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The Future of Combination Products


As of mid-2006, 130 nanotech-based drugs and delivery systems ... 2006 Nanotechnology Projections The 2005 market size for nanotechnology drug delivery systems alone ... – PowerPoint PPT presentation

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Title: The Future of Combination Products

The Future of Combination Products
  • Bradley Merrill Thompson, MBA, JD, RAC
  • Epstein Becker Green PC
  • RAPS
  • San Francisco, CA
  • April 27, 2007

  • Overview
  • Where are Combination Products Going?
  • Where is Combination Product Regulation Going?
  • Where is the Combination Product Regulatory
    Profession Going?
  • Where are the Challenges and Opportunities?

  1. What are combination products?
  2. What is the Combination Product Coalition?

What is a Combination Product?
  • Statute -- 503(g)(1)
  • Products that constitute a combination of a
    drug, device, or biologic
  • Combination products are diverse
  • Drug-device
  • Device-biologic
  • Drug-biologic
  • Drug-device-biologic

Three Types of Combination Products
  • 21 CFR 3.2(e)
  • Single-entity a product comprised of two or more
    regulated components that are physically,
    chemically or otherwise combined or mixed as a
    single entity
  • Kits two or more separate products packaged
    together (e.g., drug and device products)
  • Cross-labeled provided separately but intended
    for use together where both are required to
    achieve the intended use and where cross labeling
    is needed

Not Combination Products
  • Most concomitant use of drugs, devices and
  • Drug-drug, device-device, or biologic-biologic
  • Example Products with two biologics, even if
    shared CDER and CBER role
  • General devices intended for use with a class of
    or otherwise unspecified drug/biologic products
  • Example Unfilled syringe or diagnostic test
    without specifying a particular drug

How are they Regulated?
  • CPC Purpose
  • To clarify and streamline the regulatory paradigm
    for combination products
  • While protecting the public health

  • Up to 20 drug, device and biologics companies
    have engaged in CPC activities. Some members
  • Abbott
  • Baxter
  • Becton Dickinson
  • Pfizer
  • Roche Diagnostics
  • Most active participants are regulatory affairs
    professionals for member companies.
  • Diversity of industry representation is

  • Started in 2003 with developing consensus policy
  • Advocating policy positions and working
    collaboratively with FDA
  • Providing comments to FDA on proposed rules and
  • Partnered with RAPS to host January 2005 policy
    summit attended by about 150 people.
  • Topics included cross labeling, kit labeling and
    the labeling of single entity products.
  • The summit resulted in a consensus white paper
    that was submitted to FDA.

Current CPC Key Priorities
  • Cross labeling
  • Modification of approved combination products
  • Adverse incident reporting
  • Quality systems/GMPs
  • Clarification of OCP role

  • Companies interested in CPC should visit
  • Membership structure
  • Policy Positions

Where Are Combination Products Going?
  • Drivers
  • Examples
  • Quantitative
  • Reviews
  • Projections

Combination Product Drivers
  • Clinical
  • Need/want enhanced outcomes in both safety and
  • Systemic effects and toxicities eliminate too
    many candidates, which in turn drives localized
    delivery, targeting and individualized therapy
  • Economic
  • Slow down in pharma industry productivity
  • Cost and times for new drug development are high
  • Patent life limitations
  • Growing tendency to collaborate

Collaboration Leads to Combinations
  • Study publicized 166 intractable scientific
    problems owned by high tech companies
  • Almost 1/3 quickly solved by mostly off-the-shelf
  • Majority of solutions came from people versed in
    other fields
  • Indeed, the further from the field of the
    problem, the more likely they were to solve it

The Ice Tray Model of Convergence Dynamics
  • Silos Knowledge, methods and discoveries made
    in isolated technology sectors.
  • Connection One well connects to another.
    Knowledge can be applied quickly to adjacent
  • Convergence Greater innovation in the
    connected region than in the individual wells.

