Implementation of High-Sensitivity and Point-of-Care Cardiac Troponin Assays into Practice: Some Different Thoughts
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Clinical Chemistry 00:0
1–9 (2020) Mini-Reviews
Implementation of High-Sensitivity and Point-of-Care
Cardiac Troponin Assays into Practice: Some Different
Thoughts
Fred S. Apple,a,* Corinne R. Fantz,b and Paul O. Collinsonc, on behalf of the IFCC Committee on Clinical
Application of Cardiac Bio-Markers†
BACKGROUND: The primary role of the International hs-cTnT assays (Fig. 1) is found on the IFCC C-CB
Federation of Clinical Chemistry (IFCC) Committee on website (4). This mini-review regarding hs-cTn assays 1)
Clinical Application of Cardiac Bio-Markers (C-CB) is to highlights new IFCC C-CB/AACC Academy laboratory
provide educational materials about cardiac biomarker use, practice recommendations; 2) addresses new/updated con-
emphasizing high-sensitivity cardiac troponin assays. cepts from the Fourth Universal Definition of Myocardial
Infarction (UDMI) recommendations; 3) discusses role
CONTENT: This mini-review, regarding high-sensitivity of point-of-care (POC) assays in practice; 4) identifies
cardiac and point-of-care troponin assays, addresses 1) regulatory challenges concerning POC assays.
new IFCC C-CB/AACC Academy laboratory practice
recommendations; 2) new and updated concepts from IFCC C-CB/AACC Academy Laboratory
the Fourth Universal Definition of Myocardial Practice Recommendations for hs-cTn
Infarction; 3) the role of point-of-care assays in practice
and research; 4) regulatory challenges concerning point- Consensus recommendations by the AACC Academy,
of-care assays; e) testing in the COVID-19 world. in collaboration with the IFCC TF-CB, address conver-
sion of contemporary assays to hs-cTn. Expert opinion
SUMMARY: Implementation of high-sensitivity cardiac clinical laboratory practice recommendations for hs-cTn
troponin assays makes a difference now and into the assays focused on 10 topics: 1) quality control (QC)
future in clinical practice and research. Providing point- utilization; 2) validation of lower reportable analytical
of-care high-sensitivity cardiac troponin assays and limits; 3) units used in reporting measurable concentra-
optimizing studies to allow clearance of these assays by tions for patients and QC materials; 4) 99th percentile
regulatory agencies, in a timely fashion, may provide im- sex-specific upper reference limits (URLs); 5) criteria
proved patient management and outcomes. required to define hs-cTn assays; 6) communicating
with and educating clinicians regarding preanalytical and
How to implement high-sensitivity cardiac troponin analytical problems that confound results; 7) how authors
(hs-cTn) assays in practice is not a harmonized process need to document analytical assay details in hs-cTn studies;
(1). The International Federation of Clinical Chemistry 8) harmonizing assay results and commutable materials; 9)
(IFCC) Committee on Clinical Application of Cardiac time to reporting of results from sample collection to re-
Bio-Markers (C-CB) provides educational materials ceipt; 10) changes in serial hs-cTn concentrations over
about cardiac biomarkers, emphasizing hs-cTn assays time and role of biological variation in interpreting results.
(2, 3). Growth of regulatory clearances for hs-cTnI and New practices, shown in Table 1, include using QC at
sex-specific URLs, emphasizing not to perform an under-
powered study to establish an URL, role of appropriate sta-
tistics to define 99th percentiles, importance of limit of
detection (LoD) in defining hs-assays measuring 50% of
a
Department of Laboratory Medicine and Pathology, Hennepin County Medical Center of normal males and females individually (not combined),
Hennepin Healthcare and University of Minnesota, Minneapolis, MN; bMedical and
Scientific Affairs - POC, Roche Diagnostics Corporation, Indianapolis, IN; cDepartment of and reporting hs-cTn results with whole numbers, desig-
Clinical Blood Sciences and Cardiology, St George’s University Hospitals NHS Foundation nated ng/L, to distinguish from contemporary assays.
