The popularity of hyaluronic acid (HA) dermal filler procedures is growing. In 2018, the International Society of Plastic Surgery (ISAPS) reported an 11.6% rise in HA filler procedures, compared with the previous year (ISAPS, 2018). The public attitude seems to indicate that these procedures are becoming normalised (Cook and Dwyer, 2016; Davies, 2018). This raises the question of whether the public perceives dermal fillers as infallibly safe.
A lack of global consensus in regulation
To ensure the safety and quality of medical devices, there are regulations that must be adhered to so that manufacturers can bring them to market. These regulations are implemented differently in various markets, as there is no global harmonisation (Vila Wagner and Schanze, 2019).
It was widely accepted that previous EU Medical Device Directive (MDD) standards were inadequate (Fouretier and Bertram, 2014). Manufacturers could shop around notified bodies in various countries for CE approval, in a commercial manner. Standards across the EU were not adequate, nor uniform between member states. There were high profile medical device failings, and changes to the regulatory framework were necessary and overdue (Cohen, 2012; Bowers, 2018).
The MDD is due to be replaced by the EU Medical Device Regulation (MDR) (EU 2017/745) on 26 May 2021 (EU, 1993; EU, 2017; European Commission [EC], 2020). CE marking will continue to be used and recognised in the UK until 30 June 2023 (Gov.uk, 2020). This piece contrasts and compares the new EU MDR and US Food and Drug Administration (FDA) regulation from an injector perspective.
Innovation and improving standards
The worldwide challenge for regulatory bodies is to facilitate innovation without lowering standards. The aim of the new MDR is to establish a strong regulatory framework, overcome existing differences between EU member states, guarantee a high level of protection for human health, promote innovation, strengthen the evaluation of safety and performance of the device before a CE mark is awarded, reinforce post-market surveillance and to improve transparency (Fouretier and Bertram, 2014).
Annex XVI of the MDR redefines all dermal fillers as class III medical devices (Medicines and Healthcare products Regulatory Agency [MHRA], 2020a). Under these new classifications and regulations, dermal fillers will need to pass a conformity assessment through a notified body, and conform to pre- and post-market regulatory standards. They will require a CE mark for marketing and use in the EU. The CE mark shows that the device meets legislation relating to safety, and that it is fit for its intended purpose. Previously, under the MDD, some dermal fillers had avoided this by claiming cosmetic application, rather than medical, thereby falling outside the MDD requirement for a CE mark (EU, 1993).
Proof of safety and clinical performance
Under the new MDR 2017/745, manufacturers of class III devices must prepare a summary of safety and clinical performance, which will be published and publicly available on Eudamed (EU, 2017; Fraser et al, 2018). Chapter VI of the MDR deals with the required clinical evaluation and investigations. There is notable emphasis on safety and performance, and a manufacturer's requirement to conduct post-market surveillance, to update this data annually, and throughout the lifecycle of the device (EU, 2017; Melvin and Torre, 2019; Pane et al, 2019). As an injector, this is of value in maintaining standards with continual monitoring of safety and efficacy. Benefits must outweigh the risks, and it must be proven that the device achieves the claimed performance, with supporting clinical evidence and investigation.
Despite the ongoing efforts to persuade the Government, dermal fillers are not prescription-only devices in UK
There are important changes for the MDR clinical evidence requirements. These include EU-wide coordinated procedures for authorising multi-centre clinical investigations; application of certain common specifications, which aim for harmonised requirements for clinical evidence; and clinical evaluation consultation, which applies to some high-risk devices, and requires not only notified body scrutiny of evidence, but also expert panel analysis, giving a second layer of confidence in the scrutiny of evidence (EC, 2016; EU, 2017; Melvin and Torre, 2019). However, precise assessment of pre-market clinical trials is difficult, because information on them is scarce (Fraser et al, 2018).
Unique device identification (UDI) will ensure traceability of devices, and implant cards will need to be issued to patients (MHRA, 2020a; 2020b).
