[Federal Register Volume 71, Number 188 (Thursday, September 28, 2006)]
[Notices]
[Pages 56988-56991]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-15967]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2006N-0378]
Review of Agreements, Guidances, and Practices Specific to
Assignment of Combination Products in Compliance With the Medical
Device User Fee and Modernization Act of 2002; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Federal Food, Drug, and Cosmetic Act (the act) requires
the Food and Drug Administration (FDA) to review each agreement,
guidance, or practice that is specific to the assignment of combination
products to agency centers and to determine whether the agreement,
guidance, or practice is consistent with the requirements of the act.
In carrying out the review, the agency is to consult with stakeholders
and directors of the agency centers, and then determine whether to
continue in effect, modify, revise, or eliminate such an agreement,
guidance, or practice. The agency has completed its initial review of
relevant agreements, guidances, and practices, and has consulted with
directors of the agency centers. This document provides the preliminary
results of the agency's review and requests stakeholder comments to
fulfill the act's requirement for stakeholder consultation prior to the
agency's final determination whether to continue the agreements,
guidance, or practices in effect, or to modify, revise, or eliminate
them.
DATES: Submit written or electronic comments by November 27, 2006.
ADDRESSES: Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Suzanne O'Shea, Office of Combination
Products (HFG-3), Food and Drug Administration, 15800 Crabbs Branch
Way, suite 200, Rockville, MD 20855, 301-427-1934, FAX: 301-427-1935,
e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
In October 2002, the Medical Device User Fee and Modernization Act
(MDUFMA) added section 503(g)(4)(F) (21 U.S.C. 353(g)(4)(F)) to the
act. This new provision requires the Secretary of the Department of
Health and Human Services (the Secretary), acting through the Office of
Combination Products (OCP), to review each agreement, guidance, or
practice of the Secretary that is specific to the assignment of
combination products to agency centers and to determine whether the
agreement, guidance, or practice is consistent with the requirements of
section 503(g) of the act. In carrying out such a review, OCP is to
consult with stakeholders and the directors of the agency centers.
After such consultation, OCP is to determine whether to continue in
effect, modify, revise, or eliminate such agreement, guidance, or
practice, and publish in the Federal Register a notice of the
availability of any modified or revised agreement, guidance, or
practice.
This notice provides the preliminary results of OCP's review of
agreements, guidances, and practices that were in effect at the time
section 503(g)(4)(F) of the act was enacted for their consistency with
the act's requirement for the prompt assignment of combination products
to agency centers on the basis of the products' primary mode of action
(PMOA).\1\ The directors of relevant
[[Page 56989]]
agency centers have been consulted in this review. The agency now seeks
stakeholder comment with respect to the following issues: (1) Whether
the agency has identified all agreements, guidances, and practices
specific to the assignment of combination products that should have
been included in this review; (2) whether the agency's conclusions
regarding the consistency of the agreements, guidances, and practices
with the act's requirement that combination products be assigned
promptly based on their PMOA is accurate; and (3) whether the
identified agreements, guidances, and practices should be continued in
effect, modified, revised, or eliminated.
---------------------------------------------------------------------------
\1\ Section 503(g)(1) of the act requires that combination
products be assigned to an agency center for regulation and review
on the basis of the product's PMOA. In addition, section
503(g)(4)(B) of the act directs OCP to ensure the prompt assignment
of combination products to agency centers.
---------------------------------------------------------------------------
Upon receipt and review of stakeholder input, the agency will
publish another Federal Register notice announcing its determinations
and the availability of any modified or revised agreements, guidances,
or practices.
II. Primary Mode of Action--The Principle Underlying the Assignment of
Combination Products to Agency Centers
Section 503(g)(1) of the act requires that combination products be
assigned to a lead agency center based upon the agency's determination
of the product's PMOA. The agency published a final rule defining the
PMOA of a combination product in the Federal Register of August 25,
2005 (70 FR 49848), after consulting with directors of the relevant
agency centers and other agency officials, and obtaining stakeholder
input through notice and comment rulemaking. As defined in the
regulation, a combination product's PMOA is its single mode of action
that provides the most important therapeutic action of the product
(Sec. 3.2(m) (21 CFR 3.2(m))). The regulation includes an algorithm
that will be followed when the most important therapeutic action of a
combination product cannot be determined with reasonable certainty
(Sec. 3.4(b)). The regulation is intended to promote the public health
by codifying the agency's criteria for the assignment of combination
products in transparent, consistent, and predictable terms. The
regulation went into effect on November 23, 2005. A copy of the final
rule is available at http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.htm.
