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Food and Drug Administration
[Docket
No. OZN-04453
FDA Regulation
AGENCY:
of Combination
Products;
Public Hearing
G7/=R
Food and Drug Administration.
“, ACTION: Notice of public hearing; request for comments.
Q
J
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The Food and Drug Administration
SUMMARY:
hearing to discuss the assignment,
regulation
of combination
devices, or biological
significant
potential
premarket
products.
detail later in this document)
products
containing
These products
in more
a combination
of drugs,
often are novel and have
and views from interested
persons on the issues and
concerns relating to the assignment,
premarket
regulation
FDA is proposing
of combination
the agency is interested
DATES:
(defined
to enhance the public health. The purpose of the hearing
is to solicit information
information
a public
review, and postmarket
Combination
are products
products.
(FDA) is announcing
products.
review, and postmarket
would
like to share.
The public hearing will be held on November
to 5 p.m. Submit written
or electronic
25, 2002, from 9 a.m.
notices of participation
8, 2002. Written
and electronic
by close of
comments
will be
accepted until January 24, 2003.
ADDRESSES:
Rockville
The public hearing will be held at the DoubleTree
Pike, Rockville,
/www.doubletreerockville.com.
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and
in responses to these questions and any other pertinent
stakeholders
business on November
specific questions,
MD. Directions
Hotel, 1750
to the hotel can be found at http:/
6580/
3,
2
Submit written
or electronic
Dockets Management
notices of participation
Branch (HFA-305),
Fishers Lane, rm. 1061, Rockville,
[email protected];
and comments to the
Food and Drug Administration,
5630
MD 20852; or e-mail
or on the Internet at http://www.
scripts/oc/dockets/commentdocket.cfm.
Transcripts
available for review at the Dockets Management
accessdata.fda.gov/
of the hearing will be
Branch (see address in
previous sentence) and on the Internet at http://www.fda.gov/ohrms/dockets.
FOR FURTHER INFORMATION CONTACT:
Mark D. Kramer, Combination
Program (HF-7), Food and Drug Administration,
03, Rockville,
MD 20857,301-827-3390,
Products
5600 Fishers Lane, rm. l4B-
FAX 301-480-8039,
e-mail:
[email protected].
Registration
Information
Preregistration
and Requests for Oral Presentation
by written
procedures governing
notice is necessary to ensure participation.
The
the hearing are found in part 15 (21 CFR part 15). To
register to attend the hearing, submit your name, title, business affiliation,
address, telephone,
oral presentation
fax number, and e-mail address. If you wish to make an
during the open public comment period of the hearing, you
must state your intention
on your registration
form or with the registration
contact person listed (see FOR FURTHER INFORMATION CONTACT). You must submit
a written
statement at the time of registration
for each discussion
wish to address, the names and addresses of all individuals
participate,
Electronic
and the approximate
registration
question you
that plan to
time requested to make your presentation.
for this hearing is available at http://
www.accessdata.fda.gov/scripts/oc/dockets/meetings/meetingdocket.cfm.
Registrations
will be accepted on a first-come,
first-served
basis. Individuals
3
who register to make an oral presentation
time for their presentation
presentations,
will be notified
of the scheduled
prior to the hearing. Depending
on the number of
FDA may need to limit the time allotted for each presentation.
All participants
are encouraged to attend the entire day. Presenters must
submit two copies of each presentation
accommodations
due to a disability,
given. If you need special
please inform the registration
person when you register. Presentations
subject matter identified
will be limited
contact
to the questions and
in section III of this document.
SUPPLEMENTARY INFORMATION:
I. Background
The Safe Medical Devices Act (SMDA) of 1990 explicitly
existence of products that “constitute
biological
product”
and provided
a combination
a mechanism
component
would be assigned the administrative
a particular
combination
Administration
Modernization
product as a drug, biological
to determining
the product
of a drug, device, or
for determining
responsibility
which agency
of regulating
product (21 U.S.C. 353(g)). The Food and Drug
Act of 1997 (FDAMA)
assignment process by providing
addition
recognized the
a mechanism
product,
further refined the
to request that FDA classify a
device, or a combination
which agency component
product,
will be assigned to regulate
(21 U.S.C. 36Obbb-2).
