[Federal Register Volume 67, Number 208 (Monday, October 28, 2002)]
[Notices]
[Pages 65801-65804]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-27267]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0445]


FDA Regulation of Combination Products; Public Hearing

AGENCY: Food and Drug Administration.

ACTION: Notice of public hearing; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
hearing to discuss the assignment, premarket review, and postmarket 
regulation of combination products. Combination products (defined in 
more detail later in this document) are products containing a 
combination of drugs, devices, or biological products. These products 
often are novel and have significant potential to enhance the public 
health. The purpose of the hearing is to solicit information and views 
from interested persons on the issues and concerns relating to the 
assignment, premarket review, and postmarket regulation of combination 
products. FDA is proposing specific questions, and the agency is 
interested in responses to these questions and any other pertinent 
information stakeholders would like to share.

DATES: The public hearing will be held on November 25, 2002, from 9 
a.m. to 5 p.m. Submit written or electronic notices of participation by 
close of business on November 8, 2002. Written and electronic comments 
will be accepted until January 24, 2003.

ADDRESSES: The public hearing will be held at the DoubleTree Hotel, 
1750 Rockville Pike, Rockville, MD. Directions to the hotel can be 
found at http://www.doubletreerockville.com.
    Submit written or electronic notices of participation and comments 
to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852; or e-
mail [email protected]; or on the Internet at http://www.accessdata.fda.gov/scripts/oc/dockets/commentdocket.cfm. 
Transcripts of the hearing will be available for review at the Dockets 
Management 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 Products 
Program (HF-7), Food and Drug Administration, 5600 Fishers Lane, rm. 
14B-03, Rockville, MD 20857, 301-827-3390, FAX 301-480-8039, e-mail: 
[email protected].

Registration Information and Requests for Oral Presentation

    Preregistration by written notice is necessary to ensure 
participation. The procedures governing 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, fax number, and 
e-mail address. If you wish to make an oral presentation 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 
question you wish to address, the names and addresses of all 
individuals that plan to participate, and the approximate time 
requested to make your presentation. Electronic registration 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 who register to make an 
oral presentation will be notified of the scheduled time for their 
presentation prior to the hearing. Depending on the number of 
presentations, 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 given. If you 
need special accommodations due to a disability, please inform the 
registration contact person when you register. Presentations will be 
limited to the questions and subject matter identified in section III 
of this document.

SUPPLEMENTARY INFORMATION:

I. Background

    The Safe Medical Devices Act (SMDA) of 1990 explicitly recognized 
the existence of products that ``constitute a combination of a drug, 
device, or biological product'' and provided a mechanism for 
determining which agency component would be assigned the administrative 
responsibility of regulating a particular combination product (21 
U.S.C. 353(g)). The Food and Drug Administration Modernization Act of 
1997 (FDAMA) further refined the assignment process by providing a 
mechanism to request that FDA classify a product as a drug, biological 
product, device, or a combination product, in addition to determining 
which agency component will be assigned to regulate the product (21 
U.S.C. 360bbb-2).
    As defined in Sec.  3.2(e) (21 CFR 3.2(e)), the term combination 
product means a product comprised of two or more different regulated 
components, e.g., drug, device, or biologic (for example, a syringe 
prefilled with a drug); or two or more separate products packaged 
together as one unit (for example, a kit containing drapes, needles, a 
syringe, a local anesthetic and a topical antiseptic). A combination 
product is also defined to include a product that is intended for use 
only with an approved product where both are required to achieve the 
intended use, indication, 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 product. Finally, the combination 
product definition

