CrossLabeling: Legal and Regulatory Issues

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Cross-LabelingLegal and Regulatory Issues

• David M. Fox
• Hogan Hartson LLP
• 555 13th Street, NW
• Washington, DC 20004
• 202-637-5678
• dmfox_at_hhlaw.com

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Issues

• Does the Food, Drug, and Cosmetic Act (FDCA)
  require mutually conforming or cross-labeling of
  combination products?
• Is there room under the FDCA to create a
  cross-labeling policy that allows, e.g., medical
  devices to be approved for uses that essentially
  create new conditions of use for approved drug
  products?
• Why do we have a cross-labeling issue and is it
  solvable?

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Statutory Origins of the Cross-Labeling Issue

• Section 301, The following acts and the causing
  thereof are hereby prohibited
• Introducing a misbranded drug or device into
  commerce, misbranding a drug or device while it
  is in commerce, or receiving a drug or device in
  commerce that is misbranded
• Doing any other act while an article is held
  for sale that results in the article being
  misbranded
• Introducing an article into commerce in violation
  of the new drug approval requirements of the FDCA

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Misbranding

• Section 502, A drug or device shall be deemed
  misbranded if
• its labeling is false or misleading in any
  particular, or
• its labeling fails to bear adequate directions
  for use for each intended use.
• 21 CFR 201.128, intended use includes uses to
  which the manufacturer knows the product will be
  put the manufacturer is required to provide
  adequate labeling . . . which accords with such
  other uses to which the article is to be put.

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New Drug Approval

• Section 505(a), No person shall introduce a new
  drug into commerce unless an approved application
  is effective with respect to such drug
• Section 505(d), A new drug must be shown to be
  safe and effective for use under the conditions
  prescribed, recommended or suggested in the
  labeling thereof

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Labeling

• Section 201(m), Labeling means all labels and
  other written, printed, or graphic matter . . .
• upon any article or any of its containers or
  wrappers, or
• accompanying such article
• Kordel v. United States, 335 U.S. 345 (1948)
• the materials need not travel with the product to
  be labeling
• textual relationship between the written
  material and the product
• the presence of an integrated distribution
  program may also be a factor
• What is the status of third-party written
  materials? Can one persons labeling create
  intended uses for another persons product?

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Questions

• Can a person misbrand or cause the misbranding of
  another persons marketed drug product?
• Can a person suggest uses of another persons
  drug that, in turn, trigger the labeling and drug
  approval requirements of the FDCA?
• Is FDA required by law not to authorize the
  marketing of a product that would render another
  persons product misbranded or unapproved?

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ExamplesRequiring Cross-Labeling and Reciprocal
Approvals

• FDA Regulatory Letter on marketing a device for
  use with terbutaline and other drugs You have
  established a commercial market and intended use
  for these drugs for currently unapproved
  therapeutic uses (1989).
• Letters (1994) to device manufacturers rescinding
  or suspending 510(k) clearances
• You may neither label nor promote your device for
  use with specific drugs, nor may you package
  drugs with your device prior to FDA having
  approved the drugs for device administration.
• Your 510(k) includes inappropriate labeling for
  use with an approved new drug for an unapproved
  use.

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Examples Requiring Cross-Labeling and Reciprocal
Approvals

• RFD decisions (circa 1993-98) to device sponsors
  requiring drug approval for novel, unapproved
  drug uses proposed by the device
• Aerosolized talc (1994-96) Insulin pumps for IV
  administration (1998)
• FDA Warning Letter (1999) You cannot make any
  claims related to . . . any . . . specific drug
  or class of drugs for use in the iontophoresis
  device unless the drug has been cleared for use
  in your device by the FDA.

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Untying the Knot

• What statutory provisions might allow FDA to
  authorize the marketing of Product A for use with
  Product B without requiring conforming labeling
  for Product B?
• What are the key points of statutory
  interpretation?

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Combination Product Statutes

• Section 503(g)
• Authorizes FDA to assign jurisdiction for
  combination products based on the products
  primary mode of action (PMOA)
• Nothing in this subsection shall prevent FDA from
  using any agency resources to ensure adequate
  review of the safety, effectiveness or
  substantial equivalence of an article
• Is section 503(g) more than jurisdictional?
• Is it substantive?
• Does it put combination products in a special or
  separate class?
• See section 563, recognizing stand-alone category
  of combination products

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Section 503(g)

• Interpreted to allow a single marketing
  application for both the drug and device articles
  in a combination product, based on PMOA. See 21
  CFR 3.1, 3.4(b).
• Implemented with a delegation to CDER, CDRH, and
  CBER senior management of all authority
  necessary for premarket approval of any product
  that is a biologic, a device, or a drug, or any
  combination of two or more of these products.
  21 CFR 5.701.
• I.e., Umbrella NDAs and Umbrella PMAs

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Examples

• Albuterol MDIs, NDA-only
• Transdermal Patches, NDA-only
• Drug-eluting stents, PMA-only
• INFUSE Bone Graft, PMA-only

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Statutory Basis for Umbrella Approvals

• NDA-only
• Section 201(g)(1), drug definition, amended in
  1990 to eliminate device exclusion
• Permits device articles in combinations to be
  regulated as drugs
• Permits NDA sponsors to use single application to
  incorporate a novel use of a cleared device
• PMA-only
• Section 201(h), device definition, includes a
  component provision, but likely not enough to
  regulate a drug as a device
• However, FDA has effectively allowed drugs and
  biologics to be approved for new uses without an
  NDA or a BLA. See, e.g., drug-eluting stents.

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Non-combination, Device-only Approach

• For devices that do not require an individually
  specified drug product. See 21 CFR 3.2(e)
• Device approval that includes a novel drug use
  but is not so product specific that it triggers
  the statutory requirements of drug product
  approval and labeling.
• Policy issue interpreting whether and when
  device labeling that describes the use of a class
  of drugs or a specific drug (but not a specific
  drug product) creates a new intended use for the
  drug

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Third Party Labeling Example
Includes cross-labeled MedGuides
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Four Easy Questions

• Points of statutory interpretation that bear on
  future cross-labeling policies
• When does third party labeling create a new
  intended use for a drug?
• Can a drug be approved under a PMA?
• Is 503(g) essential? Does the drug have to be
  part of a combination for FDA to have the
  authority to approve a new use of the drug under
  a PMA?
• Can drug labeling -- and only the labeling -- be
  approved as part of a PMA?