As defined in § 3.2(e) (21 CFR 3.2(e)), the term combination
a product comprised
device, or biologic
product means
of two or more different regulated components,
(for example, a syringe prefilled
e.g., drug,
with a drug); or two or
more separate products packaged together as one unit (for example, a kit
containing
in
drapes, needles, a syringe, a local anesthetic and a topical
4
antiseptic).
A combination
product is also defined to include
is intended
for use only with an approved product where both are required
to achieve the intended use, indication,
a product that
or effect, and the labeling of the
approved product needs to be changed to reflect this use. For example, if a
device to aerosolize medication
works only with a specific aerosolized
drug,
the device would be labeled for use with this drug and the two products would
be a combination
includes
product. Finally,
any investigational
another investigational
intended
use, indication,
the combination
product
definition
product that is intended to be used only with
product where both are required to achieve the
or effect.
In accordance with section 503(g)(l)
of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 353(g)(l)), the agency is required to assign
premarket review responsibility
product’s
“primary
products based on the
mode of action.” The designation
does not preclude consultations
such consultation
for combination
of an agency component
with other agency components,
is used, the involvement
and when
of more than one center in the
premarket review process presents unique challenges in review management.
In addition,
where the agency finds it is appropriate,
option to require separate applications
or separate agency components)
combination
to be approved (by either the lead center
for the individual
product. FDA recognizes that requiring
agency component
may present additional
instances strives to coordinate
the agency reserves the
components
of a
the approval of a second
issues for the applicant
and in those
the reviews to the greatest extent possible.
A number of issues have been raised regarding FDA’s regulation
combination
predictability,
products. These include
and transparency
of
concerns about the consistency,
of the assignment (jurisdiction)
process; issues
5
related to the management
and timeliness
of the review process when two (or
more) FDA centers have review responsibilities
of clarity about the postmarket
products;
regulatory
controls
and the lack of clarity regarding
when applications
for a combination
to more than one agency component
has established
Ombudsman
a Combination
to provide
products
regulation
of standard
of combination
operating
procedures
review process, centralized
of combination
products,
that relate to combination
the Office of the
to improve
These initiatives
to improve
monitoring
In addition
Products Program is working
a variety of initiatives
products.
and
and the FDA centers on
issues, the Combination
with the centers to develop
products,
to the Centers for these activities.
to serving as a point of contact for industry
combination
that will ensure
of combination
Products Program within
support
such as
are needed.
and procedures
and effective review and regulation
lack
to combination
certain agency policies,
FDA recognizes the need to have policies
the efficient
applicable
product;
the review and
include
the development
the management
of the intercenter
of the progress of premarket
and the development
of guidance
reviews
on policy issues
products.
II. Purpose and Scope of the Hearing
The agency recognizes the importance
facilitating
the introduction
technologies
would
and products
otherwise
only unique
that result from the combination
under different
questions,
where and how such products
and consistent
regulatory
the public health by
of safe and effective new products.
be regulated
scientific
of protecting
regulatory
but also regulatory
should be regulated
oversight.
New
of components
authorities
that
raise not
challenges related to
in order to ensure adequate
6
FDA is calling this meeting to discuss the agency’s processes for the
assignment, premarket review, and postmarket
regulation
of combination
products in general. The meeting is another step in the agency’s continuing
effort to elicit information
on combination
helpful
to the refinement
of the agency’s policies
products, and will build upon the June 24, 2002, part 15
hearing held to discuss the assignment
products comprised
and premarket review of wound healing
of living human cells in combination
The hearing is limited
to discussion
§ 3.2(e). Combinations
of two devices, two drugs, or two biologics
considered
combination
products as defined in
are not
products under § 3.2(e) and are beyond the scope of
this meeting. Discussion
products,
of combination
with a device matrix.
of the assignment of specific types of combination
or of premarket review or testing requirements
for specific products,
is also beyond the scope of the meeting. Examples of issues raised for
particular
products may, however, be appropriate
for illustration
purposes.
