Definition of Primary Mode of Action of a Combination Product, 49848-49862 [05-16527]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 164 (Thursday, August 25, 2005)]
[Rules and Regulations]
[Pages 49848-49862]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-16527]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 3

[Docket No. 2004N-0194]


Definition of Primary Mode of Action of a Combination Product

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
combination product regulations to define ``mode of action'' (MOA) and 
``primary mode of action'' (PMOA). Along with these definitions, the 
final rule sets forth an algorithm the agency will use to assign 
combination products to an agency component for regulatory oversight 
when the agency cannot determine with reasonable certainty which mode 
of action provides the most important therapeutic action of the 
combination product. Finally, the final rule will require a sponsor to 
base its recommendation of the agency component with primary 
jurisdiction for regulatory oversight of its combination product by 
using the PMOA definition and, if appropriate, the assignment 
algorithm. The final rule is intended to promote the public health by 
codifying the agency's criteria for the assignment of combination 
products in transparent, consistent, and predictable terms.

DATES: The regulation is effective November 23, 2005.

FOR FURTHER INFORMATION CONTACT: Leigh Hayes, Office of Combination 
Products (HFG-3), Food and Drug Administration, 15800 Crabbs Branch 
Way, suite 200, Rockville, MD 20855, 301-427-1934.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of May 7, 2004 (69 FR 25527), FDA published 
a proposed rule that proposed to define ``mode of action'' (MOA) and 
``primary mode of action'' (PMOA) (the proposed rule). Along with these 
definitions, the proposal set forth an algorithm the agency proposed to 
use to assign combination products to an agency component for 
regulatory oversight when the agency cannot determine with reasonable 
certainty which mode of action provides the most important therapeutic 
action of the combination product. Finally, the proposal put forth a 
requirement that a sponsor make its recommendation of the agency 
component with primary jurisdiction for regulatory oversight of its 
combination product by using the PMOA definition and, if appropriate, 
the assignment algorithm.
    As set forth in part 3 (21 CFR part 3), and as described in the 
proposed rule, a combination product is a product comprised of any 
combination of a drug and a device; a device and a biological product; 
a biological product and a drug; or a drug, a device, and a biological 
product. A combination product includes: (1) A product comprised of two 
or more regulated components, i.e., drug/device, biological product/
device, drug/biological product, or drug/device/biological product, 
that are physically, chemically, or otherwise combined or mixed and 
produced as a single entity; (2) two or more separate products packaged 
together in a single package or as a unit and comprised of drug and 
device products, device and biological products, or biological and drug 
products; (3) a drug, device, or biological product packaged separately 
that, according to its investigational plan or proposed labeling, is 
intended for use only with an approved individually specified drug, 
device, or biological product where both are required to achieve the 
intended use, indication, or effect and where upon approval of the 
proposed product the labeling of the approved product would need to be 
changed, e.g., to reflect a change in intended use, dosage form, 
strength, route of administration, or significant change in dose; or 
(4) any investigational drug, device, or

[[Page 49849]]

biological product packaged separately that, according to its proposed 
labeling, is for use only with another individually specified 
investigational drug, device, or biological product where both are 
required to achieve the intended use, indication, or effect.
    Section 503(g) of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 353(g)) requires that FDA assign a component of the 
agency to have primary jurisdiction for the regulation of a combination 
product. That assignment must be based upon a determination of the PMOA 
of the combination product. For example, if the primary mode of action 
of a combination product is that of a biological product, the product 
is to be assigned to the FDA component responsible for the premarket 
review of that biological product. FDA issued a final rule in 1991 
establishing the procedures (the ``request for designation'' (RFD) 
process) for determining the assignment of combination products under 
part 3.
    The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) 
further modified section 503(g) of the act to require the establishment 
of an Office (Office of Combination Products) within the Office of the 
Commissioner. The purpose of the Office of Combination Products is to 
ensure the prompt assignment of combination products to agency 
components, the timely and effective premarket review of such products, 
and consistent and appropriate postmarket regulation of combination 
products. MDUFMA also requires the agency to review each agreement, 
guidance, or practice specific to the assignment of combination 
products to agency components, consult with stakeholders and the 
directors of the agency centers, and determine whether to continue in 
effect, modify, revise, or eliminate such agreements, guidances, or 
practices.
    Currently, Sec.  3.7 requires a sponsor submitting a request for 
designation to identify the PMOA of the combination product and 
recommend a lead agency component for its regulation. The PMOA of a 
combination product, however, is not defined in the statute or 
regulations, and at times may be difficult to identify. Requests for 
assignment of combination products are usually submitted very early in 
a product's development. This practice is encouraged because it allows 
sponsors to begin working with an agency component as early in the 
development process as possible. For some products, though, the PMOA of 
the product is not readily apparent, to either FDA or the product 
sponsor, at the time the request for assignment is submitted. 
Determining the PMOA of a combination product is also complicated for 
products that have two completely different modes of action, neither of 
which is subordinate to the other. In close cases, assignments may turn 
on subtle distinctions related to the determination of whether a mode 
of action is ``primary,'' or not. The assignment process may appear to 
be unpredictable when two slightly different products are assigned to 
different agency components based on differences in their PMOAs.
    To address these concerns, to simplify the designation process for 
sponsors, and to enhance the transparency, predictability, and 
consistency of the agency's assignment of combination products, FDA is 
issuing this final rule to define ``mode of action'' and ``primary mode 
of action.'' This final rule will clarify and codify principles the 
agency has generally used since section 503(g) of the act was enacted 
in 1990.

