Are You Ready? Impact of Upcoming Regulatory Requirements on Combination Product Reporting

Combination Products: What are they?

Any product formed from the combination of a drug, a device and a biologic is referred to as a combination product.  Under 21 CFR 3.2 (e) this includes two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity.

There are a several regulatory changes coming that may impact requirements for reporting on combination products to include:

  • EMA 28 February 2019 guidance focuses on Article 117 new medical devices regulations for marketing authorization applications for medicines with an integral medical device
  • EU MDR regulations which go into effect 26 May 2020 and IVDR regulations May 2022
  • FDA July 2019 Post marketing Safety Reporting for Combination Products Guidance for Industry and FDA Staff – 31 July 2020 for FDA Adverse Event Reporting System (FAERS) and Electronic Medical Device Reporting System (eMDR) to report Individual Case Safety Reports (ICSRs)

Highlight: The FDA identifies and describes 9 different types of combination products

What are key implications for compliance?

Companies should be prepared for the upcoming requirements both in terms of safety reporting and submissions for approval under these new guidelines.  Some of the key considerations are:

  • In the EU, submission for a medicine with an integral medical device requires conformity of the device part and must include a CE certificate from a Notified Body (NB) for the device component or a Notified Body Opinion on the conformity of the device. This demands that safety and performance data is provided as well as functionality testing for accuracy of dosage, usability testing and sterilization validation testing.  Every single device now will require these steps and an ongoing post-market surveillance of risks and complications.  Although device manufacturers are familiar with these requirements, many pharmaceutical companies with new combination products may be unaware of the significance of these requirements.  In addition, due to both BREXIT and MDR requirements there are currently limitations to the number of certified NBs that can impact a sponsor’s ability to get timely reviews.
  •  Under the new FDA guidance, Individual Case Safety Reports (ICSRs) have the following:
    • Fifteen-day reports
    • Five-day reports
    • Malfunction reports – time for malfunctions with a SAE 15-day reporting and without a SAE 30-day reporting
    • Reports of deaths or serious injuries
  • Under the new FDA guidance, Non-Individual Case Safety Reports (non ICSRs) have the following:
    • Field Action Reports
    • Biologic Product Deviation Reports
    • Correction and Removal Reports
    • Information sharing for Constituent Part Applicants within 5 days of receipt with the other Constituent Part Applicant
  • Product configuration identification of Constituent Parts (Device, Drug, Biologic)
  • Consideration for changes to SOPs, training of personnel, updates to Safety Management Plans to ensure timelines for all reporting requirements are met
  • Safety database and/or system configuration changes to ensure capture of adverse events as well as device issues and malfunctions is possible.
    • System validation
    • Impact to case processing and quality
    • Compliance and Quality Systems considerations

Suggested steps to prepare for reporting requirements

There are significant implications as of Q2 2020 that companies will need to conform with both for post-market reporting in the US and approval and post-market surveillance in the EU.  Preparations should be well underway, but what can be done to insure you are ready?

  • Build a timeline for tasks needing implementation and identify stakeholders (regulatory, manufacturing and design, medical and safety, IT)
  • Implement process updates
  • Develop a decision tree for reporting to ensure timelines are met for 5, 15 and 30-day reporting and that aggregate reporting requirements are met


Covance has safety and regulatory experts available to consult with our pharmaceutical and medical device clients to ensure you are prepared to manage safety surveillance in an ever more complex global landscape.  Through understanding the classification of your products in different countries whether it be pre- or post-approval and implementing appropriate risk mitigation strategies you can ensure compliance with the reporting requirements in any market.

If you would like to speak with one of our safety leaders about assistance and planning for these upcoming changes, please contact us or email us at