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49848 Federal Register / Vol. 70, No.

164 / Thursday, August 25, 2005 / Rules and Regulations

warrant preparation of a Regulatory effective September 16, 2004, is FOR FURTHER INFORMATION CONTACT:
Evaluation as these routine matters will amended as follows: Leigh Hayes, Office of Combination
only affect air traffic procedures and air Products (HFG–3), Food and Drug
navigation. I certify that this rule will Paragraph 6005 Class E airspace areas Administration, 15800 Crabbs Branch
not have a significant economic impact extending upward from 700 feet or more Way, suite 200, Rockville, MD 20855,
on a substantial number of small entities above the surface of the earth. 301–427–1934.
under the criteria of the Regulatory ASW NM E5 Ruidoso, NM [Revised] SUPPLEMENTARY INFORMATION:
Flexibility Act. Sierra Blanca Regional Airport, NM
Lat. 33°27′46.30″ N, Long. 105°32′05.10″ W I. Introduction
Authority for This Rulemaking
That airspace extending upward from 700 In the Federal Register of May 7, 2004
The FAA authority to issue rules feet above the surface within a 7.1-mile (69 FR 25527), FDA published a
regarding aviation safety is found in radius of the Sierra Blanca Airport and proposed rule that proposed to define
Title 49 of the United States Code. within 4 miles each side of the 241° bearing ‘‘mode of action’’ (MOA) and ‘‘primary
Subtitle I, section 106 describes the from the airport extending from 7.1-mile mode of action’’ (PMOA) (the proposed
authority of the FAA Administrator. radius to 20.60 miles northeast of the Sierra
Blanca Regional Airport.
rule). Along with these definitions, the
Subtitle VII, Aviation Programs, proposal set forth an algorithm the
describes in more detail the scope of the * * * * * agency proposed to use to assign
agency’s authority. Issued in Fort Worth, TX, on August 18, combination products to an agency
This rulemaking is promulgated 2005. component for regulatory oversight
under the authority described in subtitle Samuel J. Gill, Jr., when the agency cannot determine with
VII, part A, subpart I, section 40103, Acting Area Director, Central En Route and reasonable certainty which mode of
‘‘Sovereignty and use of airspace.’’ Oceanic Operations. action provides the most important
Under that section, the FAA is charged [FR Doc. 05–16925 Filed 8–24–05; 8:45 am] therapeutic action of the combination
with developing plans and policy for BILLING CODE 4910–13–M product. Finally, the proposal put forth
the use of the navigable airspace and a requirement that a sponsor make its
assigning by regulation or order the recommendation of the agency
airspace necessary to ensure the safety DEPARTMENT OF HEALTH AND component with primary jurisdiction for
of aircraft and the efficient use of HUMAN SERVICES regulatory oversight of its combination
airspace. The FAA may modify or product by using the PMOA definition
revoke an assignment when required in Food and Drug Administration and, if appropriate, the assignment
the public interest. This regulation is algorithm.
within the scope of that authority 21 CFR Part 3 As set forth in part 3 (21 CFR part 3),
because it is in the public interest to and as described in the proposed rule,
[Docket No. 2004N–0194]
provide greater control of the airspace a combination product is a product
for the safety of aircraft operating in the Definition of Primary Mode of Action of comprised of any combination of a drug
vicinity of the newly established a Combination Product and a device; a device and a biological
standard instrument approach product; a biological product and a
procedure. AGENCY: Food and Drug Administration, drug; or a drug, a device, and a
HHS. biological product. A combination
List of Subjects in 14 CFR Part 71
ACTION: Final rule. product includes: (1) A product
Airspace, Incorporation by reference, comprised of two or more regulated
Navigation (air). SUMMARY: The Food and Drug components, i.e., drug/device, biological
Administration (FDA) is amending its product/device, drug/biological
Adoption of the Amendment combination product regulations to product, or drug/device/biological
nAccordingly, pursuant to the authority define ‘‘mode of action’’ (MOA) and product, that are physically, chemically,
delegated to me, the Federal Aviation ‘‘primary mode of action’’ (PMOA). or otherwise combined or mixed and
Administration amends part 71 of the Along with these definitions, the final produced as a single entity; (2) two or
Federal Aviation Regulations (14 CFR rule sets forth an algorithm the agency more separate products packaged
part 71) as follows: will use to assign combination products together in a single package or as a unit
to an agency component for regulatory and comprised of drug and device
PART 71—DESIGNATION OF CLASS A, oversight when the agency cannot products, device and biological
CLASS B, CLASS C, CLASS D, AND determine with reasonable certainty products, or biological and drug
CLASS E AIRSPACE AREAS; which mode of action provides the most products; (3) a drug, device, or
AIRWAYS; ROUTES; AND REPORTING important therapeutic action of the biological product packaged separately
POINTS combination product. Finally, the final that, according to its investigational
rule will require a sponsor to base its plan or proposed labeling, is intended
n 1. The authority citation for part 71 recommendation of the agency for use only with an approved
continues to read as follows: component with primary jurisdiction for individually specified drug, device, or
Authority: 49 U.S.C. 106(g), 40103, 40113, regulatory oversight of its combination biological product where both are
40120; E.O. 10854, 24 FR 9565, 3 CFR, 1959– product by using the PMOA definition required to achieve the intended use,
1963 Comp., p. 389. and, if appropriate, the assignment indication, or effect and where upon
algorithm. The final rule is intended to approval of the proposed product the
§ 71.1 [Amended] promote the public health by codifying labeling of the approved product would
n2. The incorporation by reference in 14 the agency’s criteria for the assignment need to be changed, e.g., to reflect a
CFR 71.1 of Federal Aviation of combination products in transparent, change in intended use, dosage form,
Administration Order 7400.9M, consistent, and predictable terms. strength, route of administration, or
Airspace Designations and Reporting DATES: The regulation is effective significant change in dose; or (4) any
Points, dated August 30, 2004, and November 23, 2005. investigational drug, device, or

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Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations 49849

biological product packaged separately Determining the PMOA of a framework for the assignment process, a
that, according to its proposed labeling, combination product is also codified definition of PMOA will
is for use only with another individually complicated for products that have two further MDUFMA’s requirement that the
specified investigational drug, device, or completely different modes of action, agency ensure prompt assignment of
biological product where both are neither of which is subordinate to the combination products. Also, by issuing
required to achieve the intended use, other. In close cases, assignments may this final rule, the agency adheres to
indication, or effect. turn on subtle distinctions related to the MDUFMA’s requirement that it review
Section 503(g) of the Federal Food, determination of whether a mode of practices specific to the assignment of
Drug, and Cosmetic Act (the act) (21 action is ‘‘primary,’’ or not. The combination products, consult with
U.S.C. 353(g)) requires that FDA assign assignment process may appear to be stakeholders and center directors, and
a component of the agency to have unpredictable when two slightly make a determination whether to
primary jurisdiction for the regulation of different products are assigned to modify those practices.
a combination product. That assignment different agency components based on Not only will this final rule fulfill the
must be based upon a determination of differences in their PMOAs. objectives set forth in the preceding
the PMOA of the combination product. To address these concerns, to simplify paragraph, it will do so in a way that
For example, if the primary mode of the designation process for sponsors, remains consistent with agency practice
action of a combination product is that and to enhance the transparency, regarding the assignment of
of a biological product, the product is to predictability, and consistency of the combination products. This rulemaking
be assigned to the FDA component agency’s assignment of combination will codify criteria the agency has
responsible for the premarket review of products, FDA is issuing this final rule generally used since 1990. The final rule
that biological product. FDA issued a to define ‘‘mode of action’’ and will apply to RFD submissions received
final rule in 1991 establishing the ‘‘primary mode of action.’’ This final by the agency on or after its effective
procedures (the ‘‘request for rule will clarify and codify principles date.
designation’’ (RFD) process) for the agency has generally used since B. Stakeholder Input Prior to Proposed
determining the assignment of section 503(g) of the act was enacted in Rulemaking
combination products under part 3. 1990.
The Medical Device User Fee and Before issuance of the proposed rule,
Modernization Act of 2002 (MDUFMA) II. Description of the Final Rule FDA held public hearings on May 15,
further modified section 503(g) of the A. Introduction 2002, and on November 25, 2002, and
act to require the establishment of an a public workshop on July 8, 2003, to
Office (Office of Combination Products) FDA is finalizing its proposal to discuss various issues pertaining to
within the Office of the Commissioner. amend its combination product combination products, including the
The purpose of the Office of regulations to create new definitions in assignment of products to an agency
Combination Products is to ensure the § 3.2 of ‘‘mode of action’’ and ‘‘primary component for regulatory oversight.
prompt assignment of combination mode of action.’’ This final rule also sets Stakeholders also provided a number of
products to agency components, the forth a two-tiered assignment algorithm written comments to the dockets for
timely and effective premarket review of in § 3.4, which the agency will use to these meetings, which FDA opened to
such products, and consistent and determine assignment when it cannot further facilitate the discussion of
appropriate postmarket regulation of determine with reasonable certainty PMOA issues. The agency received
combination products. MDUFMA also which mode of action of a combination many thoughtful comments from the
requires the agency to review each product provides the most important stakeholders who participated in those
agreement, guidance, or practice therapeutic action of the product. discussions, as well as from
specific to the assignment of Finally, the rule will require that stakeholders who submitted written
combination products to agency sponsors base their recommendation of comments to the docket, including some
components, consult with stakeholders which agency component should have pertaining to a definition of PMOA as
and the directors of the agency centers, primary jurisdiction for regulatory well as others regarding the criteria for
and determine whether to continue in oversight of its product on the PMOA the assignment algorithm if PMOA
effect, modify, revise, or eliminate such definition and, if appropriate, the could not be determined. The November
agreements, guidances, or practices. assignment algorithm. 2002 meeting in particular addressed
Currently, § 3.7 requires a sponsor This final rule will fulfill the statutory questions regarding assignment. Some
submitting a request for designation to requirement to assign products based on questions raised at the meeting were:
identify the PMOA of the combination their PMOA, and will use safety and • What factors should FDA consider
product and recommend a lead agency effectiveness issues, as well as in determining the PMOA of a
component for its regulation. The consistency with the regulation of combination product?
PMOA of a combination product, similar products, to guide the • In instances where the PMOA of the
however, is not defined in the statute or assignment of products when the agency combination product cannot be
regulations, and at times may be cannot determine with reasonable determined with certainty, what other
difficult to identify. Requests for certainty which mode of action provides factors should the agency consider in
assignment of combination products are the most important therapeutic action of assigning primary jurisdiction?
usually submitted very early in a the combination product. It ensures that • Is there a hierarchy among these
product’s development. This practice is like products would be similarly additional factors that should be
encouraged because it allows sponsors assigned, and it allows new products for considered in order to ensure adequate
to begin working with an agency which the most important therapeutic review and regulation (e.g., which
component as early in the development action cannot be determined with component presents greater safety
process as possible. For some products, reasonable certainty to be assigned to questions?)
though, the PMOA of the product is not the most appropriate agency component Several common themes emerged
readily apparent, to either FDA or the based on the most significant safety and from these comments regarding the
product sponsor, at the time the request effectiveness issues they present. In definition of PMOA. For instance, many
for assignment is submitted. addition, by providing a more defined stakeholders felt that the agency should

