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Clinical Evidence Guidelines: Medical Devices - Actions on submissions

24 February 2017

The draft Medical Devices Clinical Evidence Guidelines was released for consultation on 15 March 2016, and submissions closed on 10 June 2016. Submissions were received for 24 organisations or individuals and these are available on the TGA website.

The submissions received have been closely reviewed and the Medical Devices Clinical Evidence Guidelines amended as appropriate. In some cases further input has been sought from clinical experts in response to comments included in submissions, and following analysis some comments have not been incorporated into the document.

The following points outline substantive changes to the document as a result of submissions received (or noting some items which have not been changed). In addition to the substantive issues outlined below, the document has also been amended in line with a number of suggestions to remove duplication, assist with document navigation, clarify sense and address a number of grammatical or typographical errors.

Changes to the Clinical Evidence Guidelines: Medical Devices
Suggestion/Comment Action/Change
Data requirements

Post market data - stratified by year or geographic region

Request clarification of data presentation and stratification

  • Post market data stratified by year may provide context for post market issues, such as supply patterns ( e.g. withdrawal of device from the market).
  • Annual data is relevant to implanted devices, especially joints, where revisions need to be stratified by year of implant and year of revision. Collated statistics which do not inform duration of implant prior to revision are meaningless.
  • Geographic stratification - agreed in part, as does not apply to single device CERs.

Dates of Standards

Suggest removal of dates e.g. ISO 13485:2003 on Quality Management Systems (QMS)

  • Accepted where referring to the broad requirements of the standard, in line with the expectation that manufacturers will comply with guidelines as they currently apply, and as updated from time to time.
  • Dates of standards have been maintained where referring to specific requirements outlined within the particular standard, and which may change or disappear as new versions of standards are issued.

Preference for Randomised Controlled Trials

Note that ethical concerns and practical limitations may exist precluding clinical trials

  • It is the TGA preference - it is not being mandated. Note that FDA requires randomised controlled trials for PMAs for all class 3 devices.

Funding sources

Funding sources should not be referenced, as they have no influence on safety and efficacy of device

How would the search strategy address "funding sources" - suggest removal of funding sources example

  • Funding sources may be relevant if it is one of variables for data extraction as stated in GL as it is likely to reflect robustness of results. In such cases it should be included.
  • Agree that funding sources may not be addressed in search strategy but in selection/critical analysis.

PRISMA Guidelines

Suggest removal of 'should be provided in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines referenced in ….'

  • This section refers to using PRISMA or Meta-analysis of Observational Studies in Epidemiology (MOOSE) for systematic literature searches.

Evidence base for new technologies

Technologies with clearly defined applicability would generally require PICO and CER analysis, this may not be suitable for technologies where the applicability is varied and the evidence base does not cover all relevant therapeutic and/or disease areas.

  • Noted and broadly agreed. For approval compliance with EPs is required. Compliance requires clinical evidence on the device or predicate/ substantially equivalent device to demonstrate safety and performance for ALL therapeutic indications, that is, for all conditions proposed by the applicant. However European certification from Notified Bodies is accepted for the majority of devices included on the ARTG without clinical review of this evidence by the TGA.

Health professional education

Suggest inclusion of an educational component as part of the approval requirements

  • The Instructions for Use provide detailed information for health professionals. With some high risk devices specific additional education is required. Clinical practice is outside the scope of these evidence guidelines (and the TGA regulatory scope).

Update of CER

Data to be updated 'regularly' - timeframe not defined - suggest that CER update frequency should be part of the document review and update requirements of the manufacturer's QMS

  • The CER should be updated with emergence of significant data, complaints, adverse events and newly identified risks or significant regulatory actions. As per MEDDEV 2.7/1 rev 4, the manufacturer should define and justify the frequency at which the clinical evaluation needs to be actively updated.
  • At a minimum the CER should be updated every 1-5 years. Text amended.