III. Agreements and Guidances Specific to the Assignment of Combination
Products
The agency has identified the three intercenter agreements (ICAs)
as the agreements or guidances specific to the assignment of
combination products described in section 503(g)(4)(F) of the act. The
three ICAs were entered into in 1991 by the Center for Biologics
Evaluation and Research (CBER), the Center for Drug Evaluation and
Research (CDER), and the Center for Devices and Radiological Health
(CDRH) shortly after Congress introduced the concept of combination
products in the Safe Medical Devices Act of 1990 (SMDA). Although the
three ICAs (i.e., the CDER-CDRH ICA, the CBER-CDER ICA, and the CBER-
CDRH ICA) differ in content, format, and scope, they are all specific
to the assignment of combination products because they explain how
various categories of both combination and single entity products were
classified\2\ and assigned\3\ to an agency center at the time the
documents were developed. The ICAs constitute guidance that is not
binding on the public or the agency (Sec. 3.5(a)(2)). The ICAs are
available at http://www.fda.gov/oc/combination/intercenter.html.
---------------------------------------------------------------------------
\2\ Classification refers to the determination of a product's
regulatory identity as a drug, device, biological product, or
combination product.
\3\ Assignment refers to the determination of the agency center
that will have primary jurisdiction for the review and regulation of
a product.
---------------------------------------------------------------------------
The agency has reviewed the ICAs and preliminarily determined that
they are generally consistent with the requirements of section 503(g)
of the act in that the principles used to assign combination products
described in the ICAs are based on a product's PMOA. The ICAs were
developed following the enactment of the statutory PMOA criterion used
to assign combination products to an agency center, and were developed
using the PMOA principle.
For example, the CDER-CDRH ICA assigns to CDRH products such as a
``device incorporating a drug component with the combination product
having the primary intended purpose of fulfilling a device function.''
The premise underlying the assignment to CDRH is that the device
component of such a product provides the most important therapeutic
action of the product. This ICA assigns to CDER prefilled delivery
systems, such as a ``device with primary purpose of delivering or
aiding in the delivery of a drug and distributed containing a drug.''
The premise of this assignment to CDER is that the device's primary
purpose in delivering or aiding in the delivery of a drug is
subordinate to the most important therapeutic action provided by the
drug product.
Similarly, the CBER-CDER ICA assigns to CDER ``combination products
that consist of a biological component and a drug component where the
biological component enhances the efficacy or ameliorates the toxicity
of the drug product.'' The premise underlying this assignment is that
the drug product provides the most important therapeutic action of the
product, while the biological product has a subordinate role in
enhancing such action.
FDA recognizes that, since the ICAs were written in 1991, new
products have been developed, new uses for existing products have been
devised, and additional laws, regulations, and guidances are in effect.
During this period, FDA has continued to classify and assign many new
products not specifically covered by the ICAs. In addition, some
jurisdictional decisions made since 1991 cover products that appear to
be part of a broad class of product included in an ICA, but are
classified and/or assigned in a way different from the class of product
because of the particular product's specific characteristics or use.
Many of these decisions have been made through the formal Request for
Designation (RFD) process. For these reasons, the body of
jurisdictional decisions has grown over time, and the ICAs have become
incomplete statements.
Moreover, in 2003 the agency administratively transferred many
therapeutic biological products from CBER to CDER. For this reason, the
CBER-CDER ICA is out of date.
IV. Preliminary Proposal to Continue in Effect the CDER-CDRH and CBER-
CDRH ICAs, and to Rescind the CBER-CDER ICA
The agency believes it is very important to provide transparency in
jurisdictional decisionmaking. Such transparency ensures predictability
and consistency of decisions, and decreases ambiguity and uncertainty
about agency perspectives. Moreover, as the bases for agency
decisionmaking become clearer, the need for formal RFDs and informal
inquiries covering specific products may diminish, which should
conserve resources for the industry and the agency.
