I do not object to people looking at their watches when I'm speaking. But I strongly object when they start shaking them to make sure they are still going. William Norman Birkett - PowerPoint PPT Presentation

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I do not object to people looking at their watches when I'm speaking. But I strongly object when they start shaking them to make sure they are still going. William Norman Birkett

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Title: I do not object to people looking at their watches when I'm speaking. But I strongly object when they start shaking them to make sure they are still going. William Norman Birkett


1
I do not object to people looking at their
watches when I'm speaking. But I strongly
object when they start shaking them to make
sure they are still going. William Norman
Birkett
2
Update on Regulatory Requirements for
Combination Products
  • Bradley Merrill Thompson, MBA, JD, RAC
  • Epstein Becker Green PC
  • June 2, 2009
  • Cambridge Healthtech Institute

3
Topics
  • Overview
  • What are combination products?
  • What is the Combination Product Coalition?
  • Where are Combination Products Going?
  • Where is Combination Product Regulation Going?
  • Where are the Challenges and Opportunities?

I feel like Zsa Zsa Gabors fifth husband. I
know what I'm supposed to do but I don't know if
I can make it interesting.
Al Gore
4
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

5
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

6
Not Combination Products
  • Most concomitant use of drugs, devices and
    biologics
  • Drug-drug, device-device, or biologic-biologic
    combinations
  • 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

7
How are they Regulated?
8
  • CPC Purpose
  • To clarify and streamline the regulatory paradigm
    for combination products
  • While protecting the public health

I have always wanted to be somebody. I guess I
should have been more specific. -Lily Tomlin
9
Membership
  • Up to 20 drug, device and biologics companies
    have engaged in CPC activities. Some members
    include
  • Abbott
  • Baxter
  • Becton Dickinson
  • Genentech
  • Pfizer
  • Roche Diagnostics
  • Most active participants are regulatory affairs
    professionals for member companies.
  • Diversity of industry representation is
    encouraged.

10
Activities
  • Started in 2003 with developing consensus policy
    positions
  • Advocating policy positions and working
    collaboratively with FDA
  • Providing comments to FDA on proposed rules and
    guidances
  • 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.

11
Activities
  • Will partner with RAPS to host policy summit on
    GMPs when proposed rule is published, during
    comment period.
  • Working on comments re injector guidance (more
    later)
  • Shepherding a clinical trials proposed guidance
  • Legislative work

12
2007 Survey
  • Goals
  • Evaluate current industry concerns and priorities
  • Communicate these to FDA
  • Inform CPC policy agenda
  • Why?
  • In 2007, the OCP underwent several leadership and
    personnel changes new permanent director
    effective Jan. 7, 2008
  • Also wanted to take a step back and reflect on
    CPC activities

13
Survey Scope Methodology
  • Focused questions on
  • Demographics
  • Satisfaction with existing guidance (FDA and
    non-FDA)
  • Topics on which more or better FDA guidance is
    needed
  • Disseminated widely among industry
  • Asked companies to complete only one survey, but
    to collaborate with their colleagues

14
Level of satisfaction with existing guidance (FDA
and non-FDA)
Over 56 indicated some level of dissatisfaction
with existing guidance
No one said they were very satisfied
15
Overall Weighted Rankings
(14) Post-approval inspections
(15) Resolving disputes
16
Current CPC Key Priorities
  • Draft guidance on injectors
  • Quality systems/GMPs
  • Combo product clinical trials
  • Modification of approved combination products
  • Adverse incident reporting
  • Clarification of OCP role
  • Priorities are organic and change as new
    developments occur and progress is made.

17
  • Ways to Get Involved
  • Companies interested in CPC should visit
    www.combinationproducts.com
  • Membership structure
  • Policy Positions
  • Active LinkedIn group (you dont need to be a
    member to join)
  • Free wiki experiment for drafting injector
    comment, link www.combinationproduct.com

I've often wondered how some people in positions
of this kind . . . manage without having had any
acting experience. Ronald Reagan
18
Topics
  • Overview
  • Where are Combination Products Going?
  • FDA experience
  • Trends in submissions
  • Where is Combination Product Regulation Going?
  • Where are the Challenges and Opportunities?

Politics gives guys so much power that they tend
to behave badly around women. And I hope I never
get into that.
Bill Clinton
19
Number and Types of Combination Products FY 2007
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 4 8 -- -- -- -- -- 2 -- 14
Original BLAs -- -- 3 -- -- -- -- -- -- 3
Original PMAs -- -- -- 4 -- -- -- -- -- 4
Original 510(k)s 5 2 2 72 6 1 3 5 13 109
Original INDs 2 63 18 7 7 10 10 45 4 166
Original IDEs 2 -- 1 12 10 -- 7 2 2 36
Original HDEs -- -- -- -- 1 -- -- -- -- 1
TOTALS 13 73 24 95 24 11 20 54 19 333
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
20
Consultations 2007
Primary Assigned Center Consulting Center Consulting Center Consulting Center Number of Consults
Primary Assigned Center CBER CDER CDRH Number of Consults
CBER -- 9 33 42
CDER 2 -- 87 89
CDRH 2 257 -- 259
 Totals 4 266 120 390
21
Combination Product Application Trend
Number of Submissions
22
Topics
  • Overview
  • Where are Combination Products Going?
  • Where is Combination Product Regulation Going?
  • Congress
  • FDA
  • Internationally
  • Where are the Challenges and Opportunities?

One way to make sure crime doesn't pay would be
to let the government run it. Ronald Reagan
23
Congress
  • Where has Congress been recently?
  • Where is Congress going?