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49850 Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations

base any proposed definition of PMOA questions of safety and effectiveness being metabolized for the achievement
on the combination product as a whole. presented by a combination product. of its primary intended purposes.
FDA agrees, and has crafted the Therefore, if the agency cannot • A constituent part has a drug mode
definition so that PMOA is based on the determine the most important of action if it meets the definition of
most important therapeutic action of the therapeutic action of a combination drug contained in section 201(g)(1) of
combination product as a whole. product, and there is no agency
the act and it does not have a biological
Furthermore, as detailed in the section component that regulates combination
regarding the assignment algorithm, the product or device mode of action.
products that as a whole present similar
agency will consider the combination safety and effectiveness questions as the b. Primary mode of action is defined
product as a whole when the agency combination product at issue, the as ‘‘the single mode of action of a
cannot determine with reasonable agency will assign the product to the combination product that provides the
certainty the most important therapeutic agency component with the most most important therapeutic action of the
action of the product. expertise related to the most significant combination product. The most
Another theme recurring in a number questions of safety and effectiveness of important therapeutic action is the
of comments concerned the intended the product. In situations where the new mode of action that is expected to make
use of the product. Several stakeholders product is the first such combination the greatest contribution to the overall
expressed their desire that FDA product, or where another combination intended therapeutic effects of the
construct a definition of PMOA around product exists but the intended use, combination product.’’ As with ‘‘mode
this concept. As further described in design, formulation, etc. for this of action,’’ for purposes of PMOA,
this document, mode of action is combination product raise different ‘‘therapeutic’’ effect or action includes
defined as the means by which a safety and effectiveness questions, FDA
product achieves its intended any effect or action of the combination
will assign the product to the agency product intended to diagnose, cure,
therapeutic effect or action. For over a component with the most expertise to
decade, the agency has considered in its mitigate, treat, or prevent disease, or
evaluate the most significant safety and affect the structure or any function of
determination of PMOA an assessment effectiveness issues raised by the
of the product’s intended use, as well as the body.
product.
its effect on the diagnosis, cure, 2. Assignment Algorithm
mitigation, treatment, or prevention of C. What are ‘‘Mode of Action’’ and
disease, and its effect on the structure or ‘‘Primary Mode of Action?’’ In certain cases, it is not possible for
function of the body. The agency 1. Definitions either FDA or the product sponsor to
intends to continue this practice, and determine, at the time a request is
has structured the PMOA definition to a. Mode of action is defined as ‘‘the
means by which a product achieves its submitted, which mode of action of a
include consideration of the intended combination product provides the most
use of a combination product. intended therapeutic effect or action.
For purposes of this definition, important therapeutic action.
As with the definition for PMOA,
‘therapeutic’ action or effect includes Determining the PMOA of a
several common themes emerged from
the comments regarding possible criteria any effect or action of the combination combination product is also
to be considered when the product’s product intended to diagnose, cure, complicated for products where the
most important therapeutic action mitigate, treat, or prevent disease, or product has two completely different
cannot be determined with reasonable affect the structure or any function of modes of action, neither of which is
certainty. For example, several the body.’’ Products may have a drug, subordinate to the other. To assign such
stakeholders suggested that the agency biological product, or device mode of products with as much consistency,
consider similarly situated products action. Because combination products predictability, and transparency as
when assigning a combination product are comprised of more than one type of possible, the agency is issuing an
to a lead agency component. We agree regulated article (biological product, algorithm to determine PMOA in those
that both precedent and expertise are device, or drug), and each constituent instances, to be codified at § 3.4(b). In
important when assigning a part contributes a biological product, those cases, the agency will assign the
combination product to a particular device, or drug mode of action, combination product to the agency
agency component, and we have placed combination products will typically component that regulates other
this criterion first in the algorithm’s have more than one mode of action. combination products that present
decisionmaking hierarchy. Therefore, if • A constituent part has a biological similar questions of safety and
the agency cannot determine with product mode of action if it acts by effectiveness with regard to the
reasonable certainty which mode of means of a virus, therapeutic serum, combination product as a whole. When
action provides the most important toxin, antitoxin, vaccine, blood, blood
there are no other combination products
therapeutic effect, the agency will assign component or derivative, allergenic
that present similar questions of safety
the combination product to the agency product, or analogous product
applicable to the prevention, treatment, and effectiveness with regard to the
component that regulates combination
products that present similar safety and or cure of a disease or condition of combination product as a whole (e.g., it
effectiveness questions for the product human beings, as described in section is the first such combination product, or
as a whole. 351(i) of the Public Health Service Act. differences in its intended use, design,
Another factor many stakeholders • A constituent part has a device formulation, etc. present different safety
asked the agency to consider when mode of action if it meets the definition and effectiveness questions), the agency
developing an assignment algorithm of device contained in section 201(h)(1) would assign the combination product
relates to the relative risks of a to (h)(3) of the act, it does not have a to the agency component with the most
particular combination product. We biological product mode of action, and expertise to evaluate the most
agree that this is an important it does not achieve its primary intended significant safety and effectiveness
consideration, and take that into purposes through chemical action questions presented by the combination
account with the second criterion, within or on the body of man or other product.
which considers the most significant animals and is not dependent upon

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Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations 49851

III. Comments on the Proposed Rule PMOA PROPOSED would be difficult to identify with
PMOA FINAL RULE
and FDA’s Responses RULE certainty anything but a drug mode of
action, since the statutory definition of
A. Background 3.2(m) Primary mode 3.2(m) Primary mode drug is the broadest definition of the
of action is the sin- of action is the sin- three. See, for example, 21 U.S.C.
FDA received comments from 17 gle mode of action gle mode of action
stakeholders on the proposal, and 321(g)(1)(C) (drug means articles other
of a combination of a combination
product that pro- product that pro- than food intended to affect the
almost all comments supported the rule
vides the most im- vides the most im- structure or any function of the body).
in whole or in part. For example, one Additionally, it is important to keep
comment said that ‘‘[o]verall* * * FDA’s portant therapeutic portant therapeutic
action of the com- action of the com- in mind that this construction is used
approach to primary mode of action bination product. bination product. only to determine a product’s various
faithfully implements the statute’’ and The most important The most important modes of action to be considered in
that ‘‘* * * FDA did a remarkable job in therapeutic action therapeutic action determining the PMOA. This
listening to the comments on mode of is the mode of ac- is the mode of ac- construction does not necessarily
action and primary mode of action tion expected to tion expected to determine how products will be
expressed by stakeholders in prior make the greatest make the greatest regulated or the appropriate type of
contribution to the contribution to the
hearings.’’ Another comment ‘‘agree[d] application for a combination product’s
overall therapeutic overall intended
with FDA’s proposed definition of effects of the com- therapeutic effects review.
primary mode of action’’ and ‘‘praise[d] bination product. of the combination Finally, we note that cell and gene
FDA for the simplicity and consistency product. therapy components typically have a
of the proposed assignment algorithm.’’ biological product MOA. For example,
The agency has included ‘‘intended certain cell and gene therapy
A few general themes emerged from components meet the definition of an
therapeutic effect’’ in the MOA
the comments. Though generally ‘‘analogous’’ product applicable to the
definition and ‘‘overall intended
supportive, the comments asked that prevention, treatment, or cure of a
therapeutic effects’’ in the PMOA
FDA provide the following clarification: disease or condition of human beings, as
definition. FDA made these changes
(1) Clarification of the role of precedent because the ‘‘intended’’ therapeutic described in section 351(i) of the PHS
in determining a combination product’s effect is a basic premise upon which the Act.
PMOA; (2) clarification of the role of PMOA analysis is prefaced. (Comment 2) One comment stated
intended use in determining a that FDA should clarify that the
combination product’s PMOA; (3) B. MOA, PMOA, and the Assignment definition of MOA relates only to the
clarification of the status of the Algorithm definition of each individual
Intercenter Agreements established in 1. MOA Definition component. The comment also provided
1991 and their role in determining a alternative definitions for device MOA,
(Comment 1) Two comments stated drug MOA, and biological product
product’s PMOA; and (4) more
that the definitions of drug, device, and MOA.
examples to show how the PMOA biological product MOAs meant that (Response) FDA agrees and clarifies
definition might be applied to assign an any product with a biological product that the definition of MOA relates only
agency component with primary component could never be a drug or a to the definitional status of each
jurisdiction for regulatory oversight of a device. One comment was concerned individual component. In addition, the
combination product. that this definition will cause certain comment suggested in part that FDA
After reviewing the comments, FDA cellular and tissue-based combination change ‘‘mode of action’’ to take into
made two changes to the codified products to be regulated as biological account a constituent part’s ‘‘‘intended’
portion of this rule. The differences products, or impact the classification of therapeutic * * * effect * * *.’’ Because
between the language in the proposed single entity products. One comment intended use is a basic tenet upon
and final rules are set forth in italics as stated that products relying on cell or which the PMOA determination is
follows: gene therapy would not have a premised, we agree, and have revised
biological product MOA based on the that definition accordingly. Another
PMOA PROPOSED definition provided. suggestion was that we change the word
PMOA FINAL RULE (Response) ‘‘Drug,’’ ‘‘device,’’ and
RULE ‘‘action’’ to ‘‘function’’ in both the
‘‘biological product’’ are defined by definition of MOA and PMOA. We have
3.2 (k) Mode of action 3.2 (k) Mode of action statute, and in defining MOA, FDA addressed that suggestion in the PMOA
is the means by is the means by implemented those statutory definition section. We have also
which a product which a product definitions. The statute defines
achieves a thera- achieves its in- addressed our rationale for the
biological products based on their development of the definitions of device
peutic effect. tended therapeutic
effect or action. composition rather than their effects or MOA, drug MOA, and biological
mechanisms of action. FDA adhered to product MOA in the response to
the definition of each article as set forth comment 1 of this document.
in the statutes, while focusing on the (Comment 3) One comment stated
factors that the statutes identify as that the proposed rule’s definition of
distinct for biological products, devices, mode of action ‘‘almost pre-supposes
and drugs. We followed this rationale that a constituent part itself may be a
because a biological product will also combination of items,’’ and ‘‘a
meet the statutory definition of drug or constituent part cannot itself be a
device, and a device will also meet the combination product.’’
statutory definition of drug. Without (Response) FDA agrees and here
mutually exclusive definitions of MOA, clarifies that constituent parts are
based on the unique characteristics of components and not, in themselves,
biological products and devices, it combination products.

