[Federal Register Volume 69, Number 89 (Friday, May 7, 2004)]
[Proposed Rules]
[Pages 25527-25533]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 04-10447]



[[Page 25527]]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 3

Docket No. 2004N-0194


Definition of Primary Mode of Action of a Combination Product

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its combination product regulations to define ``mode of action'' and 
``primary mode of action'' (PMOA). Along with these definitions, the 
proposed rule sets forth an algorithm the agency would use to assign 
combination products to an agency component for regulatory oversight 
when the agency cannot determine with reasonable certainty which mode 
of action provides the most important therapeutic action of the 
combination product. Finally, the proposed rule would also require a 
sponsor to base its recommendation of the agency component with primary 
jurisdiction for regulatory oversight of its combination product by 
using the PMOA definition and, if appropriate, the assignment 
algorithm. The proposed rule 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.

DATES: Submit written comments by July 6, 2004. See section IX of this 
document for the proposed effective date of a final rule based on this 
document.

ADDRESSES: You may submit comments, identified by Docket No. 2004N-
0194, by any of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include Docket No. 2004N-
0194 in the subject line of your e-mail message.
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier For paper, disk, or CD-ROM 
submissions: Division of Dockets Management, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name and 
Docket No. 2004N-0194 for this proposed rulemaking. All comments 
received will be posted without change to http://www.fda.gov/dockets/
ecomments, including any personal information provided. For detailed 
instructions on submitting comments and additional information on the 
proposed rulemaking process, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/dockets/ecomments and/or 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Leigh Hayes, Office of Combination 
Products (HFG-3), Food and Drug Administration, 15800 Crabbs Branch 
Way, suite 200, Rockville, MD 20855, 301-827-9229.

SUPPLEMENTARY INFORMATION:

I. Introduction

    As set forth in part 3 (21 CFR part 3), a combination product is a 
product comprised of any combination of a drug and a device; a device 
and a biological product; a biological product and a drug; or a drug, a 
device, and a biological product. A combination product includes: (1) A 
product comprised of two or more regulated components, i.e., drug/
device, biological product/device, drug/biological product, or drug/
device/biological product, that are physically, chemically, or 
otherwise combined or mixed and produced as a single entity; (2) two or 
more separate products packaged together in a single package or as a 
unit and comprised of drug and device products, device and biological 
products, or biological and drug products; (3) a drug, device, or 
biological product packaged separately that, according to its 
investigational plan or proposed labeling, is intended for use only 
with an approved individually specified drug, device, or biological 
product where both are required to achieve the intended use, 
indication, or effect and where upon approval of the proposed product 
the labeling of the approved product would need to be changed, e.g., to 
reflect a change in intended use, dosage form, strength, route of 
administration, or significant change in dose; or (4) any 
investigational drug, device, or biological product packaged separately 
that, according to its proposed labeling, is for use only with another 
individually specified investigational drug, device, or biological 
product where both are required to achieve the intended use, 
indication, or effect.
    Section 503(g) of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 353(g)) requires that FDA assign a component of the 
agency to have primary jurisdiction for the premarket review and 
regulation of a combination product. That assignment must be based upon 
a determination of the PMOA of the combination product. For example, if 
the primary mode of action of a combination product is that of a 
biological product, the product is to be assigned to the FDA component 
responsible for the premarket review of that biological product. FDA 
issued a final rule in 1991 establishing the procedures (the ``request 
for designation'' (RFD) process) for determining the assignment of 
combination products under part 3.
    The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) 
further modified section 503(g) of the act to require the establishment 
of an office (Office of Combination Products) within the Office of the 
Commissioner. The purpose of the Office of Combination Products is to 
ensure the prompt assignment of combination products to agency 
components, the timely and effective premarket review of such products, 
and consistent and appropriate postmarket regulation of combination 
products. MDUFMA also requires the agency to review each agreement, 
guidance, or practice specific to the assignment of combination 
products to agency components, consult with stakeholders and the 
directors of the agency centers, and determine whether to continue in 
effect, modify, revise, or eliminate such agreements, guidances, or 
practices.
    Currently, Sec.  3.7 requires a sponsor submitting a request for 
designation to identify the PMOA of the combination product and 
recommend a lead agency component for its premarket review and 
regulation. The PMOA of a combination product, however, is not defined 
in the statute or regulations, and at times may be difficult to 
identify. Requests for assignment of combination products are usually 
submitted very early in a product's development. This practice is 
encouraged because it allows sponsors to begin working with an agency 
component as early in the development process as possible and to know 
the regulatory requirements for their products. For some products, 
though, the PMOA of the product is not readily apparent, to either FDA 
or the product sponsor, at the time the request for

