Explanation of the task and expected outcome
The two key outputs of this stage are a tentative/first draft of a study/research plan and analysis of alternative/competing methods. The later will form the basis for your competitor analysis as part of your commercial development.

• Define the specific disorder, condition or risk to be analyzed.
• What is the clinical question to be solved?
• Search for solutions and information in peer-reviewed scientific literature, patent databases and commercial applications (existing or under development).
• Consider biomarkers belonging to different molecular classes and different analysis methodologies.
• Document the gold standard method currently used in the clinical practice whether it is an imaging approach or a laboratory test.
• Take into account possible different clinical viewpoints in different countries.
• Compare all the potential biomarkers and technologies for the same use/indication.
• Identify gaps that could be solved with better markers and/or in vitro diagnostic (IVD) products.
• Take into account potential limitations coming from existing intellectual property rights (IPR).
• Create an early/rough study design and describe the analysis method(s) employed.
• Set the hypothesis (the clinical question) to be answered.
• Describe the clinical study type (e.g. paired case-control study or cohort study) and provide full descriptions of the clinical specimens analyzed, including n (specimens), n (independent cohorts), specimen matrix, selection criteria (both for specimens and specimen matrices), storage conditions and time of storage, level of representativeness of the entire target population (special attention to biases in case of case-control pairing or enriched proportion of positive specimens!), geographical coverage and other demographics.  
• Evaluate the probability for inherent bias and describe the actions you have taken to control it.  

Special attention to: 

Ethics committee approvals and patient consents.

Task related (external) links:

• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix B: A Possible Format for the Literature Search Report, p. 21.
• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix C: A possible methodology for documenting the screening and selection of literature within a literature search report, p. 22.

Explanation of the task and expected outcome

• Calculate the p-value for the putative findings (ideally below < 0.05, if not what are next steps in getting acceptable statistics?)
• Calculate the effect size (quantitative difference) and confidence intervals when feasible, i.e. when a quantitative analysis method has been employed.
• Are the differences detected clinically meaningful or not - Begin to consider clinical decision making: who will act on the information provided? Is there significant priority overlap between the groups that would make clinical decision making impossible?
• Evaluate the clinical concentration ranges detected: Could the range be accurately measured with a practical, routine-applicable assay?

Explanation of the task and expected outcome

• List the names of the putative new biomarker(s) identified ( f.ex by an omics study or other). Include all synonyms/acronyms and codes both at the gene and transcript (mRNA, protein) level.
• Describe the applicable molecular forms for measurement (DNA, RNA, protein, glycovariant, metabolite etc.).
• Define the anatomic organ of origin and the specimen matrices (e.g. serum, plasma, embedded tissue, urine, saliva, etc.) proposed as suitable for analyzing the biomarker.
• Estimate the clinically relevant concentrations in the suitable specimen matrices and list the applicable analytical method(s) accordingly.

Explanation of the task and expected outcome

• Search for information available on the putative biomarker(s) finding(s) in peer-reviewed scientific literature and patent databases and where possible commercial applications.
• Make an overview of the previously published methods (including those for alternative molecular forms), intellectual property and results obtained previously.
• Consider:
  • What is the specific association between the biomarker and the disease: Is it known or can it be hypothesized?
  • Are there any associations to other diseases or benign conditions?
  • Is the biomarker elevated in alternate situations (e.g. due to systemic response or cellular stress) or is it specific to the condition investigated?
• Apply the information when planning the biomarker verification studies. For established/published biomarkers, also consider how your discovery improves current understanding, processes, etc. (i.e. what is the value of the discovery?)

Explanation of the task and expected outcome
When working on a panel of biomarkers:

• Consider the quantity of data or confirmatory tests you need to collect/perform before you are able to pick the top biomarkers for further studies.
• What is the minimum panel required to achieve the same result/accuracy/precision/significance/etc. as the full panel you are exploring?
• Evaluate differences between the relevance of the biomarkers. Are some more associated with the disease than others? Perform a pathway analysis to define how the biomarker is related to the condition of interest.
• Consider if your multiplex assay could be simplified to use biomarkers of the same molecular class so that multiple analytical methods and sample preparation methods could be avoided.
• Are the concentrations to be used in the assay relevant for clinical sample collection or are several specimen preparation or analytics methods required? Is there a path forward to simplify this process?
• Evaluate the complexity of result interpretation required. Could a computer algorithm be developed for result interpretation or are manual decision trees required? Is a sequential personalized testing scheme required?
• Considering available methods/practices, how transparent and understandable (= acceptable) is the method to a clinician?

Explanation of the task and expected outcome
It is likely that at this point of research, you are working with retrospective samples. If so, consider:

• Is a record readily available of how samples have been stored?
• Has prior storage/handling had any influence on observed results?
• As a next step, validate the results using fresh samples:
  •  How do findings from fresh samples agree with the retrospective samples?
  •  If significantly different, consider/study the impact of different storage conditions including(temperature, light, etc) and impact of other procedural steps such as multiple freeze-thaw cycles.

Upon completion of the above:

• Assess, how stable is the biomarker?
• What is the percentage of recovery by making dilutions of either a high-concentration specimen or a standard preparation in a fresh specimen matrix (negative or low sample). Can you measure the amount added? If not, consider if the biomarker becomes bound, nicked or degraded in a fresh sample and if it is stable enough for the planned clinical analysis.

Apply all of the above information when planning the verification experiments of Phase 2.

Explanation of the task and expected outcome

• Describe the purpose of the foreseeable IVD test: What is the test used for and what is the specific disorder, condition or risk to be analyzed?
• Describe the type of the test:
  • Diagnostic, prognostic, predictive (for which therapy?), screening, risk/susceptibility, companion diagnostics (for which drug?), or some other?
  • Will the test be able to detect the disease at an early stage (before clinical symptoms or directly after onset of the disease)?
  • Can the disease be successfully treated at the time of a positive test result?

Task related (external) links:

• Global Harmonization Task Force (2012), Clinical Evidence for IVD Medical Devices / Clinical Performance Studies for In Vitro Diagnostic Medical Devices - Appendix, pp. 18.

Explanation of the task and expected outcome

• Describe the current clinical care pathway (what is tested and when) and how the test/assay/analysis being developed would fit into this pathway/workflow and
• Consider:
  • Does the test depend on results from other methods (i.e., an “add-on test”), or is it a “stand-alone test” with no preceding or confirmatory testing required?
  • Will it replace or complement an existing test, if so which one?
  • What are the advantages of/reasons for using this test to existing alternatives?
  • Is there risk for over/under-diagnosis? What is the consequence of each to the patient, doctor and health system?
  • Does the test help mitigate, reduce risk of mortality?
  • Does the test generate contradictory results to currently established methods? If so, why/how can this be rationalized/understood?

Explanation of the task and expected outcome
Describe the significant, unmet medical need the test addresses.

• What are the existing therapies (or means of prevention) for the disease of interest?
• How does the result of the new test alter the treatment of the patient and how can/will it improve the patient outcome?
• How do the tested patients fare better compared to untested patients?

Consider starting dialog with clinicians early and acquire written feedback for the suggested application. How does this feedback influence your product concept and your technical development plan?

Explanation of the task and expected outcome
Collect evidence for the consistency of the results by

• repeating the analyses,
• increasing the sample size (e.g. by additional sample cohorts with a wider geographical/ethnical coverage) and
• preferably having the results confirmed by other research sites.

Explanation of the task and expected outcome
Good documentation of your work will play an important part in securing intellectual property, regulatory approvals, discussions with potential partners and overall technical development. As such, it is advised to:

• Keep track of all experiments in a laboratory notebook (consider a digital one).
• Take time to update the notebook after each activity. It is an official document that will be needed later on.
• Keep all raw data well-stored.
• In all documenting, follow the spirit of Good Laboratory Practices, Good Scientific Practice and Good Documentation Practice to the extent possible. These practices will help in ensuring high quality in experimenting (e.g. sufficient number or replicate reactions) and documenting (all relevant materials, conditions and other parameters).
• Use an organized page layout (template) to save time, improve readability and consistency.
• In addition to the experiment purpose, write down the main conclusion of the experiment in the Title (in one short sentence, similarly to when writing a title for a scientific paper).
• If possible, from project start use a suitable experiment numbering system, where related experiments can be sorted and linked.
• Create a numbering system also for the reagents and tools produced by your own experiments, so that all experimental products have a unique ID.  
• For commercial reagents, document at least the full name, manufacturer, order code, lot number, expiry date and storage conditions.
• Document the pH and contents of all buffers and reactions.
• Document actual conditions such as numerical temperatures instead of “Room Temperature (RT)” for storage or incubation.
• Document all instruments and instrument parameters (e.g. columns, filters, run parameters, measurement parameters, and wavelengths) similarly and carefully.
• Document all results and observations, including any unusual ones.
• Freely use illustrations, photos (e.g. of the setup) drawings, plots and tables for added clarity.
• Date and sign new pages after each experiment/workday.
• Make intermediate reports at specific milestones (when/if these have been identified).
• Apply the achieved knowledge in planning the next tasks and phases.

Pay special attention to:
To secure intellectual property rights, keep the results confidential until the results have been confirmed and the novelty and patentability surveys performed. If you haven’t already contact the technology transfer office (TTO) of your organization for any questions. (If unavailable, consider meeting a third party TTO to help you in the process) Note that abstract, posters, conference presentations and interviews count as publications.

Explanation of the task and expected outcome
If you have not already begun to do so, consider what problem your test will address and how will it be positioned in the clinical care pathway:

• What unmet, significant clinical need would the test solve?
• How does the test results affect treatment of patient and improve patient outcome?
• How do the tested patients fare better compared to untested patients?
• Do you have documented opinion of suggested end users?
• Is the diagnosis actionable, i.e. are there preventive steps to be taken if diagnosis is established or an existing therapy?
• Without an existing therapy, what is the value of the diagnosis?
• If no therapy exists, can the method be used in the development of novel therapies?

Explanation of the task and expected outcome
If you are working without a commercial/business development counterpart in your organization/team, this is the point at which to approach your organizations Technology Transfer Office (TTO) or someone with commercial experience to begin to plan project milestones and timelines.