II. Description of the Final Rule

A. Introduction

    FDA is finalizing its proposal to amend its combination product 
regulations to create new definitions in Sec.  3.2 of ``mode of 
action'' and ``primary mode of action.'' This final rule also sets 
forth a two-tiered assignment algorithm in Sec.  3.4, which the agency 
will use to determine assignment when it cannot determine with 
reasonable certainty which mode of action of a combination product 
provides the most important therapeutic action of the product. Finally, 
the rule will require that sponsors base their recommendation of which 
agency component should have primary jurisdiction for regulatory 
oversight of its product on the PMOA definition and, if appropriate, 
the assignment algorithm.
    This final rule will fulfill the statutory requirement to assign 
products based on their PMOA, and will use safety and effectiveness 
issues, as well as consistency with the regulation of similar products, 
to guide the assignment of products when the agency cannot determine 
with reasonable certainty which mode of action provides the most 
important therapeutic action of the combination product. It ensures 
that like products would be similarly assigned, and it allows new 
products for which the most important therapeutic action cannot be 
determined with reasonable certainty to be assigned to the most 
appropriate agency component based on the most significant safety and 
effectiveness issues they present. In addition, by providing a more 
defined framework for the assignment process, a codified definition of 
PMOA will further MDUFMA's requirement that the agency ensure prompt 
assignment of combination products. Also, by issuing this final rule, 
the agency adheres to MDUFMA's requirement that it review practices 
specific to the assignment of combination products, consult with 
stakeholders and center directors, and make a determination whether to 
modify those practices.
    Not only will this final rule fulfill the objectives set forth in 
the preceding paragraph, it will do so in a way that remains consistent 
with agency practice regarding the assignment of combination products. 
This rulemaking will codify criteria the agency has generally used 
since 1990. The final rule will apply to RFD submissions received by 
the agency on or after its effective date.

B. Stakeholder Input Prior to Proposed Rulemaking

    Before issuance of the proposed rule, FDA held public hearings on 
May 15, 2002, and on November 25, 2002, and a public workshop on July 
8, 2003, to discuss various issues pertaining to combination products, 
including the assignment of products to an agency component for 
regulatory oversight. Stakeholders also provided a number of written 
comments to the dockets for these meetings, which FDA opened to further 
facilitate the discussion of PMOA issues. The agency received many 
thoughtful comments from the stakeholders who participated in those 
discussions, as well as from stakeholders who submitted written 
comments to the docket, including some pertaining to a definition of 
PMOA as well as others regarding the criteria for the assignment 
algorithm if PMOA could not be determined. The November 2002 meeting in 
particular addressed questions regarding assignment. Some questions 
raised at the meeting were:
     What factors should FDA consider in determining the PMOA 
of a combination product?
     In instances where the PMOA of the combination product 
cannot be determined with certainty, what other factors should the 
agency consider in assigning primary jurisdiction?
     Is there a hierarchy among these additional factors that 
should be considered in order to ensure adequate review and regulation 
(e.g., which component presents greater safety questions?)
    Several common themes emerged from these comments regarding the 
definition of PMOA. For instance, many stakeholders felt that the 
agency should

[[Page 49850]]

