Drug Device Combination Products: A need for regulatory clarity
In the EU, combination products are regulated as medicinal products if the drug component is principal and not ancillary to the function of the device; or as medical devices when the drug has an integral but ancillary function. For products that fall into the first category, pharmaceutical businesses principally refer to the Medicinal Product Directive 2001/83/EC (MPD) to ensure compliance for the drug component, but this directive contains little guidance in relation to the device component. In addition, the EU MDR’s predecessor, the Medical Device Directive 93/42/EEC (MDD), did not elaborate on the requirements for device components within combination products regulated under the MPD. This lack of direction and of a link between the two directives created a regulatory gap where device components (combination product regulated as a medicine) were subject to a lesser degree of scrutiny than stand-alone medical device products.
Article 117: Demonstrating conformity of device components
A new point of reference for pharmaceutical companies is Article 117 of the EU MDR, which provides an amendment to Annex I of the Medicinal Product Directive. Article 117 outlines specific requirements for the device component, which businesses must now adhere to for their combination products to be deemed compliant. Specifically, where a product is governed by the MPD, the marketing authorization dossier submitted by pharmaceutical companies should include proof of conformity of the device component if it is available. To demonstrate proof of conformity, they must include results of the assessment of the conformity of the device component, in accordance with the relevant general safety and performance requirements of Annex I of the MDR, within their EU declaration of conformity. A second option is to submit the relevant certificate issued by a Notified Body allowing the manufacturer to affix a CE marking to the medical device. However, if the conformity assessment is missing, and requires the involvement of a Notified Body, the applicant must be able to provide an opinion issued by a Notified Body designated under MDR for the type of device in question. This opinion aims to demonstrate that a conformity assessment for the device component has been performed by a designated medical device Notified Body against the relevant requirements of the EU MDR. Essential elements of conformity include technical documentation which demonstrates the safety, performance and clinical benefit of the device, and ongoing post-market surveillance activities (inclusive of Post-Market Clinical Follow-up as needed) conducted in conjunction with risk management and clinical evaluation.
Pharmaceutical Companies: Elements to prepare for
Many medicinal product manufacturers were unaware of MDD requirements for their drug device combination products, and are therefore largely unfamiliar with device regulation. They must seek and build up expertise in this area to tackle increased scrutiny of medical device safety and performance. There are multiple elements to this: learning how to interpret the regulation, correctly developing compliance documentation, and liaising with Notified Bodies. Without prior experience and the right skills, tackling these may be challenging as medical device companies have already invested time and resources to implement compliance processes. The device industry is currently keeping watch for Notified Bodies to be designated under the EU MDR, as there have only been thirteen designations so far. Pharma companies must follow suit and ensure they are liaising with a Notified Body that is waiting for, or has already received a designation for devices that are subject to conformity assessment under the EU MDR. A final crucial point is that manufacturers can benefit from a variable extended transition period for those drug device combination products already holding a CE Mark under the current MDD 93/42/EEC until their certificate expiry date, but no later than May 26, 2024. Businesses that opt for this extension must be aware that they cannot make changes to the products unless they are re-certified according to EU MDR 2017/745, and so it is advisable not to delay in achieving compliance.
Companion Diagnostics: A new addition in the EU IVDR
The EU IVDR includes a new product category for companion diagnostics, which will now be under greater regulatory scrutiny as a result. ‘Companion diagnostic’ refers to a device which is essential for the safe and effective use of a corresponding medicinal product, and can help to identify before and/or during treatment patients who are most likely to benefit from the medicinal product; or patients likely to be at increased risk of serious adverse reactions as a result of treatment with the medicinal product. Though the transition period for the EU IVDR is longer, there are only three Notified Bodies that have been designated for IVD devices to date, and there are fewer organisations awaiting designation in comparison with the EU MDR. In addition to Notified Body timelines, companies are dependent on national Competent Authorities (or the European Medicines Agency) for reviewing the associated medicinal product. This needs to be built into compliance planning, which should also take into consideration the stricter scrutiny that companion diagnostics will be under as Class C devices (the EU IVDR’s classification system terms Class A as the lowest risk and Class D as the highest). As with the EU MDR, clinical evidence supporting the intended purpose of the devices is essential for compliance submission. Manufacturers must follow a performance evaluation plan, demonstrating the following three elements: scientific validity; analytical performance; and clinical performance. Where there is a lack of data, new clinical utility studies may be necessary, further extending the compliance process timeline.
No Grandfathering: Evaluating product portfolios
Under the new medical device regulations, grandfathering is not permitted, meaning that every medical device needs a new CE mark. There are significant business implications of this as companies that do not meet the deadlines risk losing market access until their products are compliant. Pharmaceutical companies working with contract organisations for device components must safeguard their product portfolio by ensuring that these organizations are compliant. Reviewing device compliance, whether internally or at a partner organization, may seem daunting for companies that are doing so for the first time. For this reason, it is recommended that combination product pharmaceutical companies, as well as pharmaceutical companies that present medicinal substances with a Companion Diagnostic, develop expertise and implement compliance processes that will facilitate future assessments and help to ensure regulatory compliance in the long-term.