In these discussions you should:

• discuss key activities
• plan for resource needs (time, skills and materials)
• discuss how the above could/should be funded

Explanation of the task and expected outcome
Based on discussion with your commercial counterpart/TTO develop a funding plan:

• How far can the research be taken with current/own funding?
• Are there specific funding sources you have access to?
• What are the relevant funding sources (e.g. innovation funds, charities, large company foundations, European programs, venture capital)?
• Is interest in furthering the project secured and supported by your organization?

Explanation of the task and expected outcome
Develop a collaboration/team plan for the project, if needed:

• Does the project require specific expertise that the team lacks?
• If so, have you established where this expertise is situated? Have you or do you need assistance with establishing contact?
• Does the project require clinical specimens/instrumentation/other that are not currently available?

Explanation of the task and expected outcome
Begin laying the groundwork for securing the resulting intellectual property of the project. If you have not done so at this point, take an introductory meeting with a patent lawyer.

In preparation identify and where possible prepare/document:

• the novelty of your results
• background for the invention (e.g literature references and patents/technologies identified to date)
• possible end markets/applications for your biomarker/invention

Communicate/repeat this discussion with your TTO.

Explanation of the task and expected outcome
Early stages of the IVD assay commercialization process, that do not involve the participation of a company, do not have mandatory regulatory tasks regarding placing a product on the market (as required by IVDR regulations.)Please note that, manufacturers bear the burden for ensuring compliance with all regulations during the commercialization process, however if researchers fail to maintain the IVD development standards, the manufacturer could be forced to duplicate/repeat efforts when submitting for approval.

While not regulated or legally mandated, this is a good point to begin to consider possible regulatory pathways to get a product based on your biomarker discovery on the market. Alongside these considerations, to accelerate eventual regulatory approval, you should seek to comply as soon as possible with standard best practice guidelines (see more in this section, task "Good Practices") regarding conduct of your research.

Task related (external) links

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
At present there is no European framework on the use/bio-banking of biological materials and your project may be subject to national regulations that may vary across member states. To assure compliance:

• Check if you have the appropriate and current approvals for the use of data, material, samples etc. to start your project.
• Consider if you are planning on transnational/cross-border exchange of samples. If yes, additional requirements could arise.

Consider what is the standard and if there is a difference between applying for ethical approval for a whole research project or single medical experiment. These requirements can vary significantly across nations/regions.

Task related (external) links:

• Ethics Issue Table - Checklist

Explanation of the task and expected outcome
For any invention of newly discovered biomarkers, align patent filing by crafting claims that meet future intended uses/ purposes/ indications for use of a potential IVD medical device. Patent claims ideally cover technology and use claims. These ideally should mimic future intended use claims of IVDs to make patent infringement very obvious.

Explanation of the task and expected outcome
Regulatory approval requires specialist knowledge given the breadth and depth of regulatory practices currently in place in the industry (e.g. IVD development standards, GLP, FAIR, QPBR, CMS/CLIA, etc.)

• As a first point, consider how and who should handle these various procedures. The key responsibility of the researcher will continue to be conducting well documented experiments.
• Review your plan for data collection, storage and recording. (See Section Biomarker Discovery - Guide for biomarker development - technical and clinical performance Task Documentation for suggestions on best documentation practices) Regulatory approval agencies certify only those IVD medical devices which are backed by reliable data generated by the researcher/would-be commercial entity in accordance with IVD standards. Failure to comply with these standards may result in requests for new data.
• Where possible, research should be carried out in conformity with current standards and IVD methods. It is recommended to implement a quality system and/or a data management & stewardship system e.g. GLP, FAIR.
• Work according to a quality system for non-clinical studies. Familiarize yourself or a member of your team with popular standards and norms: e.g. QPBR, GLP, FAIR (for scientific data management and stewardship.) Consider if there is any specific rule that has to be complied with.

Task related (external) links:

• GLP handbook by WHO
• U.S standards: CMS/CLIA: In the U.S quality control of laboratory process, requirements for technicians and proficiency are under CLIA regulation. Compliance with CLIA standards are not obligatory in EU, but provide comprehensive standards in field. More information can be found here:
  • Centers for Medicare & Medicaid Services
  • FDA: Clinical Laboratory Improvement Amendments (CLIA)
  • Clinical and Laboratory Standards Institute (CLSI)
• European Standards by European Committee for Standardization, e.g. EN 13612:2002 "Performance evaluation of in vitro diagnostic medical devices"

Explanation of the task and expected outcome
Continuing with the work initiated in phase 1 "Biomarker Discovery" - Technical and Clinical Evaluation, Task: Consistency of Results, the scope of the study/sample collection should be expanded.

Consider:

• To establish a plan for verifying the biomarker finding(s) using quantitative confirmatory analysis methodology and additional specimen cohorts with an increased diversity that better covers the potential target population.
• To decrease the extent of specimen picking and increase the proportion of negative specimens.
• Describe the study design and the analysis method(s) employed.
• Describe the clinical study type and provide a full description of the clinical specimens analyzed.
• Start increasing the geographical coverage to the extent possible.
• Identify and review inherent bias in the study design and describe the actions you have taken to control it.
• Prepare a statistical analysis plan.

Special attention to: 

Ethics committee approvals and patient consents.

Explanation of the task and expected outcome
Evaluate the consistency and reproducibility of results between sample cohorts, analyses, operators/instruments and methods in-house and between-site (where available).

• Are the same observations made repeatedly?
• What is the level of variation between the analyses?

Explanation of the task and expected outcome

• Re-calculate the p-value (ideally below < 0.05 for continuing, if not what steps can be taken to get to this level).
• Calculate the effect size (quantitative difference) and confidence intervals when feasible i.e. when using a quantitative analysis method.
• Based on your conversations with clinicians and practitioners, re-consider whether the differences detected are clinically meaningful and would allow for clinical decision-making.
• Note that a significant overlap between case and control groups would make clinical decision making impossible despite of the p-value (i.e. resolution) achieved.
• Consider also if the clinically relevant concentration range could be accurately measured using a practical (routine-applicable) assay.

Explanation of the task and expected outcome
Revisit and if possible expand on the biological link of the biomarker to the disease:

• Is the biomarker disease-specific or does it have a shared molecular pathology across diseases?
• Is the biochemical pathway known?
• Is the biomarker elevated in any benign conditions?

Explanation of the task and expected outcome
General interest of healthcare professionals (clinicians, laboratories) and companies in the IVD field needs to be confirmed on a non-confidential level, preferably in several areas. Make a written report on the feedback you receive.

If possible, consider drafting legally non-binding letters-of-intent (LOI) reflecting clinicians and practitioners need for and willingness to use the proposed ‘diagnostic.’

Explanation of the task and expected outcome
Revisit and if possible expand on the relevant target population:

• Male/Female?
• Certain age group?
• Apparently healthy, symptomatic, having a risk, or readily diagnosed?
• Certain subgroup of the sick?
• Which ethnicities?

Explanation of the task and expected outcome

• Give the yearly incidence of new cases/100,000.
• What fraction of cases or the population is to be tested ?
• Based on disease rates in different geographic regions, present estimates of the number of tests that would be performed yearly.

To be considered: As a rule of thumb, the business case for tests targeting patients who are either already diagnosed and or have a rare disease, is markedly lower than for tests e.g. for all symptomatic patients. Reconsider, the value created by the biomarker/diagnostic, what new information is added, what clinical challenges removed and are these improvements for instance 10 times better than current methods?

Explanation of the task and expected outcome
Using information gathered from your search of publications, patents and commercially available products:

• Begin to list companies providing diagnostic solutions for the condition of interest, expanding on your understanding of potential competition.
• Consider performing this task in conjunction with your Technology Transfer Office/commercial development officer.
• Update or make an overview of potential collaborators, commercial partners and competitors (scientific teams, companies, clinical laboratories, etc.)
   

Explanation of the task and expected outcome
Protection of intellectual property is a key consideration for funding agencies to support further development. If you have not done so, meet with a patent lawyer to discuss how the ability to patent may be impacted by existing public information (prior-art).

• In preparation for this meeting consider/prepare :
  • Novelty is the first major pre-requisite for patenting: Has the biomarker or its use in the intended indication, previously been published by the inventors or by a third party? Perform a prior-art search in both scientific and patent databases. Consider hiring the patent firm to further expand on this prior-art search.
  • Inventiveness is the second major pre-requisite for patents: Does analysis of the biomarker result in an unprecedented technical effect, such as unexpectedly informative result that is not achieved by competing methods? Describe the significant improvements compared to existing markers and methods. What problem(s) is/are solved?
• Prepare key references that a patent attorney can study to further/expand the analysis.

Consider: A space with extensive patent protection may harm the potential of developing a business. Be prepared to re-consider alternative conditions.

Explanation of the task and expected outcome
Review, and if possible, expand on further:

• Is the biomarker disease or condition specific? Or does it have a shared molecular pathology across diseases?
• What is the link between the marker and the biochemical pathway of the disease/condition?

Explanation of the task and expected outcome
If not already done, report your invention (also described under phase 1 "Biomarker Discovery" - Commercial Evaluation, Task: Summarize your results in a layman way for preparing a declaration of invention.)

Explanation of the task and expected outcome
Revisit/reflect on your partner and sample/material acquisition strategy:

•  Do you have access to relevant samples in necessary quantities?
•  Do you require development of specific antibodies?
•  Who are collaborators, institutions and companies that can help you in this?

Explanation of the task and expected outcome
As your patent advisor may have made you aware, there is a 12 month window between submission of an initial claim and full patent application. To assure sufficient content in the application, it could be in your interest to postpone filing, especially if there is no urgency to publish scientific results. Based on commercial discussions and market research begin outlining a patent strategy.

Consider:

•  The time for drafting a solid application ranges between 2-3 months.
•  How will the presence/absence of a patent impact your discussions/collaboration with potential/desired partners?
•  Are any of the competitors working on securing IP in the space?
•  Based on your geographic survey of the disease/condition, what are geographic regions of interest?

Explanation of the task and expected outcome
Having submitted an initial patent application, prepare a non-confidential slide deck/presentation to facilitate discussion with potential/existing partners and investors.

Explanation of the task and expected outcome
While there are no mandatory tasks regarding regulatory aspects of commercialization, this is a good point to re-visit/review your regulatory strategy and approach:

• What standards are relevant for your geographies of interest?
• Who will oversee the regulatory process in your team/organization?
• What standards of best practice have you/should you implement?

