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
Update on Regulatory Requirements
for Combination Products
Bradley Merrill Thompson, MBA, JD, RAC
Epstein Becker & Green PC
June 2, 2009
Cambridge Healthtech Institute
2
Topics
1.
Overview
a. What are combination products?
b. What is the Combination Product Coalition?
2. Where are Combination Products Going?
3. Where is Combination Product Regulation
Going?
4. Where are the Challenges and Opportunities?
I feel like Zsa Zsa Gabor’s fifth husband.
I know what I'm supposed to do but I
don't know if I can make it interesting.
Al Gore
3
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
4
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
5
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
6
How are they Regulated?
Different Frameworks
NDA, BLA,
PMA, 510(k),
IND, IDE
Device
CDRH
Drug
CDER
Biologic
CBER
Different Types
Different Reviews
7
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 8
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.
9
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.
10
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
11
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
12
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
13
Level of satisfaction with existing guidance
(FDA and non-FDA)
No opinion
Over 56%
indicated some
level of
dissatisfaction
with existing
guidance
Very dissatisfied
Not satisfied
Somewhat
satisfied
No one said they were “very satisfied”
Very satisfied
0
2
4
6
8
10
12
14
14
(1) Clinical Studies
(2) GMPs
(3) Premarket approval submissions
(4) Cross-labeled combination products
(5) Adverse event reporting
Overall
Weighted
Rankings
(6) Combo prod def ’n & Post-approval modifications (tie)
(7) Pre-approval inspections
(8) Preclinical Research
(9) Labeling
(10) PMOA
(11) Advertising/promotion & RFD/prod jurisdiction (tie)
(12) User Fees
(13) Recall requirements
(14) Post-approval inspections
(15) Resolving disputes
15
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.
16
Ways to Get Involved
 Companies interested in CPC should visit:
www.combinationproducts.com
►Membership structure
►Policy Positions
 Active LinkedIn group (you don’t 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
17
Topics
1. Overview
2. Where are Combination Products Going?
a. FDA experience
b. Trends in submissions
3. Where is Combination Product Regulation
Going?
4. 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 18
Number and Types of Combination Products FY 2007
COMBINATION PRODUCT KEY:
1 = convenience kit or co-package
Application
Type
Combination Product Category
1
2
3
4
5
6
7
8
9
TOTALS
Original
NDAs
4
8
--
--
--
--
--
2
--
14
Original BLAs
--
--
3
--
--
--
--
--
--
3
4 = device coated, impregnated, or
otherwise combined with drug
Original
PMAs
--
--
--
4
--
--
--
--
--
4
5 = device coated or otherwise
combined with biologic
Original
510(k)s
5
2
2
72
6
1
3
5
13
109
6 = drug/biologic combination
Original INDs
2
63
18
7
7
10
10
45
4
166
7 = separate products requiring
mutually conforming labeling
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
2 = prefilled drug delivery
device/system
3 = prefilled biologic delivery
device/system
8 = possible combination based on
mutually conforming labeling of
separate products
9 = other type of combination product
19
Consultations 2007
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
Consulting Center
20
Number of Submissions
Combination Product
Application Trend
350
300
250
CDRH
CDER
CBER
200
150
100
50
0
FY04
FY05
FY06
FY07
21
Topics
1.
2.
3.
4.
Overview
Where are Combination Products Going?
Where is Combination Product Regulation Going?
a. Congress
b. FDA
c. 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
22
Congress
Where has Congress been recently?
Where is Congress going?
The voters have spoken—the bastards.
Richard M. Nixon
23
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
24
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
25
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
26
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
►That’s not a bad thing, unless they fall too far behind
27
1.
2.
3.
4.
5.
6.
7.
Where is FDA Going?
Office of Combination Products
Clinical Trials
Injector Draft Guidance
GMPs
Adverse Events
Cross Labeling
Submissions
Actual Trial Question
How far apart were the vehicles
at the time of collision?
28
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 Counsel’s 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
29
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 industry’s 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
30
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 standalone, general use injectors
31
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
32
Draft Injector Guidance
Major concerns (con’t)
►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
33
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
34


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.
35
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
36
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
37
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
38
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 39
Submissions
Questions:
►Initial submissions—number of them
►Supplements for product modifications
Guidance
►September 2005 Concept Paper for initial
submissions
►Close to guidance on product modifications,
unless goes to rulemaking
40
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 won’t know, affect the optimal
approval route
 Not clear where the agency is going
41
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
42
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, it’s a drug
 There is a consultation procedure (MEDDEV 2.1/3 rev. 2 (2001))
 Little energy is being directed at harmonization (2008 Initiative)43
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
44
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 FDA’s 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
FDA’s product-based centers
45
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
46
Questions?
Arguing with a lawyer is like
mud wrestling with a pig: after a while
you realize that the pig actually enjoys it.
47