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49852 Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations

(Comment 4) One comment stated Moreover, FDA stated in the May specificity and that it will be applied
that the definition of MOA of 2004 PMOA proposed rule that, for appropriately, not arbitrarily.
constituent parts should take into purposes of both the MOA and PMOA (Comment 10) Two comments stated
account the intended use of a definitions, ‘‘therapeutic’’ effect or that the PMOA definition should
combination product as a whole, and action ‘‘includes any effect or action of include the intended use of the product
should not strictly rely on statutory the combination product intended to as a whole. In addition, one comment
definitions. diagnose, cure, mitigate, treat, or stated that, assuming we include
(Response) FDA agrees that the prevent disease, or affect the structure intended use of the product as a whole
intended use of a combination product or any function of the body.’’ The term and are guided by precedents, the use of
is an important factor in the PMOA ‘‘therapeutic,’’ therefore, encompasses the ‘‘reasonable certainty’’ standard is
analysis. Therefore, we have changed the actions or effects of drugs, biological acceptable.
the codified definition of MOA to take products, and devices. As a result, the (Response) As stated in the proposal,
into account a constituent part’s use of the term ‘‘therapeutic action’’ in FDA reviewed the vast majority of our
intended therapeutic effect or action. the MOA and PMOA definitions will prior jurisdictional determinations and
The MOA definition is subsumed into not cause jurisdictional determinations found that those assignments would not
the PMOA definition, where we take to be skewed toward drugs and have changed based on the definition of
into account the combination product as biological products and away from PMOA finalized here. The definition set
a whole: ‘‘The most important devices. forth here is intended to clarify and
therapeutic action is the mode of action (Comment 8) Two comments codify the principles that FDA has used
expected to make the greatest requested that FDA explain how it will since 1990 in making jurisdictional
contribution to the overall intended determine the most important assignments. FDA agrees that intended
therapeutic effects of the combination therapeutic action of a combination use plays an important role in the
product’’ (emphasis added). product. PMOA analysis. Consequently, the
revised definition of MOA will read:
(Comment 5) One comment stated (Response) As explained in new
‘‘Mode of action is the means by which
that the statutory definitions of drug, § 3.2(m), the most important therapeutic
a product achieves its intended
device, and biological product should mode of action is the mode of action
therapeutic effect or action.’’ The MOA
be updated to take into account expected to make the greatest
definition is subsumed into the PMOA
emerging product technologies. contribution to the overall intended
definition, where we take into account
(Response) Revisions of the statutory therapeutic effects of the combination
the combination product as a whole.
definitions of drug, device, and product. To make this determination,
Furthermore, we have revised the
biological product would require FDA would consider the intended use of PMOA definition to include intended
congressional action and are outside the the combination product as a whole, use as well: ‘‘The most important
scope of this rule. and how it achieves its overall intended therapeutic action is the mode of action
(Comment 6) One comment stated therapeutic effect. Though not an expected to make the greatest
that the language used to define device exhaustive list (because each contribution to the overall intended
mode of action was inconsistent with combination product presents different therapeutic effects of the combination
the language defining drug mode of questions about its scientific product’’ (emphasis added).
action. characteristics and use), some other (Comment 11) One comment stated
(Response) FDA has reviewed the factors FDA would consider in that the intended use of a product
definitions, and disagrees. The agency determining a combination product’s should dictate its PMOA. In turn,
believes that the language in the most important therapeutic action PMOA should determine assignment of
definitions clearly and consistently include: The intended therapeutic effect the product to an agency component for
defines biological product, device, and of each constituent part, the duration of review and regulation, as well as the
drug modes of action for the purposes the contribution of each constituent part regulatory authorities to be applied.
of part 3. toward the therapeutic effect of the This comment also stated that the
product as a whole, and any data or algorithm should be used only when
2. PMOA Definition information provided by the applicant PMOA cannot be determined, and if the
(Comment 7) One comment suggested or available in scientific literature that algorithm is used to determine the
that FDA change the word ‘‘action’’ in describe the mode of action expected to jurisdiction of the product, two
the MOA and PMOA definitions to make the greatest contribution to the applications and two separate approvals
‘‘function.’’ The comment also overall intended therapeutic effects of would be necessary for its review.
suggested that the term ‘‘therapeutic’’ as the combination product. (Response) As described previously in
in ‘‘therapeutic action’’ is more (Comment 9) One comment requested this document, FDA agrees that
commonly used in connection with that FDA clarify the meaning of intended use plays an integral role in
drugs and biological products. ‘‘reasonable certainty.’’ Another the PMOA analysis, and we have
Consequently, the comment stated, use comment expressed concern that the revised the MOA and PMOA definitions
of the term ‘‘therapeutic action’’ might standard was subject to abuse. accordingly.
skew jurisdictional decisions away from (Response) In general, it would be However, we do not require in this
devices and toward drugs and biological possible to determine the PMOA of a rule that PMOA dictates the regulatory
products. combination product with ‘‘reasonable authorities to be applied to a
(Response) FDA declines to make that certainty’’ when the PMOA is not in combination product’s review and
change because we believe ‘‘action’’ is a doubt among knowledgeable experts, regulation. The application of regulatory
more appropriate term than ‘‘function’’ and can be resolved to an acceptable authorities to a combination product is
as it pertains to the MOA and PMOA level in the minds of those experts outside the scope of this rule. The Safe
definitions. The term ‘‘action’’ is based on the data and information Medical Devices Act of 1990 (SMDA)
intrinsic to ‘‘primary mode of action’’ available to FDA at the time an established a rule determining which
and the term is therefore most closely assignment is made. FDA believes that ‘‘persons’’ would be responsible for
tied to the statute. this standard provides adequate regulating combination products. See 21

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U.S.C. section 353(g)(1). This law 3. Assignment Algorithm effectiveness issues it presents when no
addresses the agency component a. First criterion. agency component has direct experience
responsible for regulating a combination (Comment 13) One comment in the review of the product as a whole.
product, but does not address which suggested that we clarify that the term FDA also agrees with the comment that
authorities, including which application ‘‘direct experience,’’ as set forth in the significant safety and effectiveness
schemes, the persons identified must proposed rule’s explanation of the issues should be considered on a case-
use to regulate the combination product. algorithm, is not part of the analysis at by-case basis. As with jurisdictional
Under this SMDA provision, the the first tier of the algorithm. determinations made prior to the
agency would decide the following: (1) (Response) The term ‘‘direct issuance of this rule, FDA intends to
Whether to recommend that a single experience’’ is not part of the codified make assignments by considering the
application for the combination product language used to describe the first tier unique issues raised by each individual
be used, and if so, what kind of of the algorithm to be used when the combination product.
application should be used new drug (Comment 16) Three comments asked
agency is unable to determine the
application (NDA), abbreviated new that FDA explain how it would
PMOA with reasonable certainty. FDA
drug application (ANDA), biologics determine the most significant safety
here clarifies that its use of the term
license application (BLA), 510(k), or and effectiveness issues presented by
‘‘direct experience’’ in the proposed
premarket approval application (PMA); the product. One comment suggested
rule’s explanation of the algorithm was that the preamble to the proposal
or (2) whether to require more than one simply a reference to the first criterion
application; for example, a BLA for the implied that FDA intended to base these
of the algorithm, which states that the determinations primarily on an
biological product component, and a agency will assign a combination
PMA for the device component of a assessment of the product’s ‘‘relative
product to the agency component that risks.’’ Another comment asked that
combination product. (See 21 CFR 3.4(b) regulates other combination products
(‘‘The designation of one agency FDA issue a guidance document to
that present similar questions of safety clarify the agency’s determination of the
component as having primary and effectiveness with regard to the
jurisdiction for the premarket review most significant safety and effectiveness
combination product as a whole. issues.
and regulation of a combination product (Comment 14) One comment asked (Response) FDA agrees that risk is not
does not preclude consultations by that how FDA will determine whether a always the driving factor in determining
component with other agency product presents similar safety and appropriate jurisdiction; rather it is one
components or, in appropriate cases, the effectiveness questions. factor that the agency may consider.
requirement by FDA of separate (Response) FDA will consider The questions listed in this response
applications.’’)) products the agency has already to comment 16 of this document are
It also appears that the comment reviewed as well as products that are intended to further illustrate the kinds
presupposes that FDA would not currently under review to determine of issues FDA would consider when
identify a PMOA if there are two whether a product presents similar determining the most significant safety
independent modes of action. FDA safety and effectiveness questions. and effectiveness questions presented
disagrees. A combination product may Though the examples are not intended by a combination product, or whether a
have two independent modes of action, to be exhaustive, FDA includes in the new combination product presents
yet FDA still may be able to determine response to Comment 16 of this similar safety and effectiveness issues as
the product’s most important document the types of questions that a previous product. We note that the list
therapeutic action with reasonable FDA may consider, as appropriate, of factors is not all-inclusive. FDA
certainty. However, FDA’s experience in when making the determination of considers its ability to continue to
evaluating combination products has whether a combination product presents assess the individual characteristics of
shown that for a small subset of questions of safety and effectiveness particular products to be essential. This
products, the most important that are similar to questions presented will allow the agency to respond to
therapeutic action is not determinable by other combination products. technological developments, scientific
with reasonable certainty. Therefore, b. Second criterion. understanding, factual information
FDA needs a mechanism to ensure that (Comment 15) One comment concerning a specific product, or the
these types of products are assigned suggested that our use of the term composition, mechanism of action or
with consistency, transparency, and ‘‘expertise’’ might cause divisiveness intended use of a particular product. As
predictability. Out of necessity and with within FDA and industry. The comment described previously in this document,
the authority granted to the agency by recommended that the focus be on the need to consider appropriate issues
Congress, FDA established the algorithm safety and effectiveness issues rather on a case-by-case basis was supported
to accomplish these goals. Once an than ‘‘expertise.’’ In considering the by some of the comments. The questions
assignment is made under the most significant safety and effectiveness are not listed in order of importance;
algorithm, FDA will decide the number questions, the comment recommended indeed some factors may be weighted
(one or more), and type, of applications that FDA make these judgments on a more than others depending on various
that are necessary. case-by-case basis. issues presented by each individual
(Comment 12) One comment asked (Response) FDA agrees that the focus combination product.
that FDA clarify whether PMOA here should be on the most significant • What is the intended use of the
determined designation only, or safety and effectiveness issues presented product?
whether it also determined the by a combination product. Use of the • What is the therapeutic effect of the
controlling regulatory authorities and term ‘‘expertise’’ is not meant to be product as a whole?
the degree of collaboration between divisive or imply a value judgment. • Does the device component
Centers. Instead, the ‘‘expertise’’ criterion at this incorporate a novel or complex design
(Response) As stated in the response level is used merely as the most or have the potential for clinically
to Comment 11 of this document, FDA appropriate means to direct the significant failure modes?
here clarifies that PMOA is assignment of a combination product • Is this a new molecular entity or
determinative of assignment only. based on the most significant safety and new formulation?

