Abstract
Background
Point of care tests (POCTs) are increasingly being promoted for guiding the primary medical care of community acquired lower respiratory tract infections (CA-LRTI). POCT development has seldom been guided by explicitly identified clinical need and requirements of the intended users. Approaches for identifying POCT priorities and developing target product profiles (TPPs) for POCTs in primary medical care are not well developed, and there is no published TPP for a CA-LRTI POCT aimed at developed countries.
Methods
We conducted workshops with expert stakeholders and a survey with primary care clinicians to produce a target product profile (TPP) to guide the development of a clinically relevant and technologically feasible POCT for CA-LRTI.
Results
Participants with clinical, academic, industrial, technological and basic scientific backgrounds contributed to four expert workshops, and 45 practicing primary care clinicians responded to an online survey and prioritised community-acquired pneumonia (CAP) as the CA-LRTI where a new POCT was most urgently needed. Consensus was reached on a TPP document that included information on the intended niche in the clinical pathway in primary medical care; diagnostic product specification (intended use statement and test concept), and minimum and ideal user specifications. Clinicians minimum requirements of a CA-LRTI POCT included the use of minimally invasive samples, a result in less than 30 minutes, no more than a single preparation step, minimum operational requirements, and detection of common respiratory pathogens and their resistance to commonly prescribed antibiotics.
Conclusions
This multidisciplinary, multistage partnership approach generated a clinically-driven TPP for guiding the development of a new POCT, and this approach as well as the TPP itself may be useful to others developing a new POCT.
Introduction
A primary care point of care test (POCT) is a test carried out near to the patient that generates a result without reference to a laboratory, and rapidly enough to affect patient management at the point of care [1, 2]. POCT development has often been driven by technological innovation rather than in response to a clearly defined unmet clinical need, and as a consequence many POCTS have not been taken up into routine clinical care. There are also some clinical niches where POCTs are urgently required. For example, there is a need for improved POCTs to help primary care clinicians to safely reduce and better target antibiotic prescribing for common infections such as community acquired lower respiratory tract infections (CA-LRTIs) [3], [4]. CA-LRTIs are one of the leading acute reasons for consulting in primary care, and 20%-95% of patients are prescribed an antibiotic [5], [6]. More than 80% of these antibiotics may be unnecessary as CA-LRTIs in developed countries are largely self-limiting and the majority of patients do not benefit meaningfully from antibiotic treatment [7], [8], [9]. A rapid POCT that is feasible for use in primary care consultations that helps clinicians decide when antibiotics can safely be withheld, or when antibiotic treatment is likely to benefit patients, could improve care of this common and important condition and help combat antibiotic resistance.
A critical factor in successful POCT development is gaining an in-depth understanding of the end users’ (e.g. clinicians) priorities, needs and operational requirements for any new POCT at the outset [10], [11]. This information, summarised in a target product profile (TPP), should guide test development so that it matches clinical need and safely improves outcomes in priority conditions. [12]. TPPs for diagnosing infections disease have been developed by the World Health Organisation (WHO), Foundation for Innovative New Diagnostics (FIND) and Médecines sans Frontiéres (MSF) [13] [14] [15] and others through the identification of stakeholders for consultation, priority setting to identify the highest priority for test development, defining operational and technical test characteristics, discussing disputed criteria, and obtaining final consensus [16, 17]. To formalise TTP’s and ensure their verification (consistency and completeness) formal modelling approaches have also been helpful [18] [19]. However, as yet, there is no consensus on the priority CA-LRTI where a POCT is most urgently needed, the ideal process for developing a POCT TPP, and there is no published TPP for a CA-LRTI for use in developed countries. Our experience of developing a TPP for the exemplar condition of CA-LRTI illustrates how a TPP can be generated to inform the development of a new POCT.
Materials and methods
Ethics
This study was reviewed and approved by the Cardiff University School of Medicine Ethics Committee (SMREC Reference Number 11/32).