Application of industry best practices from an early stage should smooth later stages of commercialization and interactions with regulatory agencies and partners.

Explanation of the task and expected outcome
Review and implement good practices from Phase 1.

Explanation of the task and expected outcome
Begin to plan for ‘real-world’ validation of the bench/lab Proof-of-Concept studies:

• Describe the assay/instrumentation for developing an IVD- assay, i.e. a first prototype.
• Where possible, look for technologies/methods routinely implemented in clinical practice. (Revisit your prior discussions with clinicians and other end-users for suggested methods/technologies/etc.)
• For specific requirements not readily met by available methods/instruments, outline the technical specifications required and identify potential suppliers. If ready, proceed to order.

Explanation of the task and expected outcome
Design all internal and external controls required in the Proof of Concept assay:

• For specimen preparation, co-extracted internal controls may be added into patient specimens to monitor for the success of the extraction or concentration protocol.
• For sample analysis (especially in case of nucleic acid amplification assays), an internal control is a necessity to monitor for the success of the amplification reaction and for the presence of assay inhibitors.
• External controls (such as standard preparations or characterized clinical specimens) are required to calibrate the assay and perform regular quality control on results obtained.

Explanation of the task and expected outcome
Set up the prototype and optimize the reagents and assay conditions:

• Design the result calculation parameters and principles. Note: base all applicable calculations (such as average, coefficient of variation) on values translated into concentrations (via using a standard curve) rather than the raw signals measured.
• Assure that a statistically significant amount of replicates is used. Mimicked clinical specimens (e.g. zero samples spiked with known amounts of standard) are accepted, but always use a clinical specimen matrix instead of a simple buffer solution.

Explanation of the task and expected outcome

• List the types of clinical specimen matrices that are expected to contain the biomarker(s) in sufficiently high levels.
• Select the specimen matrices used for the study.
• For invasive (biopsy) specimens, describe if the specimen is collected routinely or if the specimen is required for the current assay only. (Consider that an invasive compliment to your assay may make this an undesirable method to be used by a clinician or for a patient)
• Provide a description for any mimicked specimens that are to be used in setting up the prototype or in evaluating its analytical performance characteristics.

Explanation of the task and expected outcome
Design the Proof of Concept clinical study (e.g. retrospective and/or prospective cohort):

• Describe the planned target population(s) and their coverage.
• Provide the inclusion and exclusion criteria and estimate the number of specimens and independent cohorts to be analyzed.
• If not done ealier, make plans for specimen collection, preparation, storage, de-identification, chain-of-custody and disposal.
• Plan and schedule the ethics committee approvals required.
• When using retrospective sample cohorts, ensure that the patient consents allow the planned use and that there are no legal restrictions (such as agreements) that would prevent the use of the specimens.
• Provide a description and plan for the mimicked samples to be used in the analytical performance characteristics assessment of the prototype, e.g. pooled depleted clinical specimens or pooled zero-specimens spiked with a standard or a known high-concentration clinical specimen.
• Evaluate the probability for inherent bias and describe the actions you have taken to control it.

Task related (external) links:

• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix E: Some Examples to Assist with the Formulation of Criteria, pp. 24.

Explanation of the task and expected outcome

• Follow the format suggested by the local ethical committee(s). In preparing the patient consent documents, note that the wording used dictates the use of the specimens.
• Draft the consent document early and ensure that the scope of use and field of research are not too strictly defined to allow the use of alternative analysis techniques and to target different biomarkers.
• Ensure long enough storage time to allow continuing research.
• State clearly/incorporate that the results may be used for commercial purposes (e.g. for patenting or in marketing materials) with the aim of producing new diagnostics and therapeutics.
• If possible, consult your legal department/legal advisor on the requirements of EU General Data Protection (GDPR) that apply to you.

Task related (external) links: 

• Simon Fraser University - Office of Research Ethics (2017), Consent form guidelines and template

Explanation of the task and expected outcome
Establish the specimen preparation protocol.

• Ensure that the protocol works both in fresh and stored clinical specimens.
• For future/commercial application, consider methods to optimize the protocol at this point (e.g. decrease number of steps, using simpler methods/reagents/instrumentation)

Explanation of the task and expected outcome

• Calculate the analytical sensitivity of the prototype assay (LoB, LoD, LoQ).
• Provide description of the clinical specimen matrix used for calculating the analytical sensitivity (e.g. pooled depleted or zero clinical specimens), the number of replicates analyzed at each concentration of the standard or calibration curve and the mathematical formula used.

Explanation of the task and expected outcome
Calculate the analytical specificity of the prototype assay.

• Assess for the presence of any non-specific increase of signal (i.e. matrix effect) in the different clinical specimen matrices evaluated.
• Has other exogenous or endogenous interference been detected? Is the cross-reactivity (%) with closely related molecules known or can it be examined?
• Similarly, do you know what different molecular forms of the biomarker (e.g. free vs. bound; glycosylated vs. unglycosylated; degraded or enzyme-cleaved, etc.) are measured?

Explanation of the task and expected outcome

• Confirm the absence of or detect the presence of systematic error (bias) by analyzing reference specimens or standards with known biomarker concentrations (Trueness).
• Calculate the repeatability of measurements in terms of standard deviation (e.g. coefficient of variation, CV %) using several concentrations along the linear measuring range. Analyze the within-run, between-run and between-day reproducibility using a sufficient number of replicates at each measurement point (e.g. 6-12) (Precision).

Explanation of the task and expected outcome
Describe the manual steps and hands-on-time required for the specimen preparation and for performing the assay.

• Estimate the total turn-around time and how many specimens can be handled at the same time.
• Which steps would be amenable to automation in a clinical laboratory?
• Can a sufficiently high throughput be achieved in the routine settings to assure that all patients needing an analysis in a particular timeframe receive one?

Consider including your business partner in this to identify sources of value.

Explanation of the task and expected outcome
Evaluate at least the following characteristics of the prototype assay:

1. Assay kinetics: What is the time required for a low-concentration specimen to become bound and measured >95%?
2. Presence of a high dose hook effect or prozone effect: What concentration of analyte is required for the assay to produce a false negative result due to blocking the specific binders (e.g. capture antibodies) on the solid phase? Can such concentrations ever be encountered in clinical specimens? Can you use the prototype assay with a single dilution of the clinical specimens or are multiple dilutions required?
3. Requirement for specialized instrumentation or modified chemistries: Consider their availability in routine clinical settings. 
4. Qualitative or quantitative assay platform: For near-patient testing, self-testing or home testing, a qualitative or semi-quantitative assay format may be sufficient and facilitate instrument-free result interpretation.

Explanation of the task and expected outcome
Document the optimized protocols and reagents.

• Establish a preliminary component plan where you list all the critical reagents and their specifications. Pay special attention to the specific binders such as antibodies and whether improvements (such as affinity maturation) are required or planned.
• Are there limitations in the availability (such as in the case of polyclonal antibodies or other single-batch reagents)?
• For critical commercial components, list alternative materials and sources (if any).

Explanation of the task and expected outcome
Summarize results of the optimization and performance evaluation experiments.

Explanation of the task and expected outcome
Working with your patent advisor establish the scope of patent protection/panels:

• In case the test uses multiple biomarkers, can the top marker(s) be selected?
• What is the drop in AUC when a top biomarker is dropped out or replaced by a non-patented alternative?
• Note that sufficiently wide scope of protection is a prerequisite for patenting.

Explanation of the task and expected outcome
Prior to continuing toward a commercial version of your assay, it may be relevant to find out if some of your components may infringe on existing patent rights. Discuss this with your TTO officer and consider having a full FTO analysis performed by your patent attorney. An FTO will enable you to minimize and address any risk of patent infringement/lawsuits as you proceed further to produce/sell/import/export your new assay.

Explanation of the task and expected outcome
Begin to work on you customer/investor facing material, when possible with your commercial advisor.

• Translate the technical benefits/advantages of your assay/biomarker into the language of your customer. A reduction in assay turn around time, reduced reagent use, reduced staff costs are all sources of value for patient/clinician/hospital administrator.
• Identify the specific sources of value. Why will someone choose this method over another?

Explanation of the task and expected outcome
Based on the analysis of the competitive landscape, formulate your competitive advantage.

• Competing methods: Describe the technical and clinical performance of existing (competing) methods for the same purpose.
• Advances of the current method: Describe the technical, clinical and/or economical advantages (known or expected) of the new test compared to the existing methods for the same purpose. Comparison is to be purpose-oriented, i.e. independent of specific biomarkers and assay platforms. Include all competing approaches.

Consider, how your technology enables you to be superior to competitors in the space. Is this a 10x advantage (If not 10x is it a significant benefit to your customer)? How long will you be able to sustain this?

Explanation of the task and expected outcome
Compile all the information that you have on the target market.

• Who will buy the tests (healthcare providers, consumers) and in what settings will they be used? By whom?
• Describe the market size, competitive positioning of the test, pricing, market barriers and risks that you foresee.
• The Business Model Canvas is a convenient model for gathering this information in one structure/document.

If no price has been decided, no market estimate made, work with an advisor or seek guidance on developing these estimates. Do not focus on getting a “right” estimate. Many of these will change as the project/product matures but is needed now for further discussion with investors.

Task related (external) links:

• Riley, K. and Associates (2013), modelH: Business Model Canvas for Healthcare.

Explanation of the task and expected outcome
Revisit the development and funding plans. Based on new information re-asses:

•  What do you need to do next to bring your invention closer to a commercially viable product?
•  Which partnerships would you need to build and when would you need to initiate contact and dialogue?
•  Plan steps for the next 12 months including budgeting, IPR and market analysis.

Explanation of the task and expected outcome
Plan the timing and content of a patent application, ideally with a patent attorney.

• Discuss the type and scope of patent protection and what experimental proof is required.
• A manuscript draft will serve as a good basis for drafting a patent application.
• Remember the timing of the priority year: What further proof will be available within one year?
   

Please keep in mind not to publish before the patent application is submitted (incl. abstracts, posters, public presentations.)

Explanation of the task and expected outcome
Select information to be included in the technology presentation, preserving as much as possible any element of novelty claimed in the patent.

