Smart combination products represent a healthcare system that is becoming increasingly patient-centric and focused on outcomes.

These products are also “part of a diverse, regulated ecosystem,” according to Napoleon Monroe, Managing Director, New Directions Technology Consulting, in the Dec. 10 Redica Systems webinar, “The Ecosystem for Smart Combination Products: What About Regulations?” He reviewed his takeaways from recent industry conferences and provided his own perspectives on the regulatory landscape for smart combination products.

What are smart combination products?
Smart combination products are combinations of drugs or biologicals and devices that are connected to the Internet, generally via a smartphone.

Buzz from the Virtual Conference Scene

Throughout 2020 Monroe attended a number of industry conferences hosted by the Parenteral Drug Association, American Dental Association, ChinaBio, and other organizations that covered smart combination products and connected health. From these conferences, he identified the following common themes:

Investment and growth in digital health, telemedicine, and connected health
COVID-19 has proven to be a catalyst for growth
Patient-centricity
Everything is digital
Importance of selecting device and intellectual property platforms for products
Overcoming barriers and silos to developing innovative products

“Interestingly, there was very little discussion on return on investment at these conferences,” Monroe said.

Regarding his second point about the COVID-19 pandemic as a catalyst for growth, he explained that the situation has led to a global emphasis on healthcare. In addition, both patient and practitioner behaviors have changed.

“COVID seems to be a lasting driver for telemedicine,” he said.

[Related: Did you miss this webinar? Download the webinar recording and view at your own pace.]

Download the Dec. 10 Smart Combination Products Webinar

And You Thought Smartphone Updates Are Difficult

A portion of Monroe’s presentation covered automated identifiers and serialized data capture requirements (unique device identifier requirements and the Drug Supply Chain Security Act). Here, regulators intend for easier post-marketing surveillance using real-world evidence. Yet smart devices and combination products with embedded software present unique challenges when it comes to post-marketing surveillance.

As most smartphone users are aware, software is often updated frequently. A “minor” software update for a smart combination product that is not documented could result in a product recall or other regulatory action.

This already occurs in other areas. In Monroe’s experience, component suppliers often make “minor” changes without updating the component lot number (these changes are usually found in supplier batch records).

Software changes, no matter how minor, will need to be recorded throughout the lifecycle of any combination product that connects to the Internet.

FDA Takes Action

Monroe provided an overview of recent regulatory developments impacting smart combination products. Below are some of the highlights from his presentation:

The FDA draft guidance, Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted under a BLA, NDA or ANDA, issued April 2020 is extensive, presaging requirements for new emergency and other delivery products. This guidance covers fast-tracking of emergency nasal delivery products, including pen, jet, and other emergency products.
The FDA’s medical device evaluation program, National Evaluation System for health Technology (NEST), uses real-world evidence and analytics to monitor medical devices throughout the lifecycle. How will this system use consumer-based complaints posted on the Internet, and how will FDA triage out erroneous complaints?
The recent guidance, Requesting FDA Feedback on Combination Products, is now available.
For the past four to five years, there has been some interpretation and relaxation of U.S. regulatory requirements for some smart devices while regulations for other smart devices have tightened. Additionally, EU requirements have tightened and remain less clear.
In September 2020, FDA’s Center for Devices and Radiological Health (CDRH) launched the Digital Health Center of Excellence to coordinate regulatory work on digital health across FDA.

MDR: Real-World Evidence

Moving from the United States to Europe, he then addressed the EU Medical Device Regulation (MDR).

“There are many unanswered questions about the European Medical Device Regulation before it goes into effect,” Monroe said. “It will have the force of law and we are suffering all of us from scarce Notified Body capabilities.”

Software changes, no matter how minor, will need to be recorded throughout the lifecycle

The new effective date is May 26, 2021; originally, the EU MDR was supposed to go into effect in 2020. While some have cited the COVID-19 pandemic and Brexit as reasons for the delay, one of his colleagues pointed out the lack of Notified Body capacity could be driving it.

Monroe’s other points about the MDR include:

Shift in evidence burdens to post-market surveillance
Competent Authorities do not have a unified position on evidence needed for CE marks on combination products that have the effect of a drug product
Greater emphasis on labeling
The EU General Data Protection Regulation concerning data privacy for EU citizens is stringent and a concern for any manufacturer of smart combination products that upload data to the Internet

ISO 13485 versus Single Audits

“The other thing that is happening is more and more reliance on ISO 13485 Quality Management System,” he said. This has led to the growth in fake ISO 13485 certificates. In fact, Monroe has been presented with bogus certificates in the past. The International Accreditation Forum is now working on a database of legitimate certificates issued for easy verification.

At the same time, FDA and other regulators have been pursuing single audits for medical devices. This has been slow to gain traction, particularly in countries with low manufacturing costs.

There are many unanswered questions about the European Medical Device Regulation before it goes into effect

“It may be that these systems run in parallel in some cases,” Monroe said. “The other fact of life is money. Audit costs have gone up substantially because audits are complex and there are fewer and fewer Notified Bodies that are qualified to do audits.”

Current Environment for Smart Combination Products

What is the current state of smart combination products? And what can that tell us about their future?

Monroe provided his own takeaways from discussions with colleagues he connected with at last year’s slate of virtual conferences.

Connectivity is increasingly becoming the norm for self-administered product; this has implications for monitoring and improving treatment outcomes
Success will require non-traditional partnerships that go beyond traditional industry silos
Intellectual property and patents for smart combination products and their components must be well-understood
There is greater investment in smart combination products

He closed his presentation with a clip from the American musician Sam Cooke, that he felt sums up the state of smart combination products:

“Change is gonna come, oh yes, it will.”

[Related: Did you miss this webinar? Download the webinar recording and view at your own pace.]