Good things come to those who wait. And when it concerns a €110 billion market representing over 22,000 companies employing more than 575,000 people across the European Union (EU), the result is eagerly anticipated.
So it was greeted with a lot of oomph when, after four years in the works, the European Parliament and the Council came to agree on the wording of the new Medical Devices Regulation (MDR) and the In Vitro Diagnostic Devices Regulation (IVDR) in mid-June 2016.
The overall process took longer than originally anticipated, and had its twists and turns, but the end product is something that has been broadly welcomed by manufacturers as well as other key stakeholders. These include European national authorities and notified bodies — the organizations that certify medical devices in the EU, and whose role the regulations greatly expand.
Once fully in force, the new regulations will govern the European Union’s market for medical devices and devices for in vitro tests, with more than 500,000 individual types of products currently on the market.
The new rules are set to replace the three directives that have governed the medical device market in the EU since the early 1990s. The crucial distinction here is that the new regulations are immediately enforceable as law across all EU member states once passed by the European Parliament, while the old directives outlined general rules to be interpreted into national laws by each country as they deemed appropriate. And differ they did.
Medical technologies have evolved considerably during the 18-26 years since the individual directives came into being. Much in and around medical devices has become digital, there has been an explosion of medical software, and there are increasingly more medical devices that are combined with medicinal products or substances, cosmetic products that border on being medical devices and so on. Regulations across that world have changed and developed accordingly in the meantime.
There are still a few steps to take, though. Formal publication of the new regulations in the Official Journal of the European Union is expected in Autumn of 2016, after being finalized and formally approved, translated into all official EU languages, and reviewed by the Commission’s legal service.
As expected, the new rules allow a certain transition period: three years for the MDR and five years for the IVDR. Manufacturers whose devices are CE-marked for sale in the European Union will have a sufficient amount of time to get ready for the new regulations. All devices currently on the market will need to be reevaluated and certified under the new rules when the existing certificates expire. Certificates issued after the enforcement of the new regulations will be valid for two years.
There were many drivers for the new regulations, but there were a few main issues that stood out. Currently, it’s not always possible to establish who produced devices sold in the EU. This lack of traceability has obvious consequences for any post-market vigilance, as well as investigating root causes in case of device-related adverse events. There is a shortage of information and clinical evidence showing that devices are truly safe and effective. Several EU member states have set up electronic registration systems for medical devices, but they are not always compatible with each other, making traceability across borders difficult.
Unlike pharmaceuticals in the EU, medical devices are not subject to pre-market authorization. Instead, they undergo a conformity assessment to establish whether they meet the applicable standards, and if so, they are given the CE mark of conformity. Depending on the risk posed by a product, the assessment may involve a group such as a notified body or national standards authority that performs the conformity assessment. The rules that determine the scope of controls carried out by these bodies vary between countries.
In this light, the new regulations require manufacturers and importers to fit their products with a Unique Device Identification (UDI). A UDI is a unique numeric or alphanumeric code that manufacturers need to include on device labels and packages. Each UDI must be provided in plain text as well as in a form that uses automatic identification and data capture technology.
UDIs allow linking specific devices to clinical information. The use of UDIs on medical devices ensures their traceability, effective aggregation of adverse event data, as well as better coordination of recalls.
UDI has been already made mandatory in the US by the Food and Drug Administration (FDA). Manufacturers had to update labels and packages with UDI-related information for certain Class III medical devices and standalone software (by September 2014), and also for labels and packages for implantable, life-supporting, and life-sustaining devices and software (by September 2015). September 2016 was the UDI implementation deadline for Class II devices. Class I devices are slated for 2018 and 2020.
In the EU, UDIs are required within one year of the regulations going into effect for implantable and Class III devices. They then allow three years for Class IIa and IIb devices, and five years for Class I devices. This gives medical device manufacturers more time to get their international operations ready for UDI implementation.
The new regulations also require manufacturers, importers and distributors to register themselves and the devices they market in the EU in Eudamed, the centralized European Databank on Medical Devices. This provides a record of who supplied them with a product, and to whom they supplied the product as well.
Eudamed has been around for some time, but it is poised to radically expand to become the “central brain” behind the new regulations. In this sense, it will take on additional functions related to the UDI system: the registration of devices and economic operators, market surveillance and vigilance, certificates, and clinical investigations. It will also become more open.
The wide range of “economic operators” (such as manufacturers and importers), notified bodies, competent authorities and the Commission will have access to it and will upload information directly. In addition, nonconfidential information will now be accessible to the public.
This database is designed to be multilingual. The user interface will be available in all of the official languages of the EU. However, to limit the extent of translation required, the use of free-text fields in the database will be minimized.
The new regulations specify translation requirements associated with marketing medical devices in the EU market. The general obligations of manufacturers are to “…ensure that the device is accompanied by the information to be supplied … in an official Union language(s) determined by the Member State where the device is made available to the user or patient.” This concerns labeling, packaging and instructions for use — the ever-growing technical documentation that goes along with medical devices.
This means that member states continue to have the final say in terms of what languages they require for medical devices in their markets. Importantly, the new IVDR maintains the provision that when the device is intended for professional use only, instructions for use may be provided to the user in non-paper format (e.g. electronic), except when the device is intended for near-patient testing.