• Prepare the presentation to be used to start dialogue with potential partners.

Detailed discussions should proceed only under NDA/ CDA/ some sort of secrecy agreement.

Explanation of the task and expected outcome
Begin to consider your future involvement in the commercialization of the technology:

• Are you ready to spend less time in the lab and more in conference rooms? Are you ready to prepare business plans and commercial marketing materials? If so, consider forming a spin-out company.
• If you are not interested in taking that role upon you, do you know people in your network that could take on that role, while you concentrate on the technical development? If so, consider forming a spin-out where you are involved in a less hands-on manner (perhaps on the board of the company)
• Do you prefer to transfer all the development work to an industrial partner? If so, consider who might be interested in buying your technology for further commercialization. Your list of competing companies is a good place to find potentially interested buyers.

Explanation of the task and expected outcome
Apply Article 26 "Registration of devices" & Article 28 "Registration of manufacturers, authorised representatives and importers"; chapter 4.2.1 of Regulatory Guide. Proceed through the registration procedure within the EUDAMED database.

Explanation of the task and expected outcome
The stage concerns assay lab research – no mandatory regulatory requirements to fulfill.

Explanation of the task and expected outcome
Determine if the assay is under jurisdiction of the EU IVDR. Apply Article 1 "Subject matter and scope", Article 2 (2) "", Article 5 (5) "Definitions" and if uncertainty exists, Article 3 "Regulatory status of products" of IVDR.

• Is the assay intended for examination of blood or other tissue specimens derived from the human body? Does it provide information on any of the following:
  • a physiological or pathological process or state
  • congenital physical or mental impairment
  • predisposition to a medical condition or disease
  • determine the safety and compatibility with potential recipients
  • predict treatment response
  • define or monitoring therapeutic measures.

Collect data related to analytical performance of the assay with respect to IVDR requirements Analytical performance data have to meet specific criteria as stipulated by the IVDR. Apply Annex I "Regulatory status of products", Chapter II (No. 9.1 (a); 9.3) "Requirements regarding performance, design and manufacture" and Annex II "Technical documentation", No. 6.1 "Information on analytical performance of the device" of IVDR.

• When planning analytical (and clinical) performance studies, remember to take into account IVDR requirements in that field. Well-structured raw data concerning specific characteristics is necessary to provide and constitute essential input for the technical documentation. The analytical performance, such as analytical sensitivity, analytical specificity, trueness (bias), precision (repeatability and reproducibility), accuracy (resulting from trueness and precision), limits of detection and quantitation, measuring range, linearity, cut-off, including determination of appropriate criteria for specimen collection and handling and control of known relevant endogenous and exogenous interference, cross-reactions.

Collect data for justification of scientific validity of further assay and apply Annex XIII "Performance evaluation, performance studies and post-market performance follow-up", Part A (No. 1.2.1) "Performance evaluation, performance studies" of IVDR.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
• Global Harmonization Task Force, Study Group 1 (2011), Summary Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices, pp. 17.
• Global Harmonization Task Force, Study Group 5 (2012), Clinical Evidence for IVD medical devices – Scientific Validity Determination and Performance Evaluation, pp. 10.
• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix B: A Possible Format for the Literature Search Report, p. 21.
• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix C: A possible methodology for documenting the screening and selection of literature within a literature search report, p. 22.

Explanation of the task and expected outcome
Provide a full description of the clinical specimens analyzed, including the demographics. Provide reasoning for selecting specimens for the study, as well as inclusion and exclusion criteria.

• How well do the specimens cover the target population as a whole?
• What are the gaps remaining (e.g. in geographical coverage or stage of disease detected)?

Ensure and document that all the specimen handling and storage conditions (especially all the time-critical steps) fulfill the requirements set by the earlier stability studies and specimen preparation protocols.

Explanation of the task and expected outcome

• Provide a description and references for the comparison method selected. Preferably, use the golden standard (imaging method or laboratory test for the same intended use) or a well-established equivalent commercial IVD-test.
• Blinding of specimens will allow avoiding bias especially in the case of marginally positive specimens.

Explanation of the task and expected outcome

• Perform a ROC (receiver operating characteristic) analysis.
• Calculate AUC-values (area under the curve) for the prototype and for the comparison method.
• Compare the results: Does the prototype reach the aims set for clinical performance?

Explanation of the task and expected outcome
Calculate the optimal suggested diagnostic (clinical) cut-off concentration and rationalize it (e.g. optimal diagnostic sensitivity, optimal diagnostic specificity or overall optimal diagnostic accuracy in the ROC analysis).

Note that the optimal cut-off value may be lower than the detection limit of the current prototype assay (i.e. lower than a concentration clearly differing from the background e.g. at conc.CV<10 % or mean blank + 3xSD).If that is the case, take efforts to increase the analytical sensitivity of the prototype.

Also:

• Document the clinically relevant concentration range detected in the specimen cohort.
• Ensure that high-concentration samples have not surpassed the measuring range of the prototype by making dilutions of at least a subset the clinical specimens.
• How well does the linear measuring range of the prototype fit with clinically relevant concentrations?

Explanation of the task and expected outcome
Using the selected optimal cut-off concentration of the ROC analysis, calculate the diagnostic (clinical) sensitivity (%) and specificity (%) of the prototype.

Explanation of the task and expected outcome
Further increase the number of specimens analyzed from apparently healthy individuals.

• Retrospective cohorts are also suitable as long as the patients have not been suspected of having the condition under investigation and the sampling and specimen handling/storage conditions are acceptable.
• Carefully analyze for differences in levels detected between cohorts or populations. If false positive results are encountered, analyze the specimens first with other methods (to detect potential true positives) and then for assay interference.

Explanation of the task and expected outcome
Calculate the PPV/ NPV (positive and negative predictive value) detected in the clinical cohort.

Explanation of the task and expected outcome
Calculate the PPV and NPV expected in the entire target population. Take into account the prevalence of the disease and the diagnostic sensitivity (%) and specificity (%) calculated for the prototype at the selected clinical cut-off concentration.

1. INPUTS:
   • Diagnostic sensitivity %
   • Diagnostic specificity %
   • Overall prevalence in population (cases / 100 000)
   • Prevalence rate in the target population (cases / 100 000)
   • Give the selection criteria for the applicable sub-population (e.g. risk, symptom, age group etc.)
2. OUTPUTS:
   • Positive Predictive Value (PPV) %
   • Negative Predictive Value (NPV) % (Either/both in unselected and selected populations)
   • False positive rate
   • False negative rate  

Consider if the clinical performance of the prototype is sufficient for the intended use. A low PPV or NPV require specific reasoning.

• For low PPV, is there a non-invasive confirmatory test readily available? Or is the disease very disabling and must be definitively ruled-out by the test?
• For low NPV, are there economic or ethical reasons to decreasing the number of false positives at the expense of increased false negatives?

Explanation of the task and expected outcome
Collection of main findings from the clinical performance studies and asses the clinical significance.

Task related (external) links:

• International Medical Device Regulators Forum (2019), Clinical Evaluation - Appendix G: A Possible Format for a Clinical Evaluation Report, pp. 28.

Explanation of the task and expected outcome
Describe the current clinical care pathway (testing sequence) and consider where the biomarker/assay fits best:

• New steps in testing chain (if yes, where?)
• Improves current steps (if yes, which?)
• Replaces current steps (if yes, which?)

Discuss and consider with your business advisor what could be applicable business models for technology transfer.

Explanation of the task and expected outcome
Continue to re-asses and improve the business/economic motivation for implementation of a new test based on the biomarker(s):

• Does the test improve patient outcome, reduce costs, shorten/reduce hospitalization, improve selection of treatment, decreases morbidity and mortality?
• Is this achieved without compromising patient outcomes?

 Perform a Cost-Benefit Analysis: do the benefits provided outweigh the costs of implementation/administration of the new test?

Explanation of the task and expected outcome
If an FTO has not been performed to date, it must be done now.

Has the target use/application/commercial use scenario changed? If so, consider to update the FTO for the relevant space. Do this jointly with a patent attorney.

Explanation of the task and expected outcome
Revise the appropriateness and scope of previously obtained ethical approvals. If necessary, obtain new ethical approval and patient consent for your clinical studies release by ethical committee.

Task related (external) links:

• Simon Fraser University - Office of Research Ethics (2017), Consent form guidelines and template.

Explanation of the task and expected outcome
Fulfil requirements for clinical studies of IVD medical devices (Article 57 "General requirements regarding performance studies" & Article 58 "Additional requirements for certain performance studies" of IVDR) and submit the application for clinical studies according to Figure 28 of Regulatory Guide and Article 66 "Application for performance studies" of IVDR. Collect data related to clinical performance of the assay in respect to IVDR requirements. Apply Annex I Chapter II (9) "Performance characteristics" of IVDR.

Task related (external) links:

• Simon Fraser University - Office of Research Ethics (2017), Consent form guidelines and template.
• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
When the request is approved,

• Start testing by using ISO 20916:2019 standard “In vitro diagnostic medical devices – Clinical performance studies using specimens from human subjects – Good study practices” and 
• Familiarize IVDR requirements, apply Annex I Chapter II (9) "Performance characteristics" of IVDR. 

During clinical (and analytical) performance studies, take into account IVDR requirements in that field. Well-structuredraw data concerning specific characteristics is necessary to provide and constitute essential input for the technical
documentation provided by the manufacturer.

Task related (external) links:

• Global Harmonization Task Force (2012), Clinical Evidence for IVD medical devices – Key Definitions and Concepts.
• Global Harmonization Task Force (2012), Clinical Evidence for IVD medical devices – Scientific Validity Determination and Performance Evaluation.
• Global Harmonization Task Force (2012), Clinical Evidence for IVD Medical Devices - Clinical Performance Studies for In Vitro Diagnostic Medical Devices.

Explanation of the task and expected outcome
Apply Article 24 "Unique Device Identification system" & Article 26 "Registration of devices" of IVDR and start process of IVD medical device registration by applying for UDI codes. UDI codes are elements of the new IVDR approach related to devices identification.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

• Design device’s label and instructions of use - apply Annex I Chapter 3 "Requirements regarding information supplied with the device" of the IVDR.
• Complete the device description which includes device description part/component drawings, assembly drawings and packaging drawings, as well as key components and its operating principles.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Perform a preliminary classification of the assay into risk classes according to IVDR guidelines. Apply Article 47 "Classification of devices" and Annex VIII "Classification Rules" of IVDR and follow Figure 36 of the Regulatory Guide. Note:

• IVD biomarker applicable assays typically fall into classes C or D of the four available classes (A, B, C and D).
• Classification into relevant risk class determines the regulatory pathway.
• Preliminary classification could be expected by a business partner.