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• Has the drug previously been with reasonable certainty. We note, too, encompass types of combination
approved as a generic drug? that if FDA fails to make a jurisdictional products developed after the
• Does the drug have a narrow determination within 60 days, the Agreements were written in 1991.
therapeutic index? combination product would then (Response) FDA confirms that the
• Is the biological product component automatically be assigned to the agency ICAs referenced at § 3.5(a)(1) continue
a particularly fragile molecule? component recommended by the to provide helpful guidance related to
• How well understood are the sponsor. FDA believes that the final product jurisdiction, including the
product’s components? Is one codified language, together with the assignment of some types of
component relatively routine, while the regulations currently in place, combination products. The ICAs were
other presents more significant safety adequately takes into account a developed following the enactment of
and effectiveness issues due to the risks sponsor’s recommendation of the PMOA criterion used to make
it poses, its effectiveness, or novelty? jurisdictional assignment of its assignments of combination products.
• Which component raises greater combination product. Consequently, PMOA principles were
risks? used in the ICAs’ development. For
• Has either of the components been 5. Flow Chart example, the ICA between CDER and
previously approved or cleared? (Comment 19) Two comments CDRH assigns to CDRH products such as
• Is there a new indication, route of suggested that FDA include the flow a ‘‘device incorporating a drug
administration or a significant change in chart in a guidance rather than the final component with the combination
dose or use of one of the components, rule. product having the primary intended
or are only secondary aspects of the (Response) FDA has not included the purpose of fulfilling a device function.’’
labeling affected? flow chart in the codified section of the The premise underlying the assignment
FDA is not issuing a guidance final rule. However, we believe that the to CDRH is that the device component
document on this topic at this time. flow chart is a useful tool to illustrate of such a product provides the most
However, FDA will take the suggestion how the PMOA process works; important therapeutic action of the
under advisement, and will reconsider therefore, we included it in the product. The CDER–CDRH ICA assigns
issuance of such guidance if it becomes preamble of the proposed rule merely to CDER prefilled delivery systems,
apparent after implementation of the for its instructional use. such as a ‘‘device with primary purpose
final rule that more clarification is (Comment 20) One comment of delivering or aiding in the delivery of
needed. suggested that FDA replace the a drug and distributed containing a
(Comment 17) One comment reference in the flow chart to ‘‘an agency drug.’’ The premise of this assignment
recommended that FDA consider the component with responsibility for that to CDER is that the device’s primary
‘‘least burdensome’’ requirements of the type of device’’ by the ‘‘agency purpose in delivering or aiding in the
device provisions of the act, as well as component with responsibility for delivery of a drug is subordinate to the
the ‘‘Improving Innovation in Medical devices’’ to ensure that CDRH has most important therapeutic action
Technology’’ and ‘‘Critical Path to New primary jurisdiction. provided by the drug product. Similarly,
Medical Products’’ initiatives, which are (Response) FDA included the the ICA between CBER and CDER
specifically intended to advance phrasing as written because it assigned to CDER ‘‘combination
innovation of new medical technologies encompasses the subsets of drugs and products that consist of a biological
by, among other things, use of a variety devices regulated by the Center for component and a drug component
of premarket resources and tools (e.g., Biologics Evaluation and Research where the biological component
early collaboration meetings, 100–day (CBER) and biological products enhances the efficacy or ameliorates the
meetings, modular reviews, etc.). regulated by the Center for Drug toxicity of the drug product.’’ The
(Response) As stated in the response Evaluation and Research (CDER). While premise underlying this assignment is
to Comments 11 and 12 of this most devices are regulated by the Center that the drug product provides the most
document, assignment only directs a for Devices and Radiological Health important therapeutic action of the
product to an agency component, and (CDRH), certain devices, such as those product, while the biological product
does not dictate the regulatory related to blood collection and has a subordinate role in enhancing
authorities that will be used. processing, have long been regulated by such action. These principles are
CBER, and while most biological preserved by the definition described in
4. Miscellaneous Algorithm Questions
products are regulated by CBER, certain this rule.
(Comment 18) One comment therapeutic biological products are now Nonetheless, the Intercenter
suggested that FDA add the sponsor’s regulated by CDER. A drug-device Agreements were developed in 1991
recommendation of assignment to the combination product with a device and do not address many types of
algorithm. PMOA, where the device is regulated by combination products developed since
(Response) FDA agrees that the CBER, would be assigned to CBER. that time. Furthermore, we note that,
sponsor’s recommendation of Similarly, a biological product-device although the ICAs were developed
jurisdictional assignment plays a combination product with a biological before the regulations governing good
significant role in the process of making product PMOA, where the biological guidance practices, the Agreements
jurisdictional determinations. Indeed, product is regulated by CDER, would be constitute guidance, which is not
the sponsor’s recommendation of assigned to CDER. binding. See 21 CFR 10.115(d)(1).
assignment is a required element of an Moreover, the ICAs describe sometimes
RFD under § 3.7(c)(3). FDA takes into C. Status of Intercenter Agreements broad categories of products, and
account the information provided by the (Comment 21) Several comments because PMOA might vary depending
sponsor as well as the sponsor’s asked that FDA confirm that the on a combination product’s specific
recommendation of jurisdictional Intercenter Agreements (ICAs) remain characteristics and use, the ICA
assignment not only when it is viable in helping FDA determine the recommendations may not be
necessary to use the algorithm, but also appropriate agency component for appropriate for every single product
when FDA initially decides whether the premarket review and regulation of within a broad category. FDA is actively
PMOA of a product can be determined products, or update the Agreements to considering whether to continue in

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effect, modify, revise, or eliminate the F. Review of Specific Types of Products algorithm, when FDA assesses the most
ICAs and plans in the near future to (Comment 24) One comment significant safety and effectiveness
further clarify the role of the ICAs in requested that FDA clarify how the rule questions presented by the combination
light of other available information, affects general-purpose drug delivery product.
such as this rule and more recent devices. Another comment asked FDA (Comment 26) One comment stated
jurisdictional information made to clarify the applicability of a particular that, without additional clarification of
available on the Office of Combination principle described in the CDER–CDRH the role of precedents, the PMOA
Products (OCP’s) Internet site. FDA ICA related to unfilled drug delivery analysis as applied to pharmacogenomic
believes the issuance of this final rule devices. The pertinent section of that drug/diagnostic device products might
will help clarify jurisdiction for ICA states that a device with the lead to uncertain results. The comment
combination products generally. primary purpose of delivering or aiding also identified a number of products
in the delivery of a drug that is and suggested that they would not be
D. Role of Precedents considered under the PMOA rule as
distributed without a drug (i.e.,
unfilled), where the drug and device precedents because historically they
(Comment 22) Several comments
would be developed and used together have not been designated as
asked that FDA clarify the role of
as a system, would be assigned to a lead combination products. In addition, the
precedent in the jurisdictional
Center after considering whether the comment expressed concern that after
determination of a combination product.
drug or device had been previously this rule’s enactment, the device
(Response) FDA believes that component of these types of products
approved and the dominance of the
precedent plays a very important role in drug or device issues. A third comment would no longer be reviewed separately
determining the assignment of a asked for clarification that delivery by CDRH, as historically has been the
combination product. First, the devices that are distributed unfilled and case.
definition of PMOA finalized here is determined not to require conforming (Response) FDA has clarified the role
based on past practice and will preserve changes to drug labeling are devices. For of precedents earlier in this section of
precedent. FDA has long considered a instance, the comment asked for the document. With regard to the
product’s most important therapeutic clarification of the regulatory status of application of the PMOA analysis to
action in determining the primary mode closed loop insulin delivery systems pharmacogenomic drug/diagnostic
of action of a combination product and and catheters to deliver clot-busting device products, the comment is correct
the concept of ‘‘most important drugs, which also act physically to in noting that not all such products are
therapeutic action’’ also underlies the dissolve the clot. combination products, and when they
assignments of combination products (Response) In order to be a are not, the drug and device would be
outlined in the Intercenter Agreements. combination product, a product must regulated as separate entities.
In addition, the role of precedent is meet one of the definitions found in (Comment 27) One comment asked
encompassed in the first criterion of the § 3.2(e). By their general nature, that OCP continue its role in the
assignment algorithm, for use when the unfilled, general-purpose drug delivery regulatory oversight of drug/biological
agency cannot determine a combination devices typically do not meet the product combinations, even when CDER
product’s PMOA with reasonable definition of a combination product has regulatory responsibility for both
certainty. That criterion directs FDA to because they are not physically the drug and biological product
assign a combination product to the combined or packaged with, or tied by components.
agency component that regulates other labeling to a particular drug, so such (Response) A drug-biological product
combination products that present products are regulated as devices. The remains a combination product even if
similar safety and effectiveness specific types of products mentioned in both components are reviewed by the
questions with regard to the product as comment 24 of this document could be same Center. FDA agrees that OCP
a whole. single-entity devices as long as they are continues to have oversight
provided without the drugs, and the responsibility, consistent with 21 USC
E. Application of Regulatory Authorities labeling of the drugs does not need to 353(g)(4) and the regulations set forth in
in the Review of Combination Products change to reflect their use. The 21 CFR Part 3, for drug/ biological
assignment of delivery devices that are product combination products even
(Comment 23) A few stakeholders when both the drug and biological
asked FDA to clarify which good not combination products as defined by
§ 3.2(e) is outside the scope of this rule. product components are regulated by
manufacturing practices and adverse CDER. FDA’s jurisdictional update on
(Comment 25) One comment asked
event reporting authorities would apply drug-biological product combination
FDA to clarify how several variables
to the regulation of a combination products, available at http://
would impact PMOA. These questions
product. Other comments asked www.fda.gov/oc/combination/
were as follows: What if the drug
whether single or separate marketing biologic.html, provides more
component is an old, generic, off-patent
applications would be appropriate for information.
drug? What if the mode of
certain types of combination products, (Comment 28) One comment asked
administration and dosage of the drug
and how user fees are handled for that over-the-counter (OTC) drug and
are changed only slightly? What if the
combination products. drug indication remains the same? What dietary supplement combinations be
(Response) As explained previously if only secondary aspects of drug classified as combination products.
in this document, this final rule applies labeling (e.g., precautions, instructions (Response) Under 21 U.S.C. 353(g)
only to the jurisdictional assignment of for use) change? and 21 CFR part 3, a combination
combination products to an agency (Response) These questions would not product is a product comprised of any
component for review and regulatory affect the determination of PMOA (i.e., combination of a drug and a device; a
oversight. The specific regulatory the most important therapeutic action of device and a biological product; a
authorities to be applied to a a combination product), but they are biological product and a drug; or a drug,
combination product are outside the factors FDA would consider, as a device, and a biological product.
scope of this rule. appropriate, at the second tier of the Classification of OTC drug and dietary