A. CDER-CDRH and CBER-CDRH ICAs
The agency has reviewed the CDER-CDRH and CBER-CDRH ICAs and
preliminarily determined that they continue to provide helpful
nonbinding guidance, and so proposes to continue them in effect, with
the understanding that they should not be independently relied upon as
the most current, complete jurisdictional statements.
[[Page 56990]]
The agency considered updating the CDER-CDRH and CBER-CDRH ICAs as
a way to continue to provide transparency to its jurisdictional
decisionmaking. After consideration, however, the agency believes that
the goal of transparency can be achieved more effectively by other
means. The process of updating the ICAs would be time consuming, and
given the quick pace of product development, the updated ICAs would
soon be out of date as well. The agency believes that transparency is
better served by articulating the principles upon which it bases
determinations of a combination product's PMOA, and by frequently
issuing jurisdictional information on particular classes of products as
that information becomes available. The agency suggests that persons
wishing to get the most current information about jurisdictional
determinations consult the numerous other sources of information about
jurisdictional determinations described in this document, as well as
the ICAs.
B. CBER-CDER ICA
The 2003 administrative transfer of many therapeutic biological
products from CBER to CDER has rendered the CBER-CDER ICA out of date.
For this reason, the agency preliminarily proposes to rescind the CBER-
CDER ICA. A statement of the current assignment of biological products
to CBER and CDER is available at http://www.fda.gov/oc/combination/transfer.html.
V. Actions Taken to Increase Transparency of Jurisdictional
Decisionmaking
Since the enactment of MDUFMA, the agency has implemented, or is
developing, the following actions to increase the transparency of
jurisdictional decisionmaking:
A. Regulatory Definition of PMOA
As described previously in this document, the agency recently
published a final rule defining ``primary mode of action,'' which is
the basis for assigning a combination product to a lead center for
review. The regulation includes an algorithm that will be followed when
the most important therapeutic action of a combination product cannot
be determined with reasonable certainty. This clarification of the PMOA
principle is expected to significantly increase the transparency of the
reasoning underlying the agency's assignment of combination products to
an agency center.
B. Guidance for Industry and FDA Staff: How to Write a Request for
Designation (RFD)
The goal of the guidance is to provide recommendations regarding
the type of information a sponsor should submit in order for the agency
to determine the regulatory identity of a product as a drug, device,
biological product, or combination product, and to assign the product
to the appropriate agency component for review and regulation. The
guidance reflects the final rule defining the PMOA of a combination
product, and is expected to increase the transparency of the RFD
process by clarifying the kind of information that enables the agency
to make a prompt and appropriate assignment decision. The guidance is
available at http://www.fda.gov/oc/combination/howtowrite.html.
C. Jurisdictional Determinations
The agency has made available on the OCP Web site more than 220
capsular descriptions of prior RFD decisions. In selecting which
jurisdictional determinations were appropriate to summarize and make
public in this way, the agency considered the extent to which the
product could be suitably described, the extent to which the existence
and description of the product or similarly described products have
been made public, and related factors. The agency will continue to
update the list of capsular descriptions as new decisions are made and
as information on these products becomes publicly available. The
capsular descriptions are available at http://www.fda.gov/oc/combination/determinations.html.
D. Jurisdictional Updates
Jurisdictional updates are more detailed statements of the
classification and assignment of various product classes. They reflect
past agency decisions, and are not intended to be policy statements.
Jurisdictional updates generally contain information about the basis
for the assignment and classification decisions that have been made.
The agency selects product classes to be the subject of jurisdictional
updates based on the agency's perception of 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. Additional jurisdictional updates will be issued as
appropriate. Jurisdictional updates are available at http://www.fda.gov/oc/combination/updates.html.