Converging Technologies
Genomics Bioinformatics Proteomics
INFOTECH Hardware Software Communications
BIOTECH Pharmaceuticals Diagnostics Research/Info
Tools Industrial
INFOTECH Hardware Software Communications
Biosensors Biochips
Bioelectronics Microfluidics Nanabiotechnology Dru
g Delivery
Nanodevices Nanosensors Nanoelectgronics
NANOTECH Electrical Structural Biomedical Energy
Adapted from Biology, Bioconvergence,
Information And Enterprise Taking the Broad of
View May 20, 2004 Alan Barrell.
Platforms to Watch
  • Tissue Engineering
  • Micro-electrical mechanical systems
  • Biomaterials
  • Gene and protein delivery
  • Targeted medicine
  • New routes for delivering drugs
  • Nature Biotechnology (March 2006)

Number and Types of Combination Products FY 2005
Application Type Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category Combination Product Category
Application Type 1 2 3 4 5 6 7 8 9 TOTALS
Original NDAs 1 8 -- 1 -- 1 1 -- -- 12
Original BLAs 1 -- 1 -- -- -- -- -- -- 2
Original PMAs -- -- -- 2 -- -- -- -- -- 2
Original 510(k)s 5 -- -- 55 9 -- 6 -- 3 78
Original INDs 1 42 14 7 4 12 17 54 1 152
Original IDEs 1 -- -- 19 7 -- 1 1 -- 29
Original HDEs -- -- -- -- -- -- -- -- -- 0
TOTALS 9 50 15 84 20 13 25 55 4 275
COMBINATION PRODUCT KEY     1    convenience
kit or co-package    2    prefilled drug
delivery device/system        3   
prefilled biologic delivery
device/system    4    device coated,
impregnated, or otherwise combined
with drug    5    device coated or
otherwise combined with biologic    6
   drug/biologic combination    7    separate
products requiring mutually conforming
labeling    8    possible combination based on
mutually conforming labeling of
separate products    9    other type of
combination product
Combination Product Applications 2005
Consultations 2005
Primary Assigned Center Consulting Center Consulting Center Consulting Center Number of Consults
Primary Assigned Center CBER CDER CDRH Number of Consults
CBER -- 9 36 45
CDER -- -- 36 36
CDRH 9 185 -- 194
 Totals 9 194 72 275
Combination Product Application Trend
Number of Submissions
Quantitative Projections
  • The combination products market is estimated at
    5.98B in 2004, and will continue to grow at a
    compound annual rate of 10 through 2009. By
    2009, the market is expected to reach
    approximately 9.5B worldwide.
  • Source Navigant Consulting, Inc.
  • The global market for drug-device combinations is
    expected to increase at an average annual growth
    rate of 13.6 and reach 11.5B in 2010, compared
    with 5.4B in 2004.
  • Source Business Communications Co., Inc.
  • The US drug delivery market is expected to reach
    nearly 91B by 2009.
  • Source Fuji-Keizai, 2006

Nanotechnology Projections
  • The 2005 market size for nanotechnology drug
    delivery systems alone was estimated at 980
    million and expected to gross 54 annually over
    the next five years.
  • Source The Nanotech Report 4th Edition, Lux
    Research, 2006.
  • The demand for nanotechnology medical products
    will grow by more than 17 annually to reach 53
    billion in 2011.
  • Source The Fredonia Group, Nanotechnology in
    Health Care to 2011 Report, February, 2007.

Nanotechnology Projections
  • With at least 12 nanomedicines already approved
    and progressively more in active development, the
    next five years should see a steady succession of
    new nanotech-based drugs, imaging agents, and
    diagnostic products entering the marketplace.
  • Source Advance Tech Monitor, 2006.
  • As of mid-2006, 130 nanotech-based drugs and
    delivery systems and 125 devices or diagnostic
    tests were in preclinical, clinical or commercial
  • Source The Nanotech Report 4th Edition, Lux
    Research, 2006.
  • The combined market for nano-enabled medicine
    (drug delivery, therapeutics and diagnostics)
    will jump from just over 1B in 2005 to almost
    10B in 2010. The US National Science Foundation
    predicts that nanotechnology will produce half of
    the pharmaceutical industry product line for
  • Source The Nanotech Report 4th Edition, Lux
    Research, 2006.

Where Is Combination Product Regulation Going?
  • Congress
  • FDA
  • Internationally

  • Where has Congress been recently?
  • Where is Congress going?