Study design
The development of our CA-LRTI TPP was an iterative process that included meetings with expert stakeholders from the EU Innovative Medicines Initiative (IMI) supported project, ‘RAPP-ID: Rapid Point-of-Care Test for Infectious Diseases’ (IMI RAPP-ID) project consortium (https://www.imi.europa.eu/content/rapp-id) and a web-based survey targeted at practicing primary care clinicians with an interest in CA-LRTI. Both qualitative and quantitative data informed the TPP.
RAPP-ID consortium expert meetings and workshops
Four 2–3 day RAPP-ID stakeholder meetings, including breakout workshops targeted to the specific disease areas, were conducted between April 2011 and January 2012 (see Table 1 for meeting objectives). Stakeholders included expert and practicing clinicians, microbiologists, scientists (molecular microbiology, chemistry and physics), diagnostic market experts and test developers from academia and industry (European Federation of Pharmaceutical Industries and Associations (EFPIA)) in Europe. Learning points from the TRANS-Atlantic Task Force on Antimicrobial Resistance (TATFAR) meeting on ‘Challenges and solutions in the development of new diagnostic tests to combat antimicrobial resistance’ informed stakeholder discussions.
Table 1. Objectives of the stakeholder planning meetings.
| No | Objective |
|---|---|
| 1 | Familiarise all stakeholders with the expertise and technologies available within the consortium |
| 2 | Discuss potential benefits of optimised disease diagnosis |
| 3 | Reach agreement on target conditions that would most benefit from improved diagnosis for adequate antimicrobial treatment |
| 4 | Consider the clinical complexity of antibiotic treatment decisions |
| 5 | Clarify the current state of the art in diagnostic tools for each disease condition |
| 6 | Reach agreement on micro-organisms, biomarkers and thresholds (e.g. limit of detection, colonisation vs. infection) |
| 7 | Discuss the availability and challenges of clinical sample availability, collection and processing |
| 8 | Develop models of therapeutic algorithms and patient stratification including POCT integration |
| 9 | Discuss potential scenarios from sample collection to read-out |
| 10 | Develop the user survey and discussing the technical feasibility of including the identified ideal user requirements |
User survey for CA-LRTI POCT
An on-line survey, informed by the stakeholder meeting outputs, was developed in collaboration with RAPP-ID consortium members to ensure questions covered information required by the test developers. The survey was piloted prior to distribution. Data collection was from 12th September to 12th December 2011. The survey was aimed at practicing primary care clinicians with an interest in respiratory tract infections and was disseminated through RAPP-ID partners, the General Practice Respiratory Infections Network (GRIN), and flyers at the European Respiratory Society Annual meeting (Netherlands, September 2011).
The survey had four parts (Fig 1). Part 1 aimed to identify the priority clinical LRTI sub-conditions that clinician’s considered would most benefit from improved rapid diagnostics. Clinical case definitions for each LRTI sub-type were included (S1 Table). Part 2 asked about clinician’s ideal and minimum user specifications for a CA-LRTI POCT. Parts 3 and 4 asked about clinician’s current POCT use and barriers to implementing POCT ‘s in routine care and microbiologists.
Fig 1. Survey to identify clinical need, minimum and ideal user requirements and perceived barriers for a new CA-LRTI POCT.
Questions to identify clinical priority or need for the POCT asked respondents to i) select their ideal requirement and ii) and assign a number of 1 to 5 (1-highest priority to 5-lowest priority) for their the requirement they considered most essential. To determine the POCT technical specifications, respondents were asked to i) select their ideal requirement and minimally acceptable requirement, and ii) select yes/no for questions asking if they would consider using a test with the listed characteristics. For all questions respondents could select more than one option and provide free text comments. Options for ‘unsure’ and ‘not relevant to my practice’ were included.
The results of the user survey were presented to all RAPP-ID partners and the technical feasibility of including the ideal user requirements into a POCT discussed with guidance from the expert clinicians
Survey data analysis
Survey results were combined for all countries to inform the TPP. Questions asking respondents to select their ideal requirements and responses to binary (yes/no) questions were analysed as number and proportion as an average. For ranking questions, the majority of respondents selected and scored more than one priority for each question. These results were therefore also analysed as numbers and proportions as an average. Free text comments were included in the appendix of the TTP.