base any proposed definition of PMOA on the combination product as a 
whole. FDA agrees, and has crafted the definition so that PMOA is based 
on the most important therapeutic action of the combination product as 
a whole. Furthermore, as detailed in the section regarding the 
assignment algorithm, the agency will consider the combination product 
as a whole when the agency cannot determine with reasonable certainty 
the most important therapeutic action of the product.
    Another theme recurring in a number of comments concerned the 
intended use of the product. Several stakeholders expressed their 
desire that FDA construct a definition of PMOA around this concept. As 
further described in this document, mode of action is defined as the 
means by which a product achieves its intended therapeutic effect or 
action. For over a decade, the agency has considered in its 
determination of PMOA an assessment of the product's intended use, as 
well as its effect on the diagnosis, cure, mitigation, treatment, or 
prevention of disease, and its effect on the structure or function of 
the body. The agency intends to continue this practice, and has 
structured the PMOA definition to include consideration of the intended 
use of a combination product.
    As with the definition for PMOA, several common themes emerged from 
the comments regarding possible criteria to be considered when the 
product's most important therapeutic action cannot be determined with 
reasonable certainty. For example, several stakeholders suggested that 
the agency consider similarly situated products when assigning a 
combination product to a lead agency component. We agree that both 
precedent and expertise are important when assigning a combination 
product to a particular agency component, and we have placed this 
criterion first in the algorithm's decisionmaking hierarchy. Therefore, 
if the agency cannot determine with reasonable certainty which mode of 
action provides the most important therapeutic effect, the agency will 
assign the combination product to the agency component that regulates 
combination products that present similar safety and effectiveness 
questions for the product as a whole.
    Another factor many stakeholders asked the agency to consider when 
developing an assignment algorithm relates to the relative risks of a 
particular combination product. We agree that this is an important 
consideration, and take that into account with the second criterion, 
which considers the most significant questions of safety and 
effectiveness presented by a combination product. Therefore, if the 
agency cannot determine the most important therapeutic action of a 
combination product, and there is no agency component that regulates 
combination products that as a whole present similar safety and 
effectiveness questions as the combination product at issue, the agency 
will assign the product to the agency component with the most expertise 
related to the most significant questions of safety and effectiveness 
of the product. In situations where the new product is the first such 
combination product, or where another combination product exists but 
the intended use, design, formulation, etc. for this combination 
product raise different safety and effectiveness questions, FDA will 
assign the product to the agency component with the most expertise to 
evaluate the most significant safety and effectiveness issues raised by 
the product.

C. What are ``Mode of Action'' and ``Primary Mode of Action?''

1. Definitions
    a. Mode of action is defined as ``the means by which a product 
achieves its intended therapeutic effect or action. For purposes of 
this definition, `therapeutic' action or effect includes any effect or 
action of the combination product intended to diagnose, cure, mitigate, 
treat, or prevent disease, or affect the structure or any function of 
the body.'' Products may have a drug, biological product, or device 
mode of action. Because combination products are comprised of more than 
one type of regulated article (biological product, device, or drug), 
and each constituent part contributes a biological product, device, or 
drug mode of action, combination products will typically have more than 
one mode of action.
     A constituent part has a biological product mode of action 
if it acts by means of a virus, therapeutic serum, toxin, antitoxin, 
vaccine, blood, blood component or derivative, allergenic product, or 
analogous product applicable to the prevention, treatment, or cure of a 
disease or condition of human beings, as described in section 351(i) of 
the Public Health Service Act.
     A constituent part has a device mode of action if it meets 
the definition of device contained in section 201(h)(1) to (h)(3) of 
the act, it does not have a biological product mode of action, and it 
does not achieve its primary intended purposes through chemical action 
within or on the body of man or other animals and is not dependent upon 
being metabolized for the achievement of its primary intended purposes.
     A constituent part has a drug mode of action if it meets 
the definition of drug contained in section 201(g)(1) of the act and it 
does not have a biological product or device mode of action.
    b. Primary mode of action is defined as ``the single mode of action 
of a combination product that provides the most important therapeutic 
action of the combination product. The most important therapeutic 
action is the mode of action that is expected to make the greatest 
contribution to the overall intended therapeutic effects of the 
combination product.'' As with ``mode of action,'' for purposes of 
PMOA, ``therapeutic'' effect or action includes any effect or action of 
the combination product intended to diagnose, cure, mitigate, treat, or 
prevent disease, or affect the structure or any function of the body.
2. Assignment Algorithm
    In certain cases, it is not possible for either FDA or the product 
sponsor to determine, at the time a request is submitted, which mode of 
action of a combination product provides the most important therapeutic 
action. Determining the PMOA of a combination product is also 
complicated for products where the product has two completely different 
modes of action, neither of which is subordinate to the other. To 
assign such products with as much consistency, predictability, and 
transparency as possible, the agency is issuing an algorithm to 
determine PMOA in those instances, to be codified at Sec.  3.4(b). In 
those cases, the agency will assign the combination product to the 
agency component that regulates other combination products that present 
similar questions of safety and effectiveness with regard to the 
combination product as a whole. When there are no other combination 
products that present similar questions of safety and effectiveness 
with regard to the combination product as a whole (e.g., it is the 
first such combination product, or differences in its intended use, 
design, formulation, etc. present different safety and effectiveness 
questions), the agency would assign the combination product to the 
agency component with the most expertise to evaluate the most 
significant safety and effectiveness questions presented by the 
combination product.

