Chapter 4: Jurisdiction and Regulatory Pathway
32
product, or analogous product applicable
to the prevention, treatment, or cure of a
disease or condition of human beings, as
described in Public Health Service Act (PHS
Act) Section 351(i).5 (Note: While not
currently reflected in the biological product
MOA definition, the statutory definition of
a biological product was amended in 2010
to include proteins (except any chemically
synthesized polypeptide).
• A constituent part has a device MOA if it
meets the definition of device contained in
Federal Food, Drug and Cosmetic Act (FD&C
Act), Section 201(h)(1)–(3),6 does not
have a biological product MOA and 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 MOA if it
meets the definition of drug contained in
FD&C Act Section 201(g)(1) and does not
have a biological product or device MOA.7
21CFR3(m) defines the PMOA as the single
MOA of a combination product that provides
the most important therapeutic action of the
combination product. The regulation further
clarifies PMOA as “the mode of action expected
to make the greatest contribution to the overall
intended therapeutic effects of the combina-
tion product.”8 For example, if a drug-device
combination product’s PMOA is attributable to
its device constituent part, CDRH would have
primary jurisdiction, whereas if a drug-device
combination product’s PMOA is attributable
to its drug constituent part, CDER would have
primary jurisdiction. If a biological-device com-
bination product’s PMOA is attributable to its
biological constituent part, CBER would have
primary jurisdiction.
For some combination products, it is a
relatively simple exercise to determine the MOA
and, subsequently, the PMOA. For some prod-
ucts, however, the PMOA 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 MOAs, neither of
which is subordinate to the other. In close cases,
assignments may turn on subtle distinctions
related to the determination of whether a MOA
is ‘‘primary’’ or not.
What is the remedy if there is confusion
regarding which constituent part is the PMOA?
What happens if FDA is unable to determine
the PMOA?
When FDA is unable to determine the
most important therapeutic action with rea-
sonable certainty, the assignment algorithm
defined in 21CFR3.4(b) is used to determine
the product’s assignment.9 First, FDA looks at
historical precedents to assign the combination
product to the agency component that regulates
other combination products presenting similar
safety and effectiveness questions regarding
the combination product as a whole. When
no other combination products present similar
safety and effectiveness questions regarding the
combination product as a whole, FDA makes
the most appropriate assignment based on the
new combination product’s safety and effective-
ness questions. FDA assigns the product to the
center with the most expertise related to the
combination product’s most significant safety
and effectiveness questions. For example, if the
most significant safety and effectiveness issues a
drug-device combination product presents in this
scenario were attributable to the drug constitu-
ent part, the combination product likely would
be assigned to CDER as the lead center. This
process is explained in more detail below.
Request for Designation (RFD)
Understanding the regulatory pathway early in
a combination product’s development phase is
essential for the sponsor to establish a realistic
regulatory strategy. There are two ways in which
a manufacturer can seek FDA feedback to deter-
mine product jurisdiction: informally or formally.
Informal processes involve seeking advice from
the appropriate center or Office of Combination
Products (OCP) staff, typically by telephone,
email, meeting, or submitting a pre-request
32
product, or analogous product applicable
to the prevention, treatment, or cure of a
disease or condition of human beings, as
described in Public Health Service Act (PHS
Act) Section 351(i).5 (Note: While not
currently reflected in the biological product
MOA definition, the statutory definition of
a biological product was amended in 2010
to include proteins (except any chemically
synthesized polypeptide).
• A constituent part has a device MOA if it
meets the definition of device contained in
Federal Food, Drug and Cosmetic Act (FD&C
Act), Section 201(h)(1)–(3),6 does not
have a biological product MOA and 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 MOA if it
meets the definition of drug contained in
FD&C Act Section 201(g)(1) and does not
have a biological product or device MOA.7
21CFR3(m) defines the PMOA as the single
MOA of a combination product that provides
the most important therapeutic action of the
combination product. The regulation further
clarifies PMOA as “the mode of action expected
to make the greatest contribution to the overall
intended therapeutic effects of the combina-
tion product.”8 For example, if a drug-device
combination product’s PMOA is attributable to
its device constituent part, CDRH would have
primary jurisdiction, whereas if a drug-device
combination product’s PMOA is attributable
to its drug constituent part, CDER would have
primary jurisdiction. If a biological-device com-
bination product’s PMOA is attributable to its
biological constituent part, CBER would have
primary jurisdiction.
For some combination products, it is a
relatively simple exercise to determine the MOA
and, subsequently, the PMOA. For some prod-
ucts, however, the PMOA 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 MOAs, neither of
which is subordinate to the other. In close cases,
assignments may turn on subtle distinctions
related to the determination of whether a MOA
is ‘‘primary’’ or not.
What is the remedy if there is confusion
regarding which constituent part is the PMOA?
What happens if FDA is unable to determine
the PMOA?
When FDA is unable to determine the
most important therapeutic action with rea-
sonable certainty, the assignment algorithm
defined in 21CFR3.4(b) is used to determine
the product’s assignment.9 First, FDA looks at
historical precedents to assign the combination
product to the agency component that regulates
other combination products presenting similar
safety and effectiveness questions regarding
the combination product as a whole. When
no other combination products present similar
safety and effectiveness questions regarding the
combination product as a whole, FDA makes
the most appropriate assignment based on the
new combination product’s safety and effective-
ness questions. FDA assigns the product to the
center with the most expertise related to the
combination product’s most significant safety
and effectiveness questions. For example, if the
most significant safety and effectiveness issues a
drug-device combination product presents in this
scenario were attributable to the drug constitu-
ent part, the combination product likely would
be assigned to CDER as the lead center. This
process is explained in more detail below.
Request for Designation (RFD)
Understanding the regulatory pathway early in
a combination product’s development phase is
essential for the sponsor to establish a realistic
regulatory strategy. There are two ways in which
a manufacturer can seek FDA feedback to deter-
mine product jurisdiction: informally or formally.
Informal processes involve seeking advice from
the appropriate center or Office of Combination
Products (OCP) staff, typically by telephone,
email, meeting, or submitting a pre-request