Asses preliminary general safety & performance requirements according to product characteristics and risks relevant to its use. (Apply Annex I "General safety and performance requirements" , Annex III "Technical documentation on post-market surveillance" of IVDR and Chapter 4.1 of Regulatory Guide.)

From a regulatory standpoint, it is crucial to establish product characteristics and identify risks associated/related to product performance/design as soon as possible. This constitutes a significant input for further technical documentation and is crucial to facilitate collaboration with a potential business partner.

Task related (external) links

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Continue to expand on and build further knowledge on the biological characteristics of the biomarker(s). If not known or previously documented:

• Where is/are the biomarker(s) produced - e.g. in which organ(s)?
• Is/are the marker(s) intracellular, intra-nuclear and/or excreted?
• What and when triggers biomarker expression and how long is the expression and presence in target tissue/organ/fluid? Is the time window sufficient for testing in routine settings?
• Does it allow detecting the disease at an early stage?
• How many different manifestations (molecular forms) exist and do they change when the disease progresses?
• Are stabilities different in the different forms?
• Can you use the same biomarkers for multiple uses, e.g. first diagnosis and then monitoring the efficiency of treatment?

Explanation of the task and expected outcome
Investigate the specific association between the biomarker(s) and mechanism of disease, as far as it is not already known.

• What is the specific association and the biological mechanism involved in the disease?
• To which patients does it apply?
• Is/are the biomarker(s) specific to this disease or is there a shared molecular pathology across diseases?
• Is there a reason for the biomarker(s) to be elevated in any benign conditions?

Explanation of the task and expected outcome

• Determine the extent of variation between individuals (e.g. gender, age) and ethnicities belonging to the target population.
• Determine the reference levels in similar healthy populations.
• Determine factors potentially affecting the level of the biomarker in-vivo (e.g. circadian rhythm, food intake) and in-vitro (e.g. stability of the targeted molecular form in different specimen matrixes and in different transport and storage conditions).

Can further contraindications for testing or limitations to the target population be identified?

Explanation of the task and expected outcome

• Analyze whether the new assay or any of the specific binders used in it cross-react with biologically related molecules.
• Analyze the effect of relevant endogenous and exogenous interference e.g. by measuring clinical samples known to contain interfering substances such as autoantibodies or certain drugs.
• Report all cross-reactions and assay interferences detected.
• Include any observations made when earlier analyzing specimen cohorts - including healthy individuals. Are there interferences that could be tackled by assay design or chemical additives?
• If not documented previously, what are the clinically relevant concentration ranges for the analyte and the biologically related molecules?
  • Is the effect of cross-reactivity diminished or increased by the difference?
  • Is there a risk for a high-dose hook effect?

Explanation of the task and expected outcome
Re-visit the clinical performance characteristics each time a new specimen cohort is analyzed:

• AUC (separately for different stages of disease/time-from-diagnosis where feasible)
• suggested cut-off value
• diagnostic sensitivity
• diagnostic specificity
• negative predictive value (NPV)
• positive predictive value (PPV)
• number of false positives for each one true positive (100/PPV)
• number of false negatives for each one true negative (100/NPV)
• and other applicable measures, e.g. relative risk ratio, hazard ratio, etc.

Explanation of the task and expected outcome
Revisit the options to bring the technology to the market (either via spin-out/company formation/sale or license to a partner). For company formation a number of general criteria should be met:

• Broad and strong patent protection (e.g. a novel platform, high technical novelty, difficult to copy/reproduce by other means)
• A large and growing market with increased need for the product
• Few competitors or unique value proposition
• Further development is technically feasible
• High potential for extension of product into new conditions/applications
• Strong team with a desire to build a company, including a business oriented leader (CEO)
• Realistic self assessment of the time and effort required to build company further
• A solid business plan with a well thought-out go-to-market strategy
• Feasible financing plan

Explanation of the task and expected outcome
Evaluate alternatives to a spin-out company. Consider licensing to an established company when:

• Narrow patent protection is foreseeable (component or improvement)  
• Product fits in an existing commercial product line
• Expected product development contributions are relatively low
• Crowded or mature markets with large dominating companies

Explanation of the task and expected outcome
Perform self assessment of team and potential company.

Questions for founders:

• What qualifications and special professional and personal strengths do the team members possess?
• What is the level of the teams:
  • commercialization experience and knowledge?
  • industry experience?
  • quality management experience?
  • knowledge of regulatory issues?
  • knowledge of IPR issues?
  • entrepreneurial dedication?
• What are the weaknesses/ deficits of the team and how can they be compensated?  

Questions about the product:

• What is special about your offering?
• What is the extent of further R&D required?
• What kind or premises and instrumentation are required for R&D?
• What kind of premises and instrumentation are required for small-scale production?
• When can zero series production be started?
• How can production be upscaled and when?
• Which quality system requirements need to be fulfilled?
• Which regulatory requirements need to be fulfilled?
• What approvals are required?
• Are there other legal requirements e.g. concerning third party IPR?
• What is the management plan for own IPR?
• What collaboration is required (e.g. all outsourcing required)?
• What are the reimbursement regulations that apply?  
• Can reimbursement be obtained? How?

Questions about the customers:

• Who are your customers?
• Where are your customers?
• Do you have reference customers or first assigned customers?
• Is there long-term sales potential associated with the pioneering customers?
• Are you dependent on a few major customers?
• What problems or specific needs do your customers have?  

Questions about the competitors:

• Who are your main competitors?
• Are competirors developing products in a similar direction?
• What is your pricing strategy and why?
• Which calculations form the basis for pricing?
• How competitive is your pricing against the competitors?
• What other advantages dose your product have against competing products?
• Why is your offer better?
• What weaknesses dose your product have compared to competing products?
• How do you compensate for these weaknesses?
• Where are your competitors located and do you have disadvantages due to your own location? How can you compensate for these disadvantages?

Questions about sales and marketing:

• What kind of sales channels and sales partners (distributors) will you use?
• What is the scale of sales pursued?
• What are the geographical areas targeted?
• What is the cost of sales?
• How do your customers find out about your product?
• What marketing measures do you plan to use and when?
• What is the cost of marketing?

Questions about opportunities and risks:

• What are the three biggest opportunities that could positively influence the further development of the company?
• What are the three most important problems that could hinder the positive development of the company?

Explanation of the task and expected outcome
If company formation is feasible and desirable, create/refine the business plan with descriptions/elaborations of:

• Team and competences
• Market opportunity (need)
• Product (approach/solution)
• Benefits (economical, technical, clinical etc.)
• Competition
• Financing strategy
• Product pricing
• Go-to-market and expansion strategies
• Timeline and milestones
• Pre-negotiated terms for acquiring the IPR, if needed from host institution

Explanation of the task and expected outcome
Establish a detailed plan of the commercial IVD assay development. Include calculations of instrumentation, facilities and resources required and the timeline of each phase.
Place special emphasis on the clinical evaluation studies, including who you will collaborate with and what golden standard technology the new product will be compared to.

Explanation of the task and expected outcome
If not done already, expand your Cost-Benefit Analysis to the individual level. Keep in mind that the estimated cost of detecting one person affected (among the population tested) needs to be economically beneficial.

Explanation of the task and expected outcome
Escalate or initiate discussions with potential investors. Keep in mind:

• Have contact with early stage investors as soon as possible, ideally right after you have an offer for acquiring the IPR  
• Present the business plan and the development plan
• Expect project valuation feedback with early assessment of the required investment.
• Revise your key documents/development plan according to common feedback received

Explanation of the task and expected outcome
In conjunction with your TTO/commercial officer, proceed to work on company formation:

•  Identify the process of company registration from your national Business Authority
•  Identify key registration documents.

If you have not done so previously, have a discussion regarding the Shareholders Agreement (SHA) which reflects expected contributions to the company, remuneration and other key benefits and requirements. Do not postpone this crucial discussion if company formation is the desired path forward.

Consider strongly having a start-up lawyer/mediator present to guide on the technicalities of the legal document as well facilitating the discussion/agreement.

Explanation of the task and expected outcome
Explore the potential/structure of a license agreement. Considerations include:

• Stage of company receiving license (stat-up/early stage v. established/mature)
• Timing and structure of payments i.e. down-payment v. royalties (In some cases, a university/host institution can also participate as a shareholder via an investment-in-kind contribution instead of down-payment).

License term sheets should include:

• Licensor, licensee, date
• Technology description - The exact IPR what is licensed
• Materials transferred
• Territories
• Field(s) of use
• Payment agreement ( up-front payments, royalties, annual fees, milestones etc.)
• Ownership of IPR
• Patenting costs (who pays)
• Sub-licensing terms
• Infringement clauses (who acts)
• Duration, diligence etc.

Note that universities in general may encourage spin-outs by offering flexible terms and sharing the market risk in the early years by putting weight on royalties rather than down-payments. Discuss what model suits the business best.

Explanation of the task and expected outcome

• Describe the components and preparations (e.g. labelling or other reagent manufacture) required for a beta version prototype.
• Identify features for optimization/removal/addition.
• Establish selection and acceptance criteria for all current/future/desired features.

The above should fit with your product roadmap for future versions of the product.

Explanation of the task and expected outcome
The stage concerns technology transfer – no mandatory regulatory requirements to fulfill until SME involvement in the process.