[[Page 49851]]

III. Comments on the Proposed Rule and FDA's Responses

A. Background

    FDA received comments from 17 stakeholders on the proposal, and 
almost all comments supported the rule in whole or in part. For 
example, one comment said that ``[o]verall* * * FDA's approach to 
primary mode of action faithfully implements the statute'' and that ``* 
* * FDA did a remarkable job in listening to the comments on mode of 
action and primary mode of action expressed by stakeholders in prior 
hearings.'' Another comment ``agree[d] with FDA's proposed definition 
of primary mode of action'' and ``praise[d] FDA for the simplicity and 
consistency of the proposed assignment algorithm.''
    A few general themes emerged from the comments. Though generally 
supportive, the comments asked that FDA provide the following 
clarification: (1) Clarification of the role of precedent in 
determining a combination product's PMOA; (2) clarification of the role 
of intended use in determining a combination product's PMOA; (3) 
clarification of the status of the Intercenter Agreements established 
in 1991 and their role in determining a product's PMOA; and (4) more 
examples to show how the PMOA definition might be applied to assign an 
agency component with primary jurisdiction for regulatory oversight of 
a combination product.
    After reviewing the comments, FDA made two changes to the codified 
portion of this rule. The differences between the language in the 
proposed and final rules are set forth in italics as follows:

------------------------------------------------------------------------
         PMOA PROPOSED RULE                    PMOA FINAL RULE
------------------------------------------------------------------------
3.2 (k) Mode of action is the means  3.2 (k) Mode of action is the means
 by which a product achieves a        by which a product achieves its
 therapeutic effect.                  intended therapeutic effect or
                                      action.
------------------------------------------------------------------------
3.2(m) Primary mode of action is     3.2(m) Primary mode of action is
 the single mode of action of a       the single mode of action of a
 combination product that provides    combination product that provides
 the most important therapeutic       the most important therapeutic
 action of the combination product.   action of the combination product.
 The most important therapeutic       The most important therapeutic
 action is the mode of action         action is the mode of action
 expected to make the greatest        expected to make the greatest
 contribution to the overall          contribution to the overall
 therapeutic effects of the           intended therapeutic effects of
 combination product.                 the combination product.
------------------------------------------------------------------------

    The agency has included ``intended therapeutic effect'' in the MOA 
definition and ``overall intended therapeutic effects'' in the PMOA 
definition. FDA made these changes because the ``intended'' therapeutic 
effect is a basic premise upon which the PMOA analysis is prefaced.

B. MOA, PMOA, and the Assignment Algorithm

1. MOA Definition
    (Comment 1) Two comments stated that the definitions of drug, 
device, and biological product MOAs meant that any product with a 
biological product component could never be a drug or a device. One 
comment was concerned that this definition will cause certain cellular 
and tissue-based combination products to be regulated as biological 
products, or impact the classification of single entity products. One 
comment stated that products relying on cell or gene therapy would not 
have a biological product MOA based on the definition provided.
    (Response) ``Drug,'' ``device,'' and ``biological product'' are 
defined by statute, and in defining MOA, FDA implemented those 
statutory definitions. The statute defines biological products based on 
their composition rather than their effects or mechanisms of action. 
FDA adhered to the definition of each article as set forth in the 
statutes, while focusing on the factors that the statutes identify as 
distinct for biological products, devices, and drugs. We followed this 
rationale because a biological product will also meet the statutory 
definition of drug or device, and a device will also meet the statutory 
definition of drug. Without mutually exclusive definitions of MOA, 
based on the unique characteristics of biological products and devices, 
it would be difficult to identify with certainty anything but a drug 
mode of action, since the statutory definition of drug is the broadest 
definition of the three. See, for example, 21 U.S.C. 321(g)(1)(C) (drug 
means articles other than food intended to affect the structure or any 
function of the body).
    Additionally, it is important to keep in mind that this 
construction is used only to determine a product's various modes of 
action to be considered in determining the PMOA. This construction does 
not necessarily determine how products will be regulated or the 
appropriate type of application for a combination product's review.
    Finally, we note that cell and gene therapy components typically 
have a biological product MOA. For example, certain cell and gene 
therapy components meet the definition of an ``analogous'' product 
applicable to the prevention, treatment, or cure of a disease or 
condition of human beings, as described in section 351(i) of the PHS 
Act.
    (Comment 2) One comment stated that FDA should clarify that the 
definition of MOA relates only to the definition of each individual 
component. The comment also provided alternative definitions for device 
MOA, drug MOA, and biological product MOA.
    (Response) FDA agrees and clarifies that the definition of MOA 
relates only to the definitional status of each individual component. 
In addition, the comment suggested in part that FDA change ``mode of 
action'' to take into account a constituent part's ```intended' 
therapeutic * * * effect * * *.'' Because intended use is a basic tenet 
upon which the PMOA determination is premised, we agree, and have 
revised that definition accordingly. Another suggestion was that we 
change the word ``action'' to ``function'' in both the definition of 
MOA and PMOA. We have addressed that suggestion in the PMOA definition 
section. We have also addressed our rationale for the development of 
the definitions of device MOA, drug MOA, and biological product MOA in 
the response to comment 1 of this document.
    (Comment 3) One comment stated that the proposed rule's definition 
of mode of action ``almost pre-supposes that a constituent part itself 
may be a combination of items,'' and ``a constituent part cannot itself 
be a combination product.''
    (Response) FDA agrees and here clarifies that constituent parts are 
components and not, in themselves, combination products.

