Jan 30 2013

Combination Products: What’s New?

Image via www.combos.com

Image via www.combos.com

A monoclonal antibody combined with a therapeutic drug. An EpiPen®. A drug packaged with its delivery device.

All of these are examples of combination products. A combination product, according to the FDA, 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, device, and a biological product.”

Until the Safe Medical Devices Act (SMDA) of 1990, there was no clear regulatory pathway for approval for combination products. SMDA provided that a combination product should be assigned to a lead FDA center (CDER, CDRH, or CBER) based on its “primary mode of action”. Thus, a drug-filled syringe would be submitted through CDER, and an orthopedic implant coated with an antibacterial would go to CDRH. Even with the primary mode of action rule, there was little centralized authority or information for combination products. Thus the Medical Device User Fee and Modernization Act of 2002 mandated the creation of the Office of Combination Products (OCP) to designate primary jurisdiction, to oversee timelines and coordinating reviews between centers, and to ensure consistent postmarketing regulation of combination products.

In the past few weeks, the FDA has released the draft guidance, Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA, and the final rule regarding current good manufacturing practices (cGMP) for combination products.

Here, we review both documents.

Submissions for Postapproval Modifications for Combination Products

Because combination products are approved under one application by one center (e.g., an NDA by CDER for a drug-device combination), there can be confusion about what type of postapproval submission to file if there is a change in the device. This draft guidance contains a brief decision tree for how to determine which submission to file:

  1. Identify the application used (NDA, PMA, BLA) for the combination product.
  2. Identify the type of submission that would have been required if the constituent part was a stand-alone product.
  3. If the original application is the same type as would have been used for the constituent part, then submit the postapproval submission identified in Step 2.

If Step 3 does not apply, the guidance contains two tables delineating the type of postapproval submission to use.

In addition to the tables, the guidance gives several examples by the type of change being made (i.e., what to do if there was a change in the indication, a modified chemical formulation, etc.).

For example, if:

  •  A product was filed under a PMA,
  • There was a postapproval manufacturing change to the drug constituent, and
  • That change required only bioequivalence or bioavailability clinical data,

then a PMA 180-day supplement should be filed.

As usual, any comments or suggestions regarding the draft guidance should be submitted within 90 days of notice of the guidance in the Federal Register (by 23 April 2013).

cGMPs for Combination Products

In 2004, the FDA released a Draft Guidance regarding cGMPs for combination products, and, in 2009, a rule was proposed to codify the recommendations from the guidance. On 22 January 2013, the rule was finalized.

In short, the final regulation states that a combination product is subject to cGMPs for each constitutent part (drug, device, biologic, or HCT/P). However, because there is a great deal of overlap between these cGMPS, the FDA allows compliance in the following ways:

  1. Comply with the specifics of each set of cGMPs as they apply to each constituent part included in the combination product, OR
  2. If the combination product consists of a device and a drug constituent part, the manufacturer can choose one of the following:
    1. Be compliant with drug cGMPS plus the following specific device cGMP sections:
      1. 820.20 (management responsibility),
      2. 820.50 (design controls),
      3. 820.100 (CAPA),
      4. 820.170 (installation), and
      5. 820.200 (servicing)
    2. Be compliant with device cGMPs plus the following specific drug cGMP sections:
      1. 211.84 (Components, containers, closures)
      2. 211.103 (calculation of yield)
      3. 211.132 (tamper-evident packaging for OTCs)
      4. 211.137 (expiration dating),
      5. 211.165 (testing and release for distribution)
      6. 211.166 (stability testing)
      7. 211.167 (special testing requirements)
      8. 211.170 (reserve samples)
  3. If the combination includes a biological constituent part, the applicable cGMPs from parts 600 to 680 must be applied.
  4. If the combination product includes a H/CTP, the cGMPs must include good tissue practices requirements in part 1271.

In the preamble to the regulation, the FDA states that in no way does this new rule add, delete, or change any of the current cGMPs, it simply clarifies the application of those cGMPs.

It is clear that the FDA and OCP are taking steps to increase consistency regarding submissions, reviews, and postmarketing requirements for combination products.