Explanation of the task and expected outcome

• Prepare an overview of the regulatory process/steps from the commercial perspective and of special obligations/requirements e.g manufacturer obligations.
  • Apply: Articles 10 to 16 of IVDR - Chapter 4 of Regulatory Guide.
  • Ideally with a specialist/advisor, begin to consider development/implementation of a formal Quality Management System (QMS) for medical devices, (minimum criteria can be founded in Article 10 (8) "General obligations of manufacturers" of IVDR). Consider the benefits of the system and costs associated since at this time there are no QMS systems available for small enterprises/researchers.
  • Review and apply ISO 13485. Review and get acquainted with the regulatory affairs guidances.
• Initiate the notified body selection process. It may take up ¾ of a year from first contact to closure of an agreement.
• Develop the roadmap for IVDR implementation, including resource requirements, steering group and distribution of responsibility for the implementation of IVDR. Remember of required registration of authorised representatives and importers according to Article 28 "Registration of manufacturers, authorised representatives and importers". According to Article 27 (2) "Electronic system for registration of economic operators" Member States may maintain or introduce national provisions on registrations of distributors of devices which have been made available on their territory.
• Review the supply chain regulations and clarify the roles and responsibilities of business partners (authorized representatives, distributors, importers). 
• Conduct regulatory training for any new team members.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
• European Union (2020), Overview: Medical devices and In Vitro Diagnostic medical devices (IVDs).
• European Union (2018), Factsheet for Menufacturers of In-Vitro Diagnostic Medical Devices.
• CAMD Implementation Taskforce (2018), Medical Devices Regulation/In-vitro Diagnostics Regulation (MDR/IVDR) Roadmap.
• European Union (2020), NANDO (New Approach Notified and Designated Organisations) database.
• International Organization for Standardization (2016), ISO 13485:2016 - Medical devices — Quality management systems — Requirements for regulatory purposes.

Explanation of the task and expected outcome

Perform feasible commercial estimations based on the points described in the BiC Guide (phases 1-5). Based on this documentation determine whether:

• the biomarker development will be overall advantageous with respect to the existing competing technologies,
• will it dominate a niche,
• or will it be otherwise sensible to commercialize.

The prioritization has to be evaluated from companies' perspective:

1. Proof-of-Principle report completed with assessment of clinical significance
2. Key assay parameters established=>defined (specificity, sensitivity, precision, etc.)
3. Freedom-to-operate search results in place for suggested methodology and components
4. Assessment of novelty and patentability completed
5. Publication plan including patent application strategy drafted
6. Commercial development plan drafted/refined including: estimate of potential market, number of potential users, feedback from potential users and more thorough analysis/understanding of the competitive landscape
7. Early assessment of competition (companies, customers, value drivers) completed, summarized
8. Business model for the new test (e.g. reimbursement strategy and market access strategy)
9. Patent application filed
10. Valid biomarker(s) specific assay prototype established
11. Report of clinical performance of the established prototype made
12. Comparing studies with generaly acknowledged state-of-the-art methodologies (golden standard) or with comparable commercial IVD assays in the clinical care pathway
13. Listing of key components and optimized assay composition completed (REACH status check)
14. Assay conditions preliminary chosen/optimization performed
15. Preliminary stability tests of components performed
16. First clinical studies completed
17. Comparison studies and assessment of accuracy and benefits made

See BiC guide phases 1-5 and assess availability of scientific research data characterizing parameters of a molecule(s) to be suggested as potential biomarker(s).

See BiC guide phases 1-5 and assess availability of clinical research data characterizing suitability for a proposed molecule(s) to be used in an IVD assay to pinpoint one or several aspects of a disease(s) or condition(s), such as acute infection, result of vaccination, inherent immunity, post-condition effects, etc.

Assess availability of technology research data characterizing technology used in the potential IVD assay, mentioned above.

Explanation of the task and expected outcome

The Technological Evaluation and Business Feasibility Studystage is the initial internal SME-performed evaluation stage, and it is based on the previous stages (Stages 1-5) of this BiC guide.

Estimate the suitability of the potential biomarker for company’s IVD platform. In other words, you should find out whether the available technology platform could handle the chosen biomarker and assay. As the result of this stage, you should be able to estimate:

• Whether it will be “feasible” to perform the assay using company’s Technology Platform, and
• Whether it will generally reflect the Voice of Customer (VOC), marketing needs and the available IPR.

Explanation of the task and expected outcome

Conduct an evaluation of the market:

• Clinical need and potential market volume
• Preliminary cost feasibility/ profitability assesment
• Competition
• Across different market segments

This evaluation incorporates the demand for a reliable and cost-effective IVD Assay such as device for near-patient testing (known also as Point-Of-Care (POC)), and the interest of Medical Device distributor(s) to sell and distribute the test to the mass markets.

Freedom to Operate analysis as part of the commercial evaluation: Evaluate the entire field of Intellectual Property Rights (IPR), including existing patents, scientific and technical publications, and registered trademarks within the markets under consideration. At this stage, an own IP Portfolio and a separate IP Overview are created, and on their basis an IP Patenting and Publication Plan is designed and written.

Explanation of the task and expected outcome

Reimbursement mechanisms differ from country to country. It is important to examine the requirements and reimbursement/market access mechanisms. It improves and speeds up the possibilities to have the new test fitting better in the system, which in turn speeds up reimbursement. The trend among European healthcare authorities is to focus on authorizing reimbursement only to the most beneficial medical and medical device products and therefore diagnostic manufacturers are continuously revising reimbursement and market access strategies to better fit lower-budget-based decision making in Europe. The demand for a proof of a product's scientific and economic value are increasingly challenging for device and diagnostic organizations, with real-world data and Randomized Control Trial -generated evidence requests.

• Successful market penetration will be achieved by starting to plan the market access in key countries well in advance
• It is important to evaluate the settings and environment in which the new biomarker or device will be used
• Evaluation of time schedules and the complexity of reimbursement approval processes is important
• It is important to identify the local decision makers related to new biomarkers and devices and to analyze the suitability of the new product in the reimbursement system as early as possible

Health technology assessment (HTA): In many countries HTA organizations give recommendations that form a basis for reimbursement assessment.

Task related (external) links:

Mapping of HTA national organisations, programmes and processes in EU and Norway

Explanation of the task and expected outcome

In order to successfully create a preliminary Marketing Plan, the company has to estimate the market needs and wants.

Following needs to be addressed:

• Short summary of market situation;
• Unique selling proposition;
• Preliminary marketing objectives;
• Preliminary analysis of stakeholders and customer segmentation;
• Competitor analysis;
• Preliminary assessment of regulatory requirements and documentation;
• Product launch, Distribution and Sales operation plans including pricing and reimbursement assessment.

The actual (or a preliminary) Marketing Plan should be created during the “Project Planning” stage prior to the “Design and Development” and “Product Verification and Validation” stages. The Marketing Plan must be updated to its final form before product launch. The final Marketing Plan can also be included as part of the business plan.

Explanation of the task and expected outcome

The goal of this stage is to evaluate and identify all resources needed to perform the further stages as efficiently as possible in order to confirm the requirements related to quantity of human resources, equipment, time schedule and funding of further operations.

Resources (technical skills, number of employees, outsourcing)

Map the quantity and quality of technical skills already available in your company and analyze what kind of technical skills are missing. Also analyze the sufficiency of resources. The missing technical skills can be recruited or the required workload can be outsourced to a collaboration partner.

Resources and skills for regulatory purposes need to be estimated, including a person responsible for regulatory compliance. Outsourcing can also be considered as an option.

Conduct a cost-benefit analysis to evaluate which model fits your company best.

Investment analysis

Make a preliminary investment analysis to evaluate financial resources needed. In this analysis, consider at least the following issues:

• acquiring the right kind of premises (including instrumentation) to adjust and control the environment in premises based on product and production requirements.
• investment into production and quality control instrumentation and management
• evaluation of patenting costs and registration fees. Geographical coverage and technological (including production methods) coverage needs to be assessed.
• other costs to be considered (e.g., samples, surveys, outsourscing).

Product development costs (including clinical trials)

Evaluate the amount of investment needed to perform all activities included in the comprehensive development project described above. Investments needed to perform outsourced clinical trials by third parties’ laboratories should also be included in a final investment calculation of a development project.

Funding and budgeting

Map possible funding sources such as public R&D grants and loans, private investors, business angels, venture capitalists, or crowdfunding on local, national and EU level. Notice that different instruments have different terms, like, for example, company type, required own contribution, age of the company, etc.

Capital seekers who can already demonstrate initial success and have a demonstrably functioning and scalable business model are suitable for approaching venture capital (VC) companies. The investment level of venture capital companies starts usually at at least 250 000 euros, depending on the company, but can also be several million euros.

Accelerator and mentoring programmes

If available, consider applying and participating in local and national accelerator and mentoring programmes.

Explanation of the task and expected outcome

Engage market demand early in the project by:

• Evaluating, consulting and interviewing relevant clinical stakeholders
• Finding and engaging well-known and relevant opinion leader(s)
• Reaching out directly to your potential customers to drum up commercial interest, for example in the form of a letter of intent (LOI) expressing how much they are willing to purchase in test phase and afterwards.
• Spreading awareness of your idea through social media to determine if your value proposition has enough organic interest to build an online following.
• Check the capacity of your distributor network/ start building your distributor network

Performing these early market validation activities will substantially mitigate the business risks of the project. If a project is able to show strong market demand early, it both improves the likelihood of attracting an investment, and it increases the chances of executing a successful go-to-market strategy.

Explanation of the task and expected outcome

The goal of this stage is to create comprehensive documentation for the project which contains all documentation available from earlier stages 1 – 5 as history files. This stage also puts together all available information and documentation of the product from technological, commercial and regulatory point of view. A project development plan is created including also an initial risk analysis.

Create a project development plan (or Project Charter): This plan is an “alive” document and should be updated during the entire development process after completion of every stage.

• Technology Aspect of the Project Charter: A Project Charter document should include all the data collected and created so far:
  • the aim of the project and its scope;
  • the need and demand for the test;
  • solution suggested to satisfy the demand, i.e. de facto application or porting of an assay within the chosen technological platform;
  • justification and feasibility of the proposed solution; and
  • resource allocation.

In addition, a Project Charter must reference external marketing and regulatory documentation, such as the Marketing Plan, Market Needs, Voice of Customer (VOC), User Requirement Specification (URS) and System Requirement Specification (SRS).

• Commercial Aspect of the Project Charter: From the commercial and organizational point of view, the Project Charter incorporates:
  • product overview;
  • project organization;
  • resources needed; and
  • identifies activities to be performed.

The Project Charter clearly describes the roles and goals of the Project Team. It also refers to Work Breakdown Structure (WBS) and Project Schedule and Gantt chart.

