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Regulation of Combination Products: Progress Report
Mark D. Kramer
Patricia Y. Love, MD, MBA
Office of Combination Products
DIA Webinar
January 19, 2004
What We'll Cover
Challenges in Regulation of Combination Products
Role of Office of Combination Products
Primary Mode of Action and Assignment Process
Premarket Review of Combination Products
Postmarket Regulation of Combination Products
The Future
Combination Products Are Diverse
Combinations of different types of products:
Drug-device
Device-biologic
Drug-biologic
Drug-device-biologic
Combination Products Are Diverse
They can be:
Physically or chemically combined
Co-packaged in a kit
Separate, cross-labeled products
Devices
PMA/510(k)/IDE
QSR
MDR
Regulatory Approaches Are Diverse
Drugs
NDA/IND
cGMP
AERS
Biologics
BLA/IND
cGMP+
AERS+
Primary Mode of Action
Consultation
Regulations
Challenges: Overall Regulation
No regulatory scheme is designed specifically for
combination products….
…..We work within existing statutory framework.
Challenges: Overall Regulation
FDA regulations and practices differ for drugs/biologics and devices:
premarket applications
good manufacturing practices
adverse event reporting
labeling
promotion and advertising…
Industries differ:
different experience and preferences
The Ultimate Regulatory Challenge
Making regulation
clear
consistent
predictable
appropriate
without raising the bar…..
Challenges: Assignment
Define primary mode of action….
And then apply it….
….Some products don't have a clearly identifiable PMOA
Challenges: Assignment
60-day RFD clock sometimes tight
complex issues
binding decisions
Challenges: Assignment
RFD's are voluntary …
we don't see all products for assignment
Transparency …
more difficult to achieve than we'd like
Challenges: Assignment
Sponsors' preferences don't always square with what the law requires
Challenges: Review
No application specifically for combination
products …
standard submission format and content must be tailored
Regulatory pathways sometimes not evident…
e.g., need for cross labeling
Challenges: Review
Two centers involved they may have different:
review time frames
clinical trial perspectives
user fees
submission tracking systems
locations
cultures
Challenges: Review
The volume!
Over 200 cross center collaborations for combination products in FY 2004.
Makes jurisdictional determinations
Oversees premarket review
Oversees postmarket regulation
Resolves disputes
Develops policy, guidance and regulations
Serves as resource for industry and review staff
Outreach
Reports to Congress
Special Initiatives
Office of Combination Products
Jurisdictional Determinations
Formal
or
Informal
--------------------------
Combination and Single Entity Products
How do we do it?
Requests for Designation 67 in 2004
100% on time !!
Informal Direction for many products phone, email, pre-RFD's
Primary Mode of Action Rule
Jurisdictional Updates
Published ~70 Jurisdictional Determinations
Resolve appeals of TRG determinations
Monthly Meetings with Jurisdictional Officers
PMOA Proposed Rule:
May 7, 2004 Federal Register
"Mode of Action" would be defined as the means by which a product achieves a therapeutic effect
"Therapeutic" includes any effect or action of the combination product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body
Three types of modes of action: biological product, device, drug
Combination products are comprised of more than one type of regulated article [or constituent part] and will typically have more than one identifiable mode of action (e.g., drug and device, device and biological product, etc.)
PMOA Proposed Rule:
May 7, 2004 Federal Register -- continued
A constituent part of a combination product has a:
Biological product MOA if it acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of a disease or condition of human beings…
Device MOA if it meets the definition of device…, it does does not have a biological product MOA, and it does not achieve its primary intended purposes through chemical action within or on the body….and is not dependent on being metabolized for the achievement of its primary intended purposes
Drug MOA if it meets the definition of drug…and it does not have a biological product or device MOA.
PMOA Proposed Rule:
May 7, 2004 Federal Register -- continued
"Primary Mode of Action":
The single mode of action of a combination product that provides the most important therapeutic action of the combination product.
PMOA Proposed Rule:
May 7, 2004 Federal Register -- continued
If unable to determine the most important therapeutic action with reasonable certainty:
Examples: early in development (just don't know) -- or two important, independent modes of action, neither of which is subordinate to the other
Follow Assignment Algorithm:
1st: CONSISTENCY: Assign to agency component that regulates other combination products that present similar questions of safety and effectiveness with regard to the combination product as a whole.
