Understanding the Growing Role of Combination Products in Biopharma Innovation

In today’s dynamic landscape, combination products are emerging as a catalyst for transformative healthcare solutions. Defined broadly as therapeutic or diagnostic products integrating drugs, medical devices, and biological components, combination products have become a growing field within modern medical innovation. 

These drug-device combination products are growing in strategic priority because they have the potential to enhance the safety and effectiveness of certain treatments through their controlled drug release or targeted drug delivery. They have also shown to impact patient adherence and overall experience because of the ease of use for the patient or caregiver.

You don’t have to look too hard to find combination products here in the Capital Region that are in development or have already successfully launched. Emergent’s Narcan® (naloxone hydrochloride; NDA 208411) nasal spray is one example of a Co-Packaged combination product that received approval via the 505(b)(2) pathway. CraniUS, a Johns Hopkins spin-out, is developing the first medical device that enables chronic medicine delivery directly to the brain, powered by a novel wireless charging system. While still in the development stages, this device will provide the potential for many combination product filings as therapeutics and drug companies look to leverage their novel drug delivery system into the brain. Companies like AstraZeneca and REGENXBIO also now have growing teams dedicated to combination products.

See Also: 5 Questions with Stephen Tyrpak, Associate VP of Medical Device Operations & Associate Partner at PQE Group

One area of strong growth continues to be the Global Cell & Gene Therapy Drug Delivery Devices Market which is anticipated to grow at a 14% CAGR from 2023-28. Since many cell therapies are showing an incredible ability to eliminate cancer cells without damaging healthy tissues, it is propelling the demand for these therapies & innovative approaches to their drug delivery devices.

Combination products can also be highly beneficial for developers who can apply 'evergreening' patent strategies that can increase the period of time during which their successful drug can remain under patent protection and increase their product revenue lifecycle. 

In this article, we delve into the intricate details of this multifaceted domain to unravel the complexities surrounding combination products.

Understanding Combination Products

Combination products manifest in various forms, ranging from traditional drug-device combinations to co-packaged or kitted products. Let's briefly define the three main types of combination products as outlined by The Code of Federal Regulations (CFR):

• Single-Entity Combination Product:
  • Definition: Comprises two or more components (drug and device, device and biologic, biologic and drug, or all three) combined or mixed to produce a single entity.
  • Examples:
    • Prefilled drug delivery devices (e.g., prefilled syringe, injector pen)
    • Prefilled biologic delivery devices (e.g., vaccine in a prefilled syringe, nasal spray)
    • Medical device coated with or combined with a drug or biologic (e.g., transdermal patch, antimicrobial wound dressing)
    • Drug/biologic combination (e.g., antibody combined with a therapeutic drug)
• Co-Packaged Combination Product:
  • Definition: Consists of two or more components packaged together as a unit or in a single package (also known as convenience kits).
  • Examples:
    • Drug or vaccine vial packaged with a syringe
    • Liquid medication with dose-dispenser
    • Surgical tray containing surgical instruments and anesthetic drugs
• Cross-Labeled Combination Product:
  • Definition: Device, drug, or biological product packaged separately but labeled for use only with an approved individually specified device, drug, or biological product.
  • Examples:
    • Photosensitizing drug and activating laser or light source
    • Light-activated biological products not co-packaged but labeled for use with a specific light source device

Device Complexity

Device challenges in the development of combination products present a significant hurdle, often stemming from the intricate interplay between drug and device or packaging components. The reliability and robustness of the delivery vehicle, in addition to packaging considerations, play a crucial role in ensuring the safe and accurate administration of medication.

The challenges associated with device development necessitate comprehensive testing, encompassing environmental and human factors. Understanding how a device and a drug interact is pivotal, requiring a collaborative effort between drug and device producers from the early stages of development. This collaboration ensures the selection of appropriate materials and mechanisms of administration, contributing to the seamless integration of components.

A central consideration in device challenges is the volume of the drug, as larger doses can introduce greater complexities. The concept of patient self-administration, especially with higher volume and higher viscosity systems, has emerged as a new frontier. However, adapting systems to meet evolving demands poses an ongoing challenge for developers. Staying abreast of these challenges and proactively addressing the evolving needs of patients are critical for the successful development and commercialization of combination products.

Navigating Regulatory Challenges

The regulatory landscape for combination products is intricate and demands careful consideration. The FDA Office of Combination Products, established in 2002, plays a pivotal role in classifying medical products in the U.S. and assigning them to appropriate FDA centers for review and regulation. The lead FDA center is determined by the product's primary mode of action (PMOA), influencing the regulatory pathway required.

For instance, a drug-device combination product with the drug as the PMOA would likely fall under the purview of the Center for Drug Evaluation and Research, necessitating regulatory submissions like Premarket Approval Application (PMA), De Novo classification request, or 510(k).

Most recently the FDA finalized its guidance on the use of human factors engineering (HFE) studies to support the development of combination products.  This new guidance focuses on applying HFE principles for combination products and replaces a draft guidance issued in 2016.

Despite the guidance provided by the Office of Combination Products, the classification of complex combination products can be challenging. Engaging with regulatory bodies and leveraging expert advice are essential strategies for successfully navigating the intricate regulatory landscape.

See also: Clinical Trials Involving Medical Devices and Medicinal Products, by Alberto Colombo, Operation Manager and Associate Partner @ PQE Group

The Evolving Landscape

As pharmaceutical, medtech, biotech, and life science companies continue to push the boundaries of innovation, the combination product market experiences exponential growth. These products offer targeted treatment options, improved drug delivery mechanisms, and enhanced efficacy for both medical devices and drugs.

Notably, the market for drug-device combination products has witnessed remarkable expansion. According to data shared in 2018 by Research and Markets, the global market is projected to surpass $177 billion by 2024. This growth is attributed to the numerous benefits these products offer, particularly in simplifying drug delivery and enhancing patient outcomes.

Patient-Centric Advancements

The impact of combination products on patient outcomes cannot be overstated. Innovations in drug delivery devices, such as single-use prefilled syringes, contribute to easier self-dosing, reducing the risk of patient dosing errors and improving compliance. Injection systems and pulmonary inhalers dominate the drug delivery combination product market, showcasing the potential to enhance patient experience and treatment adherence.

Combination products represent a convergence of diverse technologies, each with its unique regulatory challenges. As the industry evolves, it is imperative for companies to collaborate with experts who can navigate the complex regulatory landscape and ensure the successful development and commercialization of these innovative products.

In addition to engaging experts like Kymanox, you can also start with resources available from the Association for the Advancement of Medical Instrumentation (AAMI) which offers a 6-part online training series that will provide learners with an overview of FDA’s and EU's approach to the regulation of combination products including a review of the FDA’s guidance.

As the combination product landscape continues to evolve, so must regulatory pathways and policies. The collaboration between industry leaders, regulatory bodies, and consulting firms like Kymanox will be instrumental in shaping the future of combination products. 

Learn about CraniUS' Novel Drug Delivery Device to the Brain