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1. The landscape and the vocabulary

Tags: [S] primary public source (verified 2026-10-16, see claims_ledger.csv), [Y] my synthesis.

(a) Concept

Term Plain meaning Anchor
Analytical performance Does the assay measure the analyte correctly? (precision, bias, LoD, linearity, interference) IVDR Art 2(40) [S]
Scientific validity (of an analyte) Is the analyte associated with the condition? IVDR Art 2(38) [S]
Clinical performance Do results correlate with the clinical condition in the target population? (sens, spec, PPV, NPV, LR) IVDR Art 2(41) [S]
Clinical validity Same idea in non-IVDR language: does the marker discriminate the condition [Y]
Clinical utility Does using the test improve decisions or outcomes? IVDR defines no such term [Y]
IVD Device for in-vitro examination of specimens –
Companion diagnostic (CDx) Device “essential for the safe and effective use of a corresponding medicinal product” to select patients IVDR Art 2(7) [S]; FDA 2014 guidance [S]

The IVDR defines scientific validity of an analyte, not of a device.

(b) Regulatory anchor

EU: IVDR 2017/746 (original OJ text read; consolidated text not verified)

Provision What it is Note
Art 47 Classification of devices (A–D) Not safety requirements
Art 48 Conformity assessment procedures CDx consultation at 48(3)/(4) class D, 48(7)/(8) class C
Art 56 Performance evaluation and clinical evidence three pillars in 56(3); clinical performance studies unless justified (56(4)); class C/D report updated at least annually (56(6))
Art 57 General requirements for performance studies
Art 58 Additional requirements (interventional/invasive); 58(2) CDx studies included left-over-sample CDx studies are only notified
Annex I GSPR; 9.1(a) analytical parameters, 9.1(b) clinical parameters the list your statistics must cover
Annex VIII Classification rules; Rule 3(f) = CDx, class C Rule 1 D, 2 C/D, 3 C, 4 C, 5 A, 6 B, 7 B
Annex XIII Part A Performance evaluation plan (PEP), report (PER), clinical performance study plan 2.3.2 PEP includes statistical tools and acceptance criteria
Annex XIII Part B Post-market performance follow-up (PMPF)

Consultee for CDx: “a competent authority … under Directive 2001/83/EC or the EMA, as applicable” [S].

Transition (Reg (EU) 2024/1860): legacy certificates to 31 Dec 2027; first-time NB devices D 2027, C 2028, B/sterile A 2029 with conditions. COM(2025) 1023 is a proposal [S, status unverified].

Guidance

Document Facts
MDCG 2022-2 (Jan 2022) General principles of clinical evidence for IVDs; sections on performance evaluation plan/report, scientific validity, analytical and clinical performance, PMPF
ISO 20916:2019 Good study practice for clinical performance studies using specimens from human subjects; analytical studies out of scope
STARD 2015 30 items (BMJ 2015;351:h5527)
QUADAS-2 4 domains: patient selection, index test, reference standard, flow and timing
ICH E9 (1998), E9(R1) (2019) Drug-trial guidelines; used here by analogy [Y]

US pathways

Route Meaning Verb
510(k) substantial equivalence to a predicate cleared
De Novo no predicate, low/moderate risk granted
PMA class III, scientific review approved

The verb mapping is a synthesis [Y]; FDA has no single defining sentence. The Elecsys Phospho-Tau (217P) Plasma test was cleared via 510(k) K261686 (Chapter 6).

(c) Lab: the one-page map

The same table sits in the index. Question type → governing document → R tool.

m <- read.csv("../question_map.csv")
m <- m[order(m$chapter), ]
kable(m, col.names = c("Analysis question", "Governing document", "R tools", "Chapter"), row.names = FALSE)
Analysis question Governing document R tools Chapter
Which CE class and route? IVDR Annex VIII Rules 1-7; Art 47-48 - 1
What must the performance evaluation contain? IVDR Art 56, Annex XIII Part A (PEP, PER); Part B (PMPF) - 1
How imprecise is the assay (within-run, between-day, within-lab)? CLSI EP05 (Ed4, 2025; A3 design 20x2x2); lab verification EP15-A3 VCA::anovaVCA, lme4::lmer 2
Does my lab reproduce the manufacturer’s precision/bias claim? CLSI EP15-A3 (+IG1/IG2, 2021) chi-square upper verification limit (hand) 2
What is the lowest concentration reliably detected / quantified? CLSI EP17-A2 (2012) parametric and nonparametric LoB/LoD (hand); bootstrap 3
Is the assay linear over the claimed range? CLSI EP06 Ed2 (2020) lm with polynomial terms; allowable deviation 3
Do two methods agree? What is the bias at a decision level? CLSI EP09c Ed3 (2018) mcr::mcreg (Deming, Passing-Bablok), Bland-Altman 4
Does an interferent bias the result? CLSI EP07 Ed3 (2018), EP37 tables paired differences + CI (hand) 4
How long is a reagent stable? CLSI EP25 Ed2 (2023) lm over time with acceptance limit 4
Does a new reagent lot shift results? CLSI EP26 Ed2 (2022) paired lot comparison (hand) 4
Sensitivity/specificity/PPV/NPV with CI? CLSI EP12 Ed3 (2023); FDA 2007 statistical guidance; STARD 2015 binom, epiR::epi.tests, helpers::report_2x2 5
Compare two tests on the same patients? FDA 2007 guidance; McNemar DTComPair, mcnemar.test 5
Candidate vs non-reference comparator: what do I call the metrics? FDA 2007 guidance (PPA/NPA, not sensitivity/specificity) helpers::report_2x2 (label PPA/NPA) 5
ROC curve, AUC, compare AUCs? CLSI EP24-A2 (2011); DeLong 1988 pROC::roc, ci.auc, roc.test 5
How do I choose and validate a cut-off (one or two)? EP24-A2; EP12 Ed3; FDA decision summaries cutpointr, OptimalCutpoints, helpers::classify_two_cut 6
How many subjects for a sensitivity/specificity target? Buderer 1996; Flahault 2005; Annex XIII Part A 2.3.2 (population size) helpers::n_buderer, presize, MKmisc, pROC::power.roc.test 7
How do I bridge a clinical-trial assay to the final CDx? FDA 2014 CDx guidance; FDA 2016 draft codevelopment; IVDR Art 48(7)-(8), Annex IX 5.2 simulation (Chapter 8) 8
What goes in the statistical analysis plan? IVDR Annex XIII Part A 2.3.2; ISO 20916:2019; ICH E9 / E9(R1) by analogy; MDCG 2022-2 mock_sap/ 9
What is the reference interval? CLSI EP28-A3c (2010) quantile, boot, refineR 10
Is a change in a patient’s serial results real? reference change value (RCV); monitoring is a separate intended use lme4, formula (hand) 10

CLSI editions (verified, see research/clsi_notes.md): EP05 Ed4 (2025), EP06 Ed2 (2020), EP07 Ed3 (2018), EP09c Ed3 (2018), EP12 Ed3 (2023), EP15-A3 (2014), EP17-A2 (2012), EP19 Ed3 (2022), EP24-A2 (2011), EP25 Ed2 (2023), EP26 Ed2 (2022), EP28-A3c (2010), EP35 Ed2 (2025), EP37 (edition not verified). Bold = newer than the edition most references cite.

(d) Claims

Ledger rows for this chapter (IVDR, MDCG, ISO, FDA pathways, CLSI editions) were appended from the verification pass. Rows of the regulatory file carry chapter numbers 1, 5, 8, 9 by topic.