Target product profile (TPP) document
Information from the stakeholder meetings and the user survey were used to design and inform the TPP (Table 2). Stakeholder discussions aimed to reach consensus on the final TPP including the specifications for a CA-LRTI POCT and a proof of concept POCT.
Table 2. Structure of the target product profile (TPP) document.
| SECTIONS | CONTENTS |
|---|---|
| Front of document | Authorizations, appendix, glossary, definitions |
| Aim of document | Reference document for researchers, developers and manufacturers |
| Source of document information | Workshops, surveys, literature reviews |
| Clinical need and requirement for new test | Include clinical setting, fit into clinical pathway, POCT concept diagram, overview of current tests used in clinical practice |
| Information on clinical samples | Sample type, nature of samples and target molecules (e.g. biomarkers, pathogens), sampling equipment, acceptability of samples |
| Diagnostic product specification | Intended use statement, descriptions of test concept (description of the desired test) and proof of concept (test and methods that will demonstrate in principle the feasibility of developing a test with the desired TPP) |
|
TEST SPECIFICATIONS (Tables of key features including both (ideal (target) and minimum (acceptable) requirements). | |
| Technical specifications: | Intended use, clinical decision to be influenced, place of use, patient criteria, target molecule, performance against reference, type of analysis, readout system, sample type, reproducibility, compliance with regulators, reproducibility near clinical thresholds. |
| Operational characteristics: | Sample requirements (e.g. volume of sample, sample preparation, quality, requirement for precise volumes), controls, waste disposal, batching, end-user profile, training, biosafety, test speed, test stability, storage requirements, shelf life, lifetime of machine, need for additional equipment, cost. |
| Market overview | Cost of manufacturing single device, competitive landscape, regulatory pathway, competitive landscape, region of commercialization, market segmentation |
| Information on Competitor Tests | Available and those coming to market. Details on test performance, characteristics, market uptake etc. |
Results
Clinician survey
Survey respondents
45 primary care clinicians completed the survey but not all respondents completed all survey questions. The majority of the respondents (21) were from the UK, and others from Belgium (9), The Netherlands (3), Poland (3), Spain (2), USA (2), Germany (1), Finland (1), Norway (1), Sweden (1) and Australia (1). 34 (70%) respondents were clinically research active, and their clinical workload relating to infections varied from <20% to 60%.
Clinical priority for POCT development
Community acquired pneumonia (CAP) was the LRTI given the highest overall ranking with 16 (35.6%) respondents giving it a ranking of 1 (high priority) and 34 (75.6%) giving a ranking of between 1 and 3. 11 (24.4%) respondents also selected influenza and acute exacerbations of chronic obstructive airways disease (aeCOPD) as their highest priority. Acute exacerbations of asthma and bronchitis were selected as the top priority by 7 (15.6%) and 4 (8.9%) respondents.
There were 88 free text responses (S2 Table).
Ideal and minimum CA-LRTI POCT requirements
For the majority of questions, respondents selected and ranked more than one option (Table 3).
Table 3. The gaps and needs for a priority CA-LRTI POCT as defined by an expert consensus process with primary care clinicians.