Trust and St George’s University of London, London, UK.
*Address correspondence to this author at Hennepin Healthcare/Hennepin County
A recent study determined overall and sex-specific
Medical Center, Clinical Laboratories P4, 701 Park Ave, Minneapolis MN 55415. Fax 99th percentiles in 9 hs-cTnI and 3 hs-cTnT assays
612-904-4229; e-mail apple004@umn.edu. using a universal sample bank screened by health ques-
†
IFCC C-CB Members: Fred S. Apple (Chair), Richard Body, Ola Hammarsten, Pete A. tionnaire and surrogate biomarkers (5). Subjects were
Kavsak, Carolyn S.P. Lam, Amy K. Saenger; Consultants: Allan S. Jaffe, Paul O.
Collinson, Torbojn Omland, Jordi Ordó~nez-Llanos age, ethnic, and racially diverse. Overall and sex-specific
Received July 7, 2020; accepted October 12, 2020. 99th percentiles showed substantial differences between
DOI: 10.1093/clinchem/hvaa264 and within both hs-cTnI and hs-cTnT assays. Men had
C American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.
V 1Mini-Reviews
Roche hs-cTnT Abbott hs-cTnI Roche Gen 5 Siemens hs-cTnI: CE, FDA Ortho hs-cTnI: CE
CE Mark CE Mark FDA Beckman hs-cTnI: CE, FDA Abbott hs-cTnI: FDA
ET Healthcare hs-cTnI: cFDA
2007 2013 2017 2018 2019 2020
Fig. 1. Representative timeline for regulatory clearance for clinical use of hs-cTn assays.
Table 1. New and updated IFCC C-CB and AACC Academy recommendation for practice utilizing high sensitivity cardiac
troponin assays.
1. Quality control materials need to be implemented at concentrations consistent with both the male and female sex-
specific upper reference limits.
2. Quality control materials should be considered at concentrations consistent with the limit of detection (LoD) of each
hs-cTnI and hs-cTnT assay to provide ongoing confidence when used for rule out protocols.
3. Avoid implementing upper reference limits that use underpowered subject numbers to establish 99th percentiles.
4. Appropriate statistical analyses to define 99th percentiles include the non-parametric and Harrell Davis methods, with
the Robust method not acceptable.
5. High sensitivity assays are now defined base on measuring 50% of normal males and 50% normal females individu-
ally, not combined.
6. Beware of contemporary assays that report results using whole numbers, designated ng/L, that are only designated
for high sensitivity assays.
higher 99th percentiles than women (Fig. 2: A-cTnI; B- UDMI assists clinicians in a common focus on how to
cTnT). Both overall and sex-specific 99th percentiles utilize biomarkers in alignment with IFCC C-CB and
varied according to statistical method and assay used. AACC Academy guidelines (7). First, it recommends
Not all assays provided a high enough percentage of myocardial injury be used when there is evidence of
measurable concentrations in women to qualify as hs- increased cTn with at least one value above the 99th
assays, and the surrogate exclusion criteria used to define percentile sex-specific URL (3). Myocardial injury is
normality tended to lower the 99th percentiles. considered acute with a rise and/or fall of cTn between
Following a meeting between US laboratory medi- serial samplings. Fig. 3 shows representative myocardial
cine, emergency medicine, and cardiology biomarker injury. Complexity of clinical circumstances may make
experts and FDA, guidelines for uniform analytical and it difficult to discriminate specific individual mecha-
clinical standards for studies performed by manufacturers nism(s) of injury. Second, greater attention was placed
seeking cTn 510k assay clearance were published (6). on recognition of type 2 MI, defined in settings with ox-
Recommendations addressed 1) number of reference ygen demand and supply imbalance unrelated to acute
individuals for determination of 99th percentiles; 2) limit coronary thrombosis (8). If myocardial injury is not
of quantification; 3) total imprecision requirements; 4) acute and related to chronic structural heart disease, se-
enrollment of subjects for diagnostic studies; 5) patient rial cTn values may be stable and unchanging. Third,
adjudication processes; and 6) clinical end points and out- cTnI and cTnT remain standard biomarkers for ruling
comes. The focus was to ensure common protocols applied in/out MI and myocardial injury. cTn release into the
to hs-cTn assays. Unfortunately, published recommenda- circulation is dependent on blood flow around injured
tions were not endorsed by the FDA.