Registries

Emphasise the value of registries, clarify use as part of clinical evidence, suggest use available information provided via spontaneous reporting if and until registries established, and expectations from manufacturers when describing registries design; note there is no current registry for implantable pain-relieving devices.

Suggest include details of additionally known hernia registries to list.

  • TGA supports development of registries for high risk implantable devices with appropriate independent oversight and stewardship/governance.
  • MMDR Recommendation 22 (registry for all high-risk implantable devices) deferred, pending consultation with stakeholders to adequately assess the risks and benefits of establishing registries, and determine appropriate mechanisms to enable access to data.
  • Agreed - included known hernia registry in text

Post market clinical investigation

'Routine reactive post market surveillance may NOT constitute clinical investigation' - note that proactive post market surveillance ( e.g. registries) may constitute appropriate means of clinical investigations (also appropriate post-market clinical follow-up as defined in the European guidelines MEDDEV 2.12-2.)

  • This is taken from MEDDEV 1.2 rev 3 documents and routine is explained in the brackets.
  • Registries are not considered routine post market surveillance.

"Sponsors who intend to conduct clinical investigations should use study designs to the highest practical NHMRC Level of Evidence" - The TGA is relying only on the "Pre-Market" assessment especially when the rest of the regulators are reviewing and accepting innovative ways including Post Market registries. To align with the rest of the regulators, the TGA should establish a strategy for utilization of Post Market Data.

  • TGA will continue to accept post market data from other jurisdictions where the device is in use in our pre-market assessments. Australia does not mandate post market clinical trials and/or commit to registries unlike Japan and US. The sponsor/manufacturer could use innovative ways to collect post market data from other jurisdictions to provide to TGA prior to inclusion on ARTG i.e. provide data from overseas registries. FDA has not stated they no longer require clinical data.

TGA requirement for efforts to collect AE data - TGA is making assumptions that the reports provided by the industry are underestimates. Suggest TGA and industry work to develop Post Market Data in a registry type environment as part of approval.

  • It is widely recognised that spontaneous post market under-estimate adverse events. For evidence compare pre market clinical trial AEs with post market reporting of AEs.
  • See comment above on registries.

"The number of units sold…" - Suggest to also include "unit demand" as some systems may only capture this data.

  • Text amended

'Undesirable' effects

The 'undesirable' effects - ISO 14971 used terminology 'risks' - suggest replacement

  • Text amended

Insufficient clinical investigation data

Can examples be provided where it is acceptable to not have data available for the device or is insufficient in quantity and quality?

  • Paragraph specifies use of evidence for substantially equivalent device.
  • Small amendment in text "in this case situation"

Literature review and unpublished data

How is unpublished scientific literature to be obtained? Does this refer to the manufacturer's in-house data?

  • It is possible to search for grey data and 'unpublished' literature via databases such as Cochrane and US database but this may also include in-house data.

Literature review and excluded studies

"Excluded studies should be provided in an appendix with a brief justification as to why they were excluded." - criteria itself define exclusions and therefore requiring a summary again for excluded articles is an unnecessary and burdensome - suggest delete this requirement

  • More detail added on search strategy - The search strategy should include a summary justification as to how each citation did or did not fit the selection criteria for inclusion. Requirement to provide excluded studies removed.

PRISMA

Selection strategy - 'should be' in accordance with PRISMA - why mandatory? - suggest change to 'may be'

  • Not agreed - while not mandatory, where not complying with PRISMA the applicant will need to provide a justification (reflected in 'should' rather than 'must').

Review and Critical Analysis

Not always possible to "Provide a simple summary table for each intervention group and an effect size estimate and confidence interval for each study"

  • Every indication requires clinical evidence that the benefits outweigh the harms of the intervention/use of the device. If it is not possible to provide effect size/CI for outcomes (as may be the case for some lower risk devices with broad indications) then it would be appropriate to provide a justification and other supportive evidence. Text amended.

When "synthesising the results of included studies … ", suggest to add "if necessary" to allow manufacturer to estimate if it's necessary to combine the included study results.