Historical Development
  • Safe Medical Devices Act (1990)
  • Added 503(g)
  • Required determination of primary mode of
    action (i.e., drug, device, or biologic)
  • Gave primary jurisdiction to the center with
    premarket review authority for that type of

Historical Development
  • Food and Drug Administration Modernization Act of
    1997 (FDAMA)
  • Added 563, Request For Designation
  • Allowed sponsor to request designation as drug,
    biologic, device, or combination product, and/or
    reviewing center

Historical Development
  • Medical Device User Fee and Modernization Act of
    2002 (MDUFMA)
  • Established Office of Combination Products in
    order to assure
  • Prompt designations and review assignments
  • Timely and effective premarket review
  • Consistent and appropriate postmarket regulation

Where is Congress Going?
  • New user fee bill
  • No specific talk about combination products
  • Future issues
  • Some talk of unified regulation for combination
    products, but not serious yet
  • Other talk of unified adverse reporting system
  • Congress trails technology, instead of leading
  • Thats not a bad thing, unless they fall too far

Where is FDA Going?
  1. Office of Combination Products
  2. GMPs
  3. Adverse Events
  4. Cross Labeling
  5. Submissions
  6. User Fees

Office of Combination Products
  • In a state of flux, with new leadership
  • Dr. Joanne Less replaces Mark Kramer
  • Formerly Associate Director for Clinical Research
    at CDRH
  • Statutory Duties
  • Assignment of combination products
  • Ensure timely and effective premarket review
  • Consistent and appropriate postmarket regulation
  • Dispute resolution (timeliness vs. substance)
  • Review/update guidance, agreement, practices
  • Reports to Congress
  • Resource to sponsors and review staff
  • P.L. 107-250 enacted 10-26-02

  • Proposed Rule due any week/month
  • Likely themes
  • Combination product manufacturers must meet the
    requirements of both sets of applicable GMP
    regulations. Manufacturers may choose an
    umbrella system under which to operate, but
    this system must meet the requirements of both
    sets of applicable GMP regulations.
  • Manufacturers must implement certain specific
    provisions in order to achieve compliance with
    both sets of regulations (e.g., design controls,
    purchasing controls, and CAPA for devices).

  • More Likely Themes
  • May be a regulatory obligation to comply with
    certain GMP requirements even before constituent
    parts are physically combined, merged, or joined.
  • For example, design controls may come into play
    before actual physical combination of a
    combination products constituent parts.
  • Manufacturers cannot delegate ultimate
    responsibility for GMP compliance.
  • While it might be acceptable to accept supplier
    design controls, a manufacturer is ultimately
    responsible for ensuring adequate compliance with
    all GMP requirements, including those where a
    contractor helps.
  • Manufacturers should be cognizant of separate
    design control issues at the overall combination
    product level i.e., after the manufacturer
    doing the final assembly receives the
    component/constituent part from the supplier.
  • Design controls apply to all constituent parts
    and the finished combination product--not just
    the device constituent part.

Adverse Events
  • Proposed Rule expected any week/month.
  • Likely content
  • Might propose mechanisms by which the postmarket
    safety reporting requirements ordinarily
    associated with the marketing application used to
    approve or clear a combination product may be
    supplemented, as appropriate, to take into
    account the combination nature of the product, or
  • Might propose a reporting scheme in which the
    same types of postmarket safety reports would be
    submitted for a combination product, regardless
    of the type of marketing application used for its
    approval or clearance
  • Look at September 2005 Concept Paper

Cross Labeling
  • May 10, 2005 Public Meeting
  • Transcript and presentations accessible on OCP
  • New straw man proposal due out any week/month
  • New public meeting planned to discuss proposal

What is Cross Labeling?
  • A drug, device, or biological product packaged
    separately that according to its investigational
    plan or proposed labeling is intended for use
    only with an approved individually specified
    drug, device, or biological product where both
    are required to achieve the intended use,
    indication or effect and where upon approval of
    the proposed product the labeling of the approved
    product would need to be changed, e.g. to reflect
    a change in intended use, dosage form, strength,
    route of administration, or significant change in
  • 21 CFR 3.2(e)(3)

Whats So Hard About That?
  • Hypothetical
  • Company A is the sponsor of approved Drug A.
  • Company B wants to obtain premarket approval for
    Device B that will administer Drug A in a new
    dosage form, strength, route of administration,
    or intended use.
  • Company A does not want to cooperate with Company
    B in this venture.
  • Can FDA approve Device B?

Some of the Questions
  • What does individually specified mean?
  • What if Device B has other approved intended
  • When does label of Drug A need to be changed?
  • If labeling of Drug A does need to be changed,
    but Company A does not want to submit a
    supplement to its marketing application, does
    that mean that Device B cannot be approved?

Protect and Promote the Public Health
  • FDA prefers cooperation.
  • In the absence of cooperation, FDAs goal is to
    identify a regulatory pathway for Device B while
    ensuring adequate regulatory oversight.
  • Consider whether labeling of Drug A needs to be
  • Is Drug A intended to be used for a new intended
    use, dosage form, strength, or route of
  • Is end user confusion likely?
  • What would happen if Drug A is reformulated or
    redesigned without notice to Company B?
  • Would Company B rely on proprietary information
    in application covering Drug A?