myocardium, and kinetics of increasing, peaking, and
Recommendations of Fourth Universal falling values are assay dependent (9) since cTn assays
Definition of Myocardial Infarction are not standardized. Utilizing hs-cTn assays, most rule
in/rule out decisions are made within 3 hours of initial
For global harmonization of care in patients presenting sampling, based on assay-dependent algorithms (10).
with symptoms suggestive of myocardial injury, the Fourth, analytical sensitivity provided by hs-cTn assays
2 Clinical Chemistry 00:0 (2020)Implementation of High-Sensitivity and Point-of-care
A
B
Fig. 2. Men have higher 99th percentile URLs for multiple hs-cTnI (A) and cTnT (B) assays compared to most women.
Reproduced with permission from Apple et al. (5).
is critical for early rule out and assists in defining assay measure normal subjects above the LoD in 50% of
dependent deltas. Recommendations emphasize that measurements in both males and females, separately (2,
clinicians become educated about details of the specific 3), differentiating hs assays from contemporary and
assay used in their practice. Fifth, the UDMI supports POC assays that are generally analytically and clinically
IFCC guidelines for defining hs-cTn assays based on inferior for diagnostic use and unable to define biologi-
imprecision (10%CV at sex-specific URL) and ability to cal variation (1).
Clinical Chemistry 00:0 (2020) 3Mini-Reviews Fig. 3. Conceptual model for myocardial injury and myocardial infarction. Reproduced with permission from Sandoval and Thygesen (8). CLINICAL ROLE OF POC TESTING IN ERA OF LABORATORY HS- methods with comparable analytical sensitivity to those CTN in the central laboratory at the time trials were per- Rationale for POC testing The basic assumption for use formed; using diagnosis based on exceeding a diagnostic of POC testing is that rapid provision of results will cutoff in use or the 99th percentile. Although these have a direct impact on clinical decision-making. studies support a role for POC testing, they are not Evidence is limited. Randomized controlled trials compatible with current clinical diagnostic strategies. comparing POC with central laboratory testing are sum- Two key requirements for any study are that POC test- marized in Table 2 (11–15), showing inconsistent ing has 1) comparable analytical performance with the results. Some studies demonstrated a clear improvement central laboratory cTn assay, which is now hs-cTn, and in outcome as judged by treatment impact or length of 2) provision of test results is demonstrably the rate- stay, while some had no impact. One consistent finding limiting step in the diagnostic pathway. is that to have impact on clinical decision-making, bio- marker measurements had to be integrated within a de- CLINICAL DECISION-MAKING IN ERA OF HS-CTN AND RAPID fined clinical pathway. A detailed analysis of the patient DIAGNOSTIC ALGORITHMS flow within the Randomized Assessment of Treatment Introduction of hs-cTn assays into routine clinical prac- using Panel Assay of Cardiac Markers trial revealed clear tice has led to a transformation in the way cTn measure- differences between length of stay directly due to the ments are used in decision making. No longer are clinical pathways being used in different hospitals (16). diagnostic pathways based solely upon serial sampling A systematic evidence-based review of POC testing over a 6 (or more) hour period post admission until identified the need for integration of POC within the the value exceeds the 99th percentile with a significant decision-making pathway as a key requirement to dem- change between consecutive measurements (delta value). onstrate benefit (17). Studies utilized cTn POC Diagnostic pathways now exploit 2 key features of hs 4 Clinical Chemistry 00:0 (2020)
Implementation of High-Sensitivity and Point-of-care
Table 2. Clinical trials of point-of-care testing predicated on cardiac troponin monitoring.