The Keogh report
Following the PIP breast implant scandal, the Keogh report was published in 2013, (Keogh, 2013). It highlighted key failures in the non-surgical cosmetic intervention industry and advised tighter regulation. However, the recommendation that dermal fillers should be made prescription-only was not implemented by the UK Government, to the dismay of many in the industry (Hughes et al, 2013; Arie, 2017a; 2017b; Kilgariff, 2017). Taking this into account, there are provisions within the EU MDR regarding dermal filler use by a lay person (EU, 2017). Discussion as to whether they should be prescription-only is beyond the scope of this piece; save that, the author will now turn the article's attention to the US, where dermal fillers are classified as prescription-only medical devices, and must obtain FDA approval to be marketed for use (FDA, 2018a).
Fillers in the US
As in the EU, dermal fillers are classified as a class III medical device by the FDA—the highest risk level (Newburger, 2006; Maak and Wylie, 2016; EU, 2017; FDA, 2020). Class III devices will typically need pre-market approval, with significant clinical evidence in support of the application (FDA, 2020). In the US, bringing a new, high-risk medical device (such as dermal fillers) from concept to market takes an average of 3–7 years and costs around $100 million (Maak and Wylie, 2016; Van Norman, 2016a; Horvath, 2017; Purnama and Drago, 2019).
In terms of clinical evidence, generally, level I or II is required to obtain FDA approval of new class III medical devices (DeVries and Berlet, 2010; Fargen et al, 2012; Van Norman, 2016a). Typically, this requires multiple studies, and can take 2–3 years to undertake the tests and carry out follow-up studies (Van Norman, 2016a). A clinician may suggest that the rigorous pre-market approval process gives confidence that the product has been thoroughly examined; however, in 2015, Congress passed a bill that meant that the FDA could use clinical experience and observational studies, rather than randomised controlled trials (Congress.gov, 2015). This was to speed up and reduce the cost of device approval. However, in doing this, there were concerns that there would be a compromise of the quality of the approval process (Van Norman, 2016a).
Post-market surveillance
Once these medical devices are on the market, users are required to report adverse incidents to both the manufacturer and the FDA as post-market surveillance (Samuel, 1991). Sometimes, the FDA may stipulate further studies of the device to be undertaken as part of this post-market surveillance, but reporting post-market is less stringent than pre-market approval, and adverse events are thought to be underreported (Samuel, 1991; Newburger, 2006; Fargen et al, 2012; Van Norman, 2016a; FDA, 2018b; Horvath, 2017). Once pre-market approval has been gained, it could be assumed that there is less consideration made to longer term unseen adverse events, and the less stringent post-market reporting implies an institutional attitude that the pre-market approval system is foolproof. This could impact on clinicians, in that they rely more on anecdotal evidence and peer reports to evaluate problems with a product once it is on market. Being a prescription-only device, could the professional regulatory bodies enforce the reporting of adverse events and improve this system?
Post-FDA approval, a device manufacturer can then apply for a product modification through a supplement pathway, with less rigorous clinical evaluation procedures (Horvath, 2017). Such modifications can include manufacturing processes, increasing scope of applications of the product or approval of related products. There are questions as to whether using this pathway may result in reduced effectiveness and safety (Horvath, 2017; Zheng et al, 2017; Ezaldein et al, 2018). As an injector, this pathway has advantages, in that we have a greater choice of products in a shorter period of time, but do we lose confidence in the clinical evaluation of supplemental products following the reduction in clinical trial requirements?
Comparing EU and FDA processes
So, to compare the EU MDR 2017/745, and FDA processes: is one system superior to the other, and will this impact on your decision as a clinician about which product to use? There are 22 FDA-approved HA fillers in the US, though not all are marketed, and over 140 that are CE-marked in use in the UK (FDA, 2018c) (Bray et al, 2010). When deciding on a dermal filler to use, typically, FDA-approved products have been more trusted, but this raises the question of whether this will still be the case when the MDR 2017/745 comes into force.
The new EU MDR brings significant and much-needed changes to the approval process, certification and CE marking of medical devices in Europe (Maak and Wylie, 2016). The improvements reduce differences between the FDA and the European systems.