[[Page 25528]]

assignment is submitted. Determining the PMOA of a combination product 
is also complicated for products that have two completely different 
modes of action, neither of which is subordinate to the other. In close 
cases, assignments may turn on subtle distinctions related to the 
determination of whether a mode of action is ``primary,'' or not. The 
assignment process may appear to be unpredictable when two slightly 
different products are assigned to different agency components based on 
differences in their PMOAs.
    To address these concerns, simplify the designation process for 
sponsors, and enhance the transparency, predictability, and consistency 
of the agency's assignment of combination products, FDA proposes to 
define ``mode of action'' and ``primary mode of action.'' This proposal 
would merely clarify and codify principles the agency has generally 
used since section 503(g) of the act was issued in 1990.

II. Description of the Proposed Rule

A. Introduction

    FDA proposes to amend its combination product regulations to create 
new definitions in Sec.  3.2 of ``mode of action'' and ``primary mode 
of action.'' This proposal also sets forth a two-tiered assignment 
algorithm in Sec.  3.4, which the agency would use to determine 
assignment when it cannot determine which mode of action of a 
combination product provides the most important therapeutic action of 
the product. Finally, the rule proposes to require that sponsors base 
their recommendation of the agency component with primary jurisdiction 
for regulatory oversight of its product in terms of the PMOA definition 
and, if appropriate, the assignment algorithm.
    This proposal would fulfill the statutory requirement to assign 
products based on their PMOA, and would use safety and effectiveness 
issues, as well as consistency with the regulation of similar products, 
to guide the assignment of products when the agency cannot determine 
which mode of action provides the most important therapeutic action of 
the combination product. It ensures that like products would be 
similarly assigned, and it allows new products for which the most 
important therapeutic action cannot be determined to be assigned to the 
most appropriate agency component based on the most significant safety 
and effectiveness issues they present. In addition, by providing a more 
defined framework for the assignment process, a codified definition of 
PMOA would further MDUFMA's requirement that the agency ensure prompt 
assignment of combination products. Also, by issuing this proposal, the 
agency furthers MDUFMA's requirement that it review practices specific 
to the assignment of combination products, consult with stakeholders 
and center directors, and make a determination whether to modify those 
practices.
    Not only would this proposal fulfill the objectives set forth in 
the preceding paragraph, it would do so in a way that remains 
consistent with agency practice regarding the assignment of combination 
products. This rulemaking would thus codify criteria the agency has 
generally used since 1991. The proposed rule, when finalized, will 
affect RFD submissions received by the agency on or after the effective 
date of any final rule issued as a result of this proposed rule.

