(PROPOSED) Clinical Endpoints Guidance: Knee Osteoarthritis

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Clinical Endpoints Guidance

Knee Osteoarthritis

Proposed Guidance Document Issued on June 22, 2023

Contents

1. Preamble
2. Introduction
3. Background
4. Purpose of Therapeutic Outcomes Reviews
5. Technology Assessment
   Overview
   Methods
   
   Identifying the Literature
   Data Abstraction and Data Management
   Data Synthesis
   Quality Assessments
   
   Results
   
   Literature
   Data Abstraction and Data Management
   Data Synthesis
   Quality Assessments
   Consensus Assessments
   
   Discussion
6. CMS Proposed Conclusions
7. Appendix A. Search Strategies
8. Appendix B. Table of Included Publications
9. Appendix C. Table of Synthesized Outcomes and Instruments
10. References

Section 1862(l)(1) of the Social Security Act requires that the Secretary of Health and Human Services make available to the public the factors that are considered in making national coverage determinations (NCDs) of whether an item or service is reasonable and necessary. The Centers for Medicare & Medicaid Services procedures for issuing guidance documents under this authority are set forth in 69 Fed. Reg. 57 325 (September 24, 2004).

NCDs concerning whether a particular item or service is reasonable and necessary under section 1862(a)(1)(A) are based on information including clinical experience, and medical, technical, and scientific evidence.[1] The NCD process also considers public comments. The public is afforded the opportunity to comment on a proposed determination as set forth in section 1862(l). When we make an NCD, we provide a clear statement of the basis for the NCD as well as responses to the comments received from the public.

To encourage innovation and accelerate beneficiary access to new items and services, CMS is proactively publishing this proposed guidance document to provide a framework for more predictable and transparent evidence development.

This proposed guidance represents the Centers for Medicare & Medicaid Services' (CMS's) current thinking on health outcomes for the Treatment of Knee Osteoarthritis. It does not create or confer any rights for or on any person and does not operate to bind CMS or the public. Where warranted by circumstances, CMS may consider an alternative approach if it satisfies the requirements of the applicable statutes and regulations. Individuals interested in discussing an alternative approach are encouraged to contact CMS at CAGInquiries@cms.hhs.gov and reference this guidance.

CMS is seeking public comment on this proposed clinical endpoints guidance for knee osteoarthritis. CMS will review the public comments and respond to the comments in the final document.

Comments may be submitted via the blue "Submit Public Comment" button at the top of the page.

Alternatively, written comments may be submitted to the Coverage and Analysis Group, Centers for Medicare and Medicaid Services, mailstop: S3-02-01, 7500 Security Blvd. Baltimore, MD. 21244. Please refer to this guidance document when submitting comments.

To ensure consideration, comments must be received by August 21, 2023.

This proposed guidance document identifies health outcomes of interest to CMS when reviewing technologies for the treatment of knee osteoarthritis when considering reasonable and necessary NCDs. Specific technologies were not reviewed, and this guidance is not a National Coverage Analysis or National Coverage Determination.

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of an illness or injury or to improve the functioning of a malformed body member under section 1862(a)(1)(A) of the Social Security Act. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that the specific assessment questions raised in a National Coverage Analysis can be answered conclusively. In the August 7, 2013, Federal Register (78 FR 48164), we published a notice that describes the processes we use for opening, making or reconsidering national coverage determinations (NCDs).[2]

When conducting National Coverage Analyses for an item or service under the reasonable and necessary statute, CMS generally makes three kinds of assessments: (1) The quality of relevant individual studies; (2) What conclusions can be drawn from the body of the evidence on the direction and magnitude of the interventions potential harms and benefits; and (3) The generalizability of findings from relevant studies to the Medicare beneficiary population.