| Question (number of respondents completing question on ideal and minimum specification) | Answer Options | Ideal specification (number (%) selecting as top priority) | Minimum specification (number (%) selecting as top priority) |
|---|---|---|---|
| How would a new CA-LRTI POCT best guide treatment decisions? (41) |
|
Initial treatment targeting (40, (97.6)) | Initial treatment targeting (34 (82.9)) |
| What patient sub-group should the test benefit? (38) |
|
Adults aged 65–80 years (25 (65.8)) | Adults aged 65–80 years (19 (48.7)) |
| Antibiotic status of patients for testing? (41) |
|
All patients including antibiotic pre-treated and antibiotic naïve patients (17 (41.5)) | Antibiotic naïve (25 (65.8)) |
| What category of staff would use the test most often? (40) |
|
Doctors (33 (82.5)) | Doctors (29 (70.7)) |
| What aetiological agents do you think are most important for the test to detect? (42) |
|
Bacteria (36 (85.7)) | Not Available (NA) |
| Which do you think are the most important bacteria for the test to detect? (35) |
|
S. pneumoniae (26 (74.3)); H. influenzae (21 (60.0)); M. pneumoniae (17 (48.6)); Unsure (8 (22.9)). | NA |
| What level of bacterial identification is required? (34 and 19) |
|
Gram-positive / Gram-negative (9 (26.5)); Species level (8 (23.5)); Unsure (13 (38)). | Gram-positive / Gram-negative (8(50)) |
| Would information about antibiotic resistance change your clinical practice? (40) |
|
Yes (39 (97.5)) | NA |
| What resistance do you think the test should detect? (36) |
|
Penicillin’s (25 (69.4)); Macrolides (17 (47.2)); Amoxicillin-Clavulanate (16 (44.4)); Beta-lactamases (14 (38.9)); Fluoroquinolones (14 (38.9)); Cephalosporins (13 (36.1)) | NA |
| Level of antibiotic susceptibility information required? (38 and 21) |
|
Sensitive/resistant corresponding to antibiotic breakpoints (24 (63.2)); Unsure (13 (34)) | Sensitive/resistant corresponding to antibiotic breakpoints (17 (81)) |
| Which do you think are the most important viruses for the test to detect? (11) |
|
Influenza (10 (90.9)); Respiratory syncytial virus (6 (54.5)); Para-influenza and adenoviruses (4 (36.4)) | NA |
| Level of viral identification required? (12 and 9) |
|
Species level identification (6 (50)); Unsure (4 (33.3)) | Species level identification (5 (55.6)) |
| Would information about antiviral resistance change your clinical practice? (39) |
|
Yes 25 (64.1)) | NA |
| Most important antiviral resistance to detect? (14 and 8) |
|
Oseltamivir (Tamiflu) (8 (57.1)); Unsure (4(28.6)) | Oseltamivir (7 987.5)) |
| Which test prediction is important to you? (36 and 30) |
|
Rate of true positives (20 (55.6)); Rate of true negatives (16 (44.4)); Unsure (5 (13.9)) | Rate of true negatives (18 (62.1)) |
| Total time taken from taking patient sample to receiving test result? (35 and 31) |
|
<30 minutes (30 (85.7)) | <30 minutes (22 (81.5)) |
Technical and operational requirement specifications of the POCT
Questions asked respondents to i) select their ideal requirements for POCTs, and ii) select the specifications that would prevent them considering a POCT (Table 4), and were invited to provide free-text comments (S3 Table).
Table 4. Clinicians’ technical and operational requirements, and specifications preventing test use.
| TECNHICAL/OPERATIONAL FEATURE | CLINICIANS IDEAL REQUIREMENTS (number of respondents selecting as top priority (percentage)) |
SPECIFICATION THAT WOULD PREVENT CONSIDERATION OF A POCT (number of respondents (percentage)) |
|---|---|---|
| Acceptable clinical samples |
|
|
| Sample preparation procedures |
|
|
| Storage of test and reagents |
|
|
| Test kit requirements |
|
|
| Control requirements |
|
|
| Instrumentation requirements |
|
|
| Test result requirements |
|
|
| Acceptable training requirements? |
|
|
| Power requirement |
|
|
| Acceptable maximum cost per patient test |
|
NA |
| Acceptable maximum instrumentation cost |
|
NA |
Current use of POCTs
21/36 of respondents (58.3%) did not use any POCT for managing respiratory infections, 7 (19.4%) used a CRP test and five (13.9%) a ‘Strep A’ test. When suspecting a false positive POCT result, 22 (64.7%) respondents would follow-up the patient, and 16 (47.1%) would re-test; 21 (63.6%) would follow-up the patient; 16 (48.5%) would re-test; 11 (33.3%) would use clinical algorithms, and; 10 (27.8%) would refer samples to a laboratory or conduct additional tests. In relation to a question on laboratory results, 8 (24.2%) respondents indicated that they would ignore laboratory results if they suspected a false negative and 7 (21.2%) would prescribe a broad-spectrum antibiotic.
