ISS Clinical Essentials June 2020

Dear customers and partners

2020 has so far been a surprising year and has disrupted many plans including the application date for the Medical Devices Regulation (MDR). But this does not mean that the implementation of the MDR has come to a halt; the speed at which the MDCG publishes guidance documents proves the opposite. And from a manufacturer’s perspective, this guidance as well as the additional year is urgently needed to prepare for the MDR. Especially, when it comes to the stricter requirement of post-market surveillance and the time it needs to collect additional clinical data, manufacturers are well advised to take heed of the MDCG publications and make good use of the time until the MDR fully applies.

Switzerland’s aim is to move in sync with the EU legislation and, therefore, it will defer enforcing the revised Swiss medical device legislation by one year to 26 May 2021.

Find more information on the implications of the MDR postponement, recently issued guidance documents, and the expected new version of ISO 14155 in this latest issue of the Clinical Essentials.  

EU

New application date for the EU Medical Devices Regulation (MDR) 2017/745

Until the COVID-19 crisis, the European Commission (EC) held its ground refusing to accede to the requests to delay the MDR implementation. The Commission, however, responded to the exceptional circumstances of the COVID-19 pandemic and the potential impact it may have had on the MDR implementation with a proposal to defer the application date for one year. The proposal was quickly adopted and published end of April in the Official Journal as Regulation (EU) 2020/561. The one-year deferment means that the current Medical Devices Directive (MDD) and the Active Implantable Medical Devices Directive (AIMDD) will continue to apply until 26 May 2021.The additional year will be helpful as it allows clinical investigations to be started under the current medical device directives up until 26 May 2021 and to continue beyond that date. The new date of application allows device manufacturers not only to place new devices on the market under the current Directives, but also to prepare and collect necessary clinical data and start post-market clinical follow-up (PMCF) activities to fulfil the requirements of the MDR.

New EUDAMED timeline announced; guidance on safety reporting for device studies issued

The EC stated that it would begin making some Eudamed modules available next year, starting with the actor registration module. But no date for the electronic system for clinical investigations has yet been communicated. The MDR emphasizes the requirement of conducting clinical trials (clinical investigations) on certain risk classes of medical devices and introduces requirements of transparency and public disclosure of key information and documents. Until a fully functional Eudamed database is available, there will be some uncertainty on how to meet the requirement of transparency of clinical investigation information and how to prepare the data (not only on clinical trials) that will have to be uploaded retrospectively once the Eudamed is operational. Without a fully functional Eudamed provisions on clinical investigations under the MDD and AIMDD, the requirements of each Member-State continue to apply.

MDCG 2020-10/1 explains how safety reporting in clinical investigations of medical devices should be performed under the MDR. The guidance outlines the procedures for safety reporting in clinical investigations in the absence of Eudamed.

A new summary reporting form (MDCG 2020-10/2) should be used for reportable events as of 26 May 2021; and the requirement of performing safety reporting via Eudamed will apply six months after a notice regarding Eudamed’s functionality has been published in the Official Journal.

EU plans to have expert panels ready by July 2020

Expert panels will play a pivotal role in the implementation of the MDR and especially in the review of high-risk products (known as the clinical evaluation consultation procedure—CECP). The latest information entails that the EC establishes these expert panels by the end of July 2020.

The one-year postponement of the date of application of the MDR was much needed for products that had risked failing to meet the previous deadline because the expert panels were not available.

MDCG guidance documents on clinical evaluation, clinical evidence and PMCF published

 Seven MDCG guidance documents on compliance with the MDR were published in April. Four are focused on clinical evidence. The new documents clarify the important aspects of equivalence, clinical evidence and the PMCF plan.

MDCG guidelines on clinical evaluation of medical device software

The MDCG endorsed a document on the clinical evidence required for medical devices software within its conformity assessment. The guidance provides for indications on the level of clinical evidence that notified bodies will expect (quantitatively and qualitatively) from manufacturers of medical device software and also provides for practical examples of evaluation strategies.

MDCG guidance on transitional provisions for certain combination devices

MDCG 2020-12 covers transitional provisions for consultations with authorities on devices incorporating a substance that may be considered a medicinal product that has an action ancillary to that of the device, and on devices manufactured using transmissible spongiform encephalopathy (TSE)-susceptible animal tissues. The document also covers in its scope human blood derivatives which have an action ancillary to the device where the notified body is required to consult the European Medicines Agency.