Because we are interested in accelerating beneficiary access to new items and services, evidence-based decision making is an important component of establishing national coverage policies. Clinical evidence that supports a determination that an item or service is reasonable and necessary for the Medicare beneficiary population is important because these individuals are often older, with multiple comorbidities, and are often underrepresented or not represented in many clinical studies. In general, CMS looks to the evidence supporting FDA market authorization and the device indications for use for evidence generalizable to the Medicare beneficiary population, data on improvement in health outcomes, and durability of those outcomes. If there are no data on those elements, it is difficult for CMS to make a favorable evidence-based decision on whether the device is reasonable and necessary for the Medicare population.[3]

As part of CMS commitment to improve the transparency of the NCD process, we intend to publish a series of guidance documents that review important clinical outcomes for treatments addressing specific therapeutic areas. These reviews will assist interested parties seeking Medicare coverage for an item or service, such as a drug or device, in understanding the types of evidence CMS expects to review when making national coverage determinations (NCDs) as outlined in 1862(l) of the Social Security Act.

CMS undertakes a number of activities designed to improve the health care provided to Medicare beneficiaries. These activities include coverage policy decisions that determine which services can be covered as reasonable and necessary under title XVIII of the Social Security Act. These decisions consider the best available scientific and clinical evidence concerning the benefits and harms of various clinical items and services and apply the highest attainable level of expertise to evaluate such evidence.

CMS may use technology assessments (TAs) to assist in reviewing evidence in the NCD process when determining whether a particular technology is reasonable and necessary or, in some cases, to identify those areas that need further evidence development. A TA can involve the evaluation of a technologys performance characteristics, safety, efficacy, effectiveness, outcomes, and appropriateness. TAs that systematically evaluate available evidence are the most highly regarded assessments. These types of assessments include a range of related activities, such as identifying and prioritizing technologies for assessment, collecting and analyzing data, synthesizing and grading evidence, and disseminating findings and recommendations.[4]

While a TA can evaluate many aspects of a technology, interpretation and critical appraisal of the evidence on patients health outcomes constitutes its vital component. Accordingly, the performance of a systematic review of the evidence from the medical literature is at the core of every TA, whether undertaken internally or commissioned externally by CMS. Systematic reviews are scientific investigations that synthesize the results of multiple primary investigations on one or more relevant clinical questions. The evidence is then appraised to assess its validity (how credible it is), usefulness (its clinical applicability), and importance (magnitude of effect). To minimize bias, systematic reviews emphasize a comprehensive search of all potentially relevant articles and the use of explicit, reproducible criteria in selecting articles for review. Primary research designs and study characteristics are appraised, data are synthesized, and results are interpreted.[5]

By incorporating methods to assemble, sort through and integrate clinical evidence, the systematic review embedded in a TA represents a rigorous compilation of scientific evidence to answer clinical questions. It enables other parties to understand, replicate, and judge the collection, selection, and analysis of evidence and is particularly useful when the medical research literature is complex or extensive.

Prior TAs have focused on clinical factors pertinent to Medicare patients health outcomes. For the current review, CMS engaged with a contractor to complete the technology assessment of clinical endpoints in knee osteoarthritis (Section V, Technology Assessment). This topic was selected because of the high burden of osteoarthritis in the Medicare beneficiary population, because knee replacement surgeries are among the most common surgical interventions provided to Medicare beneficiaries, and because new technologies are being developed that are intended to treat this condition. In Section VI, CMS draws conclusions from the technology assessment and makes recommendations. CMS is seeking public comment on this guidance document. In particular, we are interested in public comments on the approach, the methodology, and on the utility of this guidance.

Overview
Osteoarthritis (OA) of the knee is a common form of arthritis with a broad spectrum of presentation, ranging from an asymptomatic radiological finding to a progressive disease resulting in joint failure. It typically occurs bilaterally, though severity can differ unilaterally. Primary symptoms include pain, limitation of motion, stiffness, tenderness, swelling, joint deformity, and instability. Knee OA is the leading cause of lower-limb disability in adults 50 years and older worldwide (Doherty M & A Abhishek, 2021) and assumes 80% of all OA burden, with women experiencing higher rates of radiographically confirmed symptomatic knee OA than men. Approximately 14 million people in the United States (US) experience symptomatic knee OA, and prevalence is estimated at 7%. The lifetime risk of developing symptomatic knee OA is about 40% for men and 47% for women. (March L & M Cross, 2020)