B. What Are ``Mode of Action'' and ``Primary Mode of Action''

1. Definitions
    a. Mode of action would be defined as ``the means by which a 
product achieves a therapeutic effect.'' For purposes of this 
definition, ``therapeutic'' effect or action includes any effect or 
action of the combination product intended to diagnose, cure, mitigate, 
treat, or prevent disease, or affect the structure or any function of 
the body. Products may have a drug, biological product, or device mode 
of action. Because combination products are comprised of more than one 
type of regulated article (biological product, device, or drug), and 
each constituent part contributes a biological product, device, or drug 
mode of action, combination products will typically have more than one 
mode of action.
    1. A constituent part has a biological product mode of action if it 
acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, 
blood, blood component or derivative, allergenic product, or analogous 
product applicable to the prevention, treatment, or cure of a disease 
or condition of human beings, as described in section 351(a) of the 
Public Health Service Act.
    2. A constituent part has a device mode of action if it meets the 
definition of device contained in section 201(h)(1) to (h)(3) of the 
act (21 U.S.C.321(h)(1) to (h)(3)), it does not have a biological 
product mode of action, and it does not achieve its primary intended 
purposes through chemical action within or on the body of man or other 
animals and is not dependent upon being metabolized for the achievement 
of its primary intended purposes.
    3. A constituent part has a drug mode of action if it meets the 
definition of drug contained in section 201(g)(1) of the act and it 
does not have a biological product or device mode of action.
    b. Primary mode of action would be defined as ``the single mode of 
action of a combination product that provides the most important 
therapeutic action of the combination product.'' This would be the mode 
of action that is expected to make the greatest contribution to the 
overall therapeutic effects of the combination product. As with ``mode 
of action,'' for purposes of PMOA, ``therapeutic'' effect or action 
includes any effect or action of the combination product intended to 
diagnose, cure, mitigate, treat, or prevent disease, or affect the 
structure or any function of the body.
2. Stakeholders' Comments
    FDA held public hearings on May 15, 2002, and on November 25, 2002, 
and a public workshop on July 8, 2003, to discuss various issues 
pertaining to combination products, including the assignment of 
products to an agency component for regulatory oversight. Stakeholders 
also provided a number of written comments to the docket, which FDA 
opened to further facilitate the discussion of PMOA issues. The agency 
received many thoughtful comments from the stakeholders who 
participated in those discussions, as well as from stakeholders who 
submitted written comments to the docket, including some pertaining to 
a definition of PMOA. The November 2002 meeting in particular addressed 
questions regarding assignment. Some questions raised at the meeting 
were:
     What factors should FDA consider in determining the PMOA 
of a combination product?
     In instances where the PMOA 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?)
    Several common themes emerged from these comments regarding the 
agency's definition of PMOA. For instance, many stakeholders felt that 
the agency should base any proposed definition of PMOA on the 
combination product as a whole. FDA agrees, and has crafted the 
definition so that PMOA would be based on the most important 
therapeutic action of the combination product as a whole. Furthermore, 
as

[[Page 25529]]

detailed in the section regarding the assignment algorithm, the agency 
expects to consider the combination product as a whole when the agency 
cannot determine with reasonable certainty the most important 
therapeutic action of the product.
    Another recurring theme among a number of comments concerned the 
intended use of the product. Several stakeholders expressed their 
desire that FDA construct a definition of PMOA around this concept. As 
stated previously, mode of action would be defined as the means by 
which a product achieves a therapeutic effect. For over a decade, the 
agency has considered in its determination of PMOA an assessment of the 
product's intended use, as well as its effect on the diagnosis, cure, 
mitigation, treatment, or prevention disease, and its effect on the 
structure or function of the body. The agency intends to continue this 
practice, and has structured the proposed definition of PMOA to include 
consideration of the intended use of a combination product.

C. What If We Are Unable to Determine Which Mode of Action of a 
Combination Product is its Most Important Therapeutic Action? 
Assignment Algorithm (For easy reference, a diagram of the assignment 
algorithm is included at the end of this preamble.)