III. Issues for Discussion
Combination
products often involve
raise unique scientific,
responsibility
technical,
cutting edge, novel technologies
policy and regulatory
for the premarket review and regulation
that
issues. Multi-center
of combination
products
creates special challenges with respect to both the scientific
and administrative
aspects of review management.
of components
that would normally
In addition,
the combination
be regulated under different regulatory
introduces
additional
factors to consider in the formulation
regulatory
requirements.
authorities
of appropriate
FDA recognizes the need to have policies and
procedures that will ensure the efficient
and effective review and regulation
of combination
this meeting to obtain stakeholders’
products, and is holding
_
7
.
views on the issues raised by, and suggestions for, the review and regulation
of combination
products.
To assist in the development
products and appropriate
agency invites information
of consistent
premarket
policies on assignment of these
and postmarket
regulatory
policies,
the
and comments on the issues and questions listed
in the next section of this document.
A. Assignment
and In tercen ter Agreements
Issue:
One goal of FDA’s regulatory
process has been the establishment
credible, consistent and predictable
(“transparent”)
assignment and review of human drugs, biologics,
appropriate
frequently
centers. Prior to 1991, confusion
cited complaint
was a
SMDA required that FDA
products to the FDA components
based on the product’s
in 1991, the Center for Biologics
and Research (CBER), the Center for Devices and Radiological
Health (CDRH), and the Center for Drug Evaluation
developed working
agreements (“Intercenter
assignment and regulatory pathways
products, including
identify
and devices to the
by regulated industry.
primary mode of action. Furthermore,
Evaluation
for the
over product jurisdiction
As described in section I of this document,
assign combination
framework
of a
Agreements”)
some types of combination
products. The Agreements
for regulating
of products, and in some instances, the applicable
in technology
Agreements continue
and scientific
addressing the
for specified products or classes of
the lead center that will be responsible
the Intercenter
and Research (CDER)
regulatory
particular
types
authority.
While
to provide useful guidance, the evolution
knowledge
about the mode of action of medical
products has in some cases pushed the usefulness of the current Intercenter
8
.
Agreements
past their limits.
the Intercenter
appropriate
FDA recognizes the need to revise and update
Agreements to reflect decisions made since 1991 and an
division
Stakeholders
of labor among the centers.
have voiced concern about a perceived lack of consistency
in the assignment of combination
products.
attributed
to potential
in the interpretation
product’s
“primary
differences
This perception
is sometimes
of a combination
mode of action,” a term that is not defined in the statute.
The assignment process may also appear to be inconsistent
if two products
that appear to be similar in nature are assigned to different
centers based on
differences
particular
in their primary
mode of action. When review responsibility
for
products of a given type is split between two centers, it may lead
to inconsistencies
in the type of premarket
review policies, postmarket regulatory
regulatory
authorities
applied,
controls, and other factors relevant to
product regulation.
Another
complaint
frequently
cited about the assignment of combination
products is the lack of transparency.
of significant
“jurisdictional
jurisdictional
In an effort to keep stakeholders
apprised
decisions, FDA has begun to post a series of
updates” on its Combination
www.fda.gov/oc/ombudsman/combination.html.
Products Web site http://
These jurisdictional
updates
report prior agency decisions only and are not policy statements. In
determining
whether Web publication
of a jurisdictional
update is appropriate
for a product,
FDA will take into account the current level of interest in the
jurisdictional
issue, the extent to which the class of products can be clearly
described, the extent to which the existence and description
products has been made public,
of the class of
and related factors. In cases where it is not
possible to adequately describe the subject of a jurisdictional
decision and still
9
protect confidential
and trade secret information,
jurisdictional
updates will
not be available.
Questions:
1. What types of guiding
scientific
and policy principles
in its revisions to the existing Intercenter
responsibility
should FDA use
Agreements that allocate review
for human medical products?
2. What factors should FDA consider in determining
the primary
mode
of action of a combination
product? In instances where the primary mode of
action of the combination
product
cannot be determined
with certainty,
other factors should the agency consider in assigning primary
there a hierarchy
among these additional
what
jurisdiction?
Is
factors that should be considered
order to ensure adequate review and regulation
in
(e.g., which component
presents greater safety questions)?
