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What a manufacturer needs to know about conformity assessment and declarations of conformity for IVDs

Version 1.0, November 2011

24 November 2011

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Components of the STED or design dossier

Device description

A detailed description of the IVD must be provided, including information addressing each of the following points:

  • Intended purpose;
  • Intended user;
  • Risk class according to Australian regulations;
  • Acceptable specimen types;
  • Description of principle of the assay and methodology used; and
  • Description of individual components included in the IVD.

Where applicable, the following should also be provided:

  • A description of the specimen collection and/or transport materials required or recommended to be used;
  • A description of the accessories, other IVDs and other products that are not medical devices which are intended to be used in combination with the IVD;
  • For assays requiring instrumentation, a description of the relevant instrumentation characteristics or details of dedicated instrumentation to be used;
  • A description of any software to be used; and
  • A complete list of any configurations or variants of the IVD, other than kit size, that will be made available.

Where applicable, a review of platforms/instrumentation and other materials, including dedicated specimen receptacles, that are required (or recommended) to be used in combination with an IVD will occur as part of the conformity assessment.

Device history

A summary of the product history in the Australian market and any other jurisdiction(s) in which the IVD is supplied will be requested to allow the TGA to make an assessment of the safety and efficacy of the IVD in the post-market environment. Details should include a list of countries or regulatory jurisdictions, approximate numbers of IVDs and/or period of time supplied, summary of any adverse events, recalls, corrective/preventive actions or refusal to approve for supply.

The inclusion of information clearly identifying products either as new to the Australian market, or as previously supplied in the Australian market and transitioning to the requirements of the new IVD regulatory framework, will assist the TGA in prioritising the assessment of new products, so as to reduce as much as possible any delay to the market caused by a backlog of IVDs transitioning to the requirements of the new regulations.

Essential Principles checklist

A copy of the Essential Principles checklist that summarises conformity to each applicable Essential Principle by reference to appropriately applied standards, or other appropriate means will be requested. Evidence of compliance must refer to documents, reports, internal procedures, etc and should include a cross-reference to the location of the documents listed within the checklist. In order to establish that an IVD complies with the relevant provisions of the Essential Principles, the TGA may request further information in relation to any of the documents referenced or expected to be held as part of the product technical file.

The TGA will accept a European Essential Requirements checklist to IVDD requirements provided it is also accompanied by a short statement to provide assurance from the manufacturer "that the Australian Essential Principles, as described in Schedule 1 of the Therapeutic Goods (Medical Devices) Regulations 2002, have been met".

A template Essential Principles checklist is available from the TGA website.

Risk analysis and control summary

For Class 1-3 IVDs, a summary of the risk management activities performed by the manufacturer of the device must be provided. The summary should include as a minimum:

  • a list of possible hazards arising from false positive or false negative results;
  • indirect risks which may result from IVD-associated hazards e.g. instability of test components, integrity of packaging, selection of specimens;
  • the user/operator hazards such as any risks arising from reagents and specimens containing infectious agents; and
  • the risk mitigation strategies that have been implemented to reduce unacceptable risks.

Taking into account risk mitigating activities, the results of the risk analysis should provide a conclusion that the remaining risks are acceptable when compared to the benefits. The risk analysis and control summary may be submitted either in a summary (text) format or as a reduced table. An example of such a summary is the Risk Management Report required by Clause 8 of ISO14971:2007.

For Class 4 IVDs or Class 4 in-house IVDs, detailed information about the risk management plan including risk analysis, risk evaluation and risk control, must be provided.

Design and manufacturing information

A summary of the design and manufacturing processes at a level of detail appropriate to the risk class of the device should be provided. The summary should include a review of the design features that make the IVD suitable for its intended purpose, an overview of manufacturing processes and controls, manufacturing sites, a description of critical assay ingredients, a description of the major systems or critical processes, and details of any decision pathways or algorithms used, as appropriate.

Clinical evidence report

Every medical device requires clinical evidence, and for IVDs this represents the information that supports the clinical utility and the performance of the IVD as intended by the manufacturer. A clinical evidence evaluation report that demonstrates conformity with the applicable provisions of the Essential Principles (as specified in EP14) must be available for all IVDs, other than those that are exempt from inclusion in the ARTG. The Clinical Evaluation Procedures described in Clause 8, Schedule 3 of the Regulations set out the requirements, and focus on the manufacturer obtaining clinical investigation data through conducting performance evaluations and/or carrying out a literature review of published and unpublished scientific literature.