    In certain cases, it is not possible for either FDA or the product 
sponsor to determine, at the time a request is submitted, which mode of 
action of a combination product provides the most important therapeutic 
effect. Determining the PMOA of a combination product is also 
complicated for products where the product has two completely different 
modes of action, neither of which is subordinate to the other. To 
assign such products with as much consistency, predictability, and 
transparency as possible, the agency proposes the application of an 
algorithm to determine PMOA in those instances, to be codified at Sec.  
3.4(b). In those cases, the agency would assign the combination product 
to the agency component that regulates other combination products that 
present similar questions of safety and effectiveness with regard to 
the combination product as a whole. When there are no other combination 
products that present similar questions of safety and effectiveness 
with regard to the combination product as a whole (e.g., it is the 
first such combination product, or differences in its intended use, 
design, formulation, etc. present different safety and effectiveness 
questions), the agency would assign the combination product to the 
agency component with the most expertise to evaluate the most 
significant safety and effectiveness questions presented by the 
combination product.
1. Stakeholders' Comments
    As previously mentioned, FDA held public hearings on May 15, 2002, 
and on November 25, 2002, and a public workshop on July 8, 2003, to 
discuss various issues pertaining to combination products, including 
the assignment of products to an agency component for regulatory 
oversight. Stakeholders also provided a number of written comments to 
the docket, which FDA opened to further facilitate the discussion of 
PMOA issues.
    As with the definition for PMOA, several common themes emerged from 
these comments regarding possible criteria for the algorithm. For 
example, several stakeholders suggested that the agency consider 
similarly situated products when assigning a combination product to a 
lead agency component. We agree that both precedent and expertise are 
important when assigning a combination product to a particular agency 
component, and propose that this criterion be placed first in the 
algorithm's decisionmaking hierarchy. Therefore, if the agency could 
not determine with reasonable certainty which mode of action provides 
the most important therapeutic effect, the agency would assign the 
combination product to the agency component that regulates combination 
products that present similar safety and effectiveness questions for 
the product as a whole. In other words, FDA would consider whether 
there is an agency component with direct experience related to the 
combination product in question. We note, too, that application of this 
criterion would require consideration of the product as a whole, rather 
than by its constituent parts, which is another common recommendation 
of stakeholders.
    Another factor many stakeholders asked the agency to consider when 
developing an assignment algorithm relates to the relative risks of a 
particular combination product. We agree that this is an important 
consideration, and propose that the second criterion take into account 
the most significant questions of safety and effectiveness presented by 
a combination product. Therefore, if the agency cannot determine which 
mode of action makes the greatest contribution to its overall 
therapeutic effects, and the agency has no direct experience with 
combination products that as a whole present similar safety and 
effectiveness questions as the combination product at issue, the agency 
would assign the product to the agency component with the most 
expertise related to the most significant questions of safety and 
effectiveness of the product. In situations where the new product is 
the first such combination product, or where another combination 
product exists but the intended use, design, formulation, etc. for this 
combination product raise different safety and effectiveness questions, 
FDA would assign the product to the agency component with the most 
expertise to evaluate the most significant safety and effectiveness 
issues raised by the product.
2. Application of Proposed Definitions and Proposed Algorithm: 
Examples\1\
    If the suggested definitions in the preceding section were applied 
to these products, the results would be as follows:
    a. Conventional drug-eluting stent--a vascular stent provides a 
mechanical scaffold to keep a vessel open while a drug is slowly 
released from the stent to prevent the buildup of new tissue that would 
re-occlude the artery.
---------------------------------------------------------------------------

    \1\ As stated previously, a copy of the proposed algorithm is 
attached at the end of this preamble.
---------------------------------------------------------------------------

    PMOA Analysis--Which Mode of Action Provides the Most Important 
Therapeutic Action of the Combination Product?
    In this case, the product has two modes of action. One action of 
the vascular stent is to provide a physical scaffold to be implanted in 
a coronary artery to improve the resultant arterial luminal diameter 
following angioplasty. Another action of the product is the drug 
action, with the intended effect of reducing the incidence of 
restenosis and the need for target lesion revascularization.
    Assignment of Lead Agency Component: Center for Devices and 
Radiological Health (CDRH)--The product's PMOA is attributable to the 
device component's function of physically maintaining vessel lumen 
patency, while the drug plays a secondary role in reducing restenosis 
caused by the proliferative response to the stent implantation, 
augmenting the safety and/or effectiveness of the uncoated stent. 
Accordingly, FDA would assign the product to CDRH for premarket review 
and regulation because the device component provides the most important 
therapeutic action of the product. It is unnecessary to proceed to the 
assignment algorithm because it is possible to determine which mode of 
action provides the most important

[[Page 25530]]