The EU MDR has increased requirements of mandated clinical evaluation, so they are more in line with the approach that the FDA takes, and, importantly, places emphasis on post-market surveillance (Pane et al, 2019). It would be fair to comment that manufacturers must react with continuous improvement, and these longitudinal safety and effectiveness analyses will give great weight to ongoing confidence in a dermal filler that has gained the CE mark. FDA pre-market approval requirements in clinical trials may still be more rigorous, but they fall down in allowing unlimited supplemental approvals to a product without the same level of clinical evidence, as well as a lack of robust post-market surveillance. Furthermore, note the reduction in quality of clinical evidence required since 2015. The EU has also introduced an independent panel to review the clinical evidence, as the FDA does. There is greater emphasis on the clinical benefits of the devices under the new EU MDR, which has been well established in the FDA system (Wilkinson and van Boxtel, 2020).
EU clinical evidence requirement failings
Historically, it has been easier for manufacturers to gain CE certification and place their product onto the European market, then use this approval to aid their FDA approval application (Van Norman, 2016b). However, a 2016 independent, peer-reviewed study showed that medical devices that were first approved in the EU, then the US, showed almost three-times the safety recall rate than those approved first in the US, demonstrating failings in EU clinical evidence requirements (Hwang et al, 2016). This previously easier route will not necessarily be the case now, with increased time and cost required to comply with the EU MDR, as well as the increased demand on clinical evidence.
The use of a unique device identifier and a centralised database (Eudamed) to ensure traceability to facilitate product recalls or notify patients of a potential concern has been introduced (Fargen et al, 2012). This has long been in place in the FDA system. However, critics of this new system question the level of transparency that will be offered (Fraser et al, 2018). Only the data of clinical trials conducted in the EU will be publicly available via Eudamed, further transparency will be limited, with the intention that the clinical evaluation report prepared by the notified body, and areas such as device safety corrective actions and post-market surveillance are only for review by regulators. There are also confidentiality provisions in commercially sensitive situations.
There are fewer EU-approved notified bodies, and they face higher levels of scrutiny and monitoring; however, they are still run on a commercial basis. In the US, the FDA is a governmental agency, mandated to protect the public's health (Maak and Wylie, 2016). If the conformity assessments of class III medical devices in the EU were to be undertaken by governmental authorities, rather than a notified body, it would reduce commercial conflicts of interest.
Conclusion
As clinicians, can we conclude that one system is superior to the other? To date, there is no strong consensus in the literature, as each system has specific benefits. The public, as consumers, often assume that CE-marked products are of better quality than others (Global Legal Research Center, 2014; Van Norman, 2016b). However, they do not necessarily understand the meaning of the CE logo: in a 2011 study, 66% of participants could identify the CE logo, but only 25% of could identify the meaning of it (European Commission, 2011). Hence, the public may blindly trust the CE mark. As a clinician, with more understanding of the regulatory processes, I feel the EU has taken a big step forward in its certification process, but it may not have gone far enough.
Ultimately, should there be a global consensus and standardised regulation? After all, it is the same product wherever it is sold and injected.
Bringing a new high-risk medical device to market costs approximately $100 million
Key points
- The EU Medical Device Directive (MDD) will be replaced by the EU Medical Device Regulation (MDR) 2017/745 on 26 May 2021. Although the UK will have its own regulatory system for medical devices, the EU CE mark will continue to be used and accepted in the UK until 30 June 2023
- In the US, dermal fillers are classified as a prescription-only medical device. In the EU MDR, dermal fillers are reclassified as class III medical devices, thereby removing the loophole for cosmetic classification of dermal fillers, but they are not prescription-only
- The MDR 2017/745 addresses many areas of weakness that were in the previous MDD. The US Food and Drug Administration system has long been considered more robust, and there are fewer hyaluronic acid fillers approved for use in the US than the EU.
CPD reflective questions
- What does the CE mark placed on a medical device demonstrate?
- What are the aims of the new EU Medical Device Regulation 2017/745?
- In developing legislation and regulation for medical devices post-Brexit, the UK now has an opportunity to improve its standards and regulations associated with the awarding of the new UKCA mark. What aspects do you think should be improved when considering the EU and US systems?