Meeting the Essential Principles—Principles about design and construction.

Principle 14—Clinical evidence

From the Therapeutic Goods (Medical Devices) Regulations 2002

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Clinical evidence
Every medical device requires clinical evidence, appropriate for the use and classification of the device, demonstrating that the device complies with the applicable provisions of the Essential Principles.

 

What does this mean?

The TGA expects manufacturers to hold evidence that demonstrates that:
  • the medical device achieves its intended purpose(s) during normal conditions of clinical use
  • the known and foreseeable clinical risks and any adverse effects have been minimised
  • the risk of using the medical device is acceptable when weighed against the benefits inherent in the intended purpose(s)
  • any clinical claims about the device’s performance and safety (for example on the label and the Instructions for Use) are supported by clinical data
What does clinical evidence look like?

Clinical evidence may comprise:
  • Full clinical study reports for the device in question used for the intended purpose(s) claimed, or reports for a similar device with reasoned argument as to why the safety and performance of that device may be extrapolated to the device under assessment—paying particular attention to the intended purpose(s).  Full study reports means complete reports, not publications.
  • A literature review for such devices used for similar intended purpose(s) as the device under assessment, with a documented search strategy including databases searched, search terms used and any inclusion and exclusion criteria applied, in sufficient detail to enable the search to be reproduced if desired.  This demonstrates an adequate review of current knowledge about a particular product or therapy in general. Then a critical discussion of the papers revealed by the search must be undertaken with particular emphasis on how the publications demonstrate safety and performance of the device under assessment for the indications claimed (i.e. in terms of similarity, predicates, the actual device, etc.).
  • Post-market data of the specific device under assessment, or a similar or predicate device.  These data may include adverse event or complaint information, for example.
  • If there are no actual clinical data for the specific device, depending upon the nature of it, it may be possible to provide a full clinical justification for why clinical evidence is either not required, or only partially required.  Typically, this involves referencing the performance of a predicate or similar marketed device and critically examining each change or difference in terms of materials, design, clinical use, and their likely impact on safety and performance.  If it can be established via contention that the changes made should not pose any impact on safety and performance, a clinical justification can, in some circumstances, suffice for clinical evidence.
  • All clinical reports should contain a critical review of all data presented, performed by a ‘clinical expert’ who should have appropriate clinical qualifications and experience to be able to provide an objective critical review of the clinical data for the device that is the subject of the submission.  The appropriateness of this expert will clearly vary depending upon the nature of the device. A complete curriculum vitae for such an expert, or similar documentation, is also a necessary component of the clinical evidence submission.
A properly developed risk analysis is crucial in determining what type of clinical data is required for a particular device. An outcome of the analysis is the identification of any residual risks. The clinical data are expected to quantify and address those risks.

How should the clinical evaluation be conducted?

The stages in performing a clinical evaluation are:
  • identification of any pertinent standards and the clinical data required to meet them
  • objective appraisal of each individual data set as described under clinical evidence above, in terms of its relevance, applicability, quality, and clinical significance
  • a subsequent analysis of all the data sets, whereby conclusions are reached about the performance, safety and presentational aspects (labelling, patient information and Instructions for Use) of the device.  The evaluation should consolidate the findings of all clinical data and explain why such data demonstrate acceptable safety and performance of the device under assessment.
If the manufacturer concludes there is insufficient clinical evidence to be able to declare conformity with the Essential Principles, the manufacturer will need to generate additional data (for example, conduct a clinical investigation, or broaden the scope of literature searching) to address any deficiency. In this respect clinical evaluation can be an iterative process.


Overview of process for data generation and clinical evaluation
 

What sources of clinical data can I use?

Data generated during a clinical investigation program for the device, including:
  • data from all formal clinical trials carried out using finished products
  • any other experimental use in humans using prototype devices or components for the purpose of developing or investigating their safety and performance
Please note: There is no requirement that clinical trials should be done in Australia.
 

Data from clinical experience, including:
  • manufacturer-generated post-market surveillance reports, registries or cohort studies (which may contain unpublished long-term safety and performance data)
  • adverse events databases (held by either the manufacturer or regulatory authorities)
  • data for the device in question generated from individual patients under Authorised Prescriber and/or Special Access Schemes (SAS) prior to marketing of the device
  • details of clinically relevant field corrective actions (for example, recalls, notifications, hazard alerts)
Data obtained from a review of the literature:
  • specifically about the device in question—where available, this must always be included in any review, and/or
  • for comparative and well established devices including relevant post-market information. Adequate justification should be provided to explain how data for a similar device can establish the safety and performance of the device in question
For safety data, all reports, including individual case reports and overviews relevant to the device should be considered. This would include scientific reports not suitable for assessment of performance due to poor trial design or inadequate analysis but providing safety data about the device.

How do I decide what type of data I can use?

The level and nature of the data considered in a clinical evaluation should be appropriate to the use and classification of the medical device. The data requirements will also vary according to the nature and clinical application of the technology used in or by the device.

Devices based on new or unproven technology and those that extend the intended purpose of an existing technology through a new clinical use must be supported with clinical investigation data.

