[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]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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, 
<a href="/cdn-cgi/l/email-protection#a3c0cccec1cacdc2d7cacccde3c5c7c28dc4ccd5"><span class="__cf_email__" data-cfemail="c1a2aeaca3a8afa0b5a8aeaf81a7a5a0efa6aeb7">[email protected]</span></a>.

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 
(PGE<INF>2</INF>) 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


</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>