It is important to note that evidence to support the clinical competence of the author (e.g. short curriculum vitae) must accompany the submitted clinical evidence report to provide assurance that the clinical evidence has been evaluated by a competent clinical expert.

Clinical utility

The clinical utility of a parameter is the demonstration of its potential or established usefulness for patient management decision making, and provides the means for making decisions about effective treatment or preventive strategies.

For many common IVDs with a broad history spanning many years of use, clinical utility has long been established and there are well recognised associations with a particular disease or condition. For these IVDs it is not expected that extensive information be further documented simply for the purpose of submission for premarket approval. For more recently developed IVDs which involve the use of a new technology, a new application, a new biomarker, pharmacogenomics, etc, evidence of clinical utility may be required. Where confirmation of an IVD's clinical utility is required to be documented, the process for generating appropriate evidence should commence at the research phase and often involves ongoing collaborative development over time. Evidence of clinical utility is typically established using a summary of literature searches and expert opinions, and is supplemented with appropriate clinical or research data as it becomes available.

If a manufacturer considers that evidence of an IVD's clinical utility is not required to be compiled and submitted for review due to its recognised association with a particular disease or condition, this decision is required to be documented and clearly justified as part of the clinical evidence report.

Performance evaluation

Performance evaluation studies incorporate both the clinical and analytical performance characteristics of an IVD. The analytical performance aspects of an IVD's performance evaluation are addressed under the following section - Product validation and verification

The clinical performance of an IVD is demonstrated by correlating the use of an IVD with a specific clinical condition, in accordance with the target population and intended user. Clinical performance is a measure of an IVD's ability to correctly identify patients as either having or not having a particular disease or condition, based on their true clinical status. Clinical performance characteristics include diagnostic sensitivity and diagnostic specificity, which may vary depending on the choice of a cut-off value for the assay, and the negative and positive predictive values which depend on the prevalence of the disease or condition within the population of interest.

For many IVDs, providing data that has been drawn from a clinical performance study or generated within a target population may not always be an essential component of the clinical evidence. For well established and standardised analytes, demonstration of the IVD's analytical performance characteristics may be sufficient to support the use of the IVD as intended by the manufacturer, particularly when the clinical utility for a type of IVD has been long accepted. Where it is available in a suitable form, published literature or experience gained by routine diagnostic testing which includes post market surveillance data, a summary of adverse events, and details of any field safety corrective actions (recalls, notifications, hazard alerts) may provide sufficient evidence to support the clinical performance of an IVD. The manufacturer must justify the grounds on which they are circumventing either fully or in part, the requirement to provide clinical performance data wherever this occurs.

For IVDs that are intended to be used by lay persons or at the point of care, it is expected that clinical performance studies take into consideration the level of knowledge, understanding and skills for such users by providing evidence to demonstrate appropriate performance within that target population.

Product validation and verification

Evidence to demonstrate the analytical performance characteristics of the IVD is a requirement under Essential Principle 15 and forms a critical part of the manufacturer's performance evaluation studies, as required for clinical evidence.

The information presented for each study should provide sufficient detail for the assessor to understand how the study was conducted, the characterisation of specimens/samples used, acceptance criteria, explanations for anomalous results, and the outcomes/conclusions drawn. It is acceptable to combine two or more aspects of analytical performance into fewer separate studies provided each of the studies is well designed and all relevant variables and test characteristics are effectively demonstrated. The following analytical performance characteristics should be specifically addressed, as appropriate to the type of IVD.

Specimen type

A list of all appropriate specimen type(s) suitable for use with the IVD must be provided, including anticoagulants, matrices or any special instructions or conditions associated with specimen collection. Information should also address specimen stability, appropriate storage conditions and where applicable, transport conditions. Storage includes elements such as duration, temperature limits, number of freeze/thaw cycles.

Analytical performance study reports should include information about the nature of the specimen types tested (e.g. spiked, wild type etc) and the geographic location where specimens were obtained, as appropriate.

Accuracy

The term accuracy refers to both trueness and precision (reproducibility and repeatability).

Demonstration of trueness requires utilisation of an acceptable reference method or comparison with reference material of a higher order. Reproducibility should include information about studies to estimate total variability and as appropriate, between-day, between-run, between-sites, between-lots, between-operators and between-instrument variability.

