REGULATION OF COMBINATION PRODUCTS

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REGULATION OF COMBINATION PRODUCTS

• Mark A. Heller
• Wilmer Cutler Pickering Hale and Dorr LLP
• MassMEDIC Combination Product Program,
• March 28, 2006

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SAFE MEDICAL DEVICES ACT1990

• What is a Combination Product?
• Examples are (1) monoclonal antibody combined
  with a therapeutic drug (2) drug-eluting
  stent, pacing lead with steroid-coated tip (3)
  prefilled syringes, insulin injector pens,
  metered dose inhalers and (4) surgical tray with
  surgical instruments, drapes and antimicrobial
  swabs
• Reason for Combination Product provision
• Enacted section 503(g) of the Actprimary mode
  of action basis for assigning lead jurisdiction
  to CDER, CDRH, or CBER
• (Contd)

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• Amended definitions of drug and device
  distinguished between the two based on the manner
  in which the primary intended purpose of the
  product is achieved, i.e., primary mode of action
• FDAs discretion use any resources necessary
  to ensure adequate review
• Ultimately, purpose of law was to limit FDAs
  discretion in selecting review center and to
  require the promulgation implementation
  regulations

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• Agency promulgated 21 CFR Part 3 in 1991
• Defined combination product
• Recognized Intercenter Agreements Nonbinding
  guidance created to clarify jurisdictional issues
• Created Requests for Product Designations of
  combination and single entity products
• Request for Designation content requirements
• Defined binding nature of designation
• Described reconsideration

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FDAMA 1997

• Established authority to classify drugs, devices,
  biological products and combination products, and
  identify the component of FDA that will regulate
  the product
• 60 days for agency to make determination 60 day
  hammer
• Binding unless sponsors consent to change or
  public health reasons based on scientific
  evidence

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BELIEFS LEADING TO MDUFMA 2002

• Designations generally timely but inconsistent
• No continuing oversight of review
• Issues with standards to be used when more than
  one center involved in a review
• Postmarket responsibilities not addressed
• Little transparency With the exception of two
  (now nine) jurisdictional updates posted on
  website, designation decisions were not publicly
  available
• Opportunity for reauthorization of user fees

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MDUFMA2002

• Established Office of Combination Products
  (OCP) within the Office of the Commissioner to
  promptly assign, oversee, and coordinate reviews
  of combination products
• Purpose
• Ensure timely and effective premarket review
• Ensure consistent and appropriate postmarket
  regulation

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• Duties of OCP
• Assignment of center with primary jurisdiction
  (lead center) for combinations according to
  section 503(g) (primary mode of action) within 60
  days
• Coordination of reviews involving more than one
  center and oversight of timeliness
• Resolution of disputes regarding the timeliness
  of premarket reviews unless dispute is clearly
  premature. However, no direct substantive
  dispute resolution role (dispute first considered
  by primary center, followed if necessary by
  Commissioners review Commissioner must consult
  with OCP)
• Review, update or delete existing assignments,
  agreements, guidances, and practices

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THE DESIGNATION PROCESS

• Strategically, decide whether to go to Center or
  OCP
• If OCP, meet with Office
• Submit RFD early
• OCP will assign product to lead center based on a
  determination of the primary mode of action.
• KEY PRIMARY mode of action

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• Definition of primary mode of action
• August 25, 2005 Final Federal Register Notice
• Defines primary mode of action as the single
  mode of action of a combination product that
  provides the most important therapeutic action of
  the combination product. The most important
  therapeutic action is the mode of action expected
  to make the greatest contribution to the overall
  intended therapeutic effects of the combination
  product.
• Establishes algorithm for cases in which it is
  not possible to determine which mode of action
  provides the most important therapeutic action
  Assign product to agency component that regulates
  combination products with similar safety and
  effectiveness questions, or, if no other products
  with similar safety and effectiveness questions,
  to agency component with the most expertise
  regarding the most significant safety and
  effectiveness questions presented by the
  combination product

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POSTMARKET ISSUES

• Current Good Manufacturing Practices (cGMPs) -
  FDA Guidance for Industry and FDA (Sept. 2004)
• There are no current good manufacturing practices
  (cGMPs) for combination products
• FDA believes that products that are manufactured
  separately and later combined are subject to the
  governing cGMP regulations that apply to each
  individual product
• FDA believes that combination products that are
  produced as a single entity or are co-packaged
  are subject to the cGMP regulation applicable to
  the regulated component (but compliance can
  generally be achieved by following one of the
  cGMPs)
• (Contd)

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• Labeling March 28, 2005 Federal Register Notice
  of Public Meeting
• 21 CFR Part 3 contemplates mutually conforming
  labeling
• FDA encourages sponsors to work together when
  bringing to market products that are intended to
  be used together
• FDA/Drug Information Association cross labeling
  workshop on May 10, 2005 discuss issues that
  arise when sponsors develop product for use with
  another cleared or approved product and the other
  products labeling is not changed
• (Contd)

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• Postmarket Safety Reporting
• FDA believes that appropriate reporting may be
  achieved by following the regulatory provisions
  for the type of application under which the
  product was approved/cleared but may use dual
  reporting
• In interim, consult with OCP
• Postmarket requirements should reflect the
  regulatory status of the combination product,
  i.e., device, drug or biological product. From a
  jurisdictional perspective there is no such thing
  as a combination product.