  • Questions
  • Initial submissionsnumber of them
  • Supplements for product modifications
  • Guidance
  • September 2005 Concept Paper for initial
  • Close to guidance on product modifications,
    unless goes to rulemaking

Initial Submissions
  • Agency goal seems to be to prescribe the number
    and type to be filed
  • CPC has argued for greater freedom to determine
    the approval pathway, within the confines of the
  • We explain that a lot of factors, many of which
    the agency wont know, affect the optimal
    approval route
  • Not clear where the agency is going

Submissions for Product Modifications
  • Agency has a draft guidance in hand
  • However, still grappling with fundamental
    questions such as guidance or rulemaking
  • Addresses pathway/type of submission issue,
    rather than type of evidence or data required
  • CPC has a draft guidance in hand
  • Will shift to developing questions and case

Draft User Fee Guidance
  • Single marketing application fee associated
    with that type of application
  • Multiple marketing applications fee for each
  • Sponsor may choose to submit two marketing
    applications (limited waivers/reductions
  • FDA may require multiple applications -- fees
    still required for each application
    (waivers/reductions possible)

Draft User Fee Guidance
  • Draft User Fee Guidance (cont.)
  • Waivers
  • Innovative combination products (only if FDA
    requires multiple applications)
  • MDUFMA and PDUFA waivers available

Draft User Fee Guidance
  • CPC Comments
  • FDA needs to address issue of what assignment
  • Specific enhancements recommended
  • Clarify when multiple filings required
  • Provide automatic waiver of partial fee when FDA
    requires multiple applications
  • Expand eligibility for Innovative Combination
    Product waiver to
  • Sponsors choosing to file multiple applications
  • Products approved and labeled for another use
  • Products that offer significant benefits other
    than clinical

International Trends
  • Other jurisdictions are lagging behind FDA in the
    development of new guidance and approaches
  • In Europe, specific regs not yet in place
  • Europe's approach is similarly based on primary
    mode of action, although it is determined
  • Medical Device Directive lays out pathway for
    combination products that operate as devices
  • If the drug and device are a single integral
    product that is intended exclusively for use in a
    given combination, gets regulated as a drug.
  • On the other hand, if a device incorporates a
    drug as an integral part and the drug acts on the
    body in an ancillary manner, the product is
    regulated as a device.
  • In the case of a tie, its a drug
  • There is a consultation procedure (MEDDEV 2.1/3
    rev. 2 (2001))
  • Little energy is being directed at harmonization

Where is the Regulatory Profession Going?
  • RAPS research shows steady growth in the number
    of regulatory professionals involved in
    combination products from an estimated 12 in
    1999 to nearly 30 today.
  • Source Sherry Keramidas, PhD, RAPS Executive
    Director, September 2006.

Alliances Will Govern
  • Normally core capabilities done in house
  • Convergence requires broad expertise and
    experience only available through alliances
  • Numerous special issues and challenges
  • Regulatory differences
  • Cultural differences
  • Economic interest differences

Devices Drugs
Engineering, materials Biology, chemistry
Local effects Systemic effects
Technology development Research
Systematic rapid product development Slow, trial error product development
Engineers Scientists
Product lifetime usually short Product lifetime usually long
What Are the Practical Challenges and
Practical Challenges
  • Combination products
  • Are increasingly state-of-the-art, innovative
    technologies that challenge existing regulatory
    and scientific knowledge
  • Require FDA to apply very different regulatory
    paradigms to one often unique product
  • Force FDAs nearly autonomous centers to work
  • The OCP is new, with limited resources

Practical Challenges
  • Different industries have different perspectives
    and priorities leaving OCP to weigh the options
    and make choices
  • Existing trade association structures mirror
    FDAs product-based centers

Practical Opportunities
  • The leadership of the OCP is interested in
    hearing from, and working with, industry
    opportunities exist for close collaboration.
  • The OCP is actively seeking input on its
    initiatives. For example
  • GMP
  • Adverse Events
  • Cross Labeling

Practical Opportunities
  • Because the OCP is so thinly staffed, industry
    has an opportunity to help fill the gaps with
  • Regulatory, scientific and practical knowledge
  • Research
  • Idea generation
  • Feedback

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