FY 2003 First Quarterly Progress Report

Office of Combination Products
First Quarterly Progress Report to Stakeholders
January – March 2003

The Office of Combination Products (OCP) was established on December 24, 2002. Efforts during the first quarter of 2003 have focused on establishing processes to help meet the Office’s three major statutory roles 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

OCP Performance - Formal Requests for Assignment Submitted by Industry

• Working with the Office of the Ombudsman, 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. The team is developing working definitions of primary mode of action and is currently evaluating the definitions against test cases.
  
  
• Expanded 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.
  
  
• Reviewed 21 CFR Part 3, the regulation addressing the submission and review of requests for assignment and/or classification, to identify changes that may be needed to reflect the role of OCP established under MDUFMA.
  
  
• Developed an internal precedent documentation system to facilitate the timely consideration of new requests for assignment by allowing us to more readily determine relevant precedents. The internal database will also be used to retroactively document previous assignment decisions.
  
  
• Developed a process with the Office of the Ombudsman (which retains responsibility for the classification of products as drugs, device, biologics or combination products) to ensure that requests for classification and/or assignment submitted by industry are promptly screened and assigned for review and response, as appropriate, to either OCP (for assignment) or the Office of the Ombudsman (for classification).

Ensuring Timely and Effective Premarket Review

• Revised the SOP on the Intercenter Consultative/Collaborative Review Process to provide for OCP monitoring and tracking of all consultation requests for combination products occurring between CBER, CDER, and CDRH. The revisions were signed by the CBER, CDER and CDRH Directors and implemented on February 14, 2003. The current version of the SOP is posted at http://www.fda.gov/oc/ombudsman/intercentersop.pdf.
  
  
• Actively monitored the consultation process on combination products under review to ensure that the requesting center received timely and constructive feedback. Offered assistance to requesting Centers to help obtain feedback when consulting reviews were delayed.
  
  
• Developing 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. Projected implementation (pending completion of work by IT contractor) is FY03 Q4.
  
  
• Provided support to the Centers or sponsors on a variety of specific issues that contribute to ensuring the timely and effective premarket review of combination products. Examples include:
  
  
  • Established a tailored process for consultation between two review divisions that frequently interact on a variety of combination products. The process takes into consideration each other’s particular needs and processes.
    
    
  • Established review responsibilities for an anticipated two-Center, two-application collaborative premarket review of a new combination product.
    
    
  • Debriefed Center review teams following completion of a priority, two-application collaborative review of a combination product. Additional debriefing with the sponsor is scheduled in April. Team and sponsor feedback and lessons learned will be used to ultimately develop review tools to share with review teams and sponsors of similar applications.
    
    
  • Responded to inquiries from review staff and sponsors on assignment, regulatory and coordination issues posed by a variety of types of combination products under review.
    
    
• 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 (most of which do not require intercenter consultation):
  
  
  • Worked with CBER, CDER and CDRH to reach consensus on database requirements to provide for all major premarket submissions to be categorized as to whether or not they concern a combination product, and if so, what type. Centers will begin capturing data FY03 Q3 contingent upon completion of actual database changes and training on internal processes. The first report on the activities and impact of OCP (including the numbers and types of combination products reviewed) is due to Congress on October 26, 2003.
    
    
  • Developed an algorithm and categorization scheme for combination products in collaboration with the Centers and the Office of Chief Counsel to describe the types of combination products under review in the Agency. OCP is also developing a web-based decision support tool to facilitate use of the algorithm for reviewers and project managers. This internal tool should be available in FY03 Q3 pending completion of work by IT contractor.

Postmarket Regulation of Combination Products

• Formed working groups to develop policy and guidance regarding the postmarket issues of most significance to our stakeholders. Detailed charters for these work groups are being developed that outline the objectives, deliverables, tasks, and timelines of each group. Work group operations will begin in FY03 Q3 to address the following issues:
  
  
  • The manufacturing and quality system regulations that will be required for combination products. This team is expected to develop guidance for FDA and industry on application of manufacturing/quality system regulations, and processes to ensure appropriate communication between Centers on manufacturing/quality system requirements for combination products.
    
    
  • The adverse event reporting regulations that will be required for combination products. This team is expected to develop guidance for FDA and industry on application of adverse event reporting regulations, and processes to ensure appropriate communication between Centers on postmarket safety issues for combination products.
    
    
• Established a process to ensure appropriate communication and consultation between CDRH and CDER postmarketing reviewers for a new type of combination product for which the Agency expects to receive a significant number of applications. This will serve as a model for future products.
  
  
• Began providing sponsors information regarding preliminary determinations of GMP and adverse event reporting requirements in assignment decision letters.

Other 2003 1st Quarter Accomplishments

• Commissioner’s Technology Development Initiatives. OCP is participating in the working groups established to clarify and develop the regulatory pathways for novel drug delivery systems and drug/test kit combination products based on pharmacogenomics. OCP is also participating in the working groups being established to develop guidance documents for products for diabetes and obesity, as some of these products are combination products. These activities have just begun.
  
  
• Obtained input from Internal and External Stakeholders.
  
  • Met with the CBER and CDER Directors, and the Director of the Office of Device Evaluation to determine how OCP could best provide value added to the Centers’ activities with respect to combination products.
    
  • Reviewed and considered the stakeholder comments submitted to a public docket soliciting information and views relating to the assignment, premarket review, and postmarket regulation of combination products. These comments were submitted as a follow-up to a public hearing on this subject held on November 25, 2002. Eleven presentations representing regulated industry and/or trade associations were made at the public hearing. Thirteen manufacturers and trade associations also submitted written comments to the docket. The comments will be shared with OCP working groups (e.g., manufacturing/quality systems, adverse event reporting, single vs. separate applications) to ensure that stakeholder perspectives are appropriately considered as new policies and guidance are developed.
  • Continued to seek input from stakeholders on key areas of combination product regulation. Working groups will also consider additional ways to obtain stakeholder input as new policies are developed.
• Training and Outreach
  • OCP’s internet site was launched in March at http://www.fda.gov/oc/combination/default.htm. OCP plans to further expand the site with links to guidance documents covering combination product issues and, once tracking systems are in place, information about significant approvals of combination products.
  • Established an email address (combination@fda.gov) for internal and external inquiries to be sent to OCP for resolution.
  • Provided presentations to FDA staff and stakeholders. Internal presentations were focused on raising awareness of combination product issues and providing training in the SOP on the Intercenter Consultation Process. Training efforts in FY03 Q3 will focus on the categorization and tracking of premarket submissions and use of the categorization algorithm and web-enabled consult database. Stakeholder presentations focused on OCP activities and initiatives.

OCP Presentations to FDA Staff and Stakeholders

• Guidance. In addition to the primary mode of action and postmarket working groups identified above, OCP formed a working group comprised of experts from CBER, CDER, CDRH and OCC to develop policy and guidance in premarket review processes for combination products, including agency policies such as when applications to more than one Center are needed, selection of appropriate premarket regulatory authorities for combination products, and format and content for combination product submissions. A charter for this work group is being developed that outlines the group’s objectives, deliverables, tasks, and timelines, and work group operations will begin in FY03 Q3.