[[Page 65802]]

includes any investigational product that is intended to be used only 
with another investigational product where both are required to achieve 
the intended use, indication, or effect.
    In accordance with section 503(g)(1) 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 for combination products based 
on the product's ``primary mode of action.'' The designation of an 
agency component does not preclude consultations with other agency 
components, and when such consultation is used, the involvement 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, the agency reserves the option to require separate 
applications to be approved (by either the lead center or separate 
agency components) for the individual components of a combination 
product. FDA recognizes that requiring the approval of a second agency 
component may present additional issues for the applicant and in those 
instances strives to coordinate the reviews to the greatest extent 
possible.
    A number of issues have been raised regarding FDA's regulation of 
combination products. These include concerns about the consistency, 
predictability, and transparency of the assignment (jurisdiction) 
process; issues related to the management and timeliness of the review 
process when two (or more) FDA centers have review responsibilities for 
a combination product; lack of clarity about the postmarket regulatory 
controls applicable to combination products; and the lack of clarity 
regarding certain agency policies, such as when applications to more 
than one agency component are needed.
    FDA recognizes the need to have policies and procedures that will 
ensure the efficient and effective review and regulation of combination 
products, and has established a Combination Products Program within the 
Office of the Ombudsman to provide support to the Centers for these 
activities. In addition to serving as a point of contact for industry 
and the FDA centers on combination products issues, the Combination 
Products Program is working with the centers to develop a variety of 
initiatives to improve the review and regulation of combination 
products. These initiatives include the development of standard 
operating procedures to improve the management of the intercenter 
review process, centralized monitoring of the progress of premarket 
reviews of combination products, and the development of guidance on 
policy issues that relate to combination products.

II. Purpose and Scope of the Hearing

    The agency recognizes the importance of protecting the public 
health by facilitating the introduction of safe and effective new 
products. New technologies and products that result from the 
combination of components that would otherwise be regulated under 
different regulatory authorities raise not only unique scientific 
questions, but also regulatory challenges related to where and how such 
products should be regulated in order to ensure adequate and consistent 
regulatory oversight.
    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 helpful to the 
refinement of the agency's policies on combination products, and will 
build upon the June 24, 2002, part 15 hearing held to discuss the 
assignment and premarket review of wound healing products comprised of 
living human cells in combination with a device matrix. The hearing is 
limited to discussion of combination products as defined in Sec.  
3.2(e). Combinations of two devices, two drugs, or two biologics are 
not considered combination products under Sec.  3.2(e) and are beyond 
the scope of this meeting. Discussion of the assignment of specific 
types of combination products, 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 cutting edge, novel technologies 
that raise unique scientific, technical, policy and regulatory issues. 
Multi-center responsibility for the premarket review and regulation of 
combination products creates special challenges with respect to both 
the scientific and administrative aspects of review management. In 
addition, the combination of components that would normally be 
regulated under different regulatory authorities introduces additional 
factors to consider in the formulation of appropriate regulatory 
requirements. FDA recognizes the need to have policies and procedures 
that will ensure the efficient and effective review and regulation of 
combination products, and is holding this meeting to obtain 
stakeholders' views on the issues raised by, and suggestions for, the 
review and regulation of combination products.
    To assist in the development of consistent policies on assignment 
of these products and appropriate premarket and postmarket regulatory 
policies, the agency invites information and comments on the issues and 
questions listed in the next section of this document.

A. Assignment and Intercenter Agreements

Issue:
    One goal of FDA's regulatory process has been the establishment of 
a credible, consistent and predictable (``transparent'') framework for 
the assignment and review of human drugs, biologics, and devices to the 
appropriate centers. Prior to 1991, confusion over product jurisdiction 
was a frequently cited complaint by regulated industry.
    As described in section I of this document, SMDA required that FDA 
assign combination products to the FDA components based on the 
product's primary mode of action. Furthermore, in 1991, the Center for 
Biologics Evaluation and Research (CBER), the Center for Devices and 
Radiological Health (CDRH), and the Center for Drug Evaluation and 
Research (CDER) developed working agreements (``Intercenter 
Agreements'') addressing the assignment and regulatory pathways for 
specified products or classes of products, including some types of 
combination products. The Agreements identify the lead center that will 
be responsible for regulating particular types of products, and in some 
instances, the applicable regulatory authority. While the Intercenter 
Agreements continue to provide useful guidance, the evolution in 
technology and scientific knowledge about the mode of action of medical 
products has in some cases pushed the usefulness of the current 
Intercenter Agreements past their limits. FDA recognizes the need to 
revise and update the Intercenter Agreements to reflect decisions made 
since 1991 and an appropriate division of labor among the centers.
    Stakeholders have voiced concern about a perceived lack of 
consistency in the assignment of combination products. This perception 
is sometimes attributed to potential differences in the interpretation 
of a combination product's ``primary 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

