[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]


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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.

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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.
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    \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.
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    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.
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    \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.
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    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