Maneuvering a Tricky Landscape: The Growing Interest in Combination Products

There has been a trend in the past few years of life sciences companies crossing into new territory and seeking to submit applications for combination products – in other words products that combine devices and drugs, and/or biological products. That’s hardly surprising since combination products open new market opportunities, but they also add complications for companies accustomed to one set of regulations and procedures and to working with a particular regulatory authority.

As a result, we’ve had clients come to us seeking help in merging various types of drug and device regulatory submissions spanning multiple regions, e.g., incorporating information from a premarket approval application (PMA) into a new drug application (NDA) for submission to the U.S. Food and Drug Administration (FDA). Combining such applications is further complicated by the fact that there is little guidance from the regulatory health authorities on how to navigate the process.

Weighing Concerns

To start with, simply interacting with the regulatory authorities can be daunting, because drugs and devices are typically regulated by different groups. In the case of a combination product application to FDA, while two centers (the Center for Drug Evaluation and Research and the Center for Devices and Radiological Health) get involved, one will be assigned the lead. But since the centers within FDA tend to be quite separate, with very different requirements and criteria, the process of getting started can create uncertainty.

The concerns life sciences companies have depend on their point of reference. Typically device companies are concerned about being held to drug regulatory standards that don’t apply to devices. The problem is that life sciences companies already feel weighed down by regulations; working with yet another agency adds to the sense that they will have to go above and beyond what they are accustomed to.

While the concerns are justified to an extent because the centers aren’t on the same page much of the time (e.g., different centers define the criteria for a pediatric patient differently), it usually isn’t as big an issue as companies expect.

Different Strokes

Some of the main areas of difference are related to the “quality” information required, which is Module 3 for eCTD applications, historically called the quality system section for device applications. For devices, the quality section has historically required a lot more information about internal quality policies, SOPs, quality manufacturing systems, adherence to good manufacturing practices – all areas that device manufacturers are familiar with. While drug applications require significant manufacturing information, internal quality systems information tends to be addressed during a pre-approval inspection.

Design control is another area that is often unfamiliar to drug firms. This is an area that can be a challenge and therefore getting help is highly advisable, especially if software is involved because then you have to submit test reports, validation protocols, etc. – all of which are activities that drug firms may have little experience in.

One Step at a Time

There are certainly ways you can ease the process and mitigate problems. Having been through combination product applications myself several times – both from my previous experience in industry roles and advising our DXC clients – I’d like to offer some recommendations for combination product submissions to FDA:

  • The first step, if you haven’t already started the process, is to file a request for designation (RFD) to FDA. At this point, you’ll send in some descriptive information about the combination product, its primary mode of action, manufacturing practices, constituent parts, etc. The reviewing centers will then decide which will be the lead, which in turn determines the type of application you will proceed with, such as PMA or NDA.
  • Once you’ve received your designation it’s time to go back to the lead center, and including the FDA’s Office of Combination Products in your correspondence, request a pre-submission During that meeting the various centers involved will be able to provide you with guidance on issues, such as what type and how much information to include on quality, and whether one application will be sufficient – usually it is but sometimes they ask that sponsors file two applications (such as an NDA and PMA) if combination product components, i.e., the drug portion and the device portion, are separate enough that they should be regulated separately. For example, a drug product that goes into a syringe might warrant regulating the syringe and drug separately if the action of the drug is not dependent on the type of syringe utilized.
  • Once you have greater clarification from the agency on the application pathway, it’s advisable to start your gap analysis of the requirements involved. It’s important to be clear by module (for CTD and eCTD submissions) and section as to what sort of information needs to go where.

Points to Consider

From R&D to clinical trials to manufacturing and post-marketing, there are different regulations from both drug and device regulatory authorities to consider.

When embarking on a combination product application, it’s important to be aware of the effect manufacturing changes have on your application because depending on the submission route, you might end up with two applications and then you have a report that ends up with changes to both applications.

From a clinical perspective, it’s important to be aware of different requirements for things like trial master files, the types and extent of information needs to be maintained and collected across the study, reporting requirements for adverse events, and requirements governing interactions with and reporting to independent review boards.

Throughout the process, it’s helpful to work with a partner on the sponsor side who has been through it before and who can offer guidance in areas such as quality information, design and development requirements for devices, different testing requirements for drugs and devices, and different reporting requirements. Ideally, you want to work with someone who has some experience of what works, as well as where things can go wrong, in order to avoid those pitfalls.

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