Type Methodology Diagnosis Outcome measure Result Author
Single center RCT – Roche cTnT CLT Troponin testing Duration of Positive—Reduced Collinson
CCU admissions vs. POCT at 12 hours from length of stay LOS for non-CCU et al. (11)
admission. (LOS). and total hospital
Diagnostic cut stay in pre-specified
off 0.2 mg/L rule out group.
Multicenter RCT in iSTAT cTnI vs. Serial testing over Time to dis- Inconclusive – the Ryan
the ED central 6 hours or serial charge home bedside troponin et al. (12)
Disposition laboratory testing at 8- or transfer to group had varying
Impacted by cTnI 12 hours (1 site) inpatient care and inconstant
Serial Point-of- changes in ED
care Markers in length of stay
Acute Coronary compared with the
Syndromes central laboratory
(DISPO-ACS) group. Reduction in
one site and in-
crease in another
Single center RCT Stratus CS vs. Testing post ran- Time to treat- Positive—Reduced Renaud
in the ED Dimension domization. ment Length time to commenc- et al. (13)
RxL Protocol not of stay in the ing anti-ischemic
stated. ED treatment No re-
Diagnostic cut duction in ED stay
off 0.1 mg/L
2 Center Cluster iStat vs. Protocol not Length of ED Inconclusive – Loten
randomized con- Beckman stated stay Reduced LOS but et al. (14)
trolled trial in the Coulter Accu I not significant.
ED. One center Increased propor-
did not have tion of patients dis-
24 h on site chargedMini-Reviews
diagnostic algorithms (22). Support for rapid diagnosis POC technologies, will hopefully provide diagnostic
based on hs-cTn algorithms underwent systematic re- data to be utilized in practice soon.
view by the UK National Institute for Health and Care
Excellence (23). When admission measurement exceeds ROLE OF CTN POC TESTING
the 99th percentile, serial testing needs to be carried out cTn POC testing does have a clinical role, but it is com-
to determine whether myocardial injury is acute (rising plimentary to hs-cTn laboratory measurements. When
pattern) or chronic (static, flat pattern) to allow appro- timely access to laboratory facilities for decision-making
priate triage, and may require a further 6-hour sample. is not possible, POC testing may be a solution. This is
Rapid diagnostic algorithms seem to be ideally particularly the case in rural healthcare where sample
suited for POC testing. The absolute caveat is cTn transportation time may impact turnaround time and
POC testing must demonstrate high-sensitivity analyti- where the decision to move a patient to a more central-
cal performance. Currently, the majority of POC cTn ized facility, which performs intervention, may require a
assays have, at best, performed as contemporary assays. long land journey or air evacuation. POC cTn measure-
Such systems are perfectly adequate for ruling in myo- ment has been shown to significantly improve manage-
cardial injury but require repeat sampling, typically at 3 ment of patients with suspected acute coronary
to 6 hours post admission, to achieve adequate clinical syndromes in the rural Australian environment (33). In
sensitivity for rule out. Admission measurement of cTn the Randomized Assessment of Treatment using Panel
by POC may in fact be diagnostically inferior to an Assay of Cardiac markers trial, with a contemporary
admission risk score alone (24). When sampling over POC assay and diagnosis based on the 99th percentile,
6 hours is compared with the possibility of immediate measurements on admission and 90 min were diagnosti-
discharge based on a single measurement or the possibil- cally accurate and safe in low risk patients. This study
ity of complete diagnostic categorization within 1– did not evaluate single sample rule out, but did demon-
3 hours from admission, the advantages of central strate serial testing performed well by POC. However,
laboratory-based hs-cTn assays are obvious, even with there can be downsides with diagnoses missed by overre-
60-min turnaround time. Diagnosis within 1 to 3 hours liance on test measurement which is insufficiently sensi-
of admission outweighs having to wait 3–6 hours by tive (34). POC cTn limitations must be appreciated
POC testing, even where a whole blood sample can be (potential for false negative results on admission because
used with results available in 10–15 min. lack of analytical sensitivity) and the need for repeat
testing (up to 6 hours) are built into the diagnostic
POC TESTING—ANALYTICAL VERSUS CLINICAL EVIDENCE protocol for rule out. However, a positive test by POC
Independent analytical validation of performance claims testing would allow immediate patient characterization
of a putative hs-cTn POC assay is important, but is and expedite management (35). There are risks if POC
only the background to clinical implementation and and central laboratory testing are mixed within a single
use. POC testing must have the ability to permit imme- health system. Degradation of diagnostic sensitivity
diate safe discharge by single sample rule out or support may occur as a result of attempting to harmonize differ-
a rapid diagnostic, serial testing algorithm. The majority ent assays by arbitrarily matching diagnostic cut offs
of POC assay studies claiming comparability to a hs- (36) since cTn assays are neither standardized or
cTn assay for diagnostic clinical utility and adverse out- harmonized.