[[Page 49852]]

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

[[Page 49853]]

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

[[Page 49854]]

     Has the drug previously been approved as a generic drug?
     Does the drug have a narrow therapeutic index?
     Is the biological product component a particularly fragile 
molecule?
     How well understood are the product's components? Is one 
component relatively routine, while the other presents more significant 
safety and effectiveness issues due to the risks it poses, its 
effectiveness, or novelty?
     Which component raises greater risks?
     Has either of the components been previously approved or 
cleared?
     Is there a new indication, route of administration or a 
significant change in dose or use of one of the components, or are only 
secondary aspects of the labeling affected?
    FDA is not issuing a guidance document on this topic at this time. 
However, FDA will take the suggestion under advisement, and will 
reconsider issuance of such guidance if it becomes apparent after 
implementation of the final rule that more clarification is needed.
    (Comment 17) One comment recommended that FDA consider the ``least 
burdensome'' requirements of the device provisions of the act, as well 
as the ``Improving Innovation in Medical Technology'' and ``Critical 
Path to New Medical Products'' initiatives, which are specifically 
intended to advance innovation of new medical technologies by, among 
other things, use of a variety of premarket resources and tools (e.g., 
early collaboration meetings, 100-day meetings, modular reviews, etc.).
    (Response) As stated in the response to Comments 11 and 12 of this 
document, assignment only directs a product to an agency component, and 
does not dictate the regulatory authorities that will be used.
4. Miscellaneous Algorithm Questions
    (Comment 18) One comment suggested that FDA add the sponsor's 
recommendation of assignment to the algorithm.
    (Response) FDA agrees that the sponsor's recommendation of 
jurisdictional assignment plays a significant role in the process of 
making jurisdictional determinations. Indeed, the sponsor's 
recommendation of assignment is a required element of an RFD under 
Sec.  3.7(c)(3). FDA takes into account the information provided by the 
sponsor as well as the sponsor's recommendation of jurisdictional 
assignment not only when it is necessary to use the algorithm, but also 
when FDA initially decides whether the PMOA of a product can be 
determined with reasonable certainty. We note, too, that if FDA fails 
to make a jurisdictional determination within 60 days, the combination 
product would then automatically be assigned to the agency component 
recommended by the sponsor. FDA believes that the final codified 
language, together with the regulations currently in place, adequately 
takes into account a sponsor's recommendation of jurisdictional 
assignment of its combination product.
5. Flow Chart
    (Comment 19) Two comments suggested that FDA include the flow chart 
in a guidance rather than the final rule.
    (Response) FDA has not included the flow chart in the codified 
section of the final rule. However, we believe that the flow chart is a 
useful tool to illustrate how the PMOA process works; therefore, we 
included it in the preamble of the proposed rule merely for its 
instructional use.
    (Comment 20) One comment suggested that FDA replace the reference 
in the flow chart to ``an agency component with responsibility for that 
type of device'' by the ``agency component with responsibility for 
devices'' to ensure that CDRH has primary jurisdiction.
    (Response) FDA included the phrasing as written because it 
encompasses the subsets of drugs and devices regulated by the Center 
for Biologics Evaluation and Research (CBER) and biological products 
regulated by the Center for Drug Evaluation and Research (CDER). While 
most devices are regulated by the Center for Devices and Radiological 
Health (CDRH), certain devices, such as those related to blood 
collection and processing, have long been regulated by CBER, and while 
most biological products are regulated by CBER, certain therapeutic 
biological products are now regulated by CDER. A drug-device 
combination product with a device PMOA, where the device is regulated 
by CBER, would be assigned to CBER. Similarly, a biological product-
device combination product with a biological product PMOA, where the 
biological product is regulated by CDER, would be assigned to CDER.