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supplement combinations is outside the the same device combined with some of the examples suggested and
scope of this rule. different drug products may be assigned developed additional hypothetical
(Comment 29) One comment asked to different divisions within CDER, examples. FDA believes the examples
that FDA clarify whether tissue- which could result in confusing or provided in this response to comment
engineered products, such as human- conflicting requirements for the release 34 of this document, along with the
derived fibroblasts cultured in vitro on testing or labeling of the device. capsular descriptions of prior
a synthetic scaffold, are considered to be (Response) As stated previously in jurisdictional determinations posted on
combination products. this document, FDA is required by OCP’s website, and the types of
(Response) While classification of statute to assign a product to an agency questions FDA considers when making
particular products is outside the scope component for review based on its assignments of combination products,
of this rule, we note that many tissue PMOA. FDA has developed a Standard further illustrate the process FDA uses
engineered products, such as the Operating Procedure (SOP) to help when making assignments.
product described in comment 29 of this ensure efficient and effective
document, are comprised of biological consultation and collaboration between Examples Repeated From Proposed Rule
product and device components, and the Centers on such reviews. Such a. Conventional drug-eluting stent. A
therefore meet the definition of a consultation and collaboration will also vascular stent provides a mechanical
combination product as defined in help to ensure uniformity in approaches scaffold to keep a vessel open while a
§ 3.2(e). by the review divisions. This review drug is slowly released from the stent to
(Comment 30) One comment asked process is outlined in further detail in prevent the buildup of new tissue that
FDA to note that the review timelines of the FDA SOP for Intercenter would reocclude the artery.
combination products would be Consultative/Collaborative Review • PMOA Analysis—Which mode of
consistent with the performance goals of Process, available at http:// action provides the most important
the primary review Center. Another www.fda.gov/oc/ombudsman/ therapeutic action of the combination
comment asked FDA to address the intercentersop.pdf. product?
review timelines for a combination In this case, the product has two
product in which the agency has Examples modes of action. One action of the
required that the sponsor submit (Comment 33) Several comments vascular stent is to provide a physical
separate marketing applications. asked that FDA provide more examples, scaffold to be implanted in a coronary
(Response) Review timelines are particularly examples illustrating how artery to improve the resultant arterial
outside the scope of this rule. We note drug and biological product luminal diameter following angioplasty.
that review timeframes are associated combination products would be Another action of the product is the
with the type of marketing application, reviewed. One comment recommended drug action, with the intended effect of
rather than the reviewing Center. that FDA include examples of reducing the incidence of restenosis and
Further information on these issues, as copackaged and cross-labeled the need for target lesion
well as other information regarding the combination products. revascularization.
timeliness of reviews, is discussed in (Response) FDA agrees, and we • Assignment of Lead Agency
FDA’s guidance document on dispute provide 11 hypothetical examples in Component: CDRH
resolution available at http:// this section of the document, three of The product’s primary mode of action
www.fda.gov/oc/combination/. which were also provided in the is attributable to the device component’s
(Comment 31) One comment asked proposal. We note that the interferon/ function of physically maintaining
that FDA clarify how the agency would ribavirin combination product is an vessel lumen patency, while the drug
evaluate new uses for a product using example where the two components plays a secondary role in reducing
the PMOA analysis. may be either copackaged or separately restenosis caused by the proliferative
(Response) FDA is required by statute provided but labeled to be used response to the stent implantation,
to assign a product to an agency together; the same assignment would augmenting the safety and/or
component for review based on its result in either situation. In addition, we effectiveness of the uncoated stent.
PMOA. Stakeholders have urged, and have posted a list of selected capsular Accordingly, FDA would assign the
FDA agrees, that determination of a descriptions illustrating many prior product to CDRH for regulation because
product’s PMOA should take into jurisdictional determinations, which is the device component provides the most
account the product’s intended use. available on our website at http:// important therapeutic action of the
Therefore, it is possible that a single www.fda.gov/oc/combination/ product. It is unnecessary to proceed to
product, intended for two different determinations.html. FDA believes the assignment algorithm because it is
purposes, may be assigned to different these descriptions also help to illustrate possible to determine which mode of
agency components for review of those the jurisdictional determination process. action provides the most important
different uses if the PMOA for each use (Comment 34) One comment listed a therapeutic action of this particular
directs the assignment to a different number of hypothetical products, and combination product.
agency component. However, FDA will asked that FDA explain how it would b. Drug Eluting Disc. A surgically
strive to minimize the impact of these review and regulate them, so that implanted disc contains a drug that is
assignments where possible. stakeholders would have a better slowly released for prolonged, local
(Comment 32) One comment was understanding of the process FDA uses delivery of chemotherapeutic agents to
concerned that the PMOA definition when making assignments of a tumor site.
would direct all drug delivery devices combination products. • PMOA Analysis—Which mode of
combined with a drug product to CDER. (Response) FDA notes that some of action provides the most important
The comment mentioned a specific the comment’s examples are not therapeutic action of the combination
example of an approved drug product in combination products and, therefore, product?
its approved container, with no change fall outside the scope of the rule, while In this case, the product has two
to the route of administration, combined other examples lack sufficient detail for modes of action. This product has a
with an innovative delivery device. FDA to work through as a hypothetical device mode of action because it is
Additionally, the comment stated that exercise. However, FDA used or adapted surgically implanted in the body and is

