[Federal Register Volume 83, Number 242 (Tuesday, December 18, 2018)]
[Notices]
[Pages 64844-64845]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-27351]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2018-N-4627]
Intent To Consider the Appropriate Classification of Hyaluronic
Acid Intra-articular Products Intended for the Treatment of Pain in
Osteoarthritis of the Knee Based on Scientific Evidence
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing our
intent to consider the appropriate classification of hyaluronic acid
(HA) intra-articular products intended for the treatment of pain in
osteoarthritis (OA) of the knee. Although HA products intended for this
use have been regulated as devices (Procode MOZ; acid, hyaluronic,
intra-articular), the current published scientific literature supports
that HA achieves its primary intended purpose of treatment of pain in
OA of the knee through chemical action within the body. Because HA for
this use may not meet the definition of a device, sponsors of HA
products who intend to submit a premarket approval application (PMA) or
a supplement to a PMA for a change in indications for use, formulation,
or route of administration are encouraged to obtain an informal or
formal classification and jurisdiction determination through a Pre-
Request for Designation (Pre-RFD) or Request for Designation (RFD),
respectively, from FDA prior to submission. If a sponsor believes their
product meets the device definition, they may provide relevant evidence
in the Pre-RFD or RFD.
FOR FURTHER INFORMATION CONTACT: Leigh Hayes, Office of Combination
Products, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
32, Rm. 5129, Silver Spring, MD 20993, 301-796-8938, Fax: 301-847-8619,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background
HA is a linear polysaccharide formed by repeating disaccharide
units of D-glucuronic acid and N-acetylglucosamine linked by [beta] (1,
4) and [beta] (1, 3) glycoside bonds (Ref. 1). HA is present throughout
the body and in joints where it acts as a structural element (Ref. 2).
It is also found in the cavities of synovial joints and plays a role in
promoting the viscoelastic properties of the synovial fluid and in
joint lubrication (Refs. 3 and 4).
Intra-articular administration of exogenous HA has been used to
treat pain in OA of the knee in patients who have failed to respond
adequately to conservative non-pharmacologic therapy and to certain
analgesics (e.g., acetaminophen). Although HA for this use has been
regulated as a Class III device (Procode MOZ; acid, hyaluronic, intra-
articular), as discussed further below, the current published
scientific literature supports that HA achieves its primary intended
purpose of the treatment of pain in OA of the knee through chemical
action within the body.
Under section 201(h) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 321(h)) a device ``does not achieve its primary
intended purposes through chemical action within or on the body,''
among other things. Under FDA's interpretation of this device
definition, products exhibit ``chemical action'' if they interact at
the molecular level with bodily components (e.g., cells or tissues) to
mediate (including promoting or inhibiting) a bodily response, or with
foreign entities (e.g., organisms or chemicals) to alter that entity's
interaction with the body; and interaction at the molecular level
occurs through either chemical reaction (i.e., formation or breaking of
covalent bonds), intermolecular forces (e.g., electrostatic
interactions), or both (see, e.g., FDA Guidance, ``Classification of
Products as Drugs and Devices and Additional Product Classification
Issues'', available at https://www.fda.gov/RegulatoryInformation/Guidances/ucm258946.htm).
OA pain has a complex pathophysiology and has several components,
including: (1) Neuropathic pain (related to a lesion or disease of the
somatosensory nervous system); (2) local inflammation; and (3) joint
degradation (Ref. 5). During the intra-articular injection, HA is
introduced to the synovial fluid of the affected joint. Previously, it
was suggested that mechanical or physical actions at the joint (e.g.,
shock absorption) are responsible for achieving the primary intended
purpose of the treatment of pain in OA of the knee; however, the
current scientific literature supports that the mechanisms of action of
HA also include chemical actions (e.g., chondroprotection, anti-
inflammatory effects and cartilage matrix alterations) (Refs. 6 to 9).
Published scientific literature supports that intra-articular injection
of HA achieves its primary intended purpose of the treatment of pain in
OA of the knee through multiple mechanisms (we note that the published
scientific literature discussed in this notice is not exhaustive).