Some of the working versions of the regulations required providing a list of the language variants for the member states where the device is envisaged to be marketed. But this was dropped in the final agreed wording.
Similar requirements exist for manufacturers that “…shall, upon request from a competent authority, provide it with all the information and documentation necessary to demonstrate the conformity of the device, in an official Union language determined by the Member State concerned.”
Notified bodies are set to be heavily impacted by the new regulations. In a way, their role is going to change from “industry partners” to “policing bodies.”
Since they normally operate across borders, notified bodies are now required to “…publish a publicly available description of the application procedure by which manufacturers can obtain certification by the notified body. This description shall include which languages are acceptable for submission of documentation and for any related correspondence.”
New in the regulations is also the requirement for identification of a “qualified person.” Manufacturers are required to identify at least one person within their organization who is ultimately responsible for all aspects of compliance with the new regulations. The organization must document the specific qualifications of this individual relative to the required tasks. This is potentially a headache for many small and medium-sized manufacturers which may not have such a person in place at the moment.
What is also new is that many IVD manufacturers will no longer be able to self-certify their devices. Notified body intervention will be needed for a majority of IVDs: the quality of the technical documentation has to be robust enough for external review.
The currently ongoing discussions on the Transatlantic Trade and Investment Partnership (TTIP) between the US and the EU also have a potential impact on medical devices and pharmaceuticals. Given the volume of trade in these industries between these two entities, the impact may be significant, but the success of these negotiations is currently still in the air.
Harmonizing submission forms. Some of the current efforts center on harmonizing forms (but not the overall approaches!) for getting new medical devices approved. The idea is that EU and US regulators can work on approvals at the same time, which would make new devices available more quickly. Currently, a manufacturer seeking to market a medical device in the EU and the US has to submit separate marketing applications to each jurisdiction. In addition, the required information and formatting that are required are different. The hope is that both parties could work to establish a common or at least interoperable electronic system for data submission.
Mutual recognition of Quality Management System (QMS) audits. The QMS requirements in the US and the EU are very similar, but there are still some requirements that are specific to the EU legislative framework, and others that are specific to the US. One idea discussed is that QMS auditors could check compliance of a given audited facility with the requirements of several jurisdictions at the same time — a so-called single audit. The concept of the single audit has been developed at the international level and is being tested. If this succeeds, it should be possible to allow a formal recognition of QMS audits carried out by the other party’s auditors.
Compatibility of UDI systems. The idea is to base national systems for identifying and tracing medical devices on the international UDI system, as the US did recently. Both sides could ensure that the EU and US UDI databases are compatible so that devices can be traced across the regions.
Pharmaceuticals, literature monitoring and clinical trials
But the recent regulatory developments in the EU are not limited to medical devices. In the area of pharmaceuticals, the European Medicines Agency (EMA) has recently launched the electronic repository for periodic safety update reports (PSURs). This is no small thing. Marketing authorization holders in the EU must submit PSURs at defined time frames following a medicine’s authorization. The period may range from six months to 28+ years but usually oscillates between three and 13 years.
PSURs contain a summary of the benefits and risks of a given pharmaceutical, including the results of all studies carried out with this medicine. The portal can also be used to update product information and this update will affect PSURs for both centrally and nationally authorized medicinal products. The use of the PSUR Repository has become mandatory for all PSUR submissions as of June 13, 2016.
One of the new services provided by EMA is the full medical literature monitoring service, which started on September 1, 2015. This keeps track of publications on a total of 400 active substance groups: 300 chemical active substance groups and 100 herbal active substance groups.
The idea behind this new service is to improve the safety monitoring of medicines by enhancing the quality of the data reported through EudraVigilance. This means that the industry is no longer obliged to enter literature information on suspected adverse reactions into the EudraVigilance database. It is also a great source of information for medical translators.
Clinical trials continue to be a hot topic in the world of pharmaceuticals, not least because pharma companies are under increasing pressure to publish information about trials and their results. The bestselling book Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients by Ben Goldacre was one of the most vocal examples of this call for reporting the results of past and current clinical trials.
In the EU, EMA is set to manage a portal and database for the submission, authorization and supervision of clinical trials in the EU as part of the implementation of the new Clinical Trial Regulation. The portal will provide access to a database that will serve as the source of public information on the full life cycle of all clinical trials conducted in the EU, from their initial review up to publication of their results.
The public will be able to access comprehensive details of each trial, including the major characteristics of the trial, the start and end of recruitment, the end date and substantial modifications to the trial. A summary of the results and a summary in lay language will normally be published 12 months after the end of the trial. Expected live date? October 2018 at the latest.
EMA has also recently come into the spotlight following the UK referendum and the decision to leave the EU. This puts into question the regulatory framework for medical devices and medicines in the UK post-Brexit. At the moment, the new medical device regulations as well as EMA’s guidelines apply not only to the EU countries, but also to the other members of the European Economic Area: Iceland, Liechtenstein and Norway.
The other aspect is that EMA is one of the two major EU agencies located in the UK (the other being the European Banking Authority), with a staff of over 890 employees in the current headquarters in London’s Canary Wharf financial district. Both agencies play a critical role in steering two of the Union’s most important sectors: banking and pharmaceuticals. As such, many EU countries have already expressed an interest to host these institutions. So chances are that EMA, the originator of many major changes in the EU pharmaceutical industry, will soon undergo a major transformation as well.