Germany: DIMDI updated medical devices information system (MPI)

Following the deferral of the MDR application, DIMDI has reported that it will use the additional year to adapt the Medical Devices Information System (MPI) to the new regulatory framework. Some new developments affecting the area of clinical trials have already been released, such as:

  • The system provides better support when entering two separate applications to the Higher Federal Authority (BOB) and the Ethics Committee (EC) through a changed sequence of queries with more detailed help texts and an improved copy function.
  • The system includes an optional possibility of resubmission

UK: Medicines and healthcare products regulatory agency business plan

The recently issued medicines and healthcare products regulatory agency business plan shows that speed-to-market is the cornerstone of the 2020-2021 post-Brexit strategy for the MHRA. Three fundamental shifts are outlined in the plan, with potential implications for pre- and post-market clinical data for medical devices:

  • A changed focus on UK access to products: Focus on UK patient access to highly innovative products, with oversight of safety and clinical impact from earliest (including ‘experimental’) use.
  • Transformed post-market surveillance: Shift from life-cycle monitoring to systematic data-driven analysis of real-world use in the NHS, underpinned by data analytics and increased artificial intelligence (AI) capacity.
  • Impact: Engaging patients in the Agency’s work, having a real influence on clinical practice and enabling patients to make informed decisions.

USA

More clinical data must be posted on ClinicalTrials.gov after court ruling

The results of potentially hundreds of clinical trials of approved drugs and medical devices will have to be published on the ClinicalTrials.gov website after the decision of a New York court in February 2020.

The US District Court for the Southern District of New York found that the US Department of Human Services had erred in concluding that a 2007 law requiring clinical trial sponsors to post these trial results would not apply before it issued an implementing regulation a decade later.

HHS’s interpretation of its rule was set aside and HHS was ordered to ensure that trial sponsors submit basic results of clinical trials conducted in the 10 years between the enactment of the statute and HHS implementing the regulation.

China

Draft technical guidelines for clinical evaluation of medical devices and the use of real-world data

NMPA recently published the draft guidance on technical guidelines for clinical evaluation of medical devices. The draft is aligned with IMDRF documents (guidances on clinical evaluation, clinical investigation, clinical evidence) on the similar subject published in October 2019. The draft places more emphasis on clinical data and clinical characteristics of a device than technical details. For European manufacturers the alignment with IMDRF regulations is favourable and would not impose many new requirements.

Draft on use of real-world data in clinical evaluation

The draft on “Real-world data for medical devices – Technical guidelines for clinical evaluation” published in December 2019 is part of the Real World Data (RWD) program NMPA started the pilot in 2019, and recently first products have received approval. It aims to standardise the use of real-world data in clinical evaluations for medical devices. The draft shows how to apply to use real-world data and how the authorities will review them.

  • Overview and definitions (chapter 1).
  • Sources and their classification (chapter 2).

RWD can be obtained i.a. through electronic health records, patient-generated data, data gathered from mobile devices or the complete life cycle of a device

  • Evaluation of real-world data (chapter 3).
  • Principles and methods for real-world data research and design (chapter 4).
  • Common situations to consider RWD (chapter 5).

RWD can be considered as evidence for various situations. The draft lists eleven situations, such as to compare similar products (1), for modification in the scope or intended use of a product (6), for post-market surveillance (11)

Updated guideline on adverse event monitoring

The NMPA published updated guidelines from 2011 on adverse event monitoring. Reporting timelines are slightly extended compared to the former guidance, and the requirements for periodic risk assessment reports are added.

More products exempted from mandatory clinical trial requirements

With the revision of the medical device regulation in 2014, more clinical evidence, specifically data from clinical trials have become mandatory for medical devices. To reduce the hurdles, this implies NMPA already exclude many devices from the mandatory clinical trial data several times and added those in the catalogue of products exempt from clinical trials. Recently this catalogue has been revised again, and NMPA added more medical devices to be exempt from clinical trial data requirements.

ISO 14155

New ISO 14155 version due to be published soon

The third edition of the international standard on clinical investigations, ISO 14155:2020, is due to be published soon. ISO 14155 has not been updated in nine years and the third edition will consider key regulatory developments that have been witnessed since, including the adoption of MDR. The most important change in this latest version of ISO 14155 is the emphasis on continuous benefit-risk considerations. It also includes a greater emphasis on statistical considerations and clinical investigation planning, besides providing guidance on how the standard applies to post-market surveillance studies. Manufacturers who perform clinical investigations for MDR need to adhere to the 2020 version of ISO 14155.

The third version introduces changes such as:

  • A summary section of GCP principles;
  • Reference to registration of the clinical investigation in a publicly accessible database;
  • Guidelines on clinical quality management;
  • Guidance on risk-based monitoring;
  • Guidelines on study design and statistical considerations;
  • Guidance for Ethics Committees (a new annex);
  • Guidelines on clinical investigation audits in line with clinical quality management;
  • Reinforcement of risk management throughout the entire process of a clinical investigation;
  • Requirement of specific medical expertise in the planning of clinical investigations.

The publication of the third edition of ISO 14155 should lead to a more thorough and consistent adoption of GCP principles.

Miscellaneous