[[Page 65803]]

assigned to different centers based on differences in their primary 
mode of action. When review responsibility for particular products of a 
given type is split between two centers, it may lead to inconsistencies 
in the type of premarket regulatory authorities applied, review 
policies, postmarket regulatory controls, and other factors relevant to 
product regulation.
    Another complaint frequently cited about the assignment of 
combination products is the lack of transparency. In an effort to keep 
stakeholders apprised of significant jurisdictional decisions, FDA has 
begun to post a series of ``jurisdictional updates'' on its Combination 
Products Web site http://www.fda.gov/oc/ombudsman/combination.html. 
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 of the class of products 
has been made public, and related factors. In cases where it is not 
possible to adequately describe the subject of a jurisdictional 
decision and still protect confidential and trade secret information, 
jurisdictional updates will not be available.
Questions:
    1. What types of guiding scientific and policy principles should 
FDA use in its revisions to the existing Intercenter Agreements that 
allocate review responsibility 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, what other factors should the agency consider in assigning 
primary jurisdiction? Is there a hierarchy among these additional 
factors that should be considered in order to ensure adequate review 
and regulation (e.g., which component presents greater safety 
questions)?

B. Marketing Applications

    The SMDA required that the primary mode of action of a combination 
product must determine which FDA center would be responsible for 
premarket review, but did not address which authorities, including 
which type of marketing application, should be used to review the 
combination product, beyond authorizing FDA to use any resources 
necessary to ensure an adequate premarket review. The selection of 
regulatory authorities to be applied to a combination product is 
intended to ensure appropriate review and regulation, but may also 
affect the potential for generic competition and the availability of 
certain regulatory mechanisms or processes (e.g., a device component of 
a combination product regulated solely under the new drug application 
(NDA) or biological license application (BLA) authorities would not be 
eligible for 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 
for the different components of a combination product (``The 
designation of one agency component as having primary jurisdiction for 
the premarket review and regulation of a combination product does not 
preclude consultations by that component with other agency components 
or, in appropriate cases, the requirement by FDA of separate 
applications.''). This flexibility is important because the most 
appropriate regulatory approach for a given combination product may 
need to be tailored to the associated scientific and policy issues. 
Some applicants have questioned the need for separate marketing 
applications for the components of a combination product, perhaps based 
on the perception that the regulatory burden would be less with a 
single application. On the other hand, some applicants have objected to 
FDA's decision to require only a single application because separate 
applications were considered to be advantageous for future development 
and/or marketing opportunities. While no single approach is universally 
preferred or most appropriate from a regulatory perspective, the agency 
recognizes that it is important to have established criteria for 
determining whether one application or two would be more appropriate.
Questions:
    3. What are the general scientific and policy principles that 
should be followed in selecting the premarket regulatory authorities to 
be applied to combination products? Is one premarket review mechanism 
(e.g., premarket approval (PMA), premarket notification (510(k)), new 
drug application (NDA), or biologic licensing application (BLA)) more 
suitable than another for regulating combination products?
    4. Recognizing the need to ensure product safety and effectiveness, 
what criteria should FDA use to determine whether a single application 
or separate applications for the individual components would be most 
appropriate for regulation of a combination product? For example, FDA 
may determine that it is necessary to apply elements of different 
regulatory authorities to a combination product to ensure safety and 
efficacy (e.g., device postmarketing reporting for the combination 
product, with drug current good manufacturing practices (CGMPs) 
applicable to the drug component only). Should the need to apply a 
mixed regulatory approach influence whether one application or two are 
more appropriate?