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designed for controlled drug release, effectiveness questions with regard to therapeutic protein to coat the inside
thus affecting the structure of the body the constituent parts of the product, surfaces of the device. In this
and treating disease. Another mode of neither agency component regulates hypothetical example, the fusion cage, a
action is the drug action, with the combination products that present permanent implant, maintains the
intended effect of preventing tumor similar safety and effectiveness spacing and stabilizes the diseased
recurrence at the implant site. questions with regard to the product as region of the spine, while the protein is
• Assignment of Lead Agency a whole. used to encourage the formation of bone
Component: CDER Because there is no agency within the fusion cage to further
Though the product has a device component that regulates products that stabilize this portion of the spine as well
mode of action, the product’s primary present similar safety and effectiveness as the cage itself.
mode of action is attributable to the questions with regard to the product as • PMOA Analysis—Which Mode of
drug component’s function of a whole, it is necessary to apply the Action Provides the Most Important
preventing tumor recurrence at the second criterion of the algorithm. Therapeutic Action of the Combination
implant site. Accordingly, we would • Which agency component has the Product?
assign the product to CDER for most expertise related to the most In this case, the product has two
regulation because the drug component significant safety and effectiveness modes of action. One action is the
provides the most important therapeutic questions presented by the combination device component’s action to
action of the product. It is unnecessary product? mechanically maintain the
to proceed to the assignment algorithm Assignment of Lead Agency Component: intervertrebral spacing and stabilize the
because it is possible to determine CDER— diseased region of the spine. Another
which mode of action provides the most Because there is no agency action is the therapeutic protein’s action
important therapeutic action of this component that regulates combination to encourage the formation of bone
particular product. products that present similar safety and within the fusion cage to further
c. Contact Lens Combined With Drug effectiveness issues with regard to the stabilize the cage and this portion of the
to Treat Glaucoma. In this case, a product as a whole, the agency would spine.
contact lens is placed in the eye to consider which agency component has Assignment of Lead Agency Component:
correct vision. The contact lens also the most expertise related to the most CDRH
contains a drug to treat glaucoma that significant safety and effectiveness The product’s PMOA is attributable to
will be delivered from the lens to the questions presented by the product. In the device component’s action to
eye. this hypothetical example, the most mechanically maintain the
• PMOA Analysis—Which mode of significant safety and effectiveness intervertebral spacing and stabilize the
action provides the most important questions are related to the diseased region of the spine, while the
therapeutic action of the combination characterization, manufacturing, and therapeutic protein’s action to
product? clinical performance of the drug encourage bone formation within and
This product has two modes of action. component, while the safety and around the cage plays a secondary role.
One action of the product is the device effectiveness questions raised by the In this hypothetical example, the
action, to correct vision. Another action vision-correcting contact lens are therapeutic protein does not have the
of the product is a drug action, to treat considered more routine. It should also mechanical properties necessary to
glaucoma. Though administration be noted that CDER has expertise in the maintain the spacing and stabilize the
through a contact lens is not necessary review of other drugs delivered using a spine if used alone. Furthermore,
for the drug’s delivery, the combination contact lens. Based on the application of clinically successful spinal fusion, i.e.,
product allows a patient requiring this criterion, this product would be pain reduction and stability of the
vision correction to receive glaucoma assigned to CDER because CDER has the spine, can be achieved even in the
treatment without having to undertake a most expertise related to these issues. absence of bone growth within the cage.
more complicated daily drug regimen. d. Contact Lens Combined With Drug Accordingly, FDA would assign the
Here, both actions of the product are to Treat Glaucoma. This product is product to CDRH for regulation because
independent, and neither appears to be identical to the product described in the device component provides the most
subordinate to the other. example c. in all material respects. The important therapeutic action of the
Because it is not possible to determine RFD was filed after the designation of product. It is unnecessary to proceed to
which mode of action provides the the product in example c. Since it is not the assignment algorithm because it is
greatest contribution to the overall possible to determine which mode of possible to determine which mode of
therapeutic effects of the combination action provides the greatest contribution action provides the most important
product, it is necessary to apply the to the overall therapeutic effects of the therapeutic action of this particular
assignment algorithm. combination product, we would apply combination product.
Assignment Algorithm: the assignment algorithm. This product f. Chemotherapeutic drug and
• Is there an agency component that would be assigned to CDER under the monoclonal antibody for targeted cancer
regulates other combination products first criterion of the assignment treatment. The monoclonal antibody is
that present similar questions of safety algorithm, since the product described intended to improve the drug’s
and effectiveness with regard to the in example c. presents similar questions effectiveness by directly targeting the
combination product as a whole? of safety and effectiveness with respect drug to receptors on cancer tumor cells.
CDRH regulates devices intended to to the combination product as a whole • PMOA Analysis—Which Mode of
correct vision. CDER regulates drugs and is already assigned to CDER. Action Provides the Most Important
intended to treat glaucoma. In this Additional Examples-These Therapeutic Action of the Combination
hypothetical example, no combination hypothetical examples further illustrate Product?
product intended to treat these different the designation process. In this hypothetical case, the product
conditions simultaneously has yet been e. Spinal fusion device coated with a has two modes of action. One action is
submitted to the agency for review. therapeutic protein intended to treat the chemotherapeutic drug component’s
Though both CDER and CDRH regulate degenerative disc disease. A spinal action to treat cancer. Another action is
products that raise similar safety and fusion cage soaked in a solution of a the monoclonal antibody’s (biological

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product) action to target the drug to necessary shape, the creation of a effectiveness questions with regard to
receptors on cancer tumor cells, thereby functioning organ is primarily the product as a whole.
delivering the drug directly to the tumor dependent upon the role of the cells to Because there is no agency
site. provide the tissue organization and component that regulates products that
Assignment of Lead Agency Component: muscular layer needed to function like present similar safety and effectiveness
CDER the native organ. Accordingly, FDA questions with regard to the product as
The product’s PMOA is attributable to would assign the product to CBER for a whole, it is necessary to apply the
the drug component’s cytotoxic action regulation because the biological second criterion of the hierarchy.
on cancer cells, while the biological product component provides the most • Which Agency Component Has the
product component’s action to target the important therapeutic action of the Most Expertise Related to the Most
drug to the receptors on the cancer cells product. It is unnecessary to proceed to Significant Safety and Effectiveness
enhances the efficacy of the drug. the assignment algorithm because it is Questions Presented by the Combination
Accordingly, FDA would assign the possible to determine which mode of Product?
product to CDER for regulation because action provides the most important Assignment of Lead Agency Component:
the drug component provides the most therapeutic action of this particular CBER
important therapeutic action of the combination product. Because there is no agency
product. It is unnecessary to proceed to h. Menstrual tampon impregnated component that regulates combination
the assignment algorithm because it is with genetically modified bacteria. The products that present similar safety and
possible to determine which mode of hypothetical product is intended for use effectiveness issues with regard to the
action provides the most important throughout menstruation both in the product as a whole, the agency would
therapeutic action of this particular collection of menstrual fluid and to treat consider which agency component has
combination product. Note that in June and/or prevent recurrence of bacterial the most expertise related to the most
2003, FDA transferred to CDER the vaginosis. significant safety and effectiveness
regulation of certain therapeutic • PMOA Analysis—Which Mode of
questions presented by the product. In
biological products, including Action Provides the Most Important
this case, the menstrual tampon
monoclonal antibodies, which had been Therapeutic Action of the Combination
component presents generally routine
regulated by CBER. Although CDER now Product?
In this case, the product has two safety and effectiveness questions,
has regulatory responsibility over both
modes of action. One action of the similar to those of other menstrual
the chemotherapeutic drug and
product is the action of the biological tampons. In contrast, the biological
monoclonal antibody described in this
product component to act upon the product component raises more
hypothetical example, this example is
vaginal mucus membrane to produce significant safety and effectiveness
provided for illustrative purposes. For
antimicrobial factors that will control questions, such as those related to
further information about the drug and
opportunistic pathogens. Another action bacterial strain selection and dose;
biological product consolidation, see the
of the product, like other menstrual bacterial purity, potency and metabolic
Federal Register of June 26, 2003 (68 FR
tampons, is the device component’s activity, including the impact of genetic
38067), and the OCP website at http://
action to collect menstrual fluid. Here, modifications; bacterial adherence
www.fda.gov/oc/combination/
both actions of the product are potential, microbial strain interactions,
transfer.html.
g. Scaffold seeded with autologous independent, and neither appears to be and constitutive production of ancillary
cells for organ replacement. The subordinate to the other. antimicrobial substances. Based on the
hypothetical product has the shape of Because it is not possible to determine application of this criterion, this
the target organ, and the autologous which mode of action provides the product would be assigned to CBER
cells are intended to allow the product greatest contribution to the overall because CBER has the most expertise
to ultimately function like the target therapeutic effects of the combination related to these issues.
organ in the patient. product, it is necessary to apply the i. Interferon and Ribavirin
PMOA Analysis—Which Mode of assignment algorithm. Combination Therapy. The product is
Action Provides the Most Important Assignment Algorithm: intended for use in the treatment of
Therapeutic Action of the Combination • Is There an Agency Component chronic hepatitis C. Interferon is
Product? That Regulates Other Combination approved under the licensing provisions
In this case, the product has two Products That Present Similar of the Public Health Service Act as a
modes of action. One action of the Questions of Safety and Effectiveness stand-alone product for treatment of
product is the action of the biological With Regard to the Combination chronic hepatitis C. Clinical studies
product component to help form new Product as a Whole? show that ribavirin when used alone to
tissue that will ultimately function like CDRH regulates tampons; CBER treat chronic hepatitis C can improve
the native organ. Another action of the regulates bacterial products and liver function, but most patients relapse
product is the device component’s genetically modified cells. In this with treatment of ribavirin alone.
action to provide a scaffold on which hypothetical example, no combination However, data show that ribavirin,
the new organ tissue will form. product intended both to collect when used in conjunction with
Assignment of Lead Agency Component: menstrual fluid and to treat and/or interferon, produces a more efficacious
CBER prevent recurrence of bacterial vaginosis response than when interferon is used
The product’s PMOA is attributable to through the actions of a genetically alone to treat chronic hepatitis C. The
the biological product component’s modified organism has previously been drug and biological product components
action to help form new organ tissue reviewed by the agency. Though both may be copackaged or are provided
that will ultimately function like the CDRH and CBER regulate products that separately but cross-labeled for use
native organ. The device component’s raise similar safety and effectiveness together.
action to provide a scaffold upon which questions with regard to the constituent • PMOA Analysis—Which Mode of
the new tissue will form is secondary. parts of the product, neither agency Action Provides the Most Important
Though the scaffold is necessary to component regulates combination Therapeutic Action of the Combination
create the new tissue and provide the products that present similar safety and Product?

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Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations 49859