Clinician’s perceived barriers to the uptake of a new POCT
29 respondents provided free-text comments (S4 Table). Speed and cost of the test were most frequently perceived barrier (n = 19 (65.5%)). Other barriers related to test cost versus clinical benefit (n = 5 (17.3%)); test complexity and training (n = 19 (65.5%)); time and workload (n = 10 (34.5%)); performance, accuracy and reliability (n = 7 (24.1%)), and patient acceptability (n = 3 (10.3%)).
The target product profile (TPP) document
Consensus on a final TPP to guide the CA-LRTI POCT development included the primary care clinician’s top priority and ideal and their minimum test performance requirements. The TPP document also included the POCT diagnostic product specification statement, a description of the test concept and a proposed proof of concept evaluation (Table 5). The test concept provides a detailed description of the desired POCT. The proof of concept test describes the test and methods to demonstrate, in principle, the feasibility of developing a POCT that matches the TPP. Details of the clinical pathway were also included to promote understanding of the test setting for all the project stakeholders. Examples of currently available tests and emerging technologies, the current market and regulatory pathway for POCT development were also reviewed and included as summary information in the TPP document. The TPP document is available as supplementary material (S1 File)
Table 5. The diagnostic product specification statement.
| INTENDED USE(S) OF THE TEST: |
|
| TEST CONCEPT: |
|
| PROOF OF CONCEPT TEST: |
|
Discussion
We have described an approach for ensuring that that the development of a new diagnostic is driven by clinical need and the requirements of the clinical end users. Critical steps to identify gaps and needs for a new POCT included multidisciplinary stakeholder meetings that generated critically useful information and informed a survey of clinicians, both of which identified clinical priorities and the minimum and ideal performance characteristics of a new POCT.
Nine months was allocated for the initial planning stage of the RAPP-ID project, including the development of the TPP. This included workshops to ensure a shared understanding and vision was reached between multidisciplinary stakeholders. Scientists and technologists were introduced to the clinical need, the nature of the clinical setting, the clinical samples that could be obtained, the potential pathogens and challenges of establishing minimally acceptable performance thresholds. Clinicians gained an understanding of the available broad approaches, technologies and manufacturing restrictions. Involving all stakeholders in the design of the clinician survey and the TPP ensured that all information required by the technologists, test developers and manufacturers was captured.
Community acquired pneumonia was the clinical priority for POCT development. Clinicians minimum requirements for a CA-LRTI POCT included; that the test can be performed by doctors, uses minimally invasive samples, gives a result that is easy to interpret in less than 30 minutes, requires no more than a single preparation step, has minimum operational requirements, and can detect common respiratory pathogens and resistance to antibiotics commonly prescribed in primary care.
Comparison with existing literature
Previous studies have described methods for consulting target users in the early development of new diagnostics, and have identified product failures arising from a disconnect between technology developers and the end users [11], [20] [21], [22]. Perceived barriers to involving actual users in the design and development process include lack of time and requirements for ethical approval [23].
Projects to develop new POCTs are complex and require multi-disciplinary collaborations with partners that have a wide range of expertise [24].
A number of TPPs have been developed for managing infectious diseases in resource-limited settings and these have focussed on detection of the infecting agent or differentiating between bacterial and non-bacterial infections to reduce antimicrobial overuse [13, 14, 17, 25, 26]. Clinicians’ views of POCTs for common infections including LRTI have been established in other studies [10], [27], [28], [29]. However, we were not able to identify any published TPPs for a primary care CA-LRTI POCT in developed countries or studies that identify which particular CA-LRTI condition would most benefit from a new POCT.
While our study identified many positive reasons for developing a POCT for CA-LRTI, some barriers were also highlighted. These included that a test focussing on aetiology may lead to an antibiotic prescription for all bacterial infections, including those that are self-limiting, and that in many cases, diagnosis and prognosis was obvious on clinical grounds alone.
There may be numerous current technical barriers to achieving a test to meet many of the clinicians ‘ideal’ requirements. The ideal specifications also need to be considered in light of the risks that they may pose to successful POCT development.
