FDA Public Meeting

1
FDA Public Meeting
Regulation of Combination Products

• David M. Fox
• Hogan Hartson LLP(202) 637-5678dmfox_at_hhlaw.com

November 25, 2002
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Overview

• Classification
• Jurisdiction/Assignment
• Regulation
• Process

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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 upon
• Need to understand agencys 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 driver
• at point of use, what feature will predominate
• what raises the most significant S/E issue
• what 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).