B. Marketing
Applications
The SMDA required that the primary
product must determine
mode of action of a combination
which FDA center would be responsible
review, but did not address which authorities,
marketing
application,
beyond authorizing
which type of
should be used to review the combination
product,
FDA to use any resources necessary to ensure an adequate
premarket review. The selection of regulatory
combination
including
for premarket
product is intended
but may also affect the potential
of certain regulatory mechanisms
authorities
to ensure appropriate
for generic competition
to be applied to a
review and regulation,
and the availability
or processes (e.g., a device component
combination
product regulated solely under the new drug application
or biological
license application
(BLA) authorities
of a
(NDA)
would not be eligible for
10
reclassification
or review
under
section 510(k) of the act premarket
notification).
As stated in 21 CFR 3.4(b), FDA may require separate applications
different
components
agency component
regulation
of a combination
as having primary jurisdiction
of a combination
component
requirement
product (“The designation
product
for the premarket review and
or, in appropriate
by FDA of separate applications.“).
because the most appropriate
regulatory
have questioned
for the components
is important
approach for a given combination
and policy issues.
the need for separate marketing
of a combination
application
were considered to be advantageous
for future development
and/or marketing
approach is universally
preferred or most appropriate
opportunities.
the agency recognizes that it is important
criteria for determining
On the other
have objected to FDA’s decision to require only a single
because separate applications
perspective,
applications
product, perhaps based on the perception
that the regulatory burden would be less with a single application.
hand, some applicants
by that
cases, the
This flexibility
product may need to be tailored to the associated scientific
Some applicants
of one
does not preclude consultations
with other agency components
for the
whether one application
While no single
from a regulatory
to have established
or two would be more
appropriate.
Questions:
3. What are the general scientific
followed
and policy principles
in selecting the premarket regulatory
combination
authorities
products? Is one premarket review mechanism
approval (PMA), premarket notification
that should be
to be applied to
(e.g., premarket
(510(k)), new drug application
(NDA),
11
or biologic
licensing
regulating
combination
4. Recognizing
application
(BLA)) more suitable than another for
products?
the need to ensure product safety and effectiveness,
criteria should FDA use to determine whether a single application
applications
regulation
for the individual
of a combination
components
reporting
or separate
would be most appropriate
for
product? For example, FDA may determine
it is necessary to apply elements of different
combination
what
regulatory
authorities
that
to a
product to ensure safety and efficacy (e.g., device postmarketing
for the combination
practices (CGMPs) applicable
to apply a mixed regulatory
product, with drug current good manufacturing
to the drug component
approach influence
only). Should the need
whether one application
or
two are more appropriate?
C. Other Issues
Issues:
Combination
effectiveness,
combination
and regulatory
products sometime raise concerns about safety and
or risks to the public health, arising specifically
nature of the product.
authorities
from the
The agency may draw from the statutory
applicable
to all components
of the combination
product in order to ensure adequate review of the safety and effectiveness
a product. For example, a drug-coated
Quality
Systems Regulation
manufacturing
requirements,
of
device may be subject to the device
for the device component,
to drug good
practices (GMPs) for the drug coating, and to a mix of
as appropriate,
While this flexibility
for the combined product.
is appropriate
to enable FDA to best promote and
protect public health and address unique issues arising from the combination
of two products that would otherwise be separately regulated, stakeholders
12
have complained
transparency
that there is a lack of consistency,
in the application
Since manufacturers
of postmarket
predictability,
requirements
must design their manufacturing
the types of products they produce, an applicant
and
for such products.
and quality systems for
that primarily
manufacturers
devices, for example, may not have the systems in place to manufacture
coated device that will be subject to drug GMPs. Similarly,
confusion
in deciding which adverse event monitoring
for a combination
product.
Applicants
regulations
report that reporting
has been required in some cases, and is duplicative
applicants
a drugreport
to follow
to multiple
centers
and unnecessary.
