As pharmaceutical science and innovation advance, breakthrough combination products frequently emerge that provide patients with therapeutics comprised of two or more constituents. Combination products can be either two or more active pharmaceutical molecules, combined to address different aspects of a health condition, or the combination of a medical device and a small or large molecule product.

Such products require more complex target profiling. Several components of the target product profile (TPP) can be heavily affected by a sponsor’s chosen regulatory strategy, depending on the nature of each constituent and the known and unknown interactions that could occur in the combination product. While the potential for these effects may seem more obvious in the case of two chemically interacting drug molecules, the same is true with various device-device combinations. The regulatory strategy for developing such products needs to be well-designed and should factor in both adaptability and the manufacturing process to minimize overall program risk. Having an adaptive regulatory strategy is the key to beneficial interactions with the Agency from the beginning.

Definition of Combination Products

The FDA has defined combination products under 21 CFR 3.2e, which explains the various situations in which a product is legally considered to be a “combination” and subject to review by more than one FDA office or review center. A combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, a device, and a biological product.

From the regulator’s point of view, combination products are not restricted to combined biologics, drugs, and/or devices formed into a single entity (like a drug-eluting coronary artery stent). Sometimes two separate components are co-packaged (like a kit of a syringe, mixing solvent chamber, and drug) or even packed and sold separately but meant to be used together to achieve a diagnostic or therapeutic effect (like a laser-activated drug for photodynamic therapy). In all of these scenarios, the key point is that each constituent is required to achieve the desired function for the proposed indication.

FDA Oversight for Combination Products

Jurisdiction Assignment

When considering the regulatory strategy for a combination product program, the first questions that sponsors confront are whether an IND or an IDE will be required, and who will make that decision. The FDA’s Office of Combination Products (OCP), which is separate from the centers which evaluate drugs, biologics, and devices, is the Agency’s point of contact and oversight over the life cycle of combination products. However, the OCP does not review any product on its own and relies on CDER, CBER, or CDRH (which have primary jurisdiction for review and regulation) for review and reporting purposes. Assigning jurisdiction is the first key step that the OCP attends to, by assessing the product for its mode(s) of action and deciding which one to label the “primary mode of action” for the combination product.

Sponsors can obtain official binding responses from the OCP to questions regarding classification and jurisdiction of proposed products by formally submitting a request for designation (RFD). In addition, the OCP has historically provided informal responses and non-binding feedback regarding the regulatory identity or classification of products in a process referred to as a pre-RFD. The pre-RFD program is a good example of the collegial and constructive interactions that the FDA can provide to sponsors early in the conceptualization phase. The formatting and required information for such preliminary correspondence are outlined in a guidance document called “How to Prepare a Pre-Request for Designation (Pre-RFD).”

In many instances, assigning jurisdiction might seem like a fairly straightforward process. For instance, it is easy to predict that the OCP would assign CDER as the corresponding reviewer of a prefilled delivery system for a drug product (like a metered-dose inhaler), so the sponsor will be required to conform its development plan and submissions to CDER’s regulations.

However, not every combination product can be classified so easily, and the OCP must follow certain work-flows and regulations to reach a decision. The process is a dynamic task, and as new technologies emerge and bring their own challenging considerations, the OCP will face gray-zone decisions that it must consider per regulations. Because of the potential for uncertainty, open and early communication with the Agency is critical for gaining a mutual understanding of the complexities of a product’s design and regulatory strategy. This will benefit both the FDA and the sponsor in a win-win situation.

Submission and Review Processes

In addition to streamlining the jurisdiction assignment process, developing a deliberate regulatory strategy can also help to prevent later delays in the review process. Though the OCP oversees a program prior to and after approval, it does not review submissions.

A program’s assigned FDA center leads the review of applications to conduct clinical trials and acquires input from other relevant centers and offices during the process. As a general rule, a single investigational submission suffices as long as the IND or IDE includes all the required details on all constituents of the product. This might require that sections that usually exist only in an IDE or an IND be combined into a single submission.

Marketing applications for combination products come with certain regulatory complexities, and the FDA provides guidance on the process: “Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry.” In this document, the FDA provides insight into where in Electronic Common Technical Documents (eCTDs) sponsors should place information about a product that is being reviewed by CDER but that has device constituent parts, as an example. The guidance lays out an intermediary solution for filing such submissions by modifying the approved eCTD structure so that it can include all of the information on the combination product in a single submission.

CMC and Post-Marketing

In the development of a regulatory strategy for a combination product, it is also important to determine the required set of production and post-marketing standards. The rule of thumb is that, for a drug or biologic product, good manufacturing practice standards are required, while medical device production requires quality management systems.

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Engaging the FDA early and positioning a product well in collaborative interactions can both streamline early assignment to a reviewing center and help to define which set of regulations better fit a program’s needs, in both parties’ views. Premier Consulting has extensive experience working with the FDA to define clear development pathways for combination products. Contact us to find out how we can help you advance your program.

Author:

Alborz Salavati, MD
Manager, Regulatory Strategy