comes (25, 26) have not been performed appropriately.
POC assay studies that evaluated rapid rule out algo- POC REGULATORY INNOVATION & REGULATION
rithms utilized stored, plasma samples, not fresh ‘whole Innovation and investments in research and develop-
blood, which will be required for a universally, accept- ment have led to disruptive technologies that fundamen-
able validation’ (27–29). To date, there have been no tally change patient management and/or yield
whole blood or prospective studies, either observational incremental improvements in assay performance (37).
or randomized controlled trials, that have demonstrated Innovations must prove their value before there can be
that POC testing with high sensitivity analytical perfor- widespread acceptance with stakeholders (physicians,
mance is clinically reliable, safe, and confers patient regulators, payers). Potential harm when introducing
benefit. This is in contrast with central laboratory hs- new products to market is real, and regulatory bodies
cTn methods, demonstrated by meta-analysis of trials are tasked with ensuring safety and efficacy of devices.
(30, 31). While one assay (Pathfast) has FDA clearance It took nearly a decade after regulatory clearance
for POC with preliminary data that meets hs-criteria outside the USA, supported by numerous publications,
along IFCC guidelines (32), in practice users of this for manufacturers to convince the FDA that hs-cTn
large instrument are often laboratorians and not desig- tests were not only more analytically sensitive than con-
nated POC operators. Several novel, in development temporary and POC assays but also safe and effective
6 Clinical Chemistry 00:0 (2020)Implementation of High-Sensitivity and Point-of-care
for patient care. To remedy this, the 21st Century providers (nurses, clinicians, residents, technologists),
Cures Act, signed into US law in 2016, is designed to rarely would a CLIA-waived operator with another job
help accelerate medical product development and bring class know what to do with these results unless driven
new innovations and advances to patients who need by protocol within the institution. Technology has
them faster and more efficiently (38). It provides new advanced such that simplicity of testing is seldom a con-
authority to the FDA to 1) improve recruitment and re- cern for these devices. Performing the testing in whole
tention of scientific, technical, and professional experts, blood with limited knowledge on the part of the end
2) receive alternative sources of data for regulatory user, and little to no interaction with calibration and
approvals such as real-world evidence, provided ade- quality control is a baseline expectation for POC devi-
quate quality of the data are maintained and 3) establish ces. Manufacturers are tasked with demonstrating that
new expedited product development programs, includ- typical end users can perform testing and results are
ing the Breakthrough Devices program. This allows comparable to a predicate device. For POC hs-cTn, the
opportunities for manufacturers to expand claims for expectation is that manufacturers compare their POC
on-market devices if technologies exist to capture quality device to a 510 K cleared laboratory cTn instrument.