In this case, the product has two hypothetical example, the PMOA was products that present similar safety and
modes of action. One action of the attributable to the device component. effectiveness issues with regard to the
product is the action of the biological However, we note such a product used product as a whole, the agency would
product component to treat chronic for another indication, or with another consider which agency component has
hepatitis C, which produces a dose- drug, could have a drug PMOA the most expertise related to the most
dependent decline in hepatitic C virus depending on the relative effectiveness significant safety and effectiveness
ribonucleic acid (RNA) titers. Another of the drug and device components in questions presented by the product.
action of the product is the ribavirin providing the most important Although important safety and
tablet’s action to enhance the efficacy of therapeutic action for the new use. effectiveness questions are presented by
the biological product. k. Vertebroplasty Implant With this new route of administration of an
Assignment of Lead Agency Component: Extended-Release Analgesic. This analgesic and its extended release from
CDER hypothetical product is intended to the device, and would need to be
The product’s PMOA is attributable to provide spinal stabilization in patients addressed, in this hypothetical example,
the biological product component’s with spinal bone metastases who also the most significant safety and
function, while the drug component require palliative relief of pain. effectiveness questions associated with
works to enhance its efficacy. Note that • PMOA Analysis—Which Mode of the combination product as a whole are
interferons are now reviewed in CDER Action Provides the Most Important related to the mechanical strength, wear,
following the transfer of therapeutic Therapeutic Action of the Combination and clinical performance of the
biological products to CDER in 2003. Product? vertebroplasty implant. Based on the
CDER is now the agency component One action of the product is the application of this criterion in the
responsible for review of such biological device action, to stabilize the fractured algorithm, this product would be
products (see example e. in this section spinal vertebral body bone. Another assigned to CDRH because CDRH has
of the document). action of the product is the drug action, the most expertise related to these
j. Implantable device with local to provide for extended analgesic issues. CDRH would consult or
chemotherapeutic drug. Embolization delivery as an alternative to oral collaborate with CDER on the safety and
device coated with a chemotherapeutic medication in patients expected to effectiveness issues raised by the
agent intended to treat continue to require long-term pain analgesic component.
hypervascularized tumors. management despite the stabilization
• PMOA Analysis—Which Mode of implant. In this hypothetical example, Miscellaneous Comments
Action Provides the Most Important both actions of the product are (Comment 35) Several comments
Therapeutic Action of the Combination independent, and neither is clearly asked that FDA post precedents on the
Product? subordinate to the other. Because it is Web, so that stakeholders could better
In this case, the product has two not possible to determine which mode understand the process FDA used when
modes of action. One action is the of action provides the greatest making jurisdictional determinations for
device component’s action to physically contribution to the overall therapeutic combination products submitted to FDA
occlude the tumor’s blood supply. effects of the combination product, it is prior to implementation of this final
Another action is the drug component’s necessary to apply the assignment rule.
action as it elutes from the device to the algorithm. (Response) FDA has complied with
tumor where it has a cytotoxic effect. Is there an agency component that these requests and has published a list
The embolization device is a permanent regulates other combination products of capsular descriptions of selected
implant, while the drug component is a that present similar questions of safety previous jurisdictional determinations,
short-term acting chemotherapeutic. and effectiveness with regard to the and is working to publish additional
Assignment of Lead Agency Component: combination product as a whole? such descriptions. They are available on
CDRH CDRH regulates vertebroplasty OCP’s Web site at: http://www.fda.gov/
In this hypothetical example, the implants. CDER regulates analgesic drug oc/combination/determinations.html.
product’s PMOA is attributable to the products. In this hypothetical example, (Comment 36) A few comments
device component’s role in the physical no product combining a vertebroplasty suggested that FDA issue various
occlusion of the blood supply to the implant and an extended-release guidances on PMOA, either before
tumor site through embolization, while analgesic has yet been submitted to the issuance of the final rule, concurrently
the drug component plays a subordinate agency for review, therefore neither with issuance of the final rule, or after
role in causing apoptosis in any agency component regulates issuance of the final rule.
remaining proliferating tumor cells. In combination products that present (Response) FDA believes that it has
this hypothetical example, data indicate similar safety and effectiveness provided sufficient explanation and
that the effectiveness of the questions with regard to the product as examples, both in the preamble to the
embolization device alone for the stated a whole. Because there is no agency proposed and final PMOA rules and on
indication is much greater than the component that regulates products that the PMOA analysis codified here, to
effectiveness of the drug component present similar safety and effectiveness render additional guidance unnecessary
when delivered directly to the tumor questions with regard to the product as at this time. Nonetheless, FDA will
site without use of the embolization a whole, it is necessary to apply the reconsider if implementation of this rule
agent. Accordingly, FDA would assign second criterion of the algorithm. gives rise to a need for development of
the product to CDRH for regulation Which agency component has the a guidance on this topic.
because the device component provides most expertise related to the most (Comment 37) One comment
the most important therapeutic action of significant safety and effectiveness suggested that FDA repropose the rule
the product. It is unnecessary to proceed questions presented by the combination after FDA issued a guidance.
to the assignment algorithm because it product? (Response) FDA declines to repropose
is possible to determine which mode of Assignment of Lead Agency Component: the rule. First, the majority of comments
action provides the most important CDRH were supportive of the rule in whole or
therapeutic action of this particular Because there is no agency in part, and only two minor changes
combination product. In this component that regulates combination have been made to the codified

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49860 Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations

language. Second, the majority of before moving such a product to another VIII. Analysis of Impacts
stakeholders that commented in public agency component.
A. Introduction
meetings held prior to issuance of the
proposal stressed to FDA the need to IV. Legal Authority FDA has examined the impacts of the
define PMOA and MOA in a timely final rule under Executive Order 12866,
The agency derives its authority to
manner. We have done so here in a the Regulatory Flexibility Act (5 U.S.C.
issue the regulations found in part 3 601–612), and the Unfunded Mandates
manner that, as one comment stated, from 21 U.S.C. 321, 351, 353, 355, 360,
‘‘faithfully implements the statute.’’ Reform Act of 1995 (Public Law 104–4,
360c–360f, 360h–360j, 360gg–360ss, 109 Stat. 48). Executive Order 12866
(Comment 38) One comment 360bbb–2, 371(a), 379e, 381, 394; 42
suggested that FDA withdraw the rule directs agencies to assess all costs and
U.S.C. 216, 262, and 264 as stated in the benefits of available regulatory
because it would hinder the assignment Code of Federal Regulations. Congress
process and because the algorithm is not alternatives and, when regulation is
expressly directed FDA to assign necessary, to select regulatory
set forth in the statute. The comment combination products to the appropriate
was primarily concerned that the approaches that maximize net benefits
agency component for regulation based (including potential economic,
criteria used in the algorithm did not on the agency’s assessment of PMOA as
adequately explain how FDA would environmental, public health and safety,
set forth in section 503(g) of the act. and other advantages; distributive
determine the most significant as well
Under section 701 of the act (21 U.S.C. impacts; and equity). The final rule is
as similar safety and effectiveness
371) and for the efficient enforcement of not a significant regulatory action as
questions.
the act, FDA has the authority to define defined by the Executive order.
(Response) FDA believes that it has The Regulatory Flexibility Act
and codify ‘‘mode of action’’ and PMOA
adequately addressed how it will requires agencies to analyze regulatory
and to issue the assignment algorithm.
determine these issues by providing in options that would minimize any
this preamble numerous examples as V. Environmental Impact significant impact of a rule on small
well as examples of factors FDA entities. No further analysis is required
considers when making these FDA has determined under 21 CFR
25.30(a) and (k), and 25.32(g) that this under the Regulatory Flexibility Act
determinations. Additionally, we have because the agency has determined that
published on the OCP Web site an action is of a type that does not
individually or cumulatively have a these final rule amendments have no
extensive list of capsular descriptions of compliance costs and will not have a
actual assignment decisions. The agency significant effect on the human
significant impact on a substantial
believes the issuance of this rule will environment. Therefore, neither an
number of small entities. Therefore, the
not hinder the assignment process but environmental assessment nor an
agency certifies the final rule will not
rather improve it. FDA declines to environmental impact statement is
have a significant economic impact on
withdraw this rule for the reasons stated required.
a substantial number of small entities.
in comment 38 of this document. Section 202(a) of the Unfunded
VI. Paperwork Reduction Act of 1995
Furthermore, FDA’s experience in Mandates Reform Act of 1995 requires
evaluating combination products has FDA concludes that the changes to the that agencies prepare a written
shown that for a small subset of regulations on combination products statement, which includes an
products, the most important finalized in this document are not assessment of anticipated costs and
therapeutic action is not determinable subject to review by the Office of benefits, before proposing ‘‘any rule that
with reasonable certainty, even by the Management and Budget (OMB) because includes any Federal mandate that may
product’s developer. Therefore, FDA they do not constitute a ‘‘collection of result in an expenditure by State, local,
needs a mechanism to ensure that these information’’ under the Paperwork and tribal governments, in the aggregate,
types of products are assigned with Reduction Act of 1995 (44 U.S.C. 3501– or by the private sector, of $100 million
consistency, transparency, and 3520). The information collected under or more (adjusted annually for inflation)
predictability to an appropriate agency part 3 is currently approved under OMB in any one year.’’ The current threshold
component. Out of necessity, FDA control number 0910–0523. This after adjustment for inflation is $115
established the algorithm to accomplish million, using the most current (2003)
proposal does not constitute an
these goals. implicit price deflator for the Gross
additional paperwork burden.
Implementation Domestic Product. FDA does not expect
VII. Federalism this final rule to result in any 1-year
(Comment 39) Several comments expenditure that would meet or exceed
asked FDA to clarify whether the rule FDA has analyzed this final rule in
this amount.
would affect prior RFD determinations. accordance with the principles set forth
One comment also asked that FDA in Executive Order 13132. FDA has B. The Rationale Behind This Final Rule
clarify whether the final rule is intended determined that the proposed rule does The purpose of the final rule is
to change prior jurisdictional decisions not contain policies that have twofold: (1) To codify the definition of
made outside the RFD process. substantial direct effects on the States, PMOA, a criterion the agency has used
(Response) The rule is prospective in on the relationship between the for more than a decade when assigning
nature and will apply only to National Government and the States, or combination products to agency
assignments FDA makes 90 days after on the distribution of power and components for regulatory oversight;
the rule is published in the Federal responsibilities among the various and (2) to simplify the designation
Register. This final rule is not intended levels of government. Accordingly, the process by providing a defined
to affect RFD determinations made prior agency has concluded that the rule does framework that sponsors may use when
to its implementation. For prior not contain policies that have recommending and/or considering the
jurisdictional assignments of federalism implications as defined in PMOA and assignment of a combination
combination products made outside the the Executive order and, consequently, product.
RFD process, FDA would consider the a federalism summary impact statement Indeed, as stated in the proposed rule,
facts and principles governing PMOA is not required. many stakeholders have requested that