C. Status of Intercenter Agreements

    (Comment 21) Several comments asked that FDA confirm that the 
Intercenter Agreements (ICAs) remain viable in helping FDA determine 
the appropriate agency component for premarket review and regulation of 
products, or update the Agreements to encompass types of combination 
products developed after the Agreements were written in 1991.
    (Response) FDA confirms that the ICAs referenced at Sec.  3.5(a)(1) 
continue to provide helpful guidance related to product jurisdiction, 
including the assignment of some types of combination products. The 
ICAs were developed following the enactment of the PMOA criterion used 
to make assignments of combination products. Consequently, PMOA 
principles were used in the ICAs' development. For example, the ICA 
between CDER and CDRH assigns to CDRH products such as a ``device 
incorporating a drug component with the combination product having the 
primary intended purpose of fulfilling a device function.'' The premise 
underlying the assignment to CDRH is that the device component of such 
a product provides the most important therapeutic action of the 
product. The CDER-CDRH ICA assigns to CDER prefilled delivery systems, 
such as a ``device with primary purpose of delivering or aiding in the 
delivery of a drug and distributed containing a drug.'' The premise of 
this assignment to CDER is that the device's primary purpose in 
delivering or aiding in the delivery of a drug is subordinate to the 
most important therapeutic action provided by the drug product. 
Similarly, the ICA between CBER and CDER assigned to CDER ``combination 
products that consist of a biological component and a drug component 
where the biological component enhances the efficacy or ameliorates the 
toxicity of the drug product.'' The premise underlying this assignment 
is that the drug product provides the most important therapeutic action 
of the product, while the biological product has a subordinate role in 
enhancing such action. These principles are preserved by the definition 
described in this rule.
    Nonetheless, the Intercenter Agreements were developed in 1991 and 
do not address many types of combination products developed since that 
time. Furthermore, we note that, although the ICAs were developed 
before the regulations governing good guidance practices, the 
Agreements constitute guidance, which is not binding. See 21 CFR 
10.115(d)(1). Moreover, the ICAs describe sometimes broad categories of 
products, and because PMOA might vary depending on a combination 
product's specific characteristics and use, the ICA recommendations may 
not be appropriate for every single product within a broad category. 
FDA is actively considering whether to continue in

[[Page 49855]]

effect, modify, revise, or eliminate the ICAs and plans in the near 
future to further clarify the role of the ICAs in light of other 
available information, such as this rule and more recent jurisdictional 
information made available on the Office of Combination Products 
(OCP's) Internet site. FDA believes the issuance of this final rule 
will help clarify jurisdiction for combination products generally.

D. Role of Precedents

    (Comment 22) Several comments asked that FDA clarify the role of 
precedent in the jurisdictional determination of a combination product.
    (Response) FDA believes that precedent plays a very important role 
in determining the assignment of a combination product. First, the 
definition of PMOA finalized here is based on past practice and will 
preserve precedent. FDA has long considered a product's most important 
therapeutic action in determining the primary mode of action of a 
combination product and the concept of ``most important therapeutic 
action'' also underlies the assignments of combination products 
outlined in the Intercenter Agreements. In addition, the role of 
precedent is encompassed in the first criterion of the assignment 
algorithm, for use when the agency cannot determine a combination 
product's PMOA with reasonable certainty. That criterion directs FDA to 
assign a combination product to the agency component that regulates 
other combination products that present similar safety and 
effectiveness questions with regard to the product as a whole.

E. Application of Regulatory Authorities in the Review of Combination 
Products

    (Comment 23) A few stakeholders asked FDA to clarify which good 
manufacturing practices and adverse event reporting authorities would 
apply to the regulation of a combination product. Other comments asked 
whether single or separate marketing applications would be appropriate 
for certain types of combination products, and how user fees are 
handled for combination products.
    (Response) As explained previously in this document, this final 
rule applies only to the jurisdictional assignment of combination 
products to an agency component for review and regulatory oversight. 
The specific regulatory authorities to be applied to a combination 
product are outside the scope of this rule.