real-world data. Introduction of In Vitro Diagnostic Analytical precision, linearity, accuracy, and reportable
Medical Device Regulation is strengthening the over- range need to be demonstrated because only quantita-
sight and review process in the European Union (39). tive assays are recommended for hs-cTn (3). POC
Manufacturers of currently approved in vitro diagnostic devices will need to establish their own 99th percentile
medical devices will have a transition time of 5 years to URL studies. Diagnostic accuracy needs to be per-
meet the requirements of the In Vitro Diagnostic formed, meaning analytical accuracy is not enough to
Medical Device Regulation. Some of the key changes demonstrate safety and effectiveness for FDA clearance.
are more stringent documentation, rigorous clinical evi- POC hs-cTn testing is expected to be validated no dif-
dence, and reclassification of devices according to risk. ferent than a central laboratory method. However, in
As technology advances, the ability to offer POC
the US, the FDA requirements for POC assay clearance
hs-cTn assays has been developed. New guidance from
are more difficult than a central laboratory method.
regulatory bodies demand manufacturers conduct their
clinical studies for registration in the intended care envi-
STRATEGIES FOR REGULATION GOING FORWARD
ronment or as similar to the intended care environment
Globally, 2 important questions must be considered: 1)
as possible (40). In the US, if a manufacturer desires to
are clinical studies still necessary if analytical validity can
achieve a CLIA waiver for a POC device, that device
be demonstrated from one platform to the next, and 2)
must be challenged in the environment where it will be
used and operated by typical end-users found in that do matrix studies that demonstrate similar performance
environment. FDA studies are extremely difficult to exe- with plasma and whole blood need to be repeated in
cute and are expensive because most applied research fresh whole blood collections for POC studies? It is
sites prefer to provide dedicated research personnel, who unclear what more regulation will bring in terms of cost,
qualify under CLIA as operators, to separate research timelines, and innovation in relation to balance
from clinical staff. It is a misconception by the FDA improvements in safety and efficacy of in vitro diagnos-
that research staff may not be under the same stressors tic products.
as a typical end-user managing patient care aspects while A regulatory system that allows well-characterized
performing testing. Yet, the FDA mandates these POC tests to be evaluated for modifications to occur without
studies be performed by typical end-users (such as having to submit new evidence of performance, waiting
nurses) who are responsible for routine clinical duties years to bring the next generation test to market, is
rather than allow research personnel focused only on needed. Trust in the system to allow for regulation with-
testing. This adds burden to nurses, in an already finan- out stifling innovation could bring devices to market
cially stressed, FTE-short workplace, in the pandemic more efficiently and safely. The ‘risk’ of bringing new
COVID-19 world hospitals are living through, and is hs-cTn devices to market is substantially lower today,
not realistic. based on evidence-based analytical and clinical literature
Currently, there are no CLIA-waived POC hs-cTn amassed for known intended uses. Post market analysis
assays on the market. The challenge for cTn in can help serve to mitigate risks for new intended uses or
obtaining CLIA waiver lies with the interpretation and incremental improvements over previous generations,
judgement aspects of testing. CLIA waiver requires the without having to refile for new regulatory clearances.
operators to be able to run the test without formal train- Being able to mitigate these risks with innovative
ing. The test must be designed so a lay person can run it regulatory processes will balance the need for improved
with only the instructions packed in the kit and to be products without compromising patient safety. Adverse
able to easily interpret the result. With the exception of patient outcomes will be better predicted, with
Clinical Chemistry 00:0 (2020) 7Mini-Reviews
improved patient management providing considerable pandemic (review times days to weeks vs the normal
cost savings to hospitals and patients. months to years). We feel the FDA should also find
We propose the FDA consider the following pro- more efficient paths to 510k clearances. The FDA
cess for patient enrollments into manufacturers’ 510 K should consider Emergency Use Authorization for novel
submissions. hs-cTnI and hs-cTnT POC devices and assays, without
1. Regulatory agencies, including the FDA, should write a
sacrificing quality during the COVID-19 pandemic.
