BIO Annual Meeting (6-21-05)

Mark Kramer

Outline of Slides

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

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/

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/

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