BioWest Keynote Denver , November 9, 2005

Mark D. Kramer
Director
Office of Combination Products

What is a Combination Product?

- Combinations of different types of products:
  - Drug-device
  - Device-biologic
  - Drug-biologic
  - Drug-device-biologic
  - NOT drug-drug, device-device or biologic-biologic combinations
- They can be:
  - Physically or chemically combined
  - Co-packaged in a kit
  - Separate, cross-labeled products

Examples of Combination Products

Drug-eluting cardiovascular stent
Drug-eluting disc for chemotherapy treatment
Drug-eluting, vision-correcting contact lens to treat glaucoma
Spinal fusion cage coated with therapeutic protein to treat degenerative disc disease
Chemotherapeutic drug and monoclonal antibody for targeted cancer treatment
Scaffold seeded with autologous cells for organ replacement
Menstrual tampon impregnated with genetically modified bacteria
Interferon and ribavirin combination hepatitis C therapy
Vertebroplasty implant with extended-release analgesic

Challenge

Devices

- PMA/510(k)/IDE
- QSR
- MDR

Drugs

- NDA/IND
- cGMP
- AERS

Biologics

BLA/IND
cGMP+
AERS+

Primary Mode of Action

Consultation

Regulations

Challenges

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
Two centers involved –
- Sometimes have different perspectives
Sponsors' preferences don't always square with what the law requires

Mandated by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA)
Established December 24, 2002
Organizationally within the Office of the Commissioner
Work with industry and the three medical product Centers: CBER, CDER and CDRH
- Centers responsible for review and regulation

Office of Combination Products

OCP Objective

Ensure combination product regulation is:
- Clear
- Consistent
- Appropriate
- Predictable
- Transparent

OCP Roles

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
Report to Congress
Special initiatives

Jurisdictional Determinations

Formal

and

Informal

--------------------------

Combination and Single Entity Products

Background – Section 503(g) of the Act

FDA is required to assign a combination product to a lead Center based on its "primary mode of action"
PMOA was not defined in the statute or regulations
For some products, PMOA is difficult to identify
- Early in development (just don't know)
- Products that have two (or more) completely different modes of action, neither of which is subordinate to the other

Final PMOA Rule: Definitions

MOA is the means by which a product achieves its intended therapeutic effect or action.
- Definitions of drug, device, biologic MOA
PMOA is the single mode of action of a combination product that provides the most important therapeutic action of the combination product.
- The most important therapeutic action is the MOA expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.

Final PMOA Rule:
Assignment Algorithm

If unable to determine the most important therapeutic action with reasonable certainty:
- 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.
- 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

Jurisdiction: Transparency

PMOA Final Rule
Guidance: How to Write a Request for Designation
RFD Letters for Approved Products
Published ~200 Jurisdictional Determinations
Jurisdictional Updates
Jurisdictional Update on Intercenter Agreements
Next on list: Chemical Action

Jurisdictional Update: Intercenter Agreements

ICA's were the major jurisdictional statements issued when they were written in 1991
Provide helpful guidance, but usefulness increasingly limited as new products are developed and as new laws, regulations and guidance have been promulgated
Agency's goal for robust transparency will likely be better served by means other than updating ICA's
Goal: clearly articulate principles upon which jurisdictional determinations are based, and provide examples

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 MOU's
- Facilitate meetings with sponsors
- Help ensure both Centers represented
- Monitor and facilitate the consultation process
- Monitor combination product review timeliness
- Provide training and reviewer tools

Other Areas OCP is Working to Clarify

Good Manufacturing Practices (draft guidance document on web)
Adverse Event Reporting (concepts out for stakeholder comment)
Number of Marketing Applications (concepts out for comment)
Cross Labeling (public workshop May 2005 – info on website)
User Fees… (guidance document on web)
…and more

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/

Critical Path Issues
for Combination Products

Expertise and expectations
Identification of regulatory pathway and requirements
Analytical techniques
Biocompatibility vs. toxicology
Bridging device and drug development cycles

Critical Path:
Expertise and Expectations

For drug-device combination products, recognizing the need for and hiring appropriate expertise is usually a critical path to success
- Knowledge of drug and device development
- Chemistry, manufacturing and controls
- Engineering and bench studies
- Realistic expectations for ultimate success

Critical Path:
Defining the Regulatory Pathway

Early identification and understanding of:
- Lead and consulting Agency Centers and their roles
- Regulatory vehicle that will be used for approval
  - The "drug" way, the "device" way, or some combination
- Need for cooperation between drug and device manufacturers
- Design and manufacturing requirements
Note: this is what the Office of Combination Products is all about

Critical Path: Analytical Techniques/Toxicology

Analytical Techniques
- Existing techniques and standards often not designed to assess "micro" quantities of drug
Toxicology
- Which paradigm? Biocompatibility (device) or Pharmacology-Toxicology (drug)
New techniques/standards and paradigms are needed so individual companies don't each need to develop their own

Critical Path:
Bridging Drug and Device Development

Devices tend to evolve very quickly (e.g., new generations yearly); drugs much more slowly
Post-approval modifications of drug-device combination products need to reflect combination nature of product
- Early identification of biomarkers or other surrogates
- Protocols for bridging studies
- Other methods to speed up development

Recommendations

One size doesn't fit all CPs
Keep in mind the additive/modifying effect of the new constituent
Consider full developmental scope (pre- and postmarket) throughout development
Early discussions with both centers (and manufacturers, if applicable) at the table

The Future is Bright!

Numbers and types of combination products continue to grow
Consultation and other internal processes more systematized
Clearer, more predictable process for assignment, premarket review and postmarket regulation

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/

BioWest Keynote Denver November 9, 2005

BioWest Keynote Denver
November 9, 2005