guidance document describing the minimal requirements While it is understood that when the Emergency Use
needed to submit for clearance as they have done for glu- Authorization period is over, the test will require a 510k
cose POC testing. With guidance, manufacturers would clearance to remain on the market; this period would al-
have more consistent study protocols, populations, and po- low manufacturers the ability to collect data for 510k
tential use of predicate devices. Presently, there is too much submissions. This would assist inner-city and rural pro-
variation between study protocols, and the feedback manu- viders to rapidly measure of hs-cTn, the cardiac bio-
facturers receive is inconsistent. marker that makes a difference now and into the future;
2. Revise the inconsistent and biased enrollment of subjects “the times they are a-changin’.”1
identified in the ED using the IRB informed consent process
based on new blood draws. This practice is time consum-
ing, expensive, and misses over 70% of eligible patients Nonstandard Abbreviations: hs-cTn, high-sensitivity cardiac tropo-
who would qualify for enrollment, making the study popu- nin; cTnT, cardiac troponin T; cTnI, cardiac troponin I; IFCC,
lation biased compared to the real practice. International Federation of Clinical Chemistry; C-CB, Committee on
3. Obtain IRB approved waste specimen use from patients’ Clinical Application of Cardiac Bio-Markers; UDMI, Universal
orders from their clinical indications by the provider that Definition of Myocardial Infarction; POC, point-of-care; QC, qual-
are already in the laboratory for testing for plasma and se- ity control; URL, upper reference limits; LoD, limit of detection;
rum, and likely EDTA whole blood remnant samples, ex- ESC, European Society of Cardiology
cept for capillary samples that would need to be fresh.
4. As patients present for treatment and are registered before Author Contributions: All authors confirmed they have contributed to
entering the hospital system, provide the patient with an the intellectual content of this paper and have met the following 4 require-
authorization and consent form that includes a section that ments: (a) significant contributions to the conception and design, acquisi-
clearly defines that the institution conducts research. The tion of data, or analysis and interpretation of data; (b) drafting or revising
patient can, at their choice, agree or not to agree to partici- the article for intellectual content; (c) final approval of the published arti-
pate in medical research to allow for better understanding cle; and (d) agreement to be accountable for all aspects of the article thus
of diseases and how care is provided, and by signing the ensuring that questions related to the accuracy or integrity of any part of
the article are appropriately investigated and resolved.
document agrees that investigators may use health informa-
tion and waste specimens already collected. This will allow F.S. Apple, financial support, statistical analysis, administrative sup-
for consecutive enrollment of patients, 24/7, without the port, provision of study material or patients.
bias of time delays of blood draws by informed consent,
testing whole blood in real time with matched plasma or Authors’ Disclosures or Potential Conflicts of Interest: Upon manu-
script submission, all authors completed the author disclosure form.
serum specimens allowing rapid sample processing, and use
Disclosures and/or potential conflicts of interest:
of fresh specimens that match real practice testing instead
of freezing and thawing for analysis, often in batches. Employment or Leadership: F.S. Apple, Clinical Chemistry, AACC;
5. This novel practice will allow manufacturers to enroll over C.R. Fantz, Roche Diagnostics Corporation; P. Collinson, The Journal
2500 patients in >3 selected institutions in 3 to 4 months, of Applied Laboratory Medicine, AACC.
Consultant or Advisory Role: F.S. Apple, HyTest, LumiraDx, Brava
allow more rapid acquisition and compilation data, creat-
Dx.
ing draft documents more quickly for submission to FDA Stock Ownership: C.R. Fantz, Roche Diagnostics Corporation.
for review, and provide substantial financial savings by cut- Honoraria: F.S. Apple, Siemens Heathineers, Instrumentation
ting a 2 to 3-year process to < 1 year. Laboratory.
Research Funding: None declared.
Finally, the FDA is capable of rapid review and has Expert Testimony: None declared.
been extremely flexible during the COVID-19 Patents: None declared.
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