Office of Combination Products
Second Quarterly Progress Report to Stakeholders
April – June 2003

The Office of Combination Products (OCP) was established on December 24, 2002. The Office’s three major statutory roles are to:

Promptly assign a Center with primary jurisdiction for a combination product;
Ensure the timely and effective premarket review of combination products, by overseeing the timeliness of and coordinating reviews involving more than one agency center; and
Ensure the consistency and appropriateness of postmarket regulation of combination products.

Assignment of Combination Products

Issued five assignments of combination products this quarter, all for drug-device combinations. Two products were assigned to CDER and three products were assigned to CDRH. All five assignments, including a request for reconsideration received during this period, were completed within statutory/regulatory timeframes. Table 1 in the Appendix provides mean, median and range of OCP review times for assignments this quarter, and cumulative information for FY03.
The Office of the Commissioner consolidated the product jurisdiction program within OCP in June 2003. OCP is now responsible for agency action on all Requests for Designation (RFD) submitted by industry in accordance with 21 CFR Part 3. This includes requests for classification of a product as a biological product, device or drug, as well as requests for assignments of combination products. RFD’s for products other than combination products were previously handled by the Office of the Ombudsman.
Published a final rule in the June 23, 2003 Federal Register, revising 21 CFR Part 3 to reflect the role of OCP under MDUFMA and the transfer of responsibility for the product jurisdiction program from the Office of the Ombudsman to OCP. The new regulation also provides an address for electronic submission of RFD’s concurrent with their formal submission to OCP.
Continued working with the Centers and the Office of Chief Counsel to develop for public review and comment a definition for “primary mode of action.” Primary mode of action is the statutory criterion to be used in assigning a Center to have lead premarket review responsibility for a combination product.
Developing an internal database of RFD determinations to facilitate the timely consideration of new requests.
Provided jurisdictional guidance to sponsors and industry, by telephone and through pre-RFD correspondence, on a variety of types of combination products.

Ensuring Timely and Effective Premarket Review

Continued to actively monitor the intercenter consultation process on combination products under review to ensure their timely review and completion.
Provided support to Centers to facilitate the intercenter consultation process. Examples included identification of consulting divisions and contacts, clarification of due dates and completion status, and identification and resolution of barriers to timely completion of consultation requests.
Conducted a retrospective review of issues related to the successful completion of consults during the first and second quarters. Surveyed center reviewers and consult coordinators to obtain feedback and best practices for coordinating and conducting intercenter consults. Drafted reviewer tools with tips for successful intercenter consultations.
Continued to develop an internal, web-enabled database that will provide for electronic completion, monitoring, and tracking of all consultation requests occurring between CBER, CDER and CDRH. This system will also be available for the Centers to use to track intra-Center consultative reviews.
Working with a contractor on the development of the OCP intranet site. The site will ultimately provide Agency reviewers access to an internal repository of information on the regulation of combination products.
Continued to lead an intercenter working group charged with establishing reliable, reproducible mechanisms to simplify the premarket regulatory and submission process for combination products. The group is considering the need for single vs. separate applications, the mixing of premarket regulatory authorities, and the format and content of submissions for combination products.
Solicited participation from the Centers and Office of Chief Counsel on an internal working group to consider cross-labeling issues for combination products.
Provided support to Centers and sponsors on a number of specific issues/products that contribute to ensuring the timely and effective review of combination products. Examples included: determination of product classification (e.g., whether or not a product is a combination product); establishment of regulatory pathways and review timeframes; planning review processes and respective responsibilities of Centers; selection of regulatory authorities; and suggested methods to simplify submission practices.
Continued developing and implementing processes to fulfill MDUFMA’s requirement that OCP report annually to Congress on the numbers and types of combination products under review:
- Effective April 1, 2003 (for CBER and CDER) and May 1, 2003 (for CDRH), all major premarket submissions are now categorized as to whether or not they concern a combination product, and if so, what type.
- The Centers implemented the use of an algorithm and categorization scheme, soon to also be available as a web-based decision support tool, to describe the types of combination products under review in the Agency.
- Established a timeline and outline for the first annual Report to Congress on the activities and impact of OCP due October 26, 2003. OCP is coordinating with the Office of Planning and CDER, CBER, and CDRH to collect and analyze the data required by MDUFMA for this report.