Devices based on an existing technology and intended for an established and accepted use may rely on literature review.

What are the key elements of a literature review?

A literature review consists of the following components:
  • a compilation, using documented methodology, of the relevant currently available scientific literature regarding the intended purpose of the device and the design features, consisting of:
–         clinical study reports

–         review papers

–         expert opinion
  • a report, written by an expert in the relevant field, containing a critical appraisal of this compilation. Where the review relies in part or wholly on data for a comparable device, the report should also clearly justify how the devices described in the compiled literature are relevant to the safety and performance of the device in question
It is important that the published literature be able to establish the clinical performance and safety of the device in question, and demonstrate a favourable risk profile.

A review must be supported by a detailed search of the literature, using a reproducible search strategy across a range of appropriate scientific databases. The methodology should be documented in a written report.

The search output (that is, the citations) should be assessed against clearly defined selection criteria. The report should also summarise how each citation did or did not fit the selection criteria for inclusion in the review.

When selecting papers to be included in the assessment of performance and safety, the following aspects should be considered:
  • the quality of the literature articles
  • the design of any clinical trials reported in the paper
  • the quality of the data reported in the literature
  • the clinical significance of the results of those trials
The quality of the paper can be judged by assessing its:
  • scientific impartiality
  • the completeness of reporting
  • clarity and logic of argument
  • the validity of any conclusions drawn in the article
Where can clinical data be found?

Data relevant to the clinical evaluation may be:
  • held by the manufacturer (for example, manufacturer sponsored pre- and post- market investigation reports and adverse event reports for the device in question)
  • in the scientific literature (for example, published articles of clinical investigations and adverse event reports for the device in question or for comparable devices)
The manufacturer is responsible for identifying data relevant to the device and determining the type(s) and amount of data needed for the clinical evaluation.

There may be situations where demonstration of compliance with the Essential Principles is not possible through evaluation of the published clinical data alone. This can occur because clinical data from clinical investigation and/or the published literature are either lacking or are of poor quality and therefore not sufficiently useful.

One option for the manufacturer will be to generate additional clinical investigation data by conducting a clinical trial. Alternatively, other forms of data can be considered.

This can include data from device usage registries, post-market investigations, surveillance and adverse event reports. In the absence of any recent clinical data for simple devices of a traditional nature assessed to be low risk and safe, a justification as to why no clinical data is required.

What are the requirements for clinical trials?

There is no requirement that the dossier has to include clinical data generated from clinical trials conducted within Australia. However, where a trial of a new medical device is conducted in Australia, it must be conducted in accordance with Australian legislative and regulatory requirements (at both Commonwealth and state/territory level) and Australian ethical standards.

Clinical trials in Australia are conducted under either the Clinical Trial Notification (CTN) Scheme or the Clinical Trial Exemption (CTX) Scheme. Further details can be found at <http://www.tga.gov.au>.

Australian ethical standards are determined by the National Health and Medical Research Council. The current guidelines can be found at <http://www.nhmrc.gov.au>.

Clinical trials conducted overseas are required to comply with relevant jurisdictional legislative and regulatory requirements and must be in accordance with the principles of the Declaration of Helsinki.

Clinical trial design is an important consideration. The most desirable clinical trial design is a randomised, double-blind, controlled trial. This design has the lowest risk of bias that could potentially contribute to the outcomes observed in the trial. In cases where there are numerous published reports of such trials, it is possible to focus on these trials at the expense of other studies, which, because of their design, will have higher levels of bias.

However, it may be difficult to conduct double-blind studies with medical devices, particularly for implantable devices, or to use comparator groups. It is more likely in such cases that these studies have greater potential for bias and/or that there are few published reports available to support the review. In this case, almost all papers retrieved by the search will need to be assessed. The issue of potential duplication of data in different papers will need to be addressed.

What should a sponsor look for in the manufacturer’s technical dossier when checking to see there is clinical evidence?

There should be a section in the technical dossier clearly labelled ‘Clinical Evidence’ that includes:
  • the clearly stated intended purpose(s) and application of the device
  • identification of the Essential Principles relevant to the specific design of the device
  • clinical data or justification as to why no clinical data are required
  • a clinical evaluation report containing a comprehensive analysis of the clinical data relevant to the device, authored by a clinical expert competent in the appropriate field and able to give an objective assessment of the clinical data that are present
Where can I find more information?

The TGA recognises that a flexible, case-by-case approach should be adopted so applicants are encouraged to discuss individual device requirements with the TGA.

The Global Harmonization Task Force (GHTF), an international body that was established to achieve greater uniformity between national medical device regulatory systems has developed a comprehensive guidance document on Clinical Evaluation: <http://www.imdrf.org/>.  In addition to general guidance, the document provides:
  • a possible format for a literature search report
  • a possible methodology for documenting the screening and selection of literature within a literature search report
  • some examples to assist with the formulation of criteria for data appraisal
  • a possible method of appraisal
  • a possible format for a Clinical Evaluation Report.
 

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