Repeatability should include information about studies to estimate total variability and as appropriate, within-run variability.

The results of testing should include samples that represent the full range of expected analyte concentrations within the target population, and for Class 3 and Class 4 IVDs, and Class 4 in-house IVDs, detailed information is required.

Analytical sensitivity

Demonstration of analytical sensitivity should provide as part of the study design, the analyte tested, how the levels were established, specimen characterisation and number of replicates tested at each concentration. Calculations used to determine the assay sensitivity should be included.

For Class 3 and Class 4 IVDs, and Class 4 in-house IVDs, detailed information is required.

Analytical specificity

Information relating to any studies conducted to determine the effect caused by potentially interfering or cross-reacting substances or agents on test results should be provided. Consideration should be given to both exogenous and endogenous factors expected to be encountered.

For Class 3 and Class 4 IVDs, and Class 4 in-house IVDs, detailed information is required.

Measuring range of assay

A summary of the studies conducted to define the assay measuring range should be included for both linear and non-linear systems. Information provided should describe the lower limit of detection and how this was determined (e.g. preparation of dilutions, standards, number of replicates) and include an investigation into any potential effects of prozone or high-dose hook effect, if applicable.

Traceability of calibrator and controls

Information summarising the traceability of calibrators and trueness control materials should be provided, if applicable. Methods used to determine traceability to reference material of a higher order, acceptance criteria, and the assignment and validation of values should be included.

Determination of assay cut-off

Where applicable, a summary of the process used to establish the assay cut-off should be provided. Information provided should be based on the population studied, method(s) used to establish the true status and any statistical methods used to generate results e.g. Receiver Operator characteristic (ROC) curve.

Verification and validation of instrumentation/software

For verification and validation of instrumentation and/or software IVDs, the study report should include a summary of performance testing undertaken conducted in a valid end-user environment.

Stability

Stability studies to support the claimed shelf-life under closed, in-use and transport conditions must be provided. For Class 3 and Class 4 IVDs, and Class 4 in-house IVDs, a copy of the study protocol, a detailed study report showing the results of testing, any calculations performed and conclusions drawn should be included. For Class 2 IVDs a summary report detailing the nature of the stability study conducted, any anomalous results/investigations, and a conclusion which supports the proposed shelf life and storage conditions is considered acceptable.

For closed shelf life studies, data must be generated by testing at appropriate storage time intervals using a minimum of 3 separate production batches of IVDs. Temperature ranges assigned for testing should encompass both the upper and lower storage temperatures claimed. Real time data which extends beyond the proposed shelf life should be provided for at least 1 batch of product. Accelerated data generated using product stored under exaggerated conditions (including elevated temperature, high humidity, increased light and vibration, as appropriate) will be accepted for subsequent batches of product as an interim measure until such time as real time studies can be completed. Ongoing real time studies for those products where the shelf-life has been assigned on the basis of partially-accelerated data should be monitored closely, and the manufacturer should reduce the shelf-life in line with the real-time data as appropriate.

For newly released products only, where insufficient time has passed to allow at least one production batch of product to undergo appropriate real time stability testing since the time of release, the TGA may give consideration to the assignment of a nominal (reduced) shelf life on the basis of accelerated stability studies, provided they have been conducted under exaggerated conditions that include elevated temperature, high humidity, increased light and vibration, as appropriate. Ongoing real time studies are required to be monitored closely.

In-use (open vial) stability and transport simulation studies should be conducted using at least one batch of product, with a study design which includes conditions appropriate to the intended use and expected conditions likely to be encountered for the product.

For further information refer to CLSI standard EP25-A, Evaluation of Stability of In Vitro Diagnostic Reagents.

Information to be supplied with the IVD

The sponsor is required to provide clear, legible copies of representative information that is to accompany the kind of IVD medical device when supplied in Australia, including:

  • Labelling;
  • Instructions For Use; and
  • Advertising material (e.g. brochures, web-pages, published advertisements, etc.), where available.

Labelling and instructions for use are not necessarily required for every model or variation, unless there are significant differences in content. However, the copies provided are required to be representative of what will be supplied in Australia.

The sponsor's name and address must be provided with the IVD in such a way that the user can readily identify the sponsor. Labelling requirements are prescribed in Regulation 10.2 and Essential Principle 13.2 in Schedule 1.

All representative information must be provided in English.

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