Recently two classes of implantable devices have come under a cloud in Europe.
In December 2011 the French Government recommended that all women in France who had PIP (Poly Implant Prosthese) breast implants should have them removed as a precautionary, but non-urgent measure because of concerns about high rates of rupture and because they contained a silicone filler that was of industrial rather than medical grade. It had also been discovered that the manufacturer had misrepresented the source and quality of the filler and had fraudulently reported the provenance of the silicone.
In the UK, previously commissioned toxicology testing of the filler had concluded there was no evidence of any increase in cancerassociated with these implants. The UK authorities therefore did not recommend removal at that time but commissioned reviews of all the issues raised.
The review by the NHS Medical Director’s was published on 18th June 2012. It studied information from 240,000 implants of different makes along with detailed findings from 5,600 removal operations. It concluded that there was no evidence that the implant fillers were toxic or carcinogenic and they did not pose a long term threat to public health. However, the PIP implants had a two-fold higher rupture rate than other brands. Although the siloxanes did not present a public health risk, the inferior mechanical strength of the implants led the group to consider this a substandard product.
‘Metal on Metal’ Hips
In 2012 the BMJ reported the potential for exposure to dangerously high levels of cobalt and chromium ions with metal on metal (MoM) hip implants. These can seep into the tissues of patients causing local reactions that destroy muscle and bone, leaving some patients with long term disability. The metal ions can also leach into the bloodstream, spreading to the lymph nodes, spleen, liver and kidneys, before leaving the body as urine. There were also concerns about damage to chromosomes, leading to genetic changes.
Companies have changed the design of their metal hips over the last decade (making the “head” larger and part of the “stem” shorter) in a bid to prevent dislocation and increase movement, without conducting new trials to demonstrate safety and effectiveness or post-marketing studies to detect any long-term problems. It is thought likely that these design changes were responsible for the release of toxic metals into the body. As early as 2006, evidence was mounting about high metal concentrations in patients with articular surface replacement (ASR) hips. However, it was another four years before the UK regulator, the MHRA, issued an official safety alert and the ASR hip was recalled from the market.
Local tissue reactions associated with metal ions were first described in detail as long ago as 1975. Yet a BMJ/BBC Newsnight investigation revealed that manufacturers remained silent in the face of mounting evidence of risk, and regulatory bodies failed to act to protect patients.
Is there a problem with Device Regulation?
The two examples above highlight the difficulties in monitoring for safety and taking appropriate precautionary action once medical devices have been released onto the market. There are complicated rules relating to monitoring and recall, but by this stage it is already too late for patients who have received devices which are not fit for purpose, especially those that have been implanted into patients’ bodies. Therefore, there is growing clamour for the system, under which such devices are first given approval to be placed on the European market, to be reviewed.
Regulatory Approval of Devices in Europe
Each Member State has designated a governmental authority, known as the “Competent Authority”, which is responsible for device regulation within its jurisdiction. In the UK this is the MHRA whose principal function is to ensure the safety and health of patients and users of medical devices. However, the Competent Authority does not take part in assessment or authorisation of devices for placing on the market. Instead, it delegates this responsibility to third party testing houses, known as Notified Bodies. These are private commercial enterprises (approved by the Competent Authority in their Member State). The manufacturer of a device can choose any Notified Body and will have a contractual relationship with it.
This shifting of the authority to approve a device away from the state and into the private sector is intended to drive down the cost of device approval through competition between Notified Bodies. However, operating in such a marketplace clearly means that individual Notified Bodies will be under commercial pressures to not be perceived as more ‘difficult’ than others.
Contrast with the Regulation of Medicinal Products
As well as this decentralisation of the approval process into the private sector, there is a stark contrast between the regulatory regime for devices and that for medicinal products.
For devices, manufacturers only have the duty to ensure that the product conforms with the relevant legal essential requirements which relate to the safety in use of the device and labelling requirements. These are expressed as scientific and technical performance characteristics and efficacy.
Confirmation of conformity must include evaluation of clinical data either from bibliography or clinical investigations. Conformity with essential requirements is attested by the fixing of a European CE mark by the Notified Body testing house. The CE mark acts as a passport allowing the device to be placed on the market and to circulate freely within the European Economic Area.
This contrasts with the regime for manufacturers of medicinal products, who have to submit pre-marketing data on safety and efficacy and a risk/benefit evaluation for the grant of marketing authorisation.
Contrast with the Regulation of Devices in the USA.
Unlike Europe, there is a centralised regulatory system in the U.S. This is operated by the FDA, which itself approves and regulates medical devices. Unlike the European Notified Body system, the FDA considers the severity of disease and the available alternatives when deciding whether or not to authorise a device. This US framework usually requires clinical studies evaluating the safety and efficacy of a device.
In addition, reporting of post marketing safety data under the US system is more transparent than in Europe, with adverse event reports being submitted both to the manufacturer and the FDA. These reports are available on a public system, the Manufacturer and User Facility Device Experience.
US legislation does allow for an expedited, ‘abridged’ applications of ‘substantially equivalent’ devices under the ‘510K pathway’. DePuy (Johnson and Johnson) obtained authorisation for a metal upon metal hip via this 510K procedure that subsequently had to be recalled in July 2011 for similar reasons to those discussed above. The recall has triggered major litigation. As a direct consequence, the FDA are now reviewing the safety implications of the 510K process.
It is clear then, that in the face of evidence of its procedures not functioning in the way they were designed, the US is taking action to review these. In the wake of the PIP and Hips incidents in Europe, there is clearly the need for another look to be taken at the regulatory system for implantable devices.
A regulatory system, completely free from commercial pressures, together with the inclusion of some carefully chosen features from the regulatory system for medicinal products, would be great places to start.