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Hogan & Hartson L.L.P.

FDA Public Meeting

David M. Fox

Hogan & Hartson LLP(202) 637-5678

dmfox@hhlaw.com

Regulation of Combination Products

November 25, 2002

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Overview

ClassificationJurisdiction/AssignmentRegulationProcess

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Classification

Single entity Drug Device or Biologic Product

Combination Sections 563 and 503(g), as amended,

clearly recognize “combinations” as a stand-along category

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Classification

The new Office of Combination Products, by statute, has responsibility for timely and effective reviews ensuring consistent standards, pre- and post-

market, for like products dispute resolution periodic reporting

The Office must consult with another office on whether a product is a combination

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Classification: What is a Combination Product?

Statute (503(g)(1)) Products that constitute a combination of a

drug, a device, or a biologic Regulation (21 CFR 3.2)

A combination exists when two or more articles are

physically or chemically combined packaged together or intended to be used together

Guidance

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Combinations

Pre-filled syringes Albuterol MDIs Transdermal Patches Novel delivery (Viadur, Procardia XL) Laser activated drugs (Visudyne) Drug coated catheters and stents Dental polish with drug Dental barrier with antibiotic

Tobacco products

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Single Entity Products

Gas-filled albumin microspheres Porcine cells in an implantable membrane Certain tissue-containing bone pastes Absorbable collagen/thrombin products Catheter/filtration system to locally deliver

specific drug Electrotransport systems for use with specific

drugs

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Classification

At least 300 RFD precedents (28/yr) About 1/3 found to be a combination Retrospective analysis is needed

Identify factors FDA has relied uponNeed to understand agency’s thinking on

how it decides whether a product is a “combination product”

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Issues When does labeling create a combination? Dosage forms versus delivery systems Problem of the whole versus the parts

If the whole depends on chemical or metabolic action to achieve its primary intended purposes, is it still a combination?

Or, is it enough to be able to identify separately regulated parts within the whole?

Unitary or single function products

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Assignment

Which Center has “primary jurisdiction”? Section 503(g)

What is the primary mode of action of the product?

Which article within the combination is responsible for the primary mode of action?

FDA is forced to pick one “mode of action”

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Assignment: The Gordian Knot

Is it the whole or the relative contribution of each part?

For delivery systems, focus has been on the therapeutic; what is the final, decisive action of the product?

But, “improved drug delivery” can just as easily be primary

Circular, relativistic analysis

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Assignment: Untying the Knot

Cannot be resolved through a flow chart Start with the 100 plus precedents Develop factors to be weighed

where are like products regulated what is the innovation, the driverat point of use, what feature will predominatewhat raises the most significant S/E issuewhat is likely to be changed post-market

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Assignment: A Thought Experiment

In close cases, let sponsor decide

Statutory support in section 563

Assignment is only where, not how

Less significant in light of MDUFMA

Could provide better APA defense

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Regulation: Pre-Market Approval

Single application pre-loaded syringes transdermal patches MDIs

Two or more applications laser activated drugs iontophoresis

Hybrid regulation drug eluting stents

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Regulation

Multiple applications may be less of a concern if reviews are coordinated

In most instances, all necessary data can be obtained under a PMA, NDA, or BLA

For drug delivery technologies, consider using PMA as the lead application same as using BLA/NDA to answer device issues stent precedent and tobacco suggest an NDA is not

needed for the drug component

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Process

“Lack of transparency” include decisional documents in summary approval

materials, subject to redactions include “Annex” to next generation ICAs

Make all precedents available to staff All classification and assignment decisions need a

written record of decision. See section 563 of the FDCA.

Standards for mixed or hybrid regulation should be set

forth in a rule

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Conclusion

“The [products] all likely meet both the definition of a drug and the definition of a device . . . and the FDA therefore has discretion in determining how to treat them. . . . What the FDA is not free to do, however, is to treat them dissimilarly and to permit two sets of similar products to run down two separate tracks, one more treacherous than the other, for no apparent reason.” Bracco Diagnostics v. Shalala (1997).