Project Team and their roles: The R&D Project Leader and the project team are chosen. The Project Charter is updated and clearly describes the roles and goals of the Project Team.

User Requirement Specifications (URS) and System Requirement Specifications (SRS): Translate “Market Needs and Wants” and the Voice of Customer (VOC) into User Requirement Specifications (URS) or System Requirement Specifications (SRS). URS and SRS include intended use, target customers/users, product and the regulatory requirements. They can further refer to standards recognized by the regulatory authorities of target country for its implementation.

Work Breakdown Structure (WBS): The Project Leader creates a WBS. WBS identifies all the tasks of the design and development process separated step-wise in Work Packages (WPs). For every WP, the WBS includes:

• tasks separated into sub-tasks;
• inputs needed from other WPs and sub-projects; and
• the list of deliverables.

This procedure applies to all projects, aiming to develop IVD products under the scope of a Quality Management System (QMS).

Define the Product Concept and select the assay chemistry and instrumentation: In this step define the Product Concept, which includes an overall description of the product, components, functions and interface options, accessories, consumables and additional technologies, if required.

Initial Risk Analysis: Based on the Product Concept and the preliminary Intellectual Property Rights (IPR) assessments and trademark investigations, described above, the initial Product Risk Analysis is initiated. Initial Risk Analysis, such as, for example, the risk of accessibility or unavailability of factors that may delay project objectives and deliverables, is derived from two input factors:

• assumptions on uninterrupted supply and valid certificates; and
• assessment of constraints and limitation that must be taken into consideration prior to the initiation of the project.

Create a schedule: Finally, create a project schedule.

Explanation of the task and expected outcome

Quality Management System and Certification of QMS ISO 13485

The manufacturer must have a quality management system in use (in practice according to ISO 13485). No Notified Body involvement for Class A (excluding sterile devices).

New equipment, processes or facilities must not be taken into use unless a decision about validation requirements and steps needed have been made, and any necessary validations/verifications have been carried out and accepted.

Task related (external) links:

• European Union (2020), NANDO (New Approach Notified and Designated Organisations) database.
• International Organization for Standardization (2016), ISO 13485:2016 - Medical devices — Quality management systems — Requirements for regulatory purposes.

Explanation of the task and expected outcome

Design and prepare a prototype: Based on the work breakdown structure from Stage 2, design and prepare a working prototype of the test. Here, we are not speaking about an assay to be used to detect a particular analyte, but about actual engineering a successful “port” of an assay, for example a sandwich immunoassay to the specific detection platform. As the result, we obtain a working prototype of a test.

Create a Risk Management Plan: “Risk” is a combination of the probability of occurrence of harm and severity of the harm. “Risk Management” is the systematic application of management policies, procedures, and practices to the tasks of analyzing, evaluating, controlling and monitoring risks. The Risk Management process includes:

• Identification of hazards and potential risks,
• Estimation and evaluation of the risks,
• Controlling these risks, and
• Monitoring the effectiveness of Risk Control throughout the product life cycle.

The scope of the risk management depends on the intended use of the product and its characteristics, as well as the severity of known or foreseeable hazards.

Create a Regulatory Plan: The Regulatory Plan describes the strategy to meet regulatory compliance with relevant laws, guidelines, etc. The regulatory requirements and the pathway for market clearance on specific markets (as defined in the Marketing Plan) are identified based on the description and intended use of the product.See the regulatory track.

Create a Performance Evaluation Plan: Performance evaluation of a device is a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of that device for its intended purpose as stated by the manufacturer.The performance evaluation plan includes:

• Analytical Performance Study plan: The aim of the analytical performance study is to study and record the analytical performance characteristics of used technological platform and to verify that the design outputs meet the design inputs. The study usually includes measurement of the following parameters:
  • “Proof of Precision” to determine the closeness of agreement between independent test results obtained under specified conditions (CLSI guidelines EP05-A3 and EP06-A);
  • “Detection Capability” to determine what are the Limit-Of-Blank (LOB) and Limit-Of-Detection (LOD) of the test (CLSI guideline EP17-A2);
  • “Interference” study to determine susceptibility to relevant, possibly interfering endogenous and exogenous substances/agents (CLSI guideline EP07-A2).
• Clinical Performance Study Plan: Collection, management and preparation of clinical specimens. Definition of suitable specimen collection devices and sampling methods. Description of specimen processing protocol. Performance evaluation of the specimen processing. The clinical study must deliver Clinical Specificity, Clinical Sensitivity and the Receiver Operating Characteristic (ROC) analysis. Clinical Performance Study is done by the end-user professionals with the statistically relevant number of subjects, with the preliminary determined numbers of “positives” and “negatives” towards the tested value. Prior to the clinical studies an “informed consent” must be obtained from all study participants and often, but not always, an ethical conclusion from the official Ethical Committee may be required.
• Perform analytical and clinical “Equivalence Assessment” of the tested method with respect to the already established and accepted reference method (for example, a Lateral Flow point-of-care SARS-CoV-2 antigen test versus PCR).
• Stability Study Plan: The aim of the Stability Study is to obtain objective evidence about the impact of shelf-life on the Test Kit, and its behavior following transportation.
• Software verification and validation plan: the software verification and validation plan includes:

1. ​​​​Summary: Summary includes description of software inputs, outputs and processing function;
2. Target(s) of validation: The choice of intermediate and final software markers and outputs, used to monitor proper software function, is created;
3. Reference equipment and materials: Software verification is done using (or referred to) a set of control equipment and materials to obtain predefined result. This may include a reference device, if available, or a Research Use Only (RUO) combination with the specific control hardware and tests.
4. Test methods and parameters: This point is connected to point #2, but also includes data repetition, memory verifications, export and import checks (between a computer and a smartphone, for example), and also calculating of the error of simulations.
5. Results and fulfilling of acceptance criteria: Different parameters were used to simulate different results during the measurement: (1) results observed should not show any random value or fluctuating; (2) No lag; (3) Possible error scenarios must be simulated and tested; (4) Correct error messages must be displayed.
6. Assessment of Deviations: Assessment of deviations, such as longer measurement times, device freeze, deviations arising from human error.
7. Risk assessment: Based on all the results above, assessment of risks and their probability must be made, and instructions to correct those must be created.

Identification and approval of suppliers: Supplier Selection is followed by Supplier Approval (Grade A, Grade B or Grade C, based on the following factors: ISO13485 and ISO9001; Questionnaire; Quality Agreement; Supplier History, etc.).

Preliminary material specifications: A template for component-material specification (Arrival inspection, etc.) can be used, if there is no equivalent document available.

Explanation of the task and expected outcome

Conduct verification and validation studies as planned in the previous phase and write reports (see the regulatory track of this phase)

All the Verification and Validation studies are performed and the product's Technical Documentation is created. (See complete list of elements for the Technical documentation from the regulatory track of this phase):

• Performance evaluation report shall include the scientific validity report, the analytical performance report, the clinical performance report and an assessment of those reports to allow demonstration of the clinical evidence;
• Stability Study Report;
• Software Verification and Validation Report; and
• Benefit-risk Analysis.

Finalizing the design transfer to production and manufacturing

The following Specification Documents and Instructions are written and accepted:

• Final Material Specifications;
• Final Working Instructions;
• Quality agreements for critical suppliers; and
• Labeling and packaging instructions.
• This stage aims to finalize the design transfer to production and manufacturing.

Explanation of the task and expected outcome
Apply Article 15 "Person responsible for regulatory compliance" of IVDR.

If it is confirmed that the product is within the scope of IVDR and the biomarker (research result) is already considered as a product, it is a good time to recruit a person responsible for regulatory compliance, who possesses the requisite expertise in the field of IVD medical devices.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
• Medical Device Coordination Group (2019), Guidance on Article 15 of the Medical Device Regulation (MDR) and in vitro Diagnostic Device Regulation (IVDR) regarding a "person responsible for regulatory compliance" (PRRC).

Explanation of the task and expected outcome

• Apply Article 48 "Conformity assessment procedures" of IVDR and follow Figure 37 of the Regulatory Guide.
• Note that the regulatory pathway depends on risk class and intended use of the product.
• Continue to monitor progress of the IVDR implementation plan.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Apply chapter 4.2 and 4.3 of the Regulatory Guide.

Explanation of the task and expected outcome
Apply Article 10 (No. 15) "General obligations of manufacturers" of IVDR.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

• Apply Article 47 "Classification of devices", Annex I "General safety and performance requirements" and Annex VIII "Classification rules" of IVDR and Sections 4.1 and 4.4.1 of the Regulatory Guide.
• The project team/company (if established) is responsible for the final classification of the product into risk classes (A, B, C, D) The classification should be conducted on the basis of product characteristics and risks related to its use. The team/company is able to carry out the classification internally driven primarily by team/company researchers. However, where uncertainty exists, seek the advice of a notified body or national authority.
• Familiarize/plan for the IVDR requirements regarding the GSPR.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

•  Check the completeness and quality of the data.
•  Verify that the data meets the critical criteria and determined research methods.
•  Verify which data & results you can use for purpose of the development of technical documentation.

Explanation of the task and expected outcome
Apply Annex II "Technical documentation" No. 4 "General safety and performance requirements" of IVDR.

Compliance or non-compliance with GSPR standards has to be documented. When a standard is not relevant for a product, an explanation must be provided why the standard does not apply. Currently standards under the link below are harmonised under IVDD. Monitor the standards harmonisation for IVDR and during the transition time stick to the “state of the art” approach (use relevant norms: ISO, GHTF/IMDRF, FDA and CLSI standards).

Task related (external) links:

• European Union (2020), Commission Implementing Decision (EU) 2020/439 of 24 March 2020 on the harmonised standards for in vitro diagnostic medical devices drafted in support of Directive 98/79/EC.

Explanation of the task and expected outcome
Apply:

• Annex II "Technical documentation" No. 6 "Product verification and validation" of IVDR
• Chapter 4.2.2 of Regulatory Guide.

Continue working on technical documentation for product verification & validation, integrating new research results when relevant. Well documented material benefits:

• Verification & validation: a pre-requisite for registration and placing product on the market.
• Once done, the section serves as the basis for further regulatory documentation requirements.
• Note that, the product verification & validation requires performance studies to be conducted with ethical approval and a submitted application is obligatory.
• Apply ISO 20916 for clinical performance studies.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Apply:

• Annex II "Technical documentation" and Annex III "Technical documentation on post-market surveillance" of IVDR.
• Chapter 4.2 and 4.3 of the Regulatory Guide.