These include, but are not limited to:
(1) Anti-inflammatory effects: Local inflammation is an important
part of the pathophysiology of OA joint pain (Ref. 5). As such, the
mitigation of inflammation can result in pain relief (Ref. 10). The
scientific literature supports that HA acts though chemical action to
achieve its anti-inflammatory effects. These effects are mediated
through the binding of HA to cellular receptors that include the
Cluster of Differentiation 44 Receptor (CD44), Receptor for Hyaluronan
Mediated Motility (RHAMM), and Toll-Like Receptor (TLR)2 and TLR4,
which alter numerous downstream cell signaling activities and/or
pathways resulting in anti-inflammatory effects (Refs. 9, 11, and 12).
Some of the downstream anti-inflammatory effects discussed in the
scientific literature include alteration of cytokines (e.g.,
Interleukin (IL)-1[beta]) and inducible nitric oxide synthase (iNOS),
which all have regulatory roles in inflammatory processes (Ref. 9).
(2) Analgesic effects: Joint inflammation is usually characterized
by mechanical hyperalgesia, likely caused by an increased
mechanosensitivity of joint nociceptors (Ref. 13). The scientific
literature supports that HA interacts with cellular receptors (e.g.,
nociceptors, CD44) to reduce pain (Refs. 2, 8, 9, and 11). For
instance, binding of HA to CD44 has been reported to act via signaling
pathways to reduce pain, such as by downregulating Prostaglandin E2
(PGE2) and Cyclooxygenase (COX-2) production (Refs. 2 and
11). The literature also reports that HA may also act to relieve pain
by activating opioid receptors (Ref. 11). In other words, the
literature explains that HA binds to cellular receptors that act to
alleviate pain through modification of cellular pain pathways.
[[Page 64845]]
(3) Chondroprotective effects: Pain intensity in OA is positively
associated with the degree of joint degradation (Ref. 5). HA has been
reported to have chondroprotective effects by reducing the degradation
and/or restoration of cartilage (Refs. 11 and 14). According to the
scientific literature, much of the mechanisms responsible for these
effects are through molecular pathways (e.g., CD44-initiated pathways)
that have downstream biological effects that act to alter the disease
state of the joint by the synthesis of extracellular matrix (ECM)
proteins (e.g., collagen type II) and joint components (e.g., increased
proteoglycan and glycosaminoglycan) (Refs. 2, 9, 11, and 14).
Collectively, these binding interactions of HA may act on molecular
pathways that serve to protect and restore cartilage.
Taken together, most of the effects described above (i.e., anti-
inflammatory, analgesic, and chondroprotective) are achieved through
various molecular pathways that depend on the direct interaction of HA
with bodily components (e.g., cellular receptors) and downstream
activation of specific signaling pathways.
Additionally, although injection of HA provides mechanical effects
(e.g., shock absorption), it is believed that such effects are limited
due to the short half-life of HA (Refs. 2 and 15). Exogenous-introduced
HA has been reported to have a half-life of a few days or up to 30 days
for cross-linked versions (Refs. 2 and 15). Nevertheless, treatment
with HA has been reported to result in clinical therapeutic effect for
up to 6 months following injection (Ref. 9). In other words, treatment
with HA has been reported to continue reduction in pain long after it
is cleared from the knee joint. This further supports that HA achieves
its primary intended purpose of the treatment of pain in OA of the knee
through chemical action within the body (e.g., through its anti-
inflammatory and chondroprotective effects that act to mitigate the
underlying OA condition).
Because the current published scientific literature supports that
HA achieves its primary intended purpose of the treatment of pain in OA
of the knee through chemical action, and therefore, HA for this use may
not meet the definition of a device, sponsors of HA products who intend
to submit a PMA or a supplement to a PMA for a change in indications
for use, formulation, or route of administration are encouraged to
obtain an informal or formal classification and jurisdictional
determination through a Pre-RFD or RFD, respectively, from FDA prior to
submission. If a sponsor believes their product meets the device
definition, they may provide relevant evidence in the pre-RFD or RFD.