Strengths and limitations
The clinician survey was relatively small and the sample was largely one of convenience. However, respondents were practicing primary care clinicians with an interest in CA-LRTI. The survey instrument was relatively long which may led to incomplete responses. The TPP was confidential and dissemination was initially limited to the RAPP-ID consortium until the end of the project, which resulted in a delay to placing it in the public domain. Ideally, a formal validation of the TPP would also have been conducted. To investigate interesting relations between variables and add depth to the data analysis additional methods such as association rule learning and data mining technology could have been used.
Conclusion
The development and consensus for a TPP ensures cross-disciplinary dialogue and shared understanding and focuses technological innovation on meeting prospectively identified clinical need. Looking ahead, a TPP should be regularly reviewed throughout product development to take into the account any changing clinical priorities, emerging technologies, and barriers that were unforeseen during development and evaluation stages [30].
Supporting information
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Acknowledgments
We thank Emily Bongard for attending the TRANS-Atlantic Task Force on Antimicrobial Resistance (TATFAR) meeting (Challenges and solutions in the development of new diagnostic tests to combat antimicrobial resistance), and collating relevant information from the meeting for this study. We would like to thank and acknowledge RAPP-ID consortium members who contributed to the workshops and meetings that informed this work including Arash Afshari, Annabelle Van Eeghem, Bryan Allman, Lind Anders, Annika Ahlford, Sahara Ardabili, Holger Becker, Silvia Benocci, Pieter Bienstman, Edwin Carlen, Catriona Crawford, David Herthnek, Peter Dubruel, Sylvie Dutka-Malen, Sri Ghatta, Sourav Ghosh, Jan Grawe, Justin Green, Tommy Haraldsson, Stephan Harbarth, Ivan Hernandez, Laura Huopaniemi, Jona Jarvius, Mikael Karlsson, David Klenerman, Anil Koul, Sanna Laakso, Leila Ladhani, Jeroen Lammertyn, Karen Leirs, Trevor Lewis, Linda Miller, Nacer Lounis, Mats Nilsson, Karen McGurk, Koen Meeussen, Hanne Meeuws, Annabelle Milla, Pieter Moons, Monica Moschioni, Nadine Hlawatsch, Natalia Murillo, Jaana Niittymäki, Wulf Oehlmann, Victor Ostanin, Gaspard Pardon, Katja J Pohl, Pelin Leblebici, Rohan Ranasinghe, Loi Rashpal, Debra Rasmussen, Daniela Rinaudo, Aman Russom, Niklas Sandtröm, Mahavir Singh, Kristiane Schmidt, Henrik Soderstrom, Marco Soriani, Anne Stuyven, Dragana Spasic, Liven Stuyver, Tagrid Salik, Wouter van der Wijngaart, Bieke Van Dorst, Els Vanderleyden, Sandra Van Vlierberghe, Liesbeth Van Wesenbeeck, Kris Verstreken, Sam Werquin, Justyna Wiedemair, Martin Wiklund, Katherine Young, Sergey Zelenin
This work was supported by the Innovative Medicines Initiative, a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (RAPP-ID project, grant agreement no. 115153).
Data Availability
All data that support the findings of this study are deposited in the Cardiff University Institutional repository (DOI: http://doi.org/10.17035/d.2018.0052917920).
Funding Statement
This study was part of the RAPP-ID project (https://www.uantwerpen.be/en/projects/rapp-id/about-rapp-id/) funded by the Innovative Medicines Initiative IIMI-JU-02-2009-04 - Infectious Diseases - Diagnostic Tools. Project ID/Grant Agreement number: 115153, Coordinator - Professor Herman Goossens), a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). EFPIA companies and IMI Associated Partners do not receive any EU funding through IMI, but contribute to IMI through 'in kind' contributions including the time of staff employed by EFPIA companies directly working on IMI projects. The funder provided support in the form of salaries for authors (MG, NAF, KH, JV, HG, AW, CCB), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript .JV was employed by the commercial company, "Janssen Diagnostics BVBA" (one of the 5 EFPIA member companies of the RAPP-JD consortium. Janssen Diagnostics BVBA provided support in the form of salary for author JV, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the author contributions section.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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Data Availability Statement
All data that support the findings of this study are deposited in the Cardiff University Institutional repository (DOI: http://doi.org/10.17035/d.2018.0052917920).