Initiate development of the six main parts of product documentation, according to IVDR requirements, including e.g. kit inserts, instruction manuals, labels, descriptions of the device and its parts etc., as well as technical documentation on post-market surveillance (PMS plan).

Develop technical documentation in the most practical way, until it is complete and appropriate for the relevant conformity assessment procedure.  

Check what the standard language is for the documentation in the Member State in which the notified body is established, as well as in Member States where the device is expected to be sold

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Check the availability/capacity of the notified body before submission of the application.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

The purpose of the Launch stage is to complete the information necessary for the product registration and obtain CE Marking (see also the regulatory track).

Technical documentation and the European Union (EU) Declaration of Conformity

The person responsible for regulatory compliance (PRRC) shall ensure that the technical documentation and the European Union (EU) Declaration of Conformity are prepared and kept up to date. The product is manufactured following the Final Material Specifications and Working Instructions, and all the processes are controlled.

The person responsible for regulatory compliance shall at least be responsible for ensuring that:

• the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released
• the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date
• the post-market surveillance obligations are complied
• the reporting obligations are fulfilled

The technical documentation is necessary to prove the product meets the General safety and performance requirements (Annex I) and therefore justify and support an EU Declaration of Conformity. One needs the documentation above to affix the CE marking.

Task related (external) links:

CE Marking - obtaining the certificate, EU requirements

Explanation of the task and expected outcome

Ensure proper labelling of the product. Labelling should include: instructions for use including intended use, warnings, contraindications, Unique Device Identifier (UDI), etc.

General Information:

EU regulations require that manufacturers of medical devices submit the UDI/Device information of all devices/products that they place on the market. Device module of EUDAMED is used for registration.

Registration in EUDAMED(European database on medical devices) and application of UDI (Unique Device Identification) and BUDI (Basic Unique Device Identification) identifiers concern ONLY manufacturers, which include device manufacturers, test manufacturers, component manufacturers, etc. Registration in EUDAMED is free.

Timeline for placing UDI-carriers on the labels of devices (IVDR Article 113(3)(e), Article 24(4)):

• For class D (highest risk) devices (such as COVID IVD test kits) applies from 26 May 2023 onward;
• For class B and class C devices applies from 26 May 2025 onward;
• For class A (low risk) devices (such as measurement IVD instruments, etc.) applies from 26 May 2027 onward.

Use of UDI:

UDI is a standardized identification system of all medical devices including every packaging configuration and packing level, excluding shipping containers.

• Basic UDI-DI is the access key for device-related information entered in EUDAMED;
• Reference to Basic UDI-DI must be present in all key documentation (Declaration of conformity, certificates);
• UDI shall be used for reporting serious incidents and field safety corrective actions.

Obtaining UDI:

Current UDI Issuing Entities are:

• Informationsstelle für Arzneispezialitäten (IFA GmbH),
• GS1AISBL (“GS1 Finland” for Finland, for example),
• Health Industry Business Communications Council (HIBCC), and
• International Council for Commonality in Blood Banking Automation (ICCBBA).

Procedure:

1. Obtain UDI;
2. Register UDI in EUDAMED.

Task related (external) links:

Review product labelling, see Annex I Chapter III: European Union (2017), IVD Regulation 2017/746

Explanation of the task and expected outcome

Initiate marketing and promotion activities early in the process.

Finalize the marketing plan and marketing materials

Finalize the marketing plan that you started developing in phase 6 (Preliminary Marketing Plan).

Set your budget. Example marketing expenses include outsourcing costs to a marketing agency and/or other providers, marketing software, paid promotions, events (those you'll host and/or attend).

Build your marketing plan around your competitive advantage. Conduct a SWOT analysis: what are your Strengths, Weaknesses, Opportunities, and Threats?

Find the right customers with the STP Model (Segmentation, Targeting and Positioning) and don’t forget about the 7Ps of Marketing: Product, Price, Place, Promotion, People, Process and Physical Evidence. Use the 7P Formula to continually evaluate and re-evaluate your business activities.

Your marketing plan should include SMART goals: Specific, Measurable, Attainable, Relevant, and Time-bound. In other words, all your goals should be specific and include a time frame for which you want to complete it.

Prepare your tactics on how to reach the goals, define your marketing channels and set your action items.

Businesses with extensive social media presence might consider developing a separate social media plan.

Introduce the assay into the clinical care pathway

Contact and convince key opinion leaders, end-users (hospitals, clinicians), buyers and payers about your product. Collect and present your data on key advantages, clinical utility, novelty, cost/ benefit, reimbursement.

Be visible at meetings and appropriate conferences.

Find and select distributors

Decide which intermediaries will be involved in the distribution chain and also think about the logistics behind getting the product to the end customer, including storage and transportation.

Determine your pricing and reimbursement strategies

When deciding on pricing, you shoud also consider local reimbursement mechanisms in different countries in collaboration with your distributors.

Task related (external) links:

Finding The Right Customers With The STP Model

Read more about the 7P Formula

Explanation of the task and expected outcome

Make agreements with distributors to make sure that you comply with the regulations of the country where your IVD assay is being used.

The agreement with distributors in the EU shall include provisions for the IVDR (currently, IVDR 2017/746), described in articles 13 (“General obligations of importers”) and 14 (“General obligations of distributors”), respectively. Distributors shall, in the context of their activities, act with due care in relation to the requirements of the IVDR.

Explanation of the task and expected outcome (see also the regulatory track of this phase)

Perform a post-market surveillance plan, report corrective actions and finally conduct a product review post production.

Post-market surveillance Plan & Report: produce a post-market surveillance plan to collect systematically and actively information to update the technical documentation. As defined in IVDR (currently, 2017/746), the post-market surveillance includes “all activities ... for the purpose of identifying any need to ... apply any necessary corrective or preventive actions”. The information (e.g. customer feedback, non-conformance handling), generated during the production, is the input for product maintenance and improvement. Product documentation must be updated if any changes to the product are applied.

Corrective Actions: The production manager, product manager or equivalent shall gather data to update the product information on risk management, design and manufacturing information, Instructions for Use (IFU) and labeling, performance evaluation, identification of needs for preventive, corrective or field safety corrective actions etc. The gathered data is input for Product Review. This review should be conducted within 6-12 months after product launch and is intended to confirm that the final output of the project meets the defined objectives. Corrective actions for the product are implemented as according to the “corrective and preventive actions” procedure.

Product Review: This stage is closed by the completion of the Product Review, which includes documentation on the post-market surveillance report:

• Post-market surveillance report(PMS report): Manufacturers of class A and B devices shall prepare a post-market surveillance report summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 79 together with a rationale and description of any preventive and corrective actions taken. The report shall be updated when necessary and made available to the notified body and the competent authority upon request.
• Periodic safety update report(PSUR): Manufacturers of class C and class D devices shall prepare a periodic safety update report (‘PSUR’) for each device and where relevant for each category or group of devices summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 79 together with a rationale and description of any preventive and corrective actions taken.

Explanation of the task and expected outcome
Conformity assessment procedures differ in complexity and scope. Follow the prior determined regulatory pathway relevant to the product risk class.

• Choose the notified body from the NANDO system and submit application for conformity assessment.
• Cooperate with the notified body in order to pass the procedure.

Task related (external) links:

• European Union (2020), NANDO (New Approach Notified and Designated Organisations) database.

Explanation of the task and expected outcome

• Affix CE mark according to Article 18 "CE marking of conformity" and Annex V "CE marking of conformity" of the IVDR.
• Draw up EU declaration of conformity according to Article 17 "EU declaration of conformity" and Annex IV "EU declaration of conformity" of the IVDR.
• Draw up notification to competent authority (template provided by authority website)
• Draw up the certificate of free sale according to Article 55 "Certificate of free sale" (template provided by authority website)

Good practices to keep in mind

• Check validity of templates
• The declaration of conformity shall contain all the information required for identification of the European Union legislation to which the declaration relates, therefore, if there are some aspects not covered by IVDR the manufacturer must still draft up single declaration (details as in description)
• Monitoring of expiration dates of conformity certificates

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome
Apply Article 26 "Registration of devices" ,Article 28 "Registration of manufacturers, authorised representatives and importers" and Chapter 4.2.1 of the Regulatory Guide through the registration procedure within the EUDAMED database.

Explanation of the task and expected outcome
Apply:

• Articles 80-84 of IVDR
• Chapters 3.7 and 4.3 of the Regulatory Guide

Fulfill the following obligations when the product is already on the market:

• Report any serious incident and any field safety corrective actions (in accordance with Article 82 (1) "Reporting of serious incidents and field safety corrective actions" and Article 84 (5) "Analysis of serious incidents and field safety corrective actions" of the IVDR, and also in form of periodic summary reports (Article 82 (9) "Reporting of serious incidents and field safety corrective actions" of the IVDR)
• Trend reporting (in accordance with Article 83 "Trend reporting" of the IVDR)
• Reporting on safety (Article 80 "Post-market surveillance report" and Article 81 "Periodic safety update report" of the IVDR)
• Analysis of serious incidents and field safety corrective actions a.o. prepare safety notices (in accordance with Article 84 (8) "Analysis of serious incidents and field safety corrective actions" of the IVDR).

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

• Prepare for additional requirements/reviews after the product is placed on the market:
• Anticipate for checks on the conformity, characteristics and performance of devices including, where appropriate, a review of documentation and physical or laboratory checks on the basis of adequate samples.
• Prepare to take all appropriate and duly justified corrective action to bring the device into compliance with the requirements of IVDR.
• Potentially restrict the making availability of the device on the market, modify the product to specific requirements or to withdraw the device from the market, or to recall it, within a reasonable period that is clearly defined and communicated to the relevant economic operator.

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.

Explanation of the task and expected outcome

• Continue to actively monitor the regulatory environment for amendments, new requirements
• Track the European Commission website for any potential amendments on IVDR

Task related (external) links:

• European Union (2017), IVDR: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
• European Union (2020), Overview: Medical devices and In Vitro Diagnostic medical devices (IVDs).