64844 Federal Register / Vol. 83, No. 242 / Tuesday, December 18, 2018 / Notices 

them that the plan has been recognized 

as minimum essential coverage for the 

purposes of the individual coverage 

requirement. Form Number: CMS– 

10465 (OMB control number: 0938– 

1189); Frequency: Occasionally; 

Affected Public: Public and Private 

sectors; Number of Respondents: 10; 

Total Annual Responses: 10; Total 

Annual Hours: 52.5. (For policy 

questions regarding this collection 

contact Russell Tipps at 301–492–4371). 

Dated: December 13, 2018. 

William N. Parham, III, 

Director, Paperwork Reduction Staff, Office 

of Strategic Operations and Regulatory 

Affairs. 

[FR Doc. 2018–27335 Filed 12–17–18; 8:45 am] 

BILLING CODE 4120–01–P 

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 Intraarticular 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, combination@fda.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

HA is a linear polysaccharide formed 

by repeating disaccharide units of Dglucuronic acid and Nacetylglucosamine linked by b (1, 4) and 

b (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 intraarticular 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 antiinflammatory effects discussed in the 

scientific literature include alteration of 

cytokines (e.g., Interleukin (IL)-1b) 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. 


amozie on DSK3GDR082PROD with NOTICES
Federal Register / Vol. 83, No. 242 / Tuesday, December 18, 2018 / Notices 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 antiinflammatory 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 CoCulture 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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Health Resources and Services 

Administration 

Agency Information Collection 

Activities: Proposed Collection: Public 

Comment Request Information 

Collection Request Title: HRSA AIDS 

Education and Training Centers 

Evaluation Activities, OMB No. 0915– 

0281—Revision 

AGENCY: Health Resources and Services 

Administration (HRSA), Department of 

Health and Human Services (HHS). 

ACTION: Notice. 

SUMMARY: In compliance with the 

requirement for opportunity for public 

comment on proposed data collection 

projects of the Paperwork Reduction Act 

of 1995, HRSA announces plans to 

submit an Information Collection 

Request (ICR), described below, to the 


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