therapeutic action of this particular combination product.
    b. Drug eluting disc--a surgically implanted disc contains a drug 
that is slowly released for prolonged, local delivery of 
chemotherapeutic agents.
    PMOA Analysis--Which Mode of Action Provides the Most Important 
Therapeutic Action of the Combination Product?
    In this case, the product has two modes of action. This product has 
a device mode of action because it is surgically implanted in the body 
and is designed for controlled drug release, thus affecting the 
structure of the body and treating disease. Another mode of action is 
the drug action, with the intended effect of preventing tumor 
recurrence at the implant site.
    Assignment of Lead Agency Component: Center for Drug Evaluation and 
Research (CDER)--Though the product has a device mode of action, the 
product's PMOA is attributable to the drug component's function of 
preventing tumor recurrence at the implant site. Accordingly, we would 
assign the product to CDER for premarket review and regulation because 
the drug component provides the most important therapeutic action of 
the product. It is unnecessary to proceed to the assignment algorithm 
because it is possible to determine which mode of action provides the 
most important therapeutic action of this particular product.
    c. Contact lens combined with drug to treat glaucoma--in this case, 
a contact lens is placed in the eye to correct vision. The contact lens 
also contains a drug to treat glaucoma that will be delivered from the 
lens to the eye.
    PMOA Analysis--Which Mode of Action Provides the Most Important 
Therapeutic Action of the Combination Product?
    This product has two modes of action. One action of the product is 
the device action, to correct vision. Another action of the product is 
a drug action, to treat glaucoma. Though administration through a 
contact lens is not necessary for the drug's delivery, the combination 
product allows a patient requiring vision correction to receive 
glaucoma treatment without having to undertake a more complicated daily 
drug regimen. Here, both actions of the product are independent, and 
neither appears to be subordinate to the other.
    Because it is not possible to determine which mode of action 
provides the greatest contribution to the overall therapeutic effects 
of the combination product, it is necessary to apply the assignment 
algorithm.
    Assignment Algorithm:
    Is There an Agency Component That Regulates Other Combination 
Products That Present Similar Questions of Safety and Effectiveness 
With Regard to the Combination Product as a Whole?
    CDRH regulates devices intended to correct vision. CDER regulates 
drugs intended to treat glaucoma. In this hypothetical example, no 
combination product intended to treat these different conditions 
simultaneously has yet been submitted to the agency for review. Though 
both CDER and CDRH regulate products that raise similar safety and 
effectiveness questions with regard to the constituent parts of the 
product, neither agency component regulates combination products that 
present similar safety and effectiveness questions with regard to the 
product as a whole.
    Because there is no agency component that regulates products that 
present similar safety and effectiveness questions with regard to the 
product as a whole, it is necessary to apply the second criterion of 
the hierarchy.
    Which Agency Component Has the Most Expertise Related to the Most 
Significant Safety and Effectiveness Questions Presented by the 
Combination Product?
    Assignment of Lead Agency Component: CDER--Because there is no 
agency component that regulates combination products that present 
similar safety and effectiveness issues with regard to the product as a 
whole, the agency would consider which agency component has the most 
expertise related to the most significant safety and effectiveness 
questions presented by the product. In this hypothetical example, the 
most significant safety and effectiveness questions are related to the 
characterization, manufacturing, and clinical performance of the drug 
component, while the safety and effectiveness questions raised by the 
vision-correcting contact lens are considered routine. Based on the 
application of this criterion, this product would be assigned to CDER 
because CDER has the most expertise related to these issues.\2\
---------------------------------------------------------------------------

    \2\ Had this been the second such product, it would be assigned 
to CDER based on the first criterion, assuming the first such 
product had also been assigned to CDER using the second criterion.
---------------------------------------------------------------------------

D. How Will the PMOA Definition and Assignment Algorithm Affect the 
Contents of My RFD Submission?

    A sponsor would continue to submit its assessment of PMOA and its 
recommendation of lead agency component for regulatory oversight of its 
combination product. These requirements are not new; they are currently 
codified at Sec.  3.7(c)(2)(ix) and (c)(3). Under this rule, however, a 
sponsor would present its recommendation of lead agency component in 
accordance with the PMOA definition of proposed Sec.  3.2(m) and, if 
appropriate, the assignment algorithm of proposed Sec.  3.4(b). Because 
this definition and the algorithm set forth a more defined framework on 
which to base a recommendation, the agency believes that these 
provisions will make it easier for sponsors to present their analysis 
of a product's PMOA.

III. Legal Authority

    The agency derives its authority to issue the regulations found in 
part 3 from 21 U.S.C. 321, 351, 353, 355, 360, 360c-360f, 360h-360j, 
360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216, 262, and 264 as 
stated in the Code of Federal Regulations. As stated previously in this 
document, Congress expressly directed FDA to assign combination 
products to the appropriate agency component for premarket review and 
regulation based on the agency's assessment of PMOA as set forth in 
section 503(g) of the act. Under section 701 of the act (21 U.S.C. 371) 
and for the efficient enforcement of the act, FDA has the authority to 
define and codify ``mode of action'' and PMOA and to issue the 
assignment algorithm.

