Navigating the Combination Product Pathway: Ten Practical Principles to Smooth the Way Regulatory Affairs Professionals Society Regulation of Combination Products Kathryn L. Gleason October 8, 2002

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Navigating the CombinationProduct Pathway Ten
Practical Principles to Smooth the Way
Regulatory Affairs Professionals Society
Regulation of Combination Products Kathryn L.
Gleason October 8, 2002
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Principle 1 Dont race to judgment on preferred
jurisdiction.

• 1. What do law and policy tell you?
• Section 503(g) of the Federal Food, Drug, and
  Cosmetic Act (FFDCA), 21 U.S.C. 353(g) 21
  C.F.R. Part 3.
• Section 563 of the FFDCA, 21 U.S.C. 360bbb-2.
• H.R. 3580 (still in play).
• Three Intercenter Agreements.

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Principle 1 Dont race to judgment on preferred
jurisdiction. (contd)

• 2. Is your company already oriented around a
  particular paradigm?
• 3. Are there similar combination products,
  and, if so, how are they regulated?
• 4. How will product claims affect product
  jurisdiction? What claims do you need in the
  marketplace to differentiate your product?

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Principle 1 Dont race to judgment on preferred
jurisdiction. (contd)

• 5. How will a formal jurisdictional decision
  affect your companys pipeline products?
• 6. Which Center has the greatest expertise with
  respect to your product?
• 7. Does the market/medical community have any
  expectations with respect to the products
  classification?

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Principle 1 Dont race to judgment on preferred
jurisdiction. (contd)

• 8. Should Center resources/user fees impact
  your decision?
• 9. Is the product, or will the product be,
  marketed internationally and, if so, what is
  that regulatory status?
• 10. Will reimbursement differ depending upon
  whether the product is regulated as a device,
  drug, biologic, or combination (with two
  submissions)?

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Principle 2 These are uncertain times.

• 1. Pending legislation (H.R. 3580).
• 2. Recent public hearing (June 24, 2002) on
  tissue-engineered combination products.
• 3. AdvaMed letter to Daniel Troy, Chief
  Counsel, FDA.
• 4. Forthcoming public meeting on combination
  products.

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Principle 2 These are uncertain times. (contd)

• 5. Re-write of Intercenter Agreements.
• 6. Recent proposed transfer of jurisdictional
  authority for certain products from CBER to
  CDER.
• 7. Ongoing refinement of policies through new
  guidances, e.g., dual submissions and
  cross-labeling.

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Principle 3 Seek clarification that is
appropriate for the occasion understand when to
go formal or informal.

• Reasons to seek a formal RFD
• Preferred Center is reluctant to review product.
• Uncertainty regarding data requirements.
• Investor-driven need for predictable pathway.
• Precedents support Center jurisdiction that is
  not your preference (and you think they are
  wrong).
• Corporate desire for binding determination.

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Principle 3 Seek clarification that is
appropriate for the occasion understand when to
go formal or informal. (contd)

• Reasons not to seek a formal RFD
• Precedents support Center jurisdiction that is
  your preference.
• Enthusiasm exists within your Center of
  preference to retain jurisdiction of product.
• Concerns that RFD will delay the premarket
  development program (21 C.F.R. 3.10).

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Principle 3 Seek clarification that is
appropriate for the occasion understand when to
go formal or informal. (contd)

• Concern that an adverse determination could serve
  as precedent for future company products.
• Majority of combination products, in fact, do not
  seek formal designation.

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Principle 4 Primary mode of action the past is
not always prologue.

• Legal/regulatory authorities allow case-by-case
  analysis of primary mode of action.
• Historical problems with lack of transparency.
• Intercenter Agreements do not cover or anticipate
  the types of technology now seen.

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Principle 4 Primary mode of action the past is
not always prologue. (contd)

• Primary mode of action is clearly, but not
  necessarily well, defined by law and policies
  (see 21 C.F.R. 3.4).
• Law and policies The primary function of the
  combined product.
• Primary mode of action occasionally not known or
  easily determined.
• How and whether to consider equitable and
  practical concerns, is unclear.

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Principle 5 Your RFD sets the stage, so employ
best practices.

• Rationales on primary mode of action and
  precedents are the two key areas focus your
  energy there.
• Do not consider page limitations a concern.
• Enumerate all reasons supporting your
  jurisdictional preferences -- legal, regulatory,
  scientific, corporate, investor-based,
  partner-based, harmonization, distributional,
  equitable, and practical reasons.

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Principle 6 Keep in mind the full breadth of the
RFD opportunity.

• When is it useful to define collateral
  authorities?
• Premarket 510(k) v. PMA, cross-labeling
• Postmarket GMP/QSR requirements, adverse
  experience reporting, modifications,
  promotion/compliance.
• Under what circumstances is a request for two
  applications appropriate/desirable?

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Principle 7 The RFD resolution process is
iterative.

• More than one submission may be needed to respond
  to and resolve issues.
• It often takes one or more meetings to make your
  case well, and resolve outstanding issues.
• In any request for meeting, ensure that the right
  decision-makers will be assembled.
• Understand all issues of concern to meeting
  attendees in advance, and be prepared to offer
  solutions.

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Principle 7 The RFD resolution process is
iterative. (contd)

• Understand the dynamics of the decision-making
  process.

Ombudsmans Office
Center 2
Center 1

• Balancing the extension process versus stay of
  the review clock (21 C.F.R. 3.10).

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Principle 8 Understand the rights and
limitations of the formal designation process.

• Jurisdictional designations are binding, unless
  there are public health or other compelling
  reasons. Section 563(b) of the FFDCA, 21 U.S.C.
  360bbb-2(b) 21 C.F.R. 3.9.
• Reconsideration (within 15 days of designation
  determination). 21 C.F.R. 3.8(c).
• Notwithstanding binding nature of RFD decision,
  see Bracco Diagnostics v. Shalala, 963 F. Supp.
  20 (D.D.C. 1997) (holding that similar products
  must be treated similarly).

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Principle 9 Active monitoring and management of
the collaborative/consultative process are key.

• Ensure that Center liaisons are identified and
  understood by both Centers.
• Pursuant to intent of FDAs new SOP (July 2002)
• Determine precise aspects of your submission that
  will undergo a consultative or collaborative
  review.
• Determine precise issues to be addressed in a
  consulting review.

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Principle 9 Active monitoring and management of
the collaborative/consultative process are key.
(contd)

• Identify the internal deadlines for completion of
  the consultative/collaborative review.
• Use Combination/Ombudsman personnel as active
  facilitators to ensure effective management of
  the review.
• Consider use of dispute resolution mechanisms
  when disputes over timeliness or substance cannot
  be resolved.

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Principle 10 When jurisdiction is determined,
adjust your expectations accordingly.

• If unfavorable In addition to differing legal
  and policy approaches, understand differing
  cultures of each Center.
• If favorable Bear in mind that winning the
  jurisdictional battle does not necessarily win
  the data war.

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Summary

• 7. RFD -- an iterative process.
• 8. Rights and limitations of formal process.
• 9. Active management of review process.
• 10. Adjust expectations following determination.

• 1. Dont race to judgment.
• 2. Uncertain times.
• 3. Formal vs. informal.
• 4. Past not always prologue.
• 5. RFD best practices.
• 6. Realize full breadth of RFD opportunity.