F. Review of Specific Types of Products

    (Comment 24) One comment requested that FDA clarify how the rule 
affects general-purpose drug delivery devices. Another comment asked 
FDA to clarify the applicability of a particular principle described in 
the CDER-CDRH ICA related to unfilled drug delivery devices. The 
pertinent section of that ICA states that a device with the primary 
purpose of delivering or aiding in the delivery of a drug that is 
distributed without a drug (i.e., unfilled), where the drug and device 
would be developed and used together as a system, would be assigned to 
a lead Center after considering whether the drug or device had been 
previously approved and the dominance of the drug or device issues. A 
third comment asked for clarification that delivery devices that are 
distributed unfilled and determined not to require conforming changes 
to drug labeling are devices. For instance, the comment asked for 
clarification of the regulatory status of closed loop insulin delivery 
systems and catheters to deliver clot-busting drugs, which also act 
physically to dissolve the clot.
    (Response) In order to be a combination product, a product must 
meet one of the definitions found in Sec.  3.2(e). By their general 
nature, unfilled, general-purpose drug delivery devices typically do 
not meet the definition of a combination product because they are not 
physically combined or packaged with, or tied by labeling to a 
particular drug, so such products are regulated as devices. The 
specific types of products mentioned in comment 24 of this document 
could be single-entity devices as long as they are provided without the 
drugs, and the labeling of the drugs does not need to change to reflect 
their use. The assignment of delivery devices that are not combination 
products as defined by Sec.  3.2(e) is outside the scope of this rule.
    (Comment 25) One comment asked FDA to clarify how several variables 
would impact PMOA. These questions were as follows: What if the drug 
component is an old, generic, off-patent drug? What if the mode of 
administration and dosage of the drug are changed only slightly? What 
if the drug indication remains the same? What if only secondary aspects 
of drug labeling (e.g., precautions, instructions for use) change?
    (Response) These questions would not affect the determination of 
PMOA (i.e., the most important therapeutic action of a combination 
product), but they are factors FDA would consider, as appropriate, at 
the second tier of the algorithm, when FDA assesses the most 
significant safety and effectiveness questions presented by the 
combination product.
    (Comment 26) One comment stated that, without additional 
clarification of the role of precedents, the PMOA analysis as applied 
to pharmacogenomic drug/diagnostic device products might lead to 
uncertain results. The comment also identified a number of products and 
suggested that they would not be considered under the PMOA rule as 
precedents because historically they have not been designated as 
combination products. In addition, the comment expressed concern that 
after this rule's enactment, the device component of these types of 
products would no longer be reviewed separately by CDRH, as 
historically has been the case.
    (Response) FDA has clarified the role of precedents earlier in this 
section of the document. With regard to the application of the PMOA 
analysis to pharmacogenomic drug/diagnostic device products, the 
comment is correct in noting that not all such products are combination 
products, and when they are not, the drug and device would be regulated 
as separate entities.
    (Comment 27) One comment asked that OCP continue its role in the 
regulatory oversight of drug/biological product combinations, even when 
CDER has regulatory responsibility for both the drug and biological 
product components.
    (Response) A drug-biological product remains a combination product 
even if both components are reviewed by the same Center. FDA agrees 
that OCP continues to have oversight responsibility, consistent with 21 
USC 353(g)(4) and the regulations set forth in 21 CFR Part 3, for drug/ 
biological product combination products even when both the drug and 
biological product components are regulated by CDER. FDA's 
jurisdictional update on drug-biological product combination products, 
available at https://www.fda.gov/oc/combination/biologic.html, provides 
more information.
    (Comment 28) One comment asked that over-the-counter (OTC) drug and 
dietary supplement combinations be classified as combination products.
    (Response) Under 21 U.S.C. 353(g) and 21 CFR part 3, a combination 
product is a product comprised of any combination of a drug and a 
device; a device and a biological product; a biological product and a 
drug; or a drug, a device, and a biological product. Classification of 
OTC drug and dietary

[[Page 49856]]

supplement combinations is outside the scope of this rule.
    (Comment 29) One comment asked that FDA clarify whether tissue-
engineered products, such as human-derived fibroblasts cultured in 
vitro on a synthetic scaffold, are considered to be combination 
products.
    (Response) While classification of particular products is outside 
the scope of this rule, we note that many tissue engineered products, 
such as the product described in comment 29 of this document, are 
comprised of biological product and device components, and therefore 
meet the definition of a combination product as defined in Sec.  
3.2(e).
    (Comment 30) One comment asked FDA to note that the review 
timelines of combination products would be consistent with the 
performance goals of the primary review Center. Another comment asked 
FDA to address the review timelines for a combination product in which 
the agency has required that the sponsor submit separate marketing 
applications.
    (Response) Review timelines are outside the scope of this rule. We 
note that review timeframes are associated with the type of marketing 
application, rather than the reviewing Center. Further information on 
these issues, as well as other information regarding the timeliness of 
reviews, is discussed in FDA's guidance document on dispute resolution 
available at https://www.fda.gov/oc/combination/.
    (Comment 31) One comment asked that FDA clarify how the agency 
would evaluate new uses for a product using the PMOA analysis.
    (Response) FDA is required by statute to assign a product to an 
agency component for review based on its PMOA. Stakeholders have urged, 
and FDA agrees, that determination of a product's PMOA should take into 
account the product's intended use. Therefore, it is possible that a 
single product, intended for two different purposes, may be assigned to 
different agency components for review of those different uses if the 
PMOA for each use directs the assignment to a different agency 
component. However, FDA will strive to minimize the impact of these 
assignments where possible.
    (Comment 32) One comment was concerned that the PMOA definition 
would direct all drug delivery devices combined with a drug product to 
CDER. The comment mentioned a specific example of an approved drug 
product in its approved container, with no change to the route of 
administration, combined with an innovative delivery device. 
Additionally, the comment stated that the same device combined with 
different drug products may be assigned to different divisions within 
CDER, which could result in confusing or conflicting requirements for 
the release testing or labeling of the device.
    (Response) As stated previously in this document, FDA is required 
by statute to assign a product to an agency component for review based 
on its PMOA. FDA has developed a Standard Operating Procedure (SOP) to 
help ensure efficient and effective consultation and collaboration 
between the Centers on such reviews. Such consultation and 
collaboration will also help to ensure uniformity in approaches by the 
review divisions. This review process is outlined in further detail in 
the FDA SOP for Intercenter Consultative/Collaborative Review Process, 
available at https://www.fda.gov/oc/ombudsman/intercentersop.pdf.

