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Reflector is Pharm Exec's Brussels correspondent.
Medical devices manufacturers and pharma companies alike should review their compliance strategies as the EU Medical Device Regulation Date of Application approaches.
Now that there are less than four months remaining until the EU Medical Device Regulation (EU MDR) Date of Application, it is high time that manufacturers of medical devices and pharmaceutical companies alike review their compliance strategies. Fulfilling the updated requirements of the regulation is essential for guaranteeing continued unrestricted EU market access after the deadlines. The new regulations will come into effect May 26, 2020, for EU MDR, and May 26, 2022, for EU In Vitro Diagnostic Regulation (IVDR).
The EU MDR and EU IVDR were both published in the Official Journal of the European Union on May 5, 2017 and affect manufacturers of combination products and companion diagnostics as well as many others in the industry. The new regulations introduce substantial changes that are causing unprecedented upheaval within the medical device industry. Both the EU MDR and IVDR are lengthy documents, therefore businesses intending to meet the respective deadlines should priorities developing a clear understanding of the significant changes and consider ways to implement them without delay. The requirements of the regulations are complex and require companies to re-evaluate their conformity assessment routes. Despite the roadmap to compliance being intricate in some parts, working through the compliance process provides an opportunity to improve operational and commercial conditions. A proactive approach creates sustainable regulatory compliance that will bear effect long after the implementation deadlines in May 2020 (EU MDR) and May 2022 (EU IVDR).
With the ever-increasing technological innovation on the medical device market and the growing global combination product market size as a result, the driving force behind the EU MDR and IVDR is a commitment to patient safety.
In this late stage of the regulatory transition period, the majority of medical device manufacturers state that their EU MDR remediation process is well under way. However, many cite lack of guidance, availability of notified bodies and meeting the timeline as the greatest barriers to EU MDR compliance. Many pharmaceutical companies producing combination products and companion diagnostics on the other hand are possibly facing device regulatory scrutiny on this level for the first time and may therefore be unsure about the effect of the new regulations on their range of products.
Whether you are a medical device manufacturer or a combination product pharmaceutical company, under the new regulations no medical device is exempt from regulatory scrutiny. In the case of the EU MDR, as well as the EU IVDR, grandfathering is not permitted.
The purpose of this article is to analyze the most influential changes, to outline their implications and to provide practical steps that manufacturers should take in preparation for these substantial changes within the European regulatory landscape.
Nowadays, many innovative medical devices are combination products. According to the European Medicines Agency, one in four centrally authorized medicines includes a medical device component, and the majority of these involve an integral device.
In the European Union, drug-device combination products are assessed based on their primary function; either as a medicinal product or as a medical device and are also referred to as such in the official EU legislation.
The Medical Device Regulation specifies that combination products are either:
[Chapter 1, Article 1, 8 & 9, Official Journal of the European Union, Medical Device Regulation]
The changes brought about by the EU MDR are numerous. First and foremost, manufacturers should know that the number of classification rules have increased from 18 to 22. Under the EU MDR certain products are subject to medical regulation for the first time, in some cases even reclassification (mostly to a higher risk classification). The time frames for reporting serious incidents and public health threats are shorter than before. All manufacturers are now obliged to document, implement, maintain and continually improve a quality management system. The EU MDR introduces heightened scrutiny through Notified Bodies and Competent Authorities. For some manufacturers it may be the first time that they are engaging with a Notified Body and must therefore take a closer look at the steps this process entails.
Prior to the EU MDR, combination products fell under the EU MDR’s predecessor, the Medical Device Directive (MDD), whereas products categorized as medicinal products fell under the Medicinal Product Directive (MPD). Products will continue to fall under these two categories under the EU MDR, however, the requirements for medical devices are now tighter and pharmaceutical companies will undergo heightened scrutiny in order to make sure that compliance of the device component is ensured.
The level of scrutiny performed by Competent Authorities (CAs, via 3rd party Notified Bodies) was not even across the board. The EU MDR aims to rectify these inconsistencies and entails a wealth of changes affecting medical device manufacturers and drug-device combination pharmaceutical businesses.
Manufacturers of combination products must take Article 117 of the EU MDR into close consideration. It addresses the regulatory gap between the MPD and MDD due to the lack of linking between the two pieces of legislation. It provides an amendment to Annex I of the MPD and outlining the requirements for the device component.
The deadline for EU MDR compliance is fast approaching. Manufactures have until May 26, 2020 to reach compliance.
Along with the EU MDR, the EU IVDR is causing a stir within the EU medical regulations environment. The EU IVDR will replace the In Vitro Diagnostic Medical Devices Directive (IVDD) and adds new requirements in order to overcome divergences and improve patient safety.
The EU IVDR affects manufacturers of companion diagnostics. Companion diagnostics are IVDs that have the capacity to provide insight on whether a patient will benefit from a medicinal product. They can be used before and/or during treatment and are co-developed with drugs. Digital pills, for example, can track when patients take their drugs, the size of the dose as well as the medication taken.
