Guest Column | December 15, 2023

Key Regulatory-Fueled Updates On Combination Products As We Enter 2024

By Fran L. DeGrazio, Strategic Parenteral Solutions LLC

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Drug–device combination products continue to grow in the pharmaceutical pipeline. In 2022, the FDA’s Center for Drug Evaluation & Research (CDER) completed 37 novel drug approvals. Many of the novel drugs are presented as combination products for ease of use. This pace of drug approval continued in 2023. The Code of Federal Regulations (CFR) classifies combination products into three main types: single-entity, co-packaged, and cross-labeled.

For those who aren’t combination product-savvy: An example of this is the SUNLENCA injection. SUNLENCA injection was developed by Gilead Sciences as a new treatment for HIV-1 infection in heavily treatment-experienced adults with multidrug resistance to current HIV-1 treatments. Per the prescribing information, two subcutaneous injections are given every six months by a healthcare provider in combination with some oral medication. A kit is provided for one patient’s use. The kit contains two vials holding the drug product, two vial access devices, two syringes, and two injection needles. With its combination of drug product and devices, the SUNLENCA kit is considered a co-packaged combination product.

In late November, AFDO/RAPS held their annual Combination Products Summit in Fort Worth, TX. AFDO is the Association of Food and Drug Officials and RAPS is the Regulatory Affairs Professionals Society. The meeting is co-sponsored by the FDA with heavy involvement from the Office of Combination Products, and it covered several themes on the subject as we prepare to enter 2024.

Office Of Combination Products Continues Its Work

The Office of Combination Products continues to grow and facilitate issues between pharma and other FDA divisions when it comes to combination products. They continue to advance best practices, bring additional regulatory clarity, and help to realize the potential of novel technologies and their uses. One of the major recent accomplishments was the release of Application of Human Factors Engineering Principles for Combination Products: Questions & Answers published in September 2023.

In 2023 (YTD as of the writing of this article in early December) there were 906 submissions. These were split among the lead centers as follows:

  • CDER: 503
  • CBER: 302
  • CDRH: 101

Prefilled biologic delivery systems consisted of 35% of these submissions.

Although it has many pending activities in 2024, the FDA hopes to bring additional regulatory clarity by releasing:

  • draft guidance clarifying essential performance requirements (EPRs) for combination products,
  • draft guidance on unique device identifiers (UDIs) for combination products,
  • clarification policies on combined use and cross-labeled combination products,
  • final guidance on bridging for combination products, and
  • final guidance for post-approval changes to combination products.

Interest In Global Regulatory Harmonization Continues

It is clear from an industry standpoint there is a desire for more convergence and harmonization among regulators around the globe. The challenge associated with addressing so many disparate regulations result in increasing costs and longer times in getting important drugs to the end patient.

Some of the key challenges to harmonization are:

  • a lack of alignment of definitions,
  • lack of some regulations being translated into other languages for use in other regions,
  • no unified industry guidance on changes, and
  • confusion based on the primary mode of action and how that impacts good manufacturing practices (GMPs) for combination products.

In general, the industry would like to see greater proactive alignment of the regulatory agencies before guidelines and regulations are released. This lack of harmonization does influence the regulatory strategies of companies as they define their plans for approval and commercialization.

Interest In Platforms By Industry Continues To Grow, Aided By FDORA Discussion

To simplify and accelerate development of combination products, many in the pharmaceutical industry are choosing to develop platform systems and then leverage them across their drug products.

Platform technologies are defined as a “technology that can be used across more than one drug,” per the Food and Drug Omnibus Reform Act (FDORA), section 2503. The FDA may expedite the development and review of a subsequent application that incorporates this technology. A draft guidance should be released on this sometime in the future.

Of course, with benefits come challenges. It is very important, even when using a platform technology, that a risk assessment relating to the specific drug therapy and patient group be completed at the start of the project. It is necessary to prove that the platform is appropriate for its use and to have the logic and data to support this.

One of the major benefits of a platform technology is that the platform itself can be understood to a very deep degree and that molecule-agnostic data can be generated and leveraged across multiple programs.

Of course, there are still many industry questions about how to facilitate both development and the review and approval processes. Some industry representatives would like to see new regulatory pathways for platform technologies. More to come on this topic in the future.

CDRH’s Digital Health Center Of Excellence Is Getting Busier

A Digital Health Center of Excellence was developed and has been located in the FDA’s Center for Devices & Radiological Health (CDRH) since late 2020. The center provides expertise and serves as a resource for digital health technologies and policy.

MiRa Jacobs, acting assistant director for digital health policy at the Center of Excellence, spoke about the progress made over the past year. The areas of growing activity focus on support of decentralized clinical trials and remote patient monitoring, international harmonization efforts, and the publication of numerous guidances. Since 2018, the agency has published 15 digital health guidances related to combination products. As an indicator of the growth in this space, she stated that over 100 submissions in 2023 included artificial intelligence/machine learning (AI/ML) information.

Innovation Continues

The pharmaceutical and biotechnology worlds continue to innovate and develop. This means that not only are there technical challenges but regulatory challenges relating to the new technologies. The future holds much excitement in areas such as AI, personalized medicines, advanced therapy medicinal products (ATMP), and many other areas.

Quite often, companies will bring in partners to help with the development of these new technologies. This can impact everything from intellectual property (IP) to product development, quality systems, and ethical considerations around patient information sharing, just to name a few examples for consideration. The future is very exciting and dynamic, but the traditional systems that support “typical” products and processes will be challenged. Innovation will be needed not only with products but with these processes that support them.

About The Author:

Fran DeGrazio is a Kymanox executive advisor as well as president and principal consultant for Strategic Parenteral Solutions LLC. She has more than 35 years of experience in the pharmaceutical packaging and delivery industry, with extensive expertise in sterile drug product systems, including vial container closure systems and prefillable systems for combination products.