Postmarket Regulation of Combination Products

Leading several intercenter working groups to ensure the consistency and appropriateness of the postmarket regulation of combination products:
- Adverse Events. The initial focus of this working group has been to develop internal procedures to ensure adequate intercenter communication of adverse experience for combination products. The group is also expected to develop guidance for FDA and industry on application of adverse event reporting regulations for combination products.
- Quality Systems. The initial focus of this working group has been to identify the similarities and differences between the cGMP and QSR regulations. The group will consider various product/manufacturing scenarios in drafting guiding principles for determining how cGMP and QSR authorities should be applied for combination products. This work group will also develop processes to ensure appropriate communication between Centers on manufacturing/quality system requirements for combination products. Several members of this group are also working on the CDER-led Agency GMP initiative.
- Registration and Listing. The focus of this working group has been to develop mechanisms to share registration and listing data across centers for combination products, and to develop recommendations to provide industry with a clear, consistent approach for the listing of combination products.
Provided support to Centers or sponsors on a variety of specific issues that contribute to ensuring the consistency and appropriateness of postmarket regulation of combination products.
Continued to expand the guidance provided in our assignment decision letters by providing the agency’s preliminary determination of GMP and adverse event reporting requirements to which a combination product will be subject, when such determinations can be made. This provides sponsors with a better understanding of the scope of regulatory requirements for their products. Previously only the premarket review authorities were routinely addressed.

Other 2003 2nd Quarter Accomplishments

Relocated Office of Combination Products staff into one central location. The new office is located at: 15800 Crabbs Branch Way, Suite 200, HFG-3, Rockville, MD 20855, (301) 827-9229, fax (301) 827-9230, email: combination@fda.gov.
Hired three additional staff members to implement OCP functions. At the end of the quarter, OCP had 7 employees (Director, Acting Associate Director/Medical Officer, Product Assignment Officer, Product Classification Officer, Premarket Liaison/Scientist, Program Analyst, and part-time Secretary), and a summer intern.
Continued to expand the OCP Internet site. Among the new additions:
- As an aid to sponsors seeking to develop a combination product, a compilation of guidance documents selected from those issued by CBER, CDER and CDRH has been added to the OCP Internet site. Some documents are general in nature and assist sponsors in understanding the regulatory approaches of individual FDA review Centers they may not frequently interact with, while other documents specifically address combination products or cover a broad product class but address combination product issues within the document. http://www.fda.gov/oc/combination/guidance.html
- Significant new approvals of combination products are now identified on the OCP website, along with links to review documentation when available so sponsors can be better informed about the regulatory pathways utilized for combination products. http://www.fda.gov/oc/combination/approvals.html
Training and Outreach. Provided presentations to 6 internal and 7 external stakeholder groups this quarter. Table 2 in the Appendix identifies the external stakeholder presentations this quarter and the cumulative number of presentations for FY03.
- Internal staff presentations this quarter were targeted at continuing education on the intercenter consultation process, and training staff on the use of an algorithm and categorization scheme to determine whether or not a product is a combination product and which category best describes that combination product.
- Stakeholder presentations focused on the assignment and regulation of combination products, and OCP activities and initiatives.
- Provided a variety of press interviews about combination product regulation and OCP roles and responsibilities.

Appendix

Table 1: OCP Performance – Formal Requests for Assignment of
Combination Products Submitted by Industry

April – June 2003				Cumulative FY03‡
Requests for Assignment Submitted	Assignments Issued	% Issued within 60 days	Pending at end of Quarter	Requests for Assignment Submitted	Assignments Issued	% Issued within 60 days	Pending at end of Quarter
3**	5	100%	1	10,*	9	100%	1
Mean Total FDA Review Time* = 36.2 days Median Total FDA Review Time* = 40 days Range of Total FDA Review Time* = 18-47 days Does not include one request for reconsideration submitted that was responded to within 15 day timeframe required by 21 CFR 3.8(c) ***Total FDA Review Time = calendar days from submission receipt to action letter.				Mean Total Review Time* = 36.5 days Median Total Review Time* = 38 days Range of Total Review Time*** = 18-47 days Withdrawn = 1 * Does not include one request for reconsideration submitted that was responded to within 15 day timeframe required by 21 CFR 3.8(c) ***Total FDA Review Time = calendar days from submission receipt to action letter.
Assigned to CBER: 0 Assigned to CDER: 2 (2 drug-device) Assigned to CDRH: 3 (3 drug-device)				Assigned to CBER: 2 (1 drug-biologic, 1 device-biologic) Assigned to CDER: 3 (3 drug-device) Assigned to CDRH: 4 (4 drug-device)

Table 2: OCP Presentations to FDA Staff and Stakeholders

April – June 2003		Cumulative FY03 (12/24/02 -- 6/30/03)
Internal Presentation	Stakeholder Presentations	Internal Presentations	Stakeholder Presentations
6	7	12	9
Stakeholder Presentations This Period: Food and Drug Law Institute Annual Meeting· FDA Oncology Patient Consultants Lecture Series International Society for Pharmacoeconomics and Outcomes Research AdvaMed Device Submissions Workshop FDA-OCRA 6th Annual Education Conference Drug Information Association Biotechnology Industry Organization

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Office of Combination Products Second Quarterly Progress Report to Stakeholders April – June 2003

Appendix

Table 1: OCP Performance – Formal Requests for Assignment of Combination Products Submitted by Industry

Table 2: OCP Presentations to FDA Staff and Stakeholders

Office of Combination Products
Second Quarterly Progress Report to Stakeholders
April – June 2003

Table 1: OCP Performance – Formal Requests for Assignment of
Combination Products Submitted by Industry