  • Collation, review and critique the studies is always necessary. Clarification of 'pivotal' articles added.

Risk benefit analysis - probability

Need some clarification around the term "probability" of patients receiving benefits of the device.

  • Probability can be demonstrated by providing rates of adverse events ( e.g. deaths after intervention) or rates of outcome measures e.g. increase in 6 min walk test after vascular intervention.

Risk benefit analysis -theoretical risks

ISO 14971 provides certain risks for the manufacturer to consider, is that the context of the dot point "the safety issues identified in the clinical investigation data …."

  • Yes - referencing ISO 14971. Reference now included in Guidelines.
International alignment

Essential Principles (EPs) and Essential Requirements (ERs)

  • Note that ERs and EPs are closely aligned but not identical. Full alignment to the European ERs would require amendment to Medical Devices Regulations 2002 (out of scope for these guidelines)

Application of GHTF requirements in Australia and Europe

Requests guidance on circumstances TGA does not align with MEDDEV and explain why by providing specific legislative references

  • TGA accepts European certification as evidence to support many ARTG inclusions; however has no oversight of assessments by European notified bodies. To manage this risk TGA undertakes a clinical review of all Class III and AIMDs and some Class 2A and 2B devices. This clinical review requires evidence for these devices to be provided to the TGA for assessment in order to demonstrate compliance with the EPs.
  • While Australian and European regulatory requirements broadly align, there are also classification rule differences between Europe and Australia. Inclusion of more details on these differences will be considered when this document is next revised.
Structure and scope of document

Incorporate into ARGMD

  • Agreed that multiple guidance documents can be confusing, however this will not be actioned in current context. The ARGMD is under 'review'. It is not desirable to delay finalising the Clinical Evidence Guidelines to wait for the ARGMD revision.
  • This concern may be overtaken by the web publishing approach for TGA guidance.

Duplication in Part 2 - Requirements for specific high risk devices

  • Noted that there is duplication between sections in Part 2 - Requirements for specific high risk devices, and with content in Part 1 - General Requirements. Some of this has been removed. Some readers may proceed immediately to Part 2 hence some duplication has been maintained to make these sections somewhat stand-alone.

Devices which include a medicine

Issues on evaluation of devices which contain medicines or use medicines.

  • Drug eluting stents are covered in the Guidelines. All devices containing medicines are Class III and both device and medicines components are assessed through the more rigorous conformity assessment process.
  • Devices where the medicine is a separate component are evaluated separately.
  • Note that clinical practice is outside of TGA's regulatory scope

Software as a medical device

Should be included in regulatory system

  • Software as a medical device is currently included in regulatory system under the current definition.
  • TGA is working with other international regulators to progress medical device regulation of some types of software.

Unapproved devices

Consider Special Access Scheme (SAS) and Authorised Prescriber (AP) arrangements for medical devices

  • Both SAS and AP apply to medical devices as well as medicines

Cost recovery

Cost recovery arrangements for regulatory oversight limit development and access to innovative products; and concern about 'User pays' system.

  • Cost recovery arrangements are out of scope for the Clinical Evidence Guidelines

Overseas approvals

Recommend approval based on approval elsewhere e.g. US/EU, and expressed concern that TGA acceptance of CE approved devices may cease

  • TGA already accepts EU certification for approx. 92% of medical devices.
  • MMDR recommendation 15 (accepted by Government) includes Pathway 2B, to utilise overseas marketing approvals from a comparable overseas regulator. Consultation on implementation of this recommendation has commenced. Pathway 2A (also accepted by Government) related to continued use of European approvals.
Definitions and terminology

Sponsor versus manufacturer

Manufacturer and clinical expert have role in CER, risk management etc, but largely not the Australian sponsor

  • Noted. References to 'sponsor' deleted throughout the document, expect where specifically referring to that role ( e.g. as applicant for application for inclusion in the ARTG)

'Adverse Events '

  • Guidelines now include new definitions of Adverse Events and Serious Adverse Events which align with European requirements

'Substantial equivalence'

Is 'substantial equivalence' intended to be as per the FDA definition?

