Federal Register / Vol. 83, No. 242 / Tuesday, December 18, 2018 / Notices 64843 

25. Fu R, Gartlehner G, Grant M, et al. 

Conducting quantitative synthesis when 

comparing medical interventions: AHRQ 

and the Effective Health Care Program. J 

Clin Epidemiol. 2011 Nov;64(11):1187– 

97. doi: 10.1016/j.jclinepi.2010.08.010. 

PMID: 21477993. 

26. Takwoingi Y. Meta-analysis of test 

accuracy studies in Stata: a bivariate 

model approach. Version 1.1. 

27. Owens DK, Lohr KN, Atkins D, et al. 

AHRQ series paper 5: grading the 

strength of a body of evidence when 

comparing medical interventions— 

agency for healthcare research and 

quality and the effective health-care 

program. J Clin Epidemiol. 2010 

May;63(5):513–23. doi: S0895– 

4356(09)00093–6 [pii] 10.1016/ 

j.jclinepi.2009.03.009. PMID: 19595577. 

28. Singh S, Chang SM, Matchar DB, et al. 

Chapter 7: grading a body of evidence on 

diagnostic tests. J Gen Intern Med. 2012 

Jun;27 Suppl 1:S47–55. doi: 10.1007/ 

s11606–012–2021–9. PMID: 22648675. 

29. Berkman ND, Lohr KN, Ansari M, et al. 

Grading the Strength of a Body of 

Evidence When Assessing Health Care 

Interventions for the Effective Health 

Care Program of the Agency for 

Healthcare Research and Quality: An 

Update. Methods Guide for Effectiveness 

and Comparative Effectiveness Reviews. 

Rockville (MD); 2008. 

30. Atkins D, Chang S, Gartlehner G, et al. 

Assessing the Applicability of Studies 

When Comparing Medical Interventions. 

Methods Guide for Effectiveness and 

Comparative Effectiveness Reviews. 

Rockville (MD); 2008. 

Francis D. Chesley, Jr., 

Acting Deputy Director. 

[FR Doc. 2018–27361 Filed 12–17–18; 8:45 am] 

BILLING CODE 4160–90–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Centers for Medicare & Medicaid 

Services 

[Document Identifier CMS–10465] 

Agency Information Collection 

Activities: Proposed Collection; 

Comment Request 

AGENCY: Centers for Medicare & 

Medicaid Services, HHS. 

ACTION: Notice. 

SUMMARY: The Centers for Medicare & 

Medicaid Services (CMS) is announcing 

an opportunity for the public to 

comment on CMS’ intention to collect 

information from the public. Under the 

Paperwork Reduction Act of 1995 (the 

PRA), federal agencies are required to 

publish notice in the Federal Register 

concerning each proposed collection of 

information (including each proposed 

extension or reinstatement of an existing 

collection of information) and to allow 

60 days for public comment on the 

proposed action. Interested persons are 

invited to send comments regarding our 

burden estimates or any other aspect of 

this collection of information, including 

the necessity and utility of the proposed 

information collection for the proper 

performance of the agency’s functions, 

the accuracy of the estimated burden, 

ways to enhance the quality, utility, and 

clarity of the information to be 

collected, and the use of automated 

collection techniques or other forms of 

information technology to minimize the 

information collection burden. 

DATES: Comments must be received by 

February 19, 2019. 

ADDRESSES: When commenting, please 

reference the document identifier or 

OMB control number. To be assured 

consideration, comments and 

recommendations must be submitted in 

any one of the following ways: 

1. Electronically. You may send your 

comments electronically to http://

www.regulations.gov. Follow the 

instructions for ‘‘Comment or 

Submission’’ or ‘‘More Search Options’’ 

to find the information collection 

document(s) that are accepting 

comments. 

2. By regular mail. You may mail 

written comments to the following 

address: 

CMS, Office of Strategic Operations and 

Regulatory Affairs, Division of 

Regulations Development, Attention: 

Document Identifier/OMB Control 

Number _, Room C4–26–05, 7500 

Security Boulevard, Baltimore, 

Maryland 21244–1850. 

To obtain copies of a supporting 

statement and any related forms for the 

proposed collection(s) summarized in 

this notice, you may make your request 

using one of following: 

1. Access CMS’ website address at 

https://www.cms.gov/Regulations-andGuidance/Legislation/ 

PaperworkReductionActof1995/PRAListing.html. 

2. Email your request, including your 

address, phone number, OMB number, 

and CMS document identifier, to 

Paperwork@cms.hhs.gov. 

3. Call the Reports Clearance Office at 

(410) 786–1326. 

FOR FURTHER INFORMATION CONTACT: 

William N. Parham at (410) 786–4669. 

SUPPLEMENTARY INFORMATION: 

Contents 

This notice sets out a summary of the 

use and burden associated with the 

following information collections. More 

detailed information can be found in 

each collection’s supporting statement 

and associated materials (see 

ADDRESSES). 

CMS–10465 Minimum Essential 

Coverage 

Under the PRA (44 U.S.C. 3501– 

3520), federal agencies must obtain 

approval from the Office of Management 

and Budget (OMB) for each collection of 

information they conduct or sponsor. 

The term ‘‘collection of information’’ is 

defined in 44 U.S.C. 3502(3) and 5 CFR 

1320.3(c) and includes agency requests 

or requirements that members of the 

public submit reports, keep records, or 

provide information to a third party. 

Section 3506(c)(2)(A) of the PRA 

requires federal agencies to publish a 

60-day notice in the Federal Register 

concerning each proposed collection of 

information, including each proposed 

extension or reinstatement of an existing 

collection of information, before 

submitting the collection to OMB for 

approval. To comply with this 

requirement, CMS is publishing this 

notice. 

Information Collection 

Type of Information Collection 

Request: Extension of a currently 

approved collection; Title of 

Information Collection: Minimum 

Essential Coverage; Use: The final rule 

titled ‘‘Patient Protection and Affordable 

Care Act; Exchange Functions: 

Eligibility for Exemptions; 

Miscellaneous Minimum Essential 

Coverage Provisions,’’ published July 1, 

2013 (78 FR 39494) designates certain 

types of health coverage as minimum 

essential coverage. Other types of 

coverage, not statutorily designated and 

not designated as minimum essential 

coverage in regulation, may be 

recognized by the Secretary of Health 

and Human Services (HHS) as minimum 

essential coverage if certain substantive 

and procedural requirements are met. 

To be recognized as minimum essential 

coverage, the coverage must offer 

substantially the same consumer 

protections as those enumerated in the 

Title I of Affordable Care Act relating to 

non-grandfathered, individual health 

insurance coverage to ensure consumers 

are receiving adequate coverage. The 

final rule requires sponsors of other 

coverage that seek to have such coverage 

recognized as minimum essential 

coverage to adhere to certain 

procedures. Sponsoring organizations 

must submit to HHS certain information 

about their coverage and an attestation 

that the plan substantially complies 

with the provisions of Title I of the 

Affordable Care Act applicable to nongrandfathered individual health 

insurance coverage. Sponsors must also 

provide notice to enrollees informing 


amozie on DSK3GDR082PROD with NOTICES
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. 


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