug dosing that have not been verified by the FDA. Labs are still able to test PGx-related genes and CDS tools for a variety of drug-gene pairs are still available, but their predictive statements are limited. The following URL should be referenced, in addition to the tables already referenced: https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations

• There were several interesting positive findings in the Results section that were not directly addressed in the Discussion, which I would like to see further comment on, including:

o Users reported a high level of satisfaction with the PGx training they received, which is in contrast with typical reports showing low familiarity with PGx among providers. What is it about U-PGx that led to this level of satisfaction?

o Similarly, users reported high satisfaction for workflow fit, information needs being met, and system user-friendliness. Previous projects have struggled in these areas. What did U-PGx do that made this successful?

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Reviewer #1: No

Reviewer #2: No

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Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries

PONE-D-21-24987R1

Dear Dr. Samwald,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

János G. Pitter, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your patience in the peer review period, it took longer than expected to secure the necessary peer reviews.   

Reviewers' comments: