[Federal Register: May 7, 2004 (Volume 69, Number 89)]
[Proposed Rules]
[Page 25527-25533]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07my04-22]
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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.
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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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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.
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\1\ As stated previously, a copy of the proposed algorithm is
attached at the end of this preamble.
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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\
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\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.
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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),
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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.
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[FR Doc. 04-10447 Filed 5-6-04; 8:45 am]
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