INSIGHT REPORT
Vol 8 #5 

2005

INSIGHT REPORT

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Insight Report Vol. 8  -  No.5

 ‘Combination Products’ Part II

Traditionally, sponsors have used the device approval process when presenting a new combination product before the FDA and opted for a CDRH review. Some of the benefits of this strategy include – lenient pre-clinical testing requirements, one pivotal clinical trial as opposed to two, lower application fee and less stringent post approval requirements.

Irrespective of which center gets the primary jurisdiction over the combination product, more than one center is typically involved in the review. As a result, sponsors need to be aware of the different scientific and clinical requirements of the reviewing divisions. For example, a device manufacturer submitting a device-drug combination product application for the first time might not realize that CDER (and even CBER) is very data driven and would require extensive safety information for the drug component of the application. On the other hand, CDRH focuses on design control and documentation of quality control in all the manufacturing processes. For this reason, sponsors should, very early on determine which centers would be involved, who would have the lead responsibility and what the requirements for approval would be.

Another important point for a device drug combination would be the individual regulatory status of the device and drug components. If the drug has already been approved by CDER, then approval is much easier when compared to an investigational drug. This is one major reason why drug-eluting stent manufacturer’s use already approved drugs when they submit pre-market applications for a new product.

The proposed (PMOA, assigning algorithm) rule, has however elicited some concerns from the industry. Companies hope that the FDA would consider past jurisdictional determinations when it makes future decisions about a product’s primary mode of action. In addition, industry would like ‘Intercenter Agreements’ to continue to remain in effect. These agreements listed which type of products would be reviewed by which center and what marketing applications would be needed for approval. A third concern is for the FDA to consider the intended use of the combination product as a whole when it determines the primary mode of action.

In voicing these concerns, industry representatives give examples of companies that have embarked on product development based on precedents of earlier FDA rulings.
Many companies have set up their operations based on the agency centers they thought would govern their investigational products. Any changes as a result of the proposed rule might affect these companies adversely. Similarly, products like infusion pumps that are distributed unfilled and do not require a drug label change, have traditionally been regulated as devices by CDRH. However, under the new (proposed) rule, these pumps might now come under CDER or CBER as the most important therapeutic benefit comes from the drug or the biologic and not from the delivery device.

In addition to the issue of center designation, companies have to determine which set of good manufacturing regulations they should meet. For example, a drug-device manufacturer has to determine whether to follow drug cGMP regulations or device QSR regulations or even both? FDA has addressed this issue in a draft guidance document published in September 2004 titled, “Current Good Manufacturing Practice for Combination Products”.

According to the guidance, “Constituent parts of a combination product are subject only to their usual governing regulations as long as the parts remain separate. Once the process of joining them into a single entity or packaging them together as a unit begins, both sets of manufacturing regulations apply”. FDA elaborates that in most cases, firms can use the compliance system that is already in operation at the manufacturing facility and, depending on the product, add only relevant requirements from the other regulatory system.

FDA came up with a guidance in September, 2004 that details how user fee will be determined for combination products. For combination products requiring one marketing application, user fee associated with that particular marketing application will be assessed. For example, a drug-device combination for which a PMA is required will be subjected to the PMA fee under MDUFMA.

For cases where the sponsor submits two applications instead of one, or when the FDA requires two applications, two application fees would be assessed, one fee for each application. In such situations, sponsors are eligible for any existing fee waivers or reductions. For details on the User Fee assessment, please refer to the guidance, “Application User Fees for Combination Products”.

Some of the current areas of discussion involving combination products include:  Labeling for combination products involving cross-labeling of branded products intended to be used in combination. The issue is, can generic names be used, or should only those brand names be used that were studied together during the approval process. No clear and consistent policy is available from the FDA in this regard. Another major concern involves the regulatory process for modification of approved combination products. Industry is not very clear on when modifications to combination products need to be submitted to FDA for approval. The variability among the requirements for the different product types often leads to confusion.

In addition there are several areas where industry wants better guidance from the FDA. Some of these issues include: harmonization of combination products definitions with global regulatory bodies, safety reporting of combo products, future of e-submissions for combo products – will there be changes in CTD and eCTD formats to accommodate combo product requirements, guidance on promotion and advertising of combination products, impact on reimbursement, process for review and approval of generic drug labeling for combo products etc.

In conclusion, Combination Products have grown in importance over time and are poised to deliver increasingly potent and effective treatment by combining the best of the device and drug worlds. However, there are still many issues relating to their regulation that still need to be addressed and this will require active involvement of the FDA and the Office of Combination Products with timely criticism and comments from the industry.

Any comments and questions on this Report should be emailed to info@mdiconsultants.com

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