Orthopedic products fit into one or more category of medical devices depending on the regulatory authority. Indeed, Prostheses List Advisory Committee (PLAC) considers them as prostheses devices (single or system product) or being in the human tissue category while the Therapeutic Good Administration (TGA) classifies them as joint prostheses or passive implantable medical devices and European authorities (EU) offers a flexible guidance regarding medical devices’ clinical evidence in general. The International Medical Device Regulators Forum (IMDRF) draws an international guideline that aims to harmonize processes and requirements worldwide and the present article builds on that regarding the specific requirements applied to orthopedic products.
TGA and EU always require to submit an overall clinical evidence summary including the Clinical Evaluation Report (CER) with risk analysis and quality management elaborated and signed by a competent clinical expert, whose choice is justified by the sponsor, the device specific clinical trials described in detail, a clinical literature review (and other reasonable known information) with full text key articles and translations if needed. If no literature was found, a justification should be submitted.Other clinical evidence may be submitted.
The application format for PLAC is based on the category of application (new listing, expand billing code, compress billing codes or amend listing). Overall, the following sections are related to the clinical evidence:proposed benefits (for new listing) or reasons (for expansion, compression or amendment), comparators, product setting and product purpose, overseas status and comparative clinical assessment and supportive literature.
1. It is required to provide sufficient and appropriate clinical evidence that makes the device under application meet the regulatory requirements in terms of safety and performance.
2. The nature, probability, extent, duration and frequency of benefits and risk should be provided. TGA highly recommends that for joint prostheses to list possible combinationswith other devices or components (with provision of the lineage when it is a modular system) and prove the effectiveness and safety of such combination.It requires to support particularly the safety of orthopedic implants in Magnetic Resonance Imaging (MRI) environment tested using international standards (but not necessarily clinical data).
3. Demonstrating substantial clinical equivalence in case of comparative clinical evidence (versus other device) based on technical, biological and clinical characteristics (generally no gap in safety and effectiveness, similar design, use).
Additionally, EU specifies other requirements such as similar targeted population.
4. The more the device is sensitive the more clinical data are required (in quantity and quality) in general. High-risk joint prostheses and orthopedic implants, as well as devices with little or no experience, and those that extend the intended purpose of an existing technology are the most concerned. If lack of data, a detailed justification is required, as it is the case for devices of unmet medical needs where no similar product is available.However, less data is needed when it is a well-established technology for instance.The PLAC will generally require more data when claiming for superiority than when claiming for non-inferiority.
5. High quality, scientifically valid with rigorous methodology studies are encouraged to be submitted to support application.
Typical high quality studies use a comparison (Preferably the device under application should be one of the comparators or alternatively similar devices versus one another), are large, well-designed, with appropriate follow-up time (i.e. two years for joint prostheses in Australia), published and peer reviewed studies.
Rigorous methodologytakes into account epidemiological, statistical, ethical aspects, and uses for instance international guidelines in the reporting such as the International Standard Order (ISO) 14155 orConsolidated Standards of Reporting Trials (CONSORT).
6. Primary clinical studies outcomes should be whether specific patient scores (internationally recognized assessment tool such as Harris Hip Score) for patient performance data; or demonstrating the durability of the product through studies with appropriate follow-up time and based on information provided by using an international joint registry (TGA) or Australia’s National Joint Replacement Registry (PLAC) for revision data. However, for the TGA, surrogate markers or alternatively post-market data are used to assess to the risk of delayed need in revision surgery for joint prostheses.
7. The level of evidence should be taken into account for submitted studies. Generally, an individual randomized controlled trial is considered to provide a higher level of evidence than a cohort study. It is advised to refer to international and national guidelines about the level of evidence (Grading of Recommendations Assessment, Development and Evaluation (GRADE), Australian National Health and Medical Research Council).
8. The body of evidence should be taken into account. It includes the level of evidence, number and quality of studies, effect size, the statistical and clinical significance of the results and the relevance to clinical practice.
9. Additionally, the CER and literature review should rely on robust sources like scientific literature databases (i.e.Pubmed, Embase, Cochrane Central trials register), internet searches (i.e.World Health Organization, national and international registries) ornon-published data (i.e. manufacturing data). The literature review should use appropriate, systematic and non-biased methods such as the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement. It should be critical with reference to both positive and negative studies results objectively assessed.
10. Experts should be qualified according to the device assessed and any conflict of interest should be mentioned. They are contracted by the sponsor for the CER elaboration (TGA, EU) and they are part of the Clinical Advisory Groups (CAGs) or Panel of Clinical Experts(PoCE)for PLAC’s application.
11. Adverse events should be appropriately mitigated (before applying) and/or included in the information supplied with the device.
12. Submission to PLAC requires successful registration in the Australian Register of Therapeutic Goods(ARTG), only comparative clinical effectiveness supported by only high quality studies with positive results in human settings (if not available, justification is needed).
13. The PLAC requires a length of follow up of 10 years for major joint replacement prosthesis claiming superior clinical performance, 2 years for major joint replacement prosthesis claiming noninferiority, and 1 year for bioresorbable screw, polypin resorbable bone pin and mesh.
The clinical data submitted to the EU, TGA and PLAC in terms of quality as well as quantity are decisive for the acceptance or the rejection of the application. A specific and keen attention should be paid for high-risk devices such as joint prostheses and orthopedic implants.