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Office of Combination Products:
Two-Year Progress
Mark D. Kramer
Director
Office of Combination Products
BIO 2005 Annual Meeting
June 21, 2005
Challenge
No regulatory scheme is designed specifically for
combination products….
…..We work within existing statutory framework.
Devices
PMA/510(k)/IDE
QSR
MDR
Regulatory Approaches
Drugs
NDA/IND
cGMP
AERS
Biologics
BLA/IND
cGMP+
AERS+
Primary Mode of Action
Consultation
Regulations
Office of Combination Products
Make jurisdictional determinations
Oversee/help coordinate premarket review
Ensure consistent/appropriate postmarket regulation
Resolve timeliness disputes
Develop policy, guidance and regulations
Serve as resource for industry and review staff
Outreach
Report to Congress
Special Initiatives
Progress:
"Prompt Assignment of Combination Products"
Jurisdictional Determinations
Formal
or
Informal
--------------------------
Combination and Single Entity Products
Primary Mode of Action Rule
Published proposed rule defining "primary mode of action" of combination product:
"Most important therapeutic action of a combination product"
Assignment Algorithm
PMOA rule includes an assignment algorithm that would be used when a product's most important therapeutic action cannot be determined with reasonable certainty
Consistency
Safety and Effectiveness Issues
PMOA Proposed Rule:
Selected Stakeholder Comments
Clarify roles of intended use, precedent, and ICA's
Clarify effect on existing products
Provide more examples
Post precedents on web
Clarify some terms; consider issuing companion guidance
Clarify how PMOA affects regulatory authorities and need for 1 vs. 2 marketing applications
Progress: Assignment
67 Requests for Designation in FY 2004
100% on time
Informal Direction for many products phone, email, pre-RFD's
Published ~140 Jurisdictional Determinations
Jurisdictional Updates
Next on list: Chemical Action
Premarket Review
Whatever it takes to ensure
"timely and effective"
premarket review
of combination products
How do we do it?
Establish and clarify regulatory pathways
Establish and facilitate intercenter working groups and internal MOU's
Facilitate meetings with sponsors
Monitor and facilitate the consultation process
Monitor combination product review timeliness
Provide training and reviewer tools
Check classification of all submissions as combination products
Resource for Industry
and Review Staff
Wide range of inquiries on
assignment
and
combination product
regulation
How: Phone, Email, Meetings, Web, FAQ
Cross Labeling
Is concurrent use of a drug and device:
A separately regulated drug and device?
OR
A drug-device combination product
(21 CFR 3.2(e)(3)?
Questions:
When must the labeling of an approved product be changed to reflect its use with another product?
When is inconsistency in the labeling acceptable? To what degree?
Some products may not be developed if cross labeling is required
Cross Labeling
In Progress: Cross Labeling
Held public workshop on May 10
Discussed public health & regulatory/legal issues
OCP's goal for cross labeling policymaking:
to both promote and protect public health
In Progress: Guidance on Number of Marketing Applications
Developing guidance anticipates the following:
One application will be sufficient for most combination products
Chemically, physically, or otherwise combined into a single entity; and most co-packages
Two applications may be
Necessary in some circumstances
Requested by industry in some circumstances
Published: Final Guidance on Application User Fees
Single marketing application: fee associated with that type of application
Sponsor chooses to submit two marketing applications when one would suffice: fee for each application (waivers/reductions possible)
FDA requires two marketing applications: fees for each application (waivers/reductions possible)
For innovative combination products where two applications are required: use of PDUFA barrier to innovation waiver to reduce additional fee burden associated with FDA's requirement for two marketing applications. Guidance provides factors FDA would consider.
MDUFMA and PDUFA applications: reduce PDUFA fee by amount of MDUFMA fee
Two PDUFA applications: reduce each PDUFA fee by half
Published: Final Guidance on
Dispute Resolution
Submission and Resolution of Formal Disputes Regarding Timeliness of Premarket Review of Combination Products
Any dispute regarding the timeliness of the premarket review of a combination product may be presented to OCP for resolution, unless it is clearly premature
Procedural/process information on narrow range of inquiries presented to OCP
OCP is available, formally or informally, to sponsors regarding combination product issues throughout product development
Postmarket Regulation
Ensure
"consistent and
appropriate"
postmarket regulation
How do we do it?
Draft GMP Guidance published September 2004
Adverse Event Reporting
Identify appropriate regulatory mechanisms
Help coordinate Centers and Field Offices
Published: Draft Good Manufacturing Practice Guidance
Draft guidance published September 29, 2004
CGMP and QS regulations are similar but tailored to the product for which they were designed. Parallel GMP operating systems are not needed.
Each constituent part of a combination product is subject to its governing GMP regulations before combination.
During and after combination (21 CFR 3.2(e)(1) or (e)(2)), both regulations apply.
Compliance with both regulations can generally be achieved by using either regulation (e.g., by using the system in place at a facility)
Good Manufacturing Practice Guidance
Draft guidance lists key provisions to consider in ensuring compliance with both regulations; others may be appropriate considered depending on product
If under CGMP: design controls, purchasing controls, CAPA
If under QSR: calculation of yield; expiration dating; stability testing; testing and approval/rejection of components, drug product containers and closures; testing and release for distribution; special testing requirements; reserve samples
Wrap - Up
What do we do now?
A Lot Still Left to be Done
Publish and finalize guidance/regulations in process:
PMOA, GMP's
Adverse event reporting
Number of marketing applications
Cross Labeling
Chemical Action
Publish more jurisdictional determinations and updates
Intercenter agreements
Address "follow-on" issues, such as
Post-approval changes
Labeling format
Submission format & content
Evaluate impact of new policies and need for revisions or possibly new legislation
Continued stakeholder input, outreach and training
…and more
A Lot Still Left to be Done
OCP Website: http://www.fda.gov/oc/combination/
Contact Us
Office of Combination Products
Office of Combination Products
15800 Crabbs Branch Way (HFG-3)
Rockville, MD 20855
(301) 427-1934
combination@fda.gov
http://www.fda.gov/oc/combination/