Suggest use of 'equivalent device' rather than 'predicate' to avoid confusion about different international meanings ( e.g. US FDA definition of predicate)

  • 'Substantial equivalence' as used in the Guidelines aligns with the European definition (not FDA). Technically, biologically and clinically equivalent with justification that any differences will not adversely affect risk-benefit of the device under review.
  • Definitions for 'predicate' added indicate 'a previous iteration of the device, within the same lineage of devices' as opposed to 'similar marketed device' to indicate 'existing marketed device with a similar structure and design and the same intended purpose as the device but not a predicate of the device' - either of which may be sought as 'substantially equivalent'

Benefits in being able to establish 'substantially equivalent' devices prior to submitting an application.

  • The Guideline aims to make the requirements for 'substantial equivalence' claims and clinical evidence clearer. There is provision for queries and/or pre-submission meetings. In recent experience, applicants are aware of clinical assessors' requirements; it is more of a disagreement with our requirements than a lack of knowledge or understanding of what they are.
  • This section has been amended to provide further clarification.

'Effectiveness' versus 'clinical performance'

Are 'effectiveness' and 'clinical performance' intended as synonyms?

  • Noted. Use of the term 'effectiveness' rationalised in the document. Maintained in quoted material ( e.g. MEDDEV 2.7/1 Rev 4, literature citations) or in general usage ( e.g. effectiveness of risk controls).

'Lifespan' versus 'lifetime'

EP 4 - Intended "lifetime" (rather than lifespan) is a preferred wording for consistency with other standards and regulations, such as ISO 14630

  • Noted. 'Lifespan' terminology not in EPs, so this has been changed to 'lifetime' in the Guidelines

Assessor

Add 'assessor' as this is used throughout document

  • Noted. C e.g. amended and aligned to MEDDEV definition

'Competent clinical expert'

Proposed European requirements more prescriptive that TGA requirements

  • TGA requirements considered adequate at present

Recommend broadening definition of a 'clinical expert' to include clinicians and qualified health professionals ( e.g. qualified nurse, radiographer, paramedic or audiologist where appropriate)

  • Possible for lower risk devices on a case by case basis.
  • For high risk implantables the clinical expert should be experienced in use of the device. The mentioned experts would usually have experience in monitoring or observing the use of high risk devices but not in the implantation of the device.

Any application that uses the substantial equivalence process should include a justification from a clinician person with appropriate expertise relevant to the device under assessment to substantiate the proposal put forward by the sponsor at each step of the substantial equivalence process' as a clinician may not necessarily be the most appropriate expert

  • Noted. Agreed that this may need justification from a person with appropriate expertise other than a clinician but also at final step requires justification by a clinician that any differences will not adversely impact the safety, quality and performance of the device from a clinical perspective. Amended text to add person.

Clinical expert to author or endorse CER

Must the CER be written by clinical expert or signed off by clinical expert?

Requirement for 'name and signature of the clinical expert …provided in the clinical evaluation report with the date of the report." - Suggest change to "name and signature … provided with the CER"

  • CER critically evaluated and endorsed by clinical expert (as evidenced by signature and date).
  • Guidelines amended to reflect this. The CER does not need to be written by clinical expert.
  • Now states The name and signature of the clinical expert should be provided clearly demonstrating that he/she has evaluated all the clinical data and endorses all of the clinical evaluation report

TGA should accept explanations from in-house experts of the company who write CERs and have a greater understanding of the data sets provided. It is very difficult for these "experts" in the field to understand the TGA's requirement, and queries can result in an ongoing discussion between the TGA assessors and the experts (via the manufacturer) instead of the TGA focusing on the data on hand.

  • Disagree. The competent clinical expert must evaluate all of the clinical data. TGA cannot be confident that the clinical data is valid unless endorsed by a competent clinical expert. It is not sufficient to have the CER signed by an engineer or other 'expert' or a clinician who has no knowledge/understanding or expertise in use of device and procedure.