That is, assign to the Center with direct experience in that type of combination product
PMOA Proposed Rule:
May 7, 2004 Federal Register -- continued
If there are no other combination products that present similar questions of safety and effectiveness with regard to the combination product as whole:
Examples: it is the first such combination product, or when differences in its intended use, design, formulation, etc. present different safety and effectiveness questions
Continue with assignment algorithm:
2nd: SAFETY AND EFFECTIVENESS: Assign to agency component with the most expertise related to the most significant safety and effectiveness questions presented by the combination product
That is, assign to Center with most related experience for that type of product
PMOA: Three Hypothetical Examples
Vision-correcting contact lens with drug to make lens more "comfortable"
Contact lens as drug delivery system
Vision-correcting contact lens with concurrent delivery of glaucoma drug
PMOA Proposed Rule:
Selected Stakeholder Comments
Clarify roles of intended use, precedents, and intercenter agreements
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
OCP Assignments of Combination Products (10/1/03 through 9/30/04)
OCP Classification Decisions (Non-Combination Products (10/1/03 9/30/04)
Application User Fee Guidance
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
Premarket Review and
Postmarket Regulation
Premarket Review
Whatever it takes to ensure
"timely
and effective"
premarket review of combination products
How do we do it?
SOP for intercenter consultation process
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 (> 200 in FY04)
How do we do it, more
Monitor combination product review timeliness
Advise sponsors and review staff
Provide training and reviewer tools
Check classification of all submissions as combination products
Intercenter Consultation Requests
10/01/03 through 9/30/04
Resource for Industry and Review Staff
Wide range of inquiries on
assignment
and
combination product
regulation
How do we do it?
Phone
Meetings
Web
FAQ
Common questions from industry and staff
Number of marketing applications
Post market regulation
GMP
Safety reporting
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
Required by FDA in some circumstances
Requested by industry in some circumstances
Dispute Resolution
Facilitate resolution of …
Disputes about the timeliness of premarket review of combination products
Other disputes or disagreements
How do we do it?
Dispute Resolution Guidance
Meetings
Phone Calls
Dispute Resolution Guidance, Draft
Resolution of 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 its clearly premature
Procedural/process information on narrow range of inquiries (e.g., missed due date) to be presented to OCP
OCP remains 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?
GMP Guidance
Identify appropriate regulatory mechanisms
Coordinate Centers and Field Offices
Good Manufacturing Practices 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, cont'd
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
Communication most important activity during combination product development
Manufacturers of constituent parts
FDA intercenter team
Product reviewers
GMP/QS experts
Field inspectors
OCP
Good Manufacturing Practice Guidance, cont'd
Status:
Comment period closed December 3, 2004
gov/oc/combination/default.htm
Considering comments in preparation of final guidance
Clarifications (e.g., during and after combining)
Training of inspectors
Good Manufacturing Practice Guidance, cont'd
Postmarket regulation
Safety reporting requirements: postmarket
Safety Reporting: postmarket
§ 314.80, Adverse Drug Experience (ADE)
§ 600.80, Biological product adverse experience
§ 606.170, Blood component adverse experience
§ 600.81, Vaccine adverse events (VAERS)
§ 803, Medical Device Reporting (MDR)
Safety Reporting
Centers maintain different safety reporting databases
Draft guidance on what and how to submit safety reports for combination products
Nearing completion for publication
General Considerations for combination product development
One size doesn't fit all
Review and regulatory pathway evolution; clarifications as new questions / products arise
"Additive / modifying" effect of the "new" component
Remember GMP's and postmarket issues during development
Early discussions with both Centers at table
Wrap - Up
What do we do now?
What's Still Left to be Done: A Lot
Publish and finalize guidance/regulations in process:
PMOA, Dispute Resolution, GMP's, User Fees
Adverse event reporting
Number of marketing applications
Address "follow-on" issues, such as
Cross labeling
Post-approval changes
Labeling format
Submission format & content
Promotion & Advertising
Chemical action
More jurisdictional updates
More jurisdictional determinations
Intercenter agreements
Evaluate impact of new policies and need for revisions
Continued stakeholder input, outreach and training
…and more
What's Still Left to be Done: A Lot
The Future is Bright!
Numbers and types of combination products continue to grow
Consultation process more systematized
Clearer, more predictable process for assignment, premarket review and postmarket regulation
Continued opportunities for stakeholder input at sessions like this!
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