II. References
The following references are on display with the Dockets Management
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852, and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; these are not
available electronically at https://www.regulations.gov as these
references are copyright protected. Some may be available at the
website address, if listed. FDA has verified the website addresses, as
of the date this document publishes in the Federal Register, but
websites are subject to change over time.
1. Vasi, A.M., M. Popa, M. Butnaru, et al., ``Chemical
Functionalization of Hyaluronic Acid for Drug Delivery
Applications.'' Materials Science and Engineering, 38: 177-185,
2014.
2. Altman, R.D., V. Dasa, and J. Takeuchi, ``Review of the Mechanism
of Action for Supartz FX in Knee Osteoarthritis.'' Cartilage, 9: 11-
20, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724672/
3. Greenberg, D.D., A. Stoker, S. Kane, et al., ``Biochemical
Effects of Two Different Hyaluronic Acid Products in a Co-Culture
Model of Osteoarthritis.'' OsteoArthritis and Cartilage, 14: 814-
822, 2006. https://www.sciencedirect.com/science/article/pii/S1063458406000367?via%3Dihub
4. Jahn, S., J. Seror, and J. Klein, ``Lubrication of Articular
Cartilage.'' Annual Review of Biomedical Engineering, 18: 235-258,
2016.
5. Trouvin, A.-P. and S. Perrot, ``Pain in Osteoarthritis.
Implications for Optimal Management.'' Joint Bone Spine, 85: 429-
434, 2018.
6. Balazs, E.A., ``The Physical Properties of Synovial Fluid and the
Special Role of Hyaluronic Acid.'' In Disorders of the Knee, A.
Helfet, pp. 63-75. Philadelphia: Lippincott Company, 1974.
7. Liao, Y.-H, S.A. Jones, B. Forbes, et al., ``Hyaluronan:
Pharmaceutical Characterization and Drug Delivery.'' Drug Delivery,
12: 327-342, 2005. https://www.tandfonline.com/doi/full/10.1080/10717540590952555%20
8. Moreland, L.W. ``Intra-Articular Hyaluronan (hyaluronic acid) and
Hylans for the Treatment of Osteoarthritis: Mechanisms of Action.''
Arthritis Research and Therapy, 5: 54-67, 2003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC165033/
9. Altman, R.D., A. Manjoo, A. Fierlinger, et al., ``The Mechanism
of Action for Hyaluronic Acid Treatment in the Osteoarthritic Knee:
A Systematic Review.'' BMC Musculoskeletal Disorders, 16: 321, 2015.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621876/
10. Richards, M., J. Maxwell, L. Weng, et al., ``Intra-Articular
Treatment of Knee Osteoarthritis: From Anti-inflammatories to
Products of Regenerative Medicine.'' The Physician and
Sportsmedicine, 44: 101-108, 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932822/
11. Nicholls, M., A. Fierlinger, F. Zaizi, et al., ``The Disease
Modifying Effects of Hyaluronan in the Osteoarthritic Disease
State.'' Clinical Medicine Insights: Arthritis and Musculoskeletal
Disorders, 10: 1-10, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555499/
12. Migliore, A. and S. Procopio, ``Effectiveness and Utility of
Hyaluronic Acid in Osteoarthritis.'' Clinical Cases in Mineral and
Bone Metabolism, 12: 31-33, 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469223/
13. Schaible, H.-G., F. Richter, A. Ebersberge, et al., ``Joint
Pain.'' Experimental Brain Research, 196: 153-162, 2009.
14. Chen, L., J. Xue, Z. Zheng, et al., ``Hyaluronic Acid, an
Efficient Biomacromolecule for Treatment of Inflammatory Skin and
Joint Diseases: A Review of Recent Developments and Critical
Appraisal of Preclinical and Clinical Investigations.''
International Journal of Biological Macromolecules, 116: 572-584,
2018.
15. Strauss, E., J. Hart, M. Miller, et al., ``Hyaluronic Acid
Viscosupplementation and Osteoarthritis: Current Uses and Future
Directions.'' The American Journal of Sports Medicine, 37: 1636-
1644, 2009.
Dated: December 13, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-27351 Filed 12-17-18; 8:45 am]
BILLING CODE 4164-01-P