Examples

    (Comment 33) Several comments asked that FDA provide more examples, 
particularly examples illustrating how drug and biological product 
combination products would be reviewed. One comment recommended that 
FDA include examples of copackaged and cross-labeled combination 
products.
    (Response) FDA agrees, and we provide 11 hypothetical examples in 
this section of the document, three of which were also provided in the 
proposal. We note that the interferon/ribavirin combination product is 
an example where the two components may be either copackaged or 
separately provided but labeled to be used together; the same 
assignment would result in either situation. In addition, we have 
posted a list of selected capsular descriptions illustrating many prior 
jurisdictional determinations, which is available on our website at 
https://www.fda.gov/oc/combination/determinations.html. FDA believes 
these descriptions also help to illustrate the jurisdictional 
determination process.
    (Comment 34) One comment listed a number of hypothetical products, 
and asked that FDA explain how it would review and regulate them, so 
that stakeholders would have a better understanding of the process FDA 
uses when making assignments of combination products.
    (Response) FDA notes that some of the comment's examples are not 
combination products and, therefore, fall outside the scope of the 
rule, while other examples lack sufficient detail for FDA to work 
through as a hypothetical exercise. However, FDA used or adapted some 
of the examples suggested and developed additional hypothetical 
examples. FDA believes the examples provided in this response to 
comment 34 of this document, along with the capsular descriptions of 
prior jurisdictional determinations posted on OCP's website, and the 
types of questions FDA considers when making assignments of combination 
products, further illustrate the process FDA uses when making 
assignments.

Examples Repeated From Proposed Rule

    a. Conventional drug-eluting stent. A vascular stent provides a 
mechanical scaffold to keep a vessel open while a drug is slowly 
released from the stent to prevent the buildup of new tissue that would 
reocclude the artery.
     PMOA Analysis--Which mode of action provides the most 
important therapeutic action of the combination product?
    In this case, the product has two modes of action. One action of 
the vascular stent is to provide a physical scaffold to be implanted in 
a coronary artery to improve the resultant arterial luminal diameter 
following angioplasty. Another action of the product is the drug 
action, with the intended effect of reducing the incidence of 
restenosis and the need for target lesion revascularization.
 Assignment of Lead Agency Component: CDRH
    The product's primary mode of action is attributable to the device 
component's function of physically maintaining vessel lumen patency, 
while the drug plays a secondary role in reducing restenosis caused by 
the proliferative response to the stent implantation, augmenting the 
safety and/or effectiveness of the uncoated stent. Accordingly, FDA 
would assign the product to CDRH for regulation because the device 
component provides the most important therapeutic action of the 
product. It is unnecessary to proceed to the assignment algorithm 
because it is possible to determine which mode of action provides the 
most important therapeutic action of this particular combination 
product.
    b. Drug Eluting Disc. A surgically implanted disc contains a drug 
that is slowly released for prolonged, local delivery of 
chemotherapeutic agents to a tumor site.
     PMOA Analysis--Which mode of action provides the most 
important therapeutic action of the combination product?
    In this case, the product has two modes of action. This product has 
a device mode of action because it is surgically implanted in the body 
and is

[[Page 49857]]

designed for controlled drug release, thus affecting the structure of 
the body and treating disease. Another mode of action is the drug 
action, with the intended effect of preventing tumor recurrence at the 
implant site.
 Assignment of Lead Agency Component: CDER
    Though the product has a device mode of action, the product's 
primary mode of action is attributable to the drug component's function 
of preventing tumor recurrence at the implant site. Accordingly, we 
would assign the product to CDER for regulation because the drug 
component provides the most important therapeutic action of the 
product. It is unnecessary to proceed to the assignment algorithm 
because it is possible to determine which mode of action provides the 
most important therapeutic action of this particular product.
    c. Contact Lens Combined With Drug to Treat Glaucoma. In this case, 
a contact lens is placed in the eye to correct vision. The contact lens 
also contains a drug to treat glaucoma that will be delivered from the 
lens to the eye.
     PMOA Analysis--Which mode of action provides the most 
important therapeutic action of the combination product?
    This product has two modes of action. One action of the product is 
the device action, to correct vision. Another action of the product is 
a drug action, to treat glaucoma. Though administration through a 
contact lens is not necessary for the drug's delivery, the combination 
product allows a patient requiring vision correction to receive 
glaucoma treatment without having to undertake a more complicated daily 
drug regimen. Here, both actions of the product are independent, and 
neither appears to be subordinate to the other.
    Because it is not possible to determine which mode of action 
provides the greatest contribution to the overall therapeutic effects 
of the combination product, it is necessary to apply the assignment 
algorithm.
    Assignment Algorithm:
     Is there an agency component that regulates other 
combination products that present similar questions of safety and 
effectiveness with regard to the combination product as a whole?
    CDRH regulates devices intended to correct vision. CDER regulates 
drugs intended to treat glaucoma. In this hypothetical example, no 
combination product intended to treat these different conditions 
simultaneously has yet been submitted to the agency for review. Though 
both CDER and CDRH regulate products that raise similar safety and 
effectiveness questions with regard to the constituent parts of the