Introduction

Neurological combination products—integrating drugs, devices, and/or biologics—are transforming treatment for central and peripheral nervous system disorders. As conditions like epilepsy, Parkinson’s disease, multiple sclerosis, and chronic pain demand more targeted approaches, the convergence of pharmaceuticals and medical technologies offers promising solutions. These hybrid therapies enhance delivery, address complex disease mechanisms, and improve outcomes. They are advancing neurological care and expanding clinical possibilities.

Yet, this innovation introduces significant regulatory challenges. The U.S. Food and Drug Administration (FDA) considers neurological combination products among the most difficult to evaluate due to the complexity of the nervous system, the integration of technologies, and their heightened risk profile.

The Evolving Landscape

Combination products are defined as therapeutic and diagnostic products that combine drugs, devices, and/or biological products. These products can take various forms:

• Drug-device: For example, drug-eluting stents or inhalers delivering bronchodilators
• Biologic-device: Such as scaffold-based tissue regeneration platforms using growth factors
• Drug-biologic: Like antibody-drug conjugates used in targeted therapies

In the neurological field, this convergence is especially vital. As neurological disorders often involve complex and chronic conditions, a single-modality treatment may fall short. Combining drugs with precision-targeted devices can facilitate localized delivery, sustained release, and adaptive response to real-time neural feedback. Notably, the rise in neurodegenerative diseases due to aging populations has further fuelled innovation in this domain. The industry is witnessing an explosion in brain-targeting implants, wearable neurotech, and advanced drug delivery systems—each blurring traditional therapeutic boundaries.

Real-world Example:

Intrathecal pumps: Intrathecal pumps are reshaping neuromodulation by enabling the direct infusion of potent drugs into the cerebrospinal fluid, effectively bypassing systemic circulation and the restrictive blood-brain barrier. This localized delivery achieves therapeutic concentrations at the spinal cord or brain with unmatched precision, levels that systemic administration often cannot reach. The result is a significantly enhanced clinical effect using lower drug doses, with reduced systemic toxicity and side effects.

FDA Framework and Evaluation Pathways

Combination products are regulated by the FDA’s Office of Combination Products (OCP), which determines the primary mode of action (PMOA). The PMOA dictates which FDA centre takes the lead in reviewing the application: CDER (Center for Drug Evaluation and Research), CDRH (Center for Devices and Radiological Health), or CBER (Center for Biologics Evaluation and Research).

Figure 1: Primary mode of action assignment for combination products

Key Regulatory Requirements for Neurological Combination Products

Sponsors must address a wide range of regulatory requirements—from selecting the appropriate premarket submission pathway to ensuring robust post-market surveillance. The following summary outlines key elements of the U.S. regulatory framework that govern the approval and lifecycle management of neurological combination products, highlighting critical areas such as human factors engineering, risk classification, and dual compliance with drug and device quality standards.

• Primary Mode of Action (PMOA):

Determines which FDA center (CDER, CDRH, or CBER) will lead the regulatory review. Required for center assignment in combination products.

• Pre-market Pathways:

Includes NDA/IND for drugs, 510(k)/PMA/IDE for devices, and BLA for biologics. Combination products may require dual or parallel submissions across centers.

• Risk Classification:

Devices are typically classified as Class II or III. Drugs or biologics may carry additional requirements such as Risk Evaluation and Mitigation Strategies (REMS).

• Human Factors Engineering & Usability Studies:

Required to ensure the product meets performance and safety expectations. These studies improve user experience, reduce product life cycle costs, and mitigate risk and liability.

• Post-market Surveillance:

Involves real-world data collection, adverse event reporting (e.g., through FDA’s MedWatch), and in some cases, mandated post-approval studies to monitor safety and effectiveness.

• Compliance with cGMP and QSR:

Manufacturers must comply with both Current Good Manufacturing Practices (cGMP, for drugs/biologics) and Quality System Regulation (QSR, for devices) to ensure consistent product quality and safety.

Potential Challenges

In many neurological products, the interaction is not straightforward, complicating the regulatory review.

• Disparate evidentiary standards between drug and device pathways
• Lack of clarity in submission format for hybrid products
• Need for bridging studies to demonstrate component compatibility

The FDA has issued several guidance documents to help streamline this process. Tools like the Combination Product Agreement Meeting (CPAM) and Intercenter Consult Requests (ICRs) do facilitate cross-center collaboration. It is important to note that ambiguities can hinder innovation, especially when cutting-edge neuro-technologies do not neatly fit existing categories.

Aligning Drug and Device Development

To overcome these challenges, coordinated strategies are essential.

• Developers should engage with regulators early to align on evidentiary expectations, safety protocols, and PMOA designations.
• Success requires collaboration across disciplines—including pharmacology, bioengineering, clinical medicine, and regulatory affairs—beginning at the earliest stages of design.
• A harmonized approach is critical: developing a unified preclinical plan that integrates both drug and device testing minimizes duplication and streamlines the regulatory pathway.
• Similarly, building a single, integrated project timeline that synchronizes drug and device submissions helps prevent regulatory bottlenecks and facilitates more efficient FDA review, as outlined in the Table below.

Table 1: Drug vs. Device Development Timelines — And the Value of Integration

FDA-Cleared Combination Devices

To date, 33 combination devices under the Neurology specialty have been cleared via the 510(k), PMA, or HDE pathways. The chart below (fig. 2) presents a period-wise distribution of these clearances across four-time intervals. Notable examples include Neuragen 3D (Integra), DBS therapy for OCD (Medtronic), Activa family of implantable neurostimulators (Medtronic), Precision spinal cord stimulator (SCS) system (Boston scientific), etc.

Figure 2: Combination devices under the Neurology specialty

Conclusion

Neurological combination products lie at the cutting edge of modern therapeutics. Yet their promise is matched by regulatory complexity. From the FDA’s perspective, these innovations require a nuanced, interdisciplinary review process that goes beyond the sum of their parts. For manufacturers and innovators, early and transparent engagement with the agency, combined with robust human factors and post-market strategies, will be essential to successful development and approval.

References

• Principles of Premarket Pathways for Combination Products: https://shorturl.at/MmoHc
• Bridging for Drug-Device and Biologic-Device Combination Products: https://shorturl.at/wpGMG
• Application of Human Factors Engineering Principles for Combination Products: https://shorturl.at/Nwo3W
• Definition of Primary Mode of Action of a Combination Product: https://www.federalregister.gov/d/04-10447
• Inbrija™ (levodopa) inhalation powder: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209184Orig1s000ChemR.pdf

• Medtronic SynchroMed™ II: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P860004