E. RFD Decision Letters
The agency posts on the OCP Web site RFD decision letters for
products that have been approved or cleared. These letters have been
redacted to remove trade secret and confidential commercial information
in accordance with the Freedom of Information Act. It should be noted
that, in some cases, products undergo changes in name, sponsor, design,
or other key aspects following the agency's issuance of an RFD
decision. The agency will post RFD decision letters when it is certain
that the covered product has been approved or cleared, but it should be
recognized that the posting may be incomplete. Posting of these
letters, which generally include the agency's reasoning behind the RFD
decision, is intended to provide additional transparency on the
jurisdictional process. The letters are available at http://www.fda.gov/oc/combination/rfd.html.
F. Chemical Action
In the course of assigning combination products to an agency
center, OCP must often determine whether a product is a combination
product--a determination that may turn on whether a constituent part of
the product is properly classified as a device. Section 201(h) of the
act (21 U.S.C. 321(h)) states that a device cannot achieve its primary
intended purposes through chemical action within or on the body of man,
or be dependent on being metabolized to achieve its primary intended
purposes. The agency plans to develop guidance and/or regulations to
further clarify what is meant by ``chemical action within or on the
body.'' When final, such guidance and/or regulations should be helpful
to sponsors in determining whether a product is a combination product.
G. Devices Regulated by CBER
Certain single entity (i.e., noncombination) devices are regulated
under the device provisions of the act by CBER, rather than CDRH. One
of the main purposes of the CBER-CDRH ICA is to identify categories of
devices regulated by CBER. The agency believes, however, that
additional guidance describing the assignment of devices that process
human cellular and tissue products would be helpful. This product area
was not fully envisioned at the time the CBER-CDRH ICA was developed.
The agency plans to develop such guidance to assist sponsors in
determining whether certain devices would be regulated by CDRH or CBER.
[[Page 56991]]
H. Combination Product Regulation
For some types of combination products, the CDER-CDRH ICA addresses
good manufacturing practices, registration and listing, labeling, and
other product regulation issues. The agency is developing guidance and/
or regulations to address these and other significant areas of
combination product regulation, and when final, these documents will
ultimately update the limited information provided in the CDER-CDRH ICA
on these topics.
VI. Practices Specific to Assignment of Combination Products
The agency has reviewed its practices specific to the assignment of
combination products to ensure that they are in compliance with the
requirement of section 503(g)(4)(B) of the act that the agency promptly
assign a combination product to an agency center with primary
jurisdiction in accordance with section 503(g)(1) of the act.
The agency has refined its processing of jurisdictional requests to
ensure that the agency makes its assignments promptly. For example,
section 503(g)(4)(A) of the act requires OCP, in determining whether a
product is appropriately classified as a combination product, to
consult with the component within the Office of the Commissioner that
is responsible for such determinations. In the Federal Register of June
23, 2003 (68 FR 37075), the agency issued a final rule announcing that
to enhance the efficiency of agency operations, OCP assumed
responsibility from the Office of the Ombudsman for designating the
component of FDA with primary jurisdiction for the premarket review and
regulation of any product requiring a jurisdictional determination
under part 3 (21 CFR part 3). This change consolidated the jurisdiction
program within OCP, eliminated the requirement for consultation about
the classification of a product as a combination product, and made the
RFD program more efficient to administer. The final rule also provided
for the electronic submission of RFDs (Sec. 3.7(d)).
Similarly, OCP has refined its internal processes and practices to
ensure that all RFDs are resolved within the 60-day timeframe
requirement of section 563(b) of the act (21 U.S.C. 360bbb-2(b)) (Sec.
3.8(b)). All RFDs submitted to OCP since its inception have been
resolved within the 60-day period. Furthermore, all requests for
reconsideration were responded to within the 15-day timeframe (Sec.
3.8(c)). For the period from the establishment of OCP through March 31,
2006, FDA's average RFD processing time for assignments of combination
products is 37.7 days (median 40 days, range 11-59 days). Accordingly,
the agency has preliminarily determined that its practices are
consistent with the requirement contained in section 503(g)(4)(B) of
the act that it promptly assign combination products to an agency
center based on the product's PMOA. FDA plans to continue in effect the
process improvements needed to maintain the prompt assignment of
combination products, and plans to continue to work to refine its
processes further.
VII. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
Dated: September 22, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-15967 Filed 9-27-06; 8:45 am]
BILLING CODE 4160-01-S