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Insight Report Vol. 8 - No.4

‘Combination Products’ Part I

Recently, a tapered-metallic spinal-fusion cage used in combination with recombinant human bone morphogenic protein placed on a resorbable collagen sponge was approved by the FDA. If you are one of those who has no clue as to what regulatory pathway this product took for approval, or you have an idea and you need more information on the regulations for similar products, or if you just need to refresh your memory, read on…………….

The above is an example of a Combination Product. Combination products are basically combinations of any of the following type: Drug-device, biologic-device, drug-biologic and drug-device-biologic. They can be physically or chemically combined, co-packaged in a kit or be separate, cross-labeled products. For the exact definition, please refer to the link: http://www.fda.gov/oc/combination/definition.html

Some examples of Combination products include: Drug-eluting cardiovascular stents, pre-filled syringes and insulin injector pens, monoclonal antibodies combined with chemotherapeutic drugs etc. Examples of products that don’t qualify as combination products include: Drug-drug, device-device or biologic-biologic combinations, general drug or biologic delivery devices (unfilled syringe or infusion pump) not intended to be used with a specific drug or biologic, in vitro diagnostic tests etc.

Prior to 1991, combination products were regulated on an ad-hoc basic. However, responding to an increase in the complexity and number of new applications, and as a result of the Safe Medical Devices Act of 1990, FDA formulated Intercenter Agreements, guidelines that would govern the review process by multiple centers. Since then, FDA has used these agreements to regulate Combination Products.

To further address issues arising from an increased prevalence of combination products, and a result of the Medical Device User Fee and Modernization Act (MDUFDA), the Office of Combination Products (OCP) was setup in Dec, 2002. It was charged with the following functions: assignment of combination products to a reviewing division; ensuring effective and timely pre-market review; perform consistent and appropriate post-market regulation; dispute resolution; review/update guidance documents; develop policy and regulations; serve as a resource for industry and agency reviewers and report to the congress.

A combination product is assigned to an FDA Agency center (example CDRH, CDER and CBER) that will have primary jurisdiction for its premarket review and regulation. Under section 503(g)(1) of the Act, assignment to a center with primary jurisdiction, also called the lead center, is based on a determination of the primary mode of action (PMOA) of the combination product.

As defined in the Proposed Rule, published in the Federal Register on May 7, 2004, Primary Mode of Action is the “single mode of action of a combination product that provides the most important therapeutic action of the combination product.” For example, in the case of a drug eluting stent, the PMOA is that of the stent opening up the artery while the drug preventing inflammation and restenosis of the artery is considered a secondary action. Thus, a drug eluting stent is regulated as a device and requires a PMA for approval. CDRH would be the lead center in this case, but CDER would be involved in the review of the drug component. A sponsor would need to follow the IDE process, but would also have to include sections specific to a typical IND application that are reviewed by CDER.

An industry sponsor can also request the OCP to assign the lead center. Such a proposal is called a Request for Designation, and the OCP has 60 days to assign the sponsor to the relevant agency center. The OCP made 67 RFD designations in 2004. The sponsor can also use informal correspondence with the OCP (phone, e-mail, pre-RFD’s) to determine the lead center.

Sometimes, it becomes difficult to determine the PMOA with a degree of certainty. The product might be too early in its development to determine the most important therapeutic benefit, or the product might have two independent but equally important therapeutic outcomes. In these cases, the agency proposes to use the following process, Assigning Algorithm, to assign the lead center:
Assign the product to the center that has direct experience dealing with a similar type of product. If there are no other combination products that present similar questions of safety and effectiveness, then that center is chosen which has the most related experience for that type of product. The rule would apply only to Requests for Designation submitted by companies after the effective date of the final rule.

Designation of the combination product to a ‘lead center’ has major implications for the sponsor company. Some of the areas influenced include: review timelines, clinical trial design, contents and type of regulatory filing, differences in User Fee, inspections, quality control and validation requirements etc. For example, the conduct of an inspection depends on the agency that does the inspection. CDER and CBER might focus on GMP concerns, while a CDRH inspection would have a QSIT approach. Different centers have different reporting requirements too. Annual Reports and Annual Product Quality Reviews for example, are reported differently across FDA agencies. Even Post Approval Changes, like Stability and Validation requirements for process changes have different requirements depending on the reviewing agency.

A different ‘lead center’, i.e., one that a company has not dealt with before might necessitate major changes including hiring of personnel with knowledge and skills to deal with the new requirements, educating existing employees, changes in documentation, quality control and assurance procedures etc.

To be continued next Insight Report Vol. 8 No. 5

We’d like to hear from you on how you enjoyed our Insight Report. insight@mdiconsultants.com

Next Insight Report - Vol. 8 No. 5 - 'Combination Products' Part 2

If you have any comments on these INSIGHTS we hope that you let us hear them. If you have any of your own INSIGHTS that you feel would be of value to other companies, we would be pleased to hear from you and to discuss them with you and if you allow, we would even put them up on this site for others to learn from.
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