欧盟医疗器械法规 (MDR) 和欧盟体外诊断医疗器械法规 (IVDR) 的出台，带来了一系列将会影响所有医疗器械制造商的明显变化。然而，这两项新法规对生产药械组合产品的企业也有影响。由于MDR和IVDR全面施行的最后期限很快就要到来（分别是2020年5月和2022年5月——除非监管机构对其最后期限有所调整，即延期施行），而在最后期限之后，若组合产品中的器械部分不合规，该组合产品将不得不退出市场，因此了解新的法规要求并予以实施至关重要。
The new EU MDR and its impact on drug device combination products
This article discusses the key elements of the EU MDR pertaining to drug device combination products and how life science companies can organize themselves to ensure regulatory compliance is met. The author will work through what manufacturers of these types of devices need to know in order to achieve EU MDR compliance as well as the challenges they could face and how to overcome them.
The EU Medical Device Regulation (MDR) and the EU In Vitro Device Regulation (IVDR) introduce substantial changes that impact all manufacturers of medical devices. However, these regulations also have implications for companies producing drug device combination products. Understanding the new requirements and implementing them is critical as the deadlines for compliance are approaching fast (May 2020 and May 2022 respectively – unless the governing bodies make adjustments to the deadlines for extension), and products containing non-compliant devices after these deadlines will have to be withdrawn from the market.
The EU MDR & Drug Device Combination Products
The EU MDR particularly impacts combination products currently regulated as medicinal products under the EU Medicinal Product Directive 2001/83/EC (MPD), where the drug component is principal to the function of the device. Examples of these products include insulin injector pens and metered dose inhalers, where the purpose of the device is to be the applicator for the integral drug component.
Companies that are historically drug firms and have since acquired another company which manufactures drug device combination products, often fall into the trap of assessing the newly acquired entity solely as a drug company and do not have a grasp of the 21CFR820 and EU MDR or IVDR requirements. Typically drug firms only perform three lots of validation for a product, but for a device this amount is inadequate due to the level of complexities involved in making a combination product.
Previously, there were no clear regulatory requirements for the device element, meaning that many medicinal product manufacturers may not have been aware of actions they needed to take to ensure compliance. The issue has become pressing, especially as devices become ever more sophisticated and complex. To ensure that device components do not escape regulatory scrutiny, Article 117 of the EU MDR provides an amendment to Annex I of the EUMPD, outlining specific requirements for the device component. Manufacturers have until May 26, 2020 – subject to potential adjustments from governing bodies - to comply with these requirements, though drug device combination products already holding a CE Mark under the current Medical Device Directive 93/42/EEC can benefit from an extended transition period up to May 26, 2024. However, as these products are categorised as Class III devices, no changes can be made to the products unless they are re-certified under the EU MDR.
When the FDA or EU inspect the site of manufacture of a drug device combination product, that site will have to address all regulations that govern both drugs and devices. The regulations for each are similar, but not the same for each quality system component. For example, the handling of deviation investigations is different in a drug company than in adevice firm. It is important that these differences are understood in order for the quality management system to be suitably modified to address both regulations.
The new regulations are complex and are causing unprecedented upheaval in the industry. Instead of liaising solely with national Competent Authorities (CAs) for authorization of their combination products, pharmaceutical manufacturers are now subject to regulatory oversight for both the device and medicinal parts of their combination products. This means that they must liaise with notified bodies for the ancillary device component. To date, only five notified bodies have been designated under the EU MDR putting these organisations under severe pressure due to the scale of there gulatory changes and the number of submissions to be processed, so the importance of early engagement cannot be stressed enough.
Under the EU MDR, every single device needs a new CE mark to remain on the market. An essential element of achieving compliance is submitting updated clinical evaluation reports at testing to the safety, performance and benefits of the device. Medicinal product businesses that have never managed a submission for device conformity may not have the data required and will therefore have to carry out fresh clinical testing. This can be time-consuming and costly, so it is imperative to determine which information is needed, whether it is already available and the steps needed to procure missing data.
It is worth investing resources the first time round to guarantee a smooth and successful submission, and to put standardized procedures in place so that the relevant data is continually updated and always readily available. Notified bodies will look out for evidence of ongoing post-market surveillance activities to assess real world use and to manage unforeseen risks or complications.
It is highly recommended that manufacturers of these products bring in external device and combination product experts; the risk of missing a major compliance or quality issue is huge as expertise is usually siloed into just drugs or just devices. In today's manufacturing world the modus operandi is ‘lean manufacturing’, meaning there are few internal compliance specialists. Harnessing external third-party support will be key to achieving regulatory goals.
Most medical device companies have already invested time and resources in understanding and interpreting the relevant regulations and developing the necessary procedures and documentation. In contrast, it is likely that pharmaceutical regulatory teams will find themselves in new territory, and will have to start from scratch. Planning is crucial to meet the deadlines in time and efficiently manage compliance timelines and expectations. Manufacturers must adjust expectations by taking into account notified body liaison and procedures, as well as the level of device risk and therefore the level of scrutiny required. To ensure that this process is as efficient as possible, advice and practical support from a third party specialist may be invaluable for ensuring patient safety, avoiding any cessation to market access and the subsequent impact on the bottom line and company reputation.