IV. Environmental Impact

    FDA has determined under 21 CFR 25.30(a) and (k), and 25.32(g) that 
this action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

V. Paperwork Reduction of 1995

    FDA tentatively concludes that the changes to the regulations on 
combination products proposed in this document are not subject to 
review by the Office of Management and Budget (OMB) because they do not 
constitute a ``collection of information'' under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520). The information collected 
under part 3 is currently approved under OMB control number 0910-0523. 
This proposal does not constitute an additional paperwork burden.

VI. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set

[[Page 25531]]

forth in Executive Order 13132. FDA has determined that the proposed 
rule does not contain policies that have substantial direct effects on 
the States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Section 202(a) of the 
Unfunded Mandates Reform Act of 1995 requires that agencies prepare a 
written statement of anticipated costs and benefits before proposing 
any rule that may result in an expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of $100 
million (adjusted annually for inflation) in any one year. Under the 
Regulatory Flexibility Act, unless an agency certifies that a rule will 
not have a significant economic impact on a substantial number of small 
entities, the agency must analyze whether a rule may have a substantial 
impact on a substantial number of small entities and, if it does, to 
analyze regulatory options that would minimize the impact.
    The agency believes that this proposed rule is consistent with the 
regulatory philosophy and principles identified in the Executive order 
and these two statutes. The proposed rule is not a significant 
regulatory action as defined by the Executive order and so is not 
subject to review under the Executive order. No further analysis is 
required under the Regulatory Flexibility Act because the agency has 
determined that these proposed rule amendments have no compliance costs 
and will not have a significant effect on a substantial number of small 
entities. Therefore the agency certifies they will not have a 
significant economic impact on a substantial number of small entities.
    This proposed rule also does not trigger the requirements for a 
written statement under section 202(a) of the Unfunded Mandates Reform 
Act because it does not impose a mandate that results in expenditure of 
$100 million or more by State, local, and tribal governments in the 
aggregate, or by the private sector in any one year.

B. The Rationale Behind This Proposed Rule

    The purpose of the proposed rule amendments is twofold: (1) To 
codify the definition of PMOA, a criterion the agency has used for more 
than a decade when assigning combination products to agency components 
for regulatory oversight; and (2) to simplify the designation process 
by providing a defined framework that sponsors may use when 
recommending and/or considering the PMOA and assignment of a 
combination product.
    Indeed, many stakeholders have requested that the agency propose a 
rule defining PMOA because, without a definition of this statutory 
criterion, the assignment process has at times appeared to lack 
transparency. We believe that the proposal addresses many of the 
concerns stakeholders have expressed regarding the assignment process. 
Moreover, we have incorporated many of the suggestions stakeholders 
have provided regarding the PMOA definition and assignment algorithm.
    The codification of these principles would also simplify the 
designation process for sponsors. For years, a sponsor has been 
required to determine PMOA and make a recommendation of lead agency 
component for regulatory oversight of its combination product, without 
a codified definition of PMOA. When the rule is finalized, a sponsor 
would be able to base its determination of PMOA and recommendation of 
lead agency component for regulatory oversight of its product on 
defined factors.
    As mentioned previously in this proposal, the amendments proposed 
here would fulfill the statutory requirement to assign products based 
on their PMOA, and would use safety and effectiveness issues as well as 
consistency with the regulation of similar products to guide the 
assignment of products when the agency cannot determine which mode of 
action provides the most important therapeutic action of a combination 
product. It ensures that like products would be similarly assigned and 
regulated, and it allows new products for which the most important 
therapeutic action cannot be determined to be assigned to the most 
appropriate agency component based on the most significant safety and 
effectiveness issues they present. In addition, by providing a more 
defined framework for the assignment process, a codified definition of 
PMOA would further MDUFMA's requirement that the agency ensure prompt 
assignment of combination products. Also, by issuing this proposal, the 
agency furthers MDUFMA's requirement that it review practices specific 
to the assignment of combination products, consult with stakeholders 
and center directors, and make a determination whether to modify those 
practices.
    In general, the agency believes the proposed rule will have no 
compliance costs and pose no additional burden to industry.

VIII. Request for 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.

IX. Proposed Effective Date

    The agency is proposing that any final rule that may issue based 
upon this proposed rule become effective 90 days after its date of 
publication in the Federal Register.