Questions:
5. What scientific
the appropriate
and policy principles
manufacturing
Current Good Manufacturing
applicable
6.
to combination
What scientific
the appropriate
and quality system regulatory
adverse event reporting
should be followed
requirements
of combination
(e.g., the drugs and
other issues related to
products? (Examples may include cross
to be used together, though manufactured
companies; and application
products.)
in determining
product?
labeling of products intended
combination
(e.g.,
system, Medical Device Reporting) to be
7. What other comments do you have concerning
different
authorities
products?
biologics adverse event reporting
FDA regulation
in determining
Practices versus Quality System Regulation)
and policy principles
applied to a combination
should be followed
of promotion
and advertising
by
policies to
13
IV. Notice of Hearing Under Part 15
The Commissioner
of Food and Drugs (the Commissioner)
is announcing
that the public hearing will be held in accordance with part 15. The hearing
will have a presiding
officer, who will be accompanied
by senior management
from CBER, CDER, CDRH, and the agency’s Combination
Persons who wish to participate
Products Program.
in the part 15 hearing must file a written
or electronic
notice of participation
with the Dockets Management
ADDRESSES].
To ensure timely handling,
Branch (see
any outer envelope should be clearly
marked with the docket number listed at the head of this notice along with
the statement “Combination
written
Products Hearing.” Groups should submit two
copies. The notice of participation
address; telephone number; affiliation,
(e.g., the organization
of the presentation
should contain the person’s name;
if any; the sponsor of the presentation
paying travel expenses or fees), if any; a brief summary
(including
addressed); and approximate
the specific discussion
questions that will be
amount of time requested for the presentation.
The agency requests that interested persons and groups having similar interests
consolidate
their comments and present them through a single representative.
After reviewing
the notices of participation
and accompanying
information,
FDA will schedule each appearance and notify each participant
of the time allotted to the person and the approximate
presentation
time the person’s oral
is scheduled to begin. If time permits, FDA may allow interested
persons attending the hearing who did not submit a written
of participation
by telephone
in advance to make an oral presentation
or electronic
at the conclusion
notice
of
the hearing. The hearing schedule will be available at the hearing. After the
hearing, the hearing schedule will be placed on file in the Dockets Management
Branch under the docket number listed at the head of this notice.
14
Under § 15.30(f), the hearing is informal,
apply. No participant
Only the presiding
may interrupt
and the rules of evidence do not
the presentation
of another participant.
officer and panel members may question any person during
or at the conclusion
of each presentation.
Public hearings under part 15 are subject to FDA’s policy and procedures
for electronic
media coverage of FDA’s public administrative
proceedings
(part
10, subpart C (21 CFR part 10, subpart C)). Under § 10.205, representatives
the electronic media may be permitted,
videotape,
subject to certain limitations,
film, or otherwise record FDA’s public administrative
including
presentations
by participants.
stipulated
in § 15.30(b). The transcript
to
proceedings,
The hearing will be transcribed
as
of the hearing will be available on the
Internet at http://www.fda.gov/ohrms/dockets,
transcript
of
and orders for copies of the
can be placed at the meeting or through the Freedom of Information
Staff (HFI-35),
Food and Drug Administration,
5600 Fishers Lane, Rockville,
MD 20857.
Any handicapped
persons requiring
special accommodations
to attend the
hearing should direct those needs to the contact person (see FOR FURTHER
INFORMATION CONTACT).
To the extent that the conditions
notice, conflict
with any provisions
waiver of those provisions
for the hearing, as described in this
set out in part 15, this notice acts as a
as specified in § 15.30(h).
V. Request for Comments
Interested persons may submit to the Dockets Management
ADDRESSES)
consideration
written
or electronic
notices of participation
Branch (see
and comments for
at the hearing. To permit time for all interested persons to submit
data, information,
or views on this subject, the administrative
record of the
15
a
hearing will remain open following
additional
the hearing. Persons who wish to provide
materials for consideration
Dockets Management
Branch (see ADDRESSES). You should annotate and
organize your comments to identify
(see section III of this document).
to be submitted,
to be identified
should file these materials with the
the specific questions to which they refer
Two copies of any mailed comments are
except that individuals
may submit one copy. Comments are
with the docket number at the heading of this document.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday. Transcipts
for review at the Dockets Management
VI. Electronic
of the hearing also will be available
Branch.
Access
Persons with access to the Internet may obtain more information
this hearing or combination
ombudsman/combination.html.
about
products in general at http://www.fda.gov/oc/
16
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