For this reason, the new EU IVDR has an impact on IVD manufacturers as well as pharmaceutical companies that presents the medicinal substance with a Companion Diagnostic. Under the risk-based classification system, companion diagnostics will fall under class C devices, with class A representing the lowest risk and D representing the highest risk. Lying in the upper range of the risk-based classification system will make manufacturers of companion diagnostics subject to increased scrutiny by Notified Bodies and Competent Authorities.
The EU IVDR profits from a longer transition deadline than the EU MDR. Manufacturers have time to demonstrate compliance until May 26, 2022.
The number of definitions of an IVD has expanded to 74. The biggest change concerns the risk-based classification system of IVD devices. The EU IVDR assigns each device to one of the four risk categories, with class A representing the lowest risk and class D the highest risk. Along with heightened monitoring by Notified Bodies and Competent Authorities, the EU IVDR also brings tightened requirements for clinical evidence and conformity assessment.
For many manufacturers but especially pharmaceutical companies, it may possibly be the first time that they are being asked to engage with a Notified Body and may therefore be unaware of the time-consuming process this entails. Due to the extent of regulatory changes, the designation of Notified Bodies has been moving at a slow pace. Notified Bodies are currently operating under immense pressure, for which reason the importance of early engagement cannot be highlighted enough. Nine Notified Bodies are currently designated under the EU MDR and three under the IVDR; however, for the EU IVDR there are far fewer Notified Bodies awaiting designation.
Conducting thorough clinical evaluations is an essential part of achieving compliance for medical devices. Compiling the essential documentation requires time and any form of delay could prove to be detrimental. Technical data demonstrates safety, performance and clinical benefit of the device and ultimately facilitates market access. Particularly with the heightened monitoring by Notified Bodies, clinical evaluation plays a central role in achieving EU MDR.
In the case of combination products (EU MDR), the Clinical Evaluation Report (CER) is a part of technical documentation. The CER analyses clinical data gathered through clinical evaluation and market surveillance for the device.
Clinical evidence of IVDs must support the intended purpose of the devices. Manufacturers are advised to implement a continuous cycle of performance evaluation on the basis of a performance evaluation plan through which scientific validity, analytical performance and clinical performance are demonstrated. If there is insufficient data to complete these sections, evaluation gaps must be conducted in order to determine how much further clinical activity is needed. A performance evaluation report should entail clinical assessment and evidence. As with combination products, the clinical documentation of companion diagnostics must be reviewed throughout the life-cycles to reflect post-market surveillance.
In a recent survey from June 2019, the main challenges observed have to do with the designation of Notified Bodies, lack of internal resources and the compiling of clinical data and technical documentation. Taking strategic steps to combat these challenges is necessary if manufacturers wish to be successful in reaching compliance. Making compliance a priority task goes without saying. Sticking to timescales and developing standardized procedures facilitate the process. Making sure that all the relevant clinical data has been accumulated is essential when dealing with a Notified Body. Manufacturers who may not be familiar with the process are advised to invest in third-party specialists who can offer guidance and support throughout the process towards compliance.
In order to pave the way to compliance, manufacturers must put it at the top of their to-do list. Developing timescales and sticking to them ensures that deadlines are met in a timely manner. Additionally, the development of standardized procedures makes the compliance process easier. Ensuring that essential clinical data and technical documentation has been accumulated before submitting it to a Notified Body saves time on both ends and facilitates the process. Manufacturers who may be undergoing the compliance process for the first time are advised to partner with a third-party specialist in order to facilitate the process.
The changes in the regulatory system are not to be taken lightly. Most medical device manufacturers have already taken the essential steps towards ensuring compliance by understanding and interpreting the relevant regulations and developing the necessary procedures and documentation. Pharmaceutical companies on the other hand, might be finding themselves in unchartered territory. Keeping in line with timescales and planning every step is therefore essential. Taking Notified Body liaison and processes into consideration is a key element of compliance. Manufacturers going through this process for the first time are advised to invest in resources to make sure that the transition runs smoothly. Whether your company is familiar with compliance procedures or is undergoing this for the first time; viewing this transition period as an opportunity to refine and improve internal strategies will be helpful in moving through the essential steps and conforming to the requirements of the new regulations. Lastly, being proactive plays into compliance. Compliance is an ongoing process, therefore making sure compliance is achieved is not only beneficial for meeting the EU MDR and EU IVDR deadlines but aids in guaranteeing compliance in the future.
Elizma Parry is Director, Global Clinical Practice at Maetrics.
 KPG and RAPS EU MDR Survey Results and Key Findings, p.17
 KPG and RAPS EU MDR Survey Results and Key Findings, p. 24.
 European Medicines Agency https://www.ema.europa.eu/en/news/first-guidance-new-rules-certain-medical-devices
 EU MDR Insight: Ancillary Drug Substance, Biologically Active Material, and Drug Device Combination Products. What manufacturers need to know to achieve compliance, Maetrics, June 2019, https://maetrics.com/wp-content/uploads/2019/06/MAET_DDC_WHITEPAPER_JUNE2019.pdf
 Official Journal of the European Union, Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC
 FDA publishes premarket guidance on combination products , Pharmaphorum, 07 February 2019.
 The Race to EU MDR Compliance Continues, KPMG & RAPS, 2019.