Is the clinical expert able to be compensated for time spent providing this service

  • Clinical expert is able to be compensated for work involved in evaluating all of the clinical data and justifying substantial equivalence.

Indications need to be substantiated (EP 3)

Suggest guidance where the indication is very broad for one device. It is very difficult to have literature reviews specific to each indication.

  • Noted. Generally if a device is indicated for use in cardiovascular surgery then evidence of safety and performance needs to be provided for THIS indication. When the range of indications is large and diverse it may be reasonable to provide evidence of safety and performance for the higher risk and most common indications with a justification provided that these results can be extrapolated to lower risk uses. Text amended.

Inclusion of supporting documents

Some supporting documents are not required in CER in Europe, such as regulatory status in other countries, summary of relevant pre-clinical data, risk analysis and risk management

Assessment of risk mitigation is the role of the regulatory authority and auditing agency, not clinical expert.

  • Agreed that supporting documents (risk analysis and risk management report, IFU, regulatory status in other countries, etc) are not content of the CER (though are likely to form part of the broader application dossier). Text amended to reflect this.
  • The following may be relevant to the clinical assessment:
    • Regulatory status in other countries is helpful for the TGA as if device is approved by another similar regulatory body ( e.g. FDA, Health Canada) and this is taken into account by clinical assessor when making a recommendation, particularly if clinical evidence is borderline. May be limited to IMDRF countries where appropriate.
    • In the CER the clinical expert should comment on the risk analysis and risk management approach by the manufacturer and discuss the risk mitigation strategies (aligns with MEDDEV 2.7.1 rev 4). Assessment of clinical risk and clinical benefit requires clinical expertise.
    • TGA does not rely solely on notified body assessment processes, and clinical audits may be undertaken of many CE marked devices. Appropriate and rigorous risk analysis and risk mitigation is critical to ensure the safety of a device once on the market and therefore these documents must be reviewed by the clinical assessor. TGA does and will continue to review additional materials when necessary for conformity assessment, inclusions and post market reviews.

Data from preclinical assessment may constitute a relevant source of information for identifying potential safety concerns / risks.

  • CER only includes clinical evidence. As clinical assessors not credentialed to evaluate non clinical data this text has been deleted.

Full text articles from literature review

Suggest change "Full text articles to "pivotal articles" from literature review

  • Agreed - text amended.

Favourable risk profile

Clarification sought on the directive that the published literature be able to establish a 'favourable risk profile

Clarify requirement to demonstrate favourable risk profile

  • Additional information statement refers to NHMRC website which is not under TGA jurisdiction
  • It is not necessary to use tables but may be useful - reference to MEDDEV 2.7/1 revision
  • Noted - document amended

Requirement for conclusion

Europe also requires documented justification for no clinical investigation and documented justification for no post-market clinical follow-up if applicable.

  • Note that compliance with EP 14 every medical device requires clinical evidence appropriate for the use and classification of the device

Combinations

Suggest changing the wording from 'nominated combinations' to 'common combinations'.

  • Wording in Guidelines is 'Likely combinations ….data to support these nominated combinations'. This indicates that the nominated combinations are the likely ones. To improve clarity wording changed from likely to common.

Predicate

Suggest amendment to clarify devices as part of a modular system and lineage

  • Suggested text accepted and implemented

Full description

Suggest clarify "full description" and limit to the name of the device.

  • Agree do not need full description of device but require full name/model/system of device to be identifiable in the literature article. Wording clarified.

Surrogate markets for prediction implant failure for AAA

Suggest change to surrogate marker based on TGA - ref# 88 - Chaikof EL et al.

  • C e.g. states Type II endoleak with an aneurysm expansion
    • Chaikof EL et al endoleak remains an important measure of clinical outcome.
      …surrogate markers that suggest a continuing or increasing risk of rupture, such as aneurysm enlargement or endoleak

      and ….a type II endoleak represents flow from visceral vessel (lumbar, IMA, accessory renal, hypogastric ) without attachment site connection

EVAR replacing Open Repair for AAA

Suggest qualification of implants for AAA repair and correction of wording.