C. Other Issues

Issues:
    Combination products sometime raise concerns about safety and 
effectiveness, or risks to the public health, arising specifically from 
the combination nature of the product. The agency may draw from the 
statutory and regulatory authorities applicable to all components of 
the combination product in order to ensure adequate review of the 
safety and effectiveness of a product. For example, a drug-coated 
device may be subject to the device Quality Systems Regulation for the 
device component, to drug good manufacturing practices (GMPs) for the 
drug coating, and to a mix of requirements, as appropriate, for the 
combined product.
    While this flexibility 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 have complained that there is a lack of 
consistency, predictability, and transparency in the application of 
postmarket requirements for such products. Since manufacturers must 
design their manufacturing and quality systems for the types of 
products they produce, an applicant that primarily manufacturers 
devices, for example, may not have the systems in place to manufacture 
a drug-coated device that will be subject to drug GMPs. Similarly, 
applicants report confusion in deciding which adverse event monitoring 
regulations to follow for a combination product. Applicants report that 
reporting to multiple centers has been required in some cases, and is 
duplicative and unnecessary.
Questions:
    5. What scientific and policy principles should be followed in 
determining the appropriate manufacturing and quality system regulatory 
authorities (e.g., Current

[[Page 65804]]

Good Manufacturing Practices versus Quality System Regulation) 
applicable to combination products?
    6. What scientific and policy principles should be followed in 
determining the appropriate adverse event reporting requirements (e.g., 
the drugs and biologics adverse event reporting system, Medical Device 
Reporting) to be applied to a combination product?
    7. What other comments do you have concerning other issues related 
to FDA regulation of combination products? (Examples may include cross 
labeling of products intended to be used together, though manufactured 
by different companies; and application of promotion and advertising 
policies to combination products.)

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 
Products Program.
    Persons who wish to participate in the part 15 hearing must file a 
written or electronic notice of participation with the Dockets 
Management Branch (see ADDRESSES). To ensure timely handling, any outer 
envelope should be clearly marked with the docket number listed at the 
head of this notice along with the statement ``Combination Products 
Hearing.'' Groups should submit two written copies. The notice of 
participation should contain the person's name; address; telephone 
number; affiliation, if any; the sponsor of the presentation (e.g., the 
organization paying travel expenses or fees), if any; a brief summary 
of the presentation (including the specific discussion questions that 
will be addressed); and approximate 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 by telephone of the time 
allotted to the person and the approximate time the person's oral 
presentation is scheduled to begin. If time permits, FDA may allow 
interested persons attending the hearing who did not submit a written 
or electronic notice of participation in advance to make an oral 
presentation at the conclusion 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.
    Under Sec.  15.30(f), the hearing is informal, and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding 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 
Sec.  10.205, representatives of the electronic media may be permitted, 
subject to certain limitations, to videotape, film, or otherwise record 
FDA's public administrative proceedings, including presentations by 
participants. The hearing will be transcribed as stipulated in Sec.  
15.30(b). The transcript of the hearing will be available on the 
Internet at http://www.fda.gov/ohrms/dockets, and orders for copies of 
the transcript 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 for the hearing, as described in 
this notice, conflict with any provisions set out in part 15, this 
notice acts as a waiver of those provisions as specified in Sec.  
15.30(h).

V. Request for Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic notices of participation and comments 
for consideration at the hearing. To permit time for all interested 
persons to submit data, information, or views on this subject, the 
administrative record of the hearing will remain open following the 
hearing. Persons who wish to provide additional materials for 
consideration should file these materials with the Dockets Management 
Branch (see ADDRESSES). You should annotate and organize your comments 
to identify the specific questions to which they refer (see section III 
of this document). Two copies of any mailed comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified 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 of the hearing also will be 
available for review at the Dockets Management Branch.

VI. Electronic Access

    Persons with access to the Internet may obtain more information 
about this hearing or combination products in general at http://www.fda.gov/oc/ombudsman/combination.html.

    Dated: October 18, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-27267 Filed 10-25-02; 8:45 am]
BILLING CODE 4160-01-S