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Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations 49861

the agency issue a rule defining PMOA List of Subjects in 21 CFR Part 3 purposes through chemical action
because, without a definition of this Administrative practice and within or on the body of man or other
statutory criterion, the assignment procedure, Biologics, Drugs, Medical animals and is not dependent upon
process has at times appeared to lack devices. being metabolized for the achievement
transparency. We believe that this final of its primary intended purposes.
n Therefore, under the Federal Food,
rule and its preamble address the (3) A constituent part has a drug mode
Drug, and Cosmetic Act, the Public of action if it meets the definition of
significant concerns stakeholders have Health Service Act, and under authority
expressed regarding the assignment drug contained in section 201(g)(1) of
delegated to the Commissioner of Food the act and it does not have a biological
process, and address the significant and Drugs, 21 CFR part 3 is amended as
concerns expressed in the comments to product or device mode of action.
follows:
the proposal. Moreover, we have * * * * *
incorporated into the codified section of PART 3—PRODUCT JURISDICTION (m) Primary mode of action is the
this final rule suggestions provided by single mode of action of a combination
n1. The authority citation for 21 CFR product that provides the most
the comments to the proposal regarding
part 3 is revised to read as follows: important therapeutic action of the
the MOA and PMOA definitions.
Authority: 21 U.S.C. 321, 351, 353, 355, combination product. The most
The codification of these principles 360, 360c–360f, 360h–360j, 360gg–360ss, important therapeutic action is the
will also simplify the designation 360bbb–2, 371(a), 379e, 381, 394; 42 U.S.C. mode of action expected to make the
process for sponsors. For years, a 216, 262, 264. greatest contribution to the overall
sponsor has been required to determine intended therapeutic effects of the
n 2. Section 3.2 is amended by
PMOA and make a recommendation of combination product.
redesignating paragraph (k) as paragraph
lead agency component for regulatory * * * * *
(l), paragraph (l) as paragraph (n),
oversight of its combination product, paragraph (m) as paragraph (o), n 3. Section 3.4 is amended by
without a codified definition of PMOA. paragraph (n) as paragraph (p); and by redesignating paragraph (b) as paragraph
The finalization of this rule will allow adding new paragraphs (k) and (m) to (c) and by adding a new paragraph (b) to
a sponsor to base its determination of read as follows: read as follows:
PMOA and recommendation of lead
agency component for regulatory § 3.2 Definitions. § 3.4 Designated agency component.
oversight of its product on defined * * * * * * * * * *
factors. (k) Mode of action is the means by (b) In some situations, it is not
which a product achieves an intended possible to determine, with reasonable
As mentioned previously in this final certainty, which one mode of action will
therapeutic effect or action. For
rule, as well as in the proposed rule, the provide a greater contribution than any
purposes of this definition,
amendments finalized here will fulfill other mode of action to the overall
‘‘therapeutic’’ action or effect includes
the statutory requirement to assign therapeutic effects of the combination
any effect or action of the combination
products based on their PMOA, and will product intended to diagnose, cure, product. In such a case, the agency will
use safety and effectiveness issues as mitigate, treat, or prevent disease, or assign the combination product to the
well as consistency with the regulation affect the structure or any function of agency component that regulates other
of similar products to guide the the body. When making assignments of combination products that present
assignment of products when the agency combination products under this part, similar questions of safety and
cannot determine which mode of action the agency will consider three types of effectiveness with regard to the
provides the most important therapeutic mode of action: The actions provided by combination product as a whole. When
action of a combination product. The a biological product, a device, and a there are no other combination products
final rule ensures that like products will drug. Because combination products are that present similar questions of safety
be similarly assigned and regulated, and comprised of more than one type of and effectiveness with regard to the
it allows new products for which the regulated article (biological product, combination product as a whole, the
most important therapeutic action device, or drug), and each constituent agency will assign the combination
cannot be determined to be assigned to part contributes a biological product, product to the agency component with
the most appropriate agency component device, or drug mode of action, the most expertise related to the most
based on the most significant safety and combination products will typically significant safety and effectiveness
effectiveness issues they present. In have more than one identifiable mode of questions presented by the combination
addition, by providing a more defined action. product.
framework for the assignment process, a (1) A constituent part has a biological * * * * *
codified definition of PMOA will product mode of action if it acts by n 4. Section 3.7 is amended by revising
further MDUFMA’s requirement that the means of a virus, therapeutic serum, paragraph (c)(2)(ix) and (c)(3) to read as
agency ensure prompt assignment of toxin, antitoxin, vaccine, blood, blood follows:
combination products. Also, by issuing component or derivative, allergenic
product, or analogous product § 3.7 Request for designation.
this final rule, the agency furthers
applicable to the prevention, treatment, * * * * *
MDUFMA’s requirement that it review
or cure of a disease or condition of (c) * * *
practices specific to the assignment of (2) * * *
human beings, as described in section
combination products, consult with (ix) Description of all known modes of
351(i) of the Public Health Service Act.
stakeholders and center directors, and (2) A constituent part has a device action, the sponsor’s identification of
make a determination whether to mode of action if it meets the definition the single mode of action that provides
modify those practices. of device contained in section 201(h)(1) the most important therapeutic action of
The agency believes the final rule will to (h)(3) of the act, it does not have a the product, and the basis for that
have no compliance costs and poses no biological product mode of action, and determination.
additional burden to industry. it does not achieve its primary intended * * * * *

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49862 Federal Register / Vol. 70, No. 164 / Thursday, August 25, 2005 / Rules and Regulations

(3) The sponsor’s recommendation as and Drug Administration, 2098 Gaither RNA System under section 513(f)(2) of
to which agency component should Rd., Rockville, MD 20850, 240–276– the act. The manufacturer recommended
have primary jurisdiction based on the 0496. that the device be classified into class II.
mode of action that provides the most In accordance with 513(f)(2) of the
SUPPLEMENTARY INFORMATION:
important therapeutic action of the act, FDA reviewed the petition in order
combination product. If the sponsor I. What is the Background of this to classify the device under the criteria
cannot determine with reasonable Rulemaking? for classification set forth in 513(a)(1) of
certainty which mode of action provides In accordance with section 513(f)(1) of the act. Devices are to be classified into
the most important therapeutic action of the Federal Food, Drug, and Cosmetic class II if general controls, by
the combination product, the sponsor’s Act (the act) (21 U.S.C. 360c(f)(1)), themselves, are insufficient to provide
recommendation must be based on the devices that were not in commercial reasonable assurance of safety and
assignment algorithm set forth in distribution before May 28, 1976, the effectiveness, but there is sufficient
§ 3.4(b) and an assessment of the information to establish special controls
date of enactment of the Medical Device
assignment of other combination to provide reasonable assurance of the
Amendments of 1976 (the amendments),
products the sponsor wishes FDA to safety and effectiveness of the device for
generally referred to as postamendments
consider during the assignment of its its intended use. After review of the
devices, are classified automatically by
combination product. information submitted in the petition,
statute into class III without any FDA
* * * * * FDA determined that the PAXgeneTM
rulemaking process. These devices
Blood RNA System can be classified
Dated: August 9, 2005. remain in class III and require
into class II with the establishment of
Jeffrey Shuren, premarket approval, unless and until
special controls. FDA believes these
the device is classified or reclassified
Assistant Commissioner for Policy. special controls will provide reasonable
into class I or II, or FDA issues an order
[FR Doc. 05–16527 Filed 8–24–05; 8:45 am] assurance of the safety and effectiveness
finding the device to be substantially of the device.
BILLING CODE 4160–01–S
equivalent, in accordance with section The device is assigned the generic
513(i) of the act, to a predicate device name RNA Preanalytical Systems and it
DEPARTMENT OF HEALTH AND that does not require premarket is identified as a device intended to
HUMAN SERVICES approval. collect, store, and transport patient
The agency determines whether new specimens, and stabilize intracellular
Food and Drug Administration devices are substantially equivalent to RNA from the specimens, for
previous marketed devices by means of subsequent isolation and purification of
21 CFR Part 866 premarket notification procedures in the intracellular RNA for reverse
section 510(k) of the act (21 U.S.C. transcriptase polymerase chain reaction
[Docket No. 2005N–0263] 360(k)) and 21 CFR part 807 of FDA’s (RT–PCR) used in in vitro molecular
Medical Devices; Immunology and regulations. diagnostic testing. The device may
Section 513(f)(2) of the act provides consist of sample collection devices,
Microbiology Devices; Classification of
that any person who submits a nucleic acid isolation and purification
Ribonucleic Acid Preanalytical
premarket notification under section reagents, and processing reagents/
Systems
510(k) of the act for a device that has not equipment (tubes, columns, etc.). It also
AGENCY: Food and Drug Administration, previously been classified may, within may contain instruments for automation
HHS. 30 days after receiving an order of the nucleic acid isolation and
ACTION: Final rule. classifying the device in class III under purification steps.
section 513(f)(1) of the act, request FDA FDA has identified the following risks
SUMMARY: The Food and Drug to classify the device under the criteria to health associated specifically with
Administration (FDA) is classifying set forth in section 513(a)(1) of the act. this type of device: (1) Inaccurate results
ribonucleic acid (RNA) preanalytical FDA shall, within 60 days of receiving and improper patient management, (2)
systems into class II (special controls). such a request, classify the device by delay in diagnosis, and (3) a need for
The special control that will apply to written order. This classification shall patient specimen recollection.
the device is the guidance document be the initial classification of the device. Failure of the system during specimen
entitled ‘‘Class II Special Controls Within 30 days after the issuance of an collection, or during RNA stabilization
Guidance Document: RNA Preanalytical order classifying the device, FDA must or purification could yield an RNA
Systems (RNA Collection, Stabilization, publish a notice in the Federal Register sample of low quality and quantity. Low
and Purification Systems for RT–PCR announcing such classification (section quality RNA, when tested, could result
Used in Molecular Diagnostic Testing).’’ 513(f)(2) of the act). in falsely low or falsely high RNA
The agency is classifying the device into In accordance with section 513(f)(1) of transcript signal levels leading to
class II (special controls) in order to the act, FDA issued an order on inaccurate diagnosis and/or improper
provide a reasonable assurance of safety February 18, 2005, classifying the patient management. Low quantity of
and effectiveness of the device. PAXgeneTM Blood RNA System into RNA could render the samples unusable
Elsewhere in this issue of the Federal class III, because it was not substantially for downstream RT–PCR applications;
Register, FDA is announcing the equivalent to a device that was specimens would need to be recollected,
availability of a guidance document that introduced or delivered for introduction causing possible delay in diagnosis. In
will serve as the special control for the into interstate commerce for commercial addition, depending on specimen type,
device. distribution before May 28, 1976, or a recollection could pose additional
DATES: This rule is effective September device which was subsequently patient risk (e.g., tissue biopsy). The
26, 2005. The classification was reclassified into class I or class II. On degree of risk varies depending on the
effective April 18, 2005. February 28, 2005, PreAnalytiX GmbH, disease or condition/stage being
FOR FURTHER INFORMATION CONTACT: Uwe c/o Becton, Dickinson and Co., diagnosed or managed. Results of RNA
Scherf, Center for Devices and submitted a petition requesting testing should always be considered in
Radiological Health (HFZ–440), Food classification of the PAXgeneTM Blood conjunction with other clinical factors.

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