  • Agreed - amended and 'excision' replaced with 'repair' replaced.

Cardiac device terminology

Terms, definitions for clinical success and outcome measures do not reflect contemporary cardiology literature

  • Corrected in text
  • TAVIs covered in heart valve section

Clinical trials - new versus next generation

Suggest mechanism for sponsors to establish if a device is "next generation" or not before the application is made so that there is no gap between the understanding of the TGA's interpretation and that of other regulators.

  • Noted. Assessors use substantial equivalence process to allow use of evidence for earlier generation device when assessing new device.
  • TGA can is some instances accommodate pre-assessment meetings to discuss 'substantial equivalence' however any advice would not be binding and assessors may reach different opinion after assessing data in full.

Risk analysis versus QMS

Suggest improve wording - risk analysis / QMS

  • Agreed - QMS removed in text

Comments on clinical evidence requirements

  • Distinguish hernia from POP/SUI for both safety and performance
  • Meshes are typically knitted rather than woven - suggested to refer to a textile-based sheet instead
  • Commercial meshes are typically made of polypropylene… synthetic material such as Vicryl (polyglactin 910)" - description is not exhaustive - suggest refer to as many types of mesh material that are typically available and in use
  • Meshes can be used for either a primary or secondary repair and it is imperative that the clinical evidence reflects the indication for use of the mesh under review" - important to also refer to use of meshes as suture line reinforcement materials
  • List of possible complications is mixing various hernia indications and techniques: adhesions, bowel obstruction and mesh erosion are not seen in extra peritoneal mesh placement
  • Suggest clarify that the "typical study design for a general population treated for hernia repair with a permanent mesh implant and focusing on clinical signs of hernia recurrence would have a follow-up of 2 years" and to adapt study design to other factors such as mesh design, residual risks, modes of action, modifications from previous generations and the intended lifetime etc
  • Surgeons and Treatment teams - information is usually not available and difficult to obtain for hernia repair. It shall be noted that hernia repair is a conventional procedure that is performed routinely - years of experience of the investigator as determined upon review of the resume should be deemed sufficient.
  • This section amended based on feedback and after consultation with clinical experts ( e.g. PLAC CAG)
  • Partially actioned - some feedback not agreed with, for example:
    • Mesh for suture line repair included in text as example
    • Adhesion and mesh erosion can occur with all meshes including intra-peritoneal. Expert advice: disagrees that mesh erosion is not a complication in itself. The term "mesh erosion" is widely used in the literature and during discussion between surgeons to describe this event as a complication of hernia repair. It does apply equally to UG procedures as well as general surgery in this context.
    • Expert advice: I agree that the VHWG grading system is only used to stratify patient risks of complications post ventral hernia repair. However the VHWG does have a staging system which does predict both risk and likely outcome in terms of both recurrence and SSO. It is made up of the VHWG grading system plus a defect size component to predict SSO and recurrence and has been validated for clinical application. The staging system stratifies risk and predicts outcomes particularly for complex hernia cases. The VHWG staging system does allow clinicians to compare different groups of hernia patients as well look at outcomes. Recommend that the grading system is included in the text.
    • Agree surgeon and treatment team information may not always be available. If possible inserted in text and removed. If this is NOT possible for any given study, that study should be excluded from the review.

Scope of MRI section

  • Scope has been reduced, with details such as labelling and patient information cards removed from the Guidelines. While out of scope for the Guidelines, TGA is continuing to work with stakeholders and other regulators (including the FDA) to produce clear guidance on these issues.
  • Remaining content has been revised based on submissions received and expert advice.