The voters have spokenthe bastards.
Richard M. Nixon
24
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
    product

25
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

26
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

27
Where is Congress Going?
  • FDA Commissioner confirmation hearings and budget
    discussions
  • The need for combination product policy
    development specifically discussed
  • 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
    behind

28
Where is FDA Going?
  1. Office of Combination Products
  2. Clinical Trials
  3. Injector Draft Guidance
  4. GMPs
  5. Adverse Events
  6. Cross Labeling
  7. Submissions

Actual Trial Question How far apart were the
vehicles at the time of collision?
29
Office of Combination Products
  • Relatively new leadership
  • Thinh Nguyen replaced Dr. Joanne Less who
    replaced Mark Kramer
  • Formerly Director Premarket Approval Section at
    ODE/CDRH
  • Patricia Y. Love, MD, MBA - Associate Director
  • Barr Weiner, from Chief Counsels Office
  • Leigh Hayes, JD - Product Assignment Officer
  • 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

30
CPC Draft Clinical Trial Guidance
  • Feb. 27, 2009, the CPC filed draft guidance, FAQs
    on Pre-Clinical and Clinical Research on
    Combination Products
  • Developed in response to industrys desire for
    guidance in this area
  • Topics addressed include
  • Pre-clinical safety studies
  • IND and IDE submissions
  • Clinical study design
  • Labeling, GMP, and safety reporting issues
  • Issues pertaining to specific technologies

31
Draft Injector Guidance
  • FDA released draft injector guidance on April 27,
    2009 - Technical Considerations for Pen, Jet, and
    Related Injectors Intended for Use with Drugs and
    Biological Products
  • Comments due July 27, 2009
  • CPC soliciting open/public comments via Wiki
  • Very broad scope
  • Injector jet injectors, pen injectors, piston
    syringes, needle-free injectors, mechanically
    operated injectors, and injectors with
    computerized or electronic elements
  • Combination products with injector part and
    stand-alone, general use injectors

32
Draft Injector Guidance
  • Major concerns
  • Could significantly increase burden for certain
    injectors (maybe 3X), for example stand-alone
    device injectors and simpler types of injectors
  • Potential inconsistencies with existing device
    guidance (e.g., piston syringe guidance)
  • Laundry list of data requirements, rather than
    focused, least burdensome guidance

33
Draft Injector Guidance
  • Major concerns (cont)
  • Omits discussion of fundamental policy issues,
    for example
  • How the type/composition of injector influences
    regulatory requirements
  • Types of submissions, e.g., when an injector
    requires a separate clearance or approval
  • Post-market modifications to injectors
  • Any specific expectations for GMP or adverse
    event reporting

34
Draft Injector Guidance
  • More specific concerns
  • Definitions
  • Scope of injector currently the definition
    seems all encompassing
  • Other terms (e.g., product class, product
    line)
  • Clinical studies
  • Implies that there should be a clinical study for
    all types of injectors
  • Needs to clarify when FDA believes clinical data
    are needed
  • Very prescriptive data requirements

35
GMPs
  • Proposed Rule expected anytime
  • 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).
  • May be a regulatory obligation to comply with
    certain GMP requirements even before constituent
    parts are physically combined, merged, or joined.
  • Manufacturers cannot delegate ultimate
    responsibility for GMP compliance.

36
GMP Comment Meeting with FDA and RAPS
  • Will be organized quickly during comment period
  • Will focus on pre-written case studies
  • Will be in person and virtual

37
Adverse Events
  • Proposed Rule expected anytime.
  • 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
  • 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

38
Cross Labeling
  • May 10, 2005 Public Meeting
  • Transcript and presentations accessible on OCP
    website
  • New straw man proposal likely
  • New public meeting planned to discuss proposal

My mother never saw the irony in calling me a
son-of-a-bitch. Jack Nicholson
39
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
    dose.
  • 21 CFR 3.2(e)(3)

Winter related injuries occur more often in the
winter. -newswoman for WHIZ-TV, Zanesville, Ohio
40
Submissions
  • Questions
  • Initial submissionsnumber of them
  • Supplements for product modifications
  • Guidance
  • September 2005 Concept Paper for initial
    submissions
  • Close to guidance on product modifications,
    unless goes to rulemaking

41
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
    law.
  • 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

42
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 drafted its own guidance
  • Will shift to developing questions and case
    studies

43
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
    differently
  • 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
    (2008 Initiative)

44
Topics
  1. Overview
  2. Where are Combination Products Going?
  3. Where is Combination Product Regulation Going?
  4. Where are the Challenges and Opportunities?

What orators lack in depth, they make up for in
length. Charles-Louis De
Secondat Montesquieu
45
Practical Challenges
  • Combination products
  • Increasingly state-of-the-art, innovative
    technologies that challenge existing regulatory
    and scientific knowledge
  • Require regulators to apply very different
    regulatory paradigms to one often unique
    product
  • Force FDAs nearly autonomous centers to work
    together
  • The OCP is still somewhat new, with limited
    resources
  • Different industries have different perspectives
    and priorities leaving OCP to weigh the options
    and make choices
  • Most existing trade association structures mirror
    FDAs product-based centers

46
Practical Opportunities
  • The OCP will actively seek input on its
    initiatives. For example
  • Injectors
  • GMP
  • Adverse Events
  • 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

47
Questions?
  • Arguing with a lawyer is like
  • mud wrestling with a pig after a while
  • you realize that the pig actually enjoys it.
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