List of Subjects in 21 CFR Part 3

    Administrative practice and procedure, Biologics, Drugs, Medical 
devices.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR part 3 be 
amended as follows:

PART 3--PRODUCT JURISDICTION

    1. The authority citation for 21 CFR part 3 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 353, 355, 360, 360c-360f, 360h-
360j, 360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216, 262, 264.
    2. Section 3.2 is amended by redesignating paragraph (k) as 
paragraph (l), paragraph (l) as paragraph (n), paragraph (m) as 
paragraph (o),

[[Page 25532]]

paragraph (n) as paragraph (p); and by adding new paragraphs (k) and 
(m) to read as follows:


Sec.  3.2  Definitions.

* * * * *
    (k) Mode of action is the means by which a product achieves a 
therapeutic effect. For purposes of this definition, ``therapeutic'' 
action or effect includes any effect or action of the combination 
product intended to diagnose, cure, mitigate, treat, or prevent 
disease, or affect the structure or any function of the body. When 
making assignments of combination products under this part, the agency 
will consider three types of mode of action: The actions provided by a 
biological product, a device, and a drug. Because combination products 
are comprised of more than one type of regulated article (biological 
product, device, or drug), and each constituent part contributes a 
biological product, device, or drug mode of action, combination 
products will typically have more than one identifiable mode of action.
    (1) A constituent part has a biological product mode of action if 
it acts by means of a virus, therapeutic serum, toxin, antitoxin, 
vaccine, blood, blood component or derivative, allergenic product, or 
analogous product applicable to the prevention, treatment, or cure of a 
disease or condition of human beings, as described in section 351(i) of 
the Public Health Service Act.
    (2) A constituent part has a device mode of action if it meets the 
definition of device contained in section 201(h)(1) to (h)(3) of the 
act, it does not have a biological product mode of action, and it does 
not achieve its primary intended purposes through chemical action 
within or on the body of man or other animals and is not dependent upon 
being metabolized for the achievement of its primary intended purposes.
    (3) A constituent part has a drug mode of action if it meets the 
definition of drug contained in section 201(g)(1) of the act and it 
does not have a biological product or device mode of action.
* * * * *
    (m) Primary mode of action is the single mode of action of a 
combination product that provides the most important therapeutic action 
of the combination product. The most important therapeutic action is 
the mode of action expected to make the greatest contribution to the 
overall therapeutic effects of the combination product.
* * * * *
    3. Section 3.4 is amended by redesignating paragraph (b) as 
paragraph (c) and by adding a new paragraph (b) to read as follows:


Sec.  3.4  Designated agency component.

* * * * *
    (b) In some situations, it is not possible to determine, with 
reasonable certainty, which one mode of action will provide a greater 
contribution than any other mode of action to the overall therapeutic 
effects of the combination product. Then, the agency will assign the 
combination product to the agency component that regulates other 
combination products that present similar questions of safety and 
effectiveness with regard to the combination product as a whole. When 
there are no other combination products that present similar questions 
of safety and effectiveness with regard to the combination product as a 
whole, the agency will assign the combination product to the agency 
component with the most expertise related to the most significant 
safety and effectiveness questions presented by the combination 
product.
* * * * *
    4. Section 3.7 is amended by revising paragraphs (c)(2)(ix) and 
(c)(3) to read as follows:


Sec.  3.7  Request for designation.

* * * * *
    (c) * * *
    (2) * * *
    (ix) Description of all known modes of action, the sponsor's 
identification of the single mode of action that provides the most 
important therapeutic action of the product, and the basis for that 
determination.
* * * * *
    (3) The sponsor's recommendation as to which agency component 
should have primary jurisdiction based on the mode of action that 
provides the most important therapeutic action of the combination 
product. If the sponsor cannot determine with reasonable certainty 
which mode of action provides the most important therapeutic action of 
the combination product, the sponsor's recommendation must be based on 
the assignment algorithm set forth in Sec.  3.4(b) and an assessment of 
the assignment of other combination products the sponsor wishes FDA to 
consider during the assignment of its combination product.
* * * * *

    Dated: May 3, 2004.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
    Note: The following appendix will not appear in the Code of Federal 
Regulations.
BILLING CODE 4160-01-S

[[Page 25533]]

[GRAPHIC] [TIFF OMITTED] TP07MY04.011

[FR Doc. 04-10447 Filed 5-6-04; 8:45 am]
BILLING CODE 4160-01-C