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U.S. Department of Health and Human Services

Combination Products

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Meetings, Conferences, & Workshops

Text Version of PowerPoint Presentation by F. Owen Fields, Ph.D.

Slide 1 - Comments Before FDA Hearing on Combination Products

F. Owen Fields, Ph.D.
Worldwide Regulatory Affairs
Wyeth Pharmaceuticals, Inc.

Slide 2 - Overview

Will provide comments on:

  • Question 1: Revisions to the Intercenter Agreements
  • Question 2: Assigning primary mode of action
  • Question 3: Is one procedure better than others for combination products?
  • Question 4: Multiple applications vs. single applications
  • Question 5: Which quality system to use?

Slide 3 - Preface

Comments based on experience with at least one combination product.

Suggestions do not imply that FDA is not already generally conducting combo product reviews appropriately.

In many cases we suggest that FDA continue current practices, but standardize procedures in order to increase predictability.

Slide 4 - Question 1: Revisions to Intercenter Agreements

What principles should FDA use in revisions to existing Intercenter Agreements that allocate review responsibility?

Roles and responsibilities of the different reviewing centers should be clearly defined.

  • Following a jurisdictional ruling, FDA should devise, and sponsors be provided, a review plan identifying the roles and responsibilities of Centers.

Slide 5 - Question 2: Primary Mode of Action

What factors should FDA consider in determining the primary mode of action of a combination product? Is there a hierarchy?

If one component clearly serves only as a delivery vehicle for biologically active component:

  • Straightforward to assign the primary mechanism of action to the biologically active component.
  • Delivery component should be considered as an excipient or a container/closure system.

Slide 6 - Question 2: Primary Mode of Action

If two components, both possess biological and/or structural activity:

  • Which of the components contributes the primary (determinative) biological/structural activity, and which contributes the secondary (enabling) biological/structural activity?
  • How to define determinative vs. enabling? Must consider intended therapeutic clinical effect. i.e. which component is primary will be determined by clinical purpose.

Slide 7 - Question 2: Primary Mode of Action

If the primary mode of action cannot be assigned with any certainty, additional criteria (in order of importance):

  • Which component presents the greatest safety risk, and which Center has the greatest experience managing this risk.
  • The Center’s experience with clinical, preclinical, and manufacturing aspects of product.
  • Precedence - i.e., how related products were handled.
  • Practical concerns - such as Agency resources, review timelines, procedural simplicity and flexibility, and
  • Sponsor’s familiarity with given procedure.

Slide 8 - Question 3: Regulatory Authority/Procedure

What are the general scientific and policy principles that should be followed in selecting the premarket regulatory authorities to be applied to combination products?

Is one premarket review mechanism more suitable than others for combination products?

  • As there is no fundamental scientific difference between the NDA, BLA, and PMA mechanisms, the one most familiar to lead center is advisable.

Slide 9 - Question 3: Regulatory Authority/Procedure

There are, however, differences in documentation formats which should be considered due to practical considerations.

  • Because all Combination Products will contain either drug or biologic component, the ICH CTD should be permitted format; this will soon be global application standard
  • Some device combination products in US are “drugs” in the EU
  • ICH CTD format designed to allow independent review of individual sections

Slide 10 - Question 4: Single or Multiple Applications

What criteria should FDA use to determine whether single application or separate applications for the individual components?

  • Separate applications are not generally advisable.
  • Rationale:
    • For any given combination product a single approval decision and conditions of approval are ultimately needed. Single decision best reached through one application.
    • Further, to make dual applications workable, following must be addressed:

Slide 11 - Question 4: Single or Multiple Applications

To Make Two Applications Generally Practical

  • FDA would need to develop internal procedures which counterbalance the tendency of the Centers to work in procedural and scientific isolation.
  • Isolation is highly undesirable - the CMC, preclinical, and clinical data necessary to support the approval of a medical product are highly inter-related.
  • Dual applications are procedurally complicated for Sponsors.
  • Two review clocks would be involved. Harmonization could prove complicated.
  • Policies on the applicability of user fees needed.

Slide 12 - Question 4: Single or Multiple Applications

Overall Proposal

  • In those cases in which the various major components of an application are not separable, the involved Center should follow the procedures in July 2002 SOP on Intercenter Consultative/Collaborative Review Processes.
  • In those cases in which components of application are cleanly separable, the inter-center process could be standardized.

Slide 13 - Question 4: Single or Multiple Applications

Suggestions for ‘separable’ inter-Center reviews:

  • Establish clear primary and secondary roles and responsibilities to eliminate duplicative reviews; the secondary Center should take ownership of the review of the relevant section of the application
  • Establish an Intercenter scientific review team with a consistent structure and charter
  • At regular intervals, Intercenter review team should meet to consolidate and discuss the meaningfulness/applicability of various issues/questions (Why do we care about this issue? Why don’t we care this issue?).
  • In Sponsor interactions, the involvement of the Project Manager/Lead Reviewer from the lead Center required (procedural consistency).

Slide 14 - Question 4: Single or Multiple Applications

(Recommendations, continued)

  • Clearly define who has final decision-making authority regarding each section and for overall application.
  • Encourage ICH CTD format; modularity of CTD format facilitates separate review.
  • Establish an integrated policy to ensure a consistent administrative record.
  • The review clock, user fees, and other procedural details associated with the lead Center would continue to apply.
  • Eventually establish compatibility (not necessarily uniformity) in IT systems among the various Centers.

Slide 15 - Question 5: Quality System

What scientific and policy principles should be followed in determining the appropriate manufacturing and quality system (e.g., cGMPs versus Quality System Regulations) applicable to combination products?

  • Quality systems for devices and pharmaceuticals are different; but both are adequate within their scope.
  • From a practical perspective, it is difficult and confusing to apply two conceptually similar but administratively different quality systems (e.g., device Quality Systems and pharmaceutical cGMPs) within the same manufacturing facility. This should be avoided.

Slide 16 - Question 5: Quality System

Other considerations:

  • In absence of scientific need, components of combination products should be controlled by quality system already established by their manufacturer. Once a component enters the control of combo product sponsor, quality system already in use should normally apply.
  • If the component is an existing approved medical device, the quality system established by its manufacturer should normally apply until it joins with other component.
  • If the component is an existing approved pharmaceutical/biologic, the quality system established by its manufacturer should normally apply until joined with other component.
  • Additional specifications and/or requirements may apply (based on scientific considerations) to assure component is appropriate for intended clinical use.