Use of standard

Ethical considerations in undertaking clinical review to ascertain MRI safety - suggest use of ISO 10974 - Assessment of the safety of MRI for patients with an active implantable device

ISO/TS 10974 - technical specification only

  • ISO/TS 10974 is not a standard it is a technical specification. It is anticipated that a standard based on this TS will be developed by 2019-20.
  • TGA has not required or requested studies involving unnecessary MRI examinations. Active post market surveillance in jurisdictions where MRIs are undertaken with the device implanted would be sufficient.
  • ISO/TS 10974 does indicate that clinical evidence is required in some circumstances

MRI designation in other jurisdictions

Suggest example of MRI designation as a specific condition should be removed as it is not necessarily a specific condition linked to the intended purpose or the regulatory approval of the device in another jurisdiction.

  • MRI designation in other jurisdictions, whether or not specifically linked to intended purpose, is relevant to TGA assessors and will be sought. It is therefore in the interests of manufacturers/sponsors to include this information.

MRI status

Suggest a fourth option of "MR condition unknown" as per FDA guidance to allow manufacturers time to conduct the testing and transition into the other classifications.

  • FDA guidance referenced provides caveats around when the category MRI status not tested can be used and specifically mentions that this designation is not appropriate for devices or device types which usually have MR conditional designation. Wording amended. Text indicates MRI status need not be specified where not relevant.

MRI equivalence

Define equivalence for MR safety using aspects that are relevant to MR safety only

  • Noted - Equivalence with MR conditional devices on ARTG determined on a case by case basis

MRI modelling

"Simulations or modelled data may support the clinical data…modelling approach has been validated clinically." -Beneficial if the TGA could define what "an acceptable clinically validated modelling data" would be. It is not clear if the TGA are referring to a human clinical study?

Companies within the JWG are not observing serious adverse events related to patients with implanted cardiac systems undergoing MRI scans.

Management of RF-induced heating is under active discussion in the industry, particularly due to the inhomogeneity of RF-induced heating at higher field strengths

  • It should be clearly stated that this technical specification describes tests that are necessary but not sufficient to provide reasonable assurance of patient safety for MR conditional use of AIMDs.
  • Small clinical study does not validate pre-clinical models/simulation. TGA referring to a clinical study in live humans-as per definition of clinical in MEDDEV 2.7.1 rev 4, in the device system under assessment or a similar/substantially equivalent system. Study can be small and confirmatory in scope. 'Validate' replaced with 'confirm'.
  • Studies in live humans confirm that the modelling framework is appropriate to predict clinically significant events from lead heating only. There are other clinically significant events possible from MRI exposure which is not tested via modelling/simulation. Arrhythmias can and do occur during MRI scans.
  • Damaged cardiac muscle may behave differently during exposure to MRI (German Roentgen Society guidance document) hence clinical confirmation required as per ISO/TS 10974 and feedback on guidelines.
Coverage of In Vitro Diagnostic (IVD) devices

Scope of document does not address IVDs well (specific purpose, risk and performance characteristics, different risk classification, etc).

Important that guidance not imply clinical evidence for IVDs is less than for other medical devices, but acknowledges that the process for development of that evidence may differ.

  • Agreed that references to IVDs are incomplete in this document. It is intended that IVDs will be incorporated into the CEGs in the future. A statement to that effect has been added: "….however the information provided on IVDs is at this point brief and incomplete".
  • Future development to consider inclusion of IVD specific sections in Part 2 - Requirements for specific high risk devices. Review of the main body will also be required to note differences for IVDs compared with other devices.

Updates to Clinical Evidence Guidelines

The Guidelines need to be maintained over time to incorporate new benchmarks and outcome measures as a consequence of innovation and the introduction of new high risk devices limitations/issues with the guidelines that may become known be acknowledged and addressed within a reasonable time frame.

  • It is intended that the Guidelines will be periodically updated.
  • Suggest there is a role for RegTech, PLAC and its CAGs and TGA to review whether changes required and decide if the changes are minor or complete review (with full consultation with industry).
  • Anticipated that initial workplan will comprise consideration of items suggested for the Future Work Program (section below)