Management is contingent on levels of pain, functional and participatory impairments, and impacts on quality of life. Nonpharmacologic therapies, topical therapies, or analgesics as needed are the first avenues of care usually administered for mild cases. (Deveza L & K Bennell, 2022) For moderate to severe cases, oral nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine for patients contraindicated or refractory to NSAIDs, intraarticular glucocorticoid injections, and adjunctive braces or walking devices, as appropriate, are given. If significant symptoms persist after exhausting these options, then surgery is often considered. (Deveza L & K Bennell, 2022) Surgical procedures include total knee replacement (TKR), unicompartmental knee replacement, and knee osteotomy. (Mandl L & G Martin, 2020)

Recent advancements to enhance surgical accuracy have led to an array of new technologies, such as patient-specific instrumentation, sensors, accelerometers, and robotic-assisted surgery. (Batailler C et al., 2020) As the field evolves to increase the types of innovations available, it becomes imperative to consistently measure outcomes that demonstrate improvements relevant to patients, providers, payers, and other key healthcare stakeholders for evidence-based decision-making. Development and uptake of a core outcome set (COS), a minimum set of outcomes that should be measured and reported in all clinical trials for a given condition (Williamson P et al., 2012) for knee OA is a means to that end. Furthermore, having a COS will promote transparency for innovators seeking to anticipate the evidence needs of healthcare decision-makers.

Objective: This report aims to compile a succinct list of prioritized outcomes and instruments that represent the most relevant, meaningful outcomes that should be used to evaluate medical technologies that treat knee OA.

Methods
Identifying the Literature
Searches were conducted in multiple databases and evidence-based sources to comprehensively capture prioritized outcome measures and instruments related to surgical and other device interventions for knee OA. A systematic search using the terms knee osteoarthritis or osteoarthritis of the knee and core measures or core outcomes or outcome measures was done in Embase/Science Direct on February 14, 2022, and a corresponding search was completed in PubMed/MEDLINE on February 21, 2022, to retrieve systematic reviews or consensus statements around knee OA outcomes. Search strings are detailed in Appendix A, and eligibility criteria are listed in Table 1. The project team reviewed all articles at the title and abstract levels. We obtained for full review any articles possibly meeting the inclusion criteria. Individual team members reviewed all retrieved articles for inclusion; discussion and consensus between two team members resolved uncertainty about full-length article inclusion.

Table 1. Eligibility Criteria for PubMed/MEDLINE Screening

Additional searches were conducted to supplement the findings from PubMed and Embase. A search was done in the Cochrane Library on February 22, 2022, using the term osteoarthritis of the knee to retrieve relevant protocols and systematic reviews, as well a search of all systematic reviews published from 2012 onwards filed under the full list of reviews on the Cochrane Musculoskeletal groups (CMSG) evidence webpage. To ascertain whether added research on knee OA core outcomes was available, two searches were executed in the Core Outcome Measures in Effectiveness Trials (COMET) Initiatives database on February 14, 2022, one for knee osteoarthritis and the other for total joint replacement. Supplementary scans were also completed within the following sources for peer-reviewed or gray literature relevant to the project scope: Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness reviews, Food and Drug Administration (FDA) Patient-Focused Drug Development meeting reports and guidance documents, National Institute on Agings Osteoarthritis Initiative (OAI), National Institute of Arthritis and Musculoskeletal and Skin Diseases Orthopedic Research Program, Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT), Osteoarthritis Research Society International (OARSI), European Alliance for Health Outcomes Measurement (EULAR), and the International Consortium for Health Outcomes Measurement (ICHOM). Details of these scans are documented in Appendix A.

Data Abstraction and Data Management
Included publications were categorized as follows: (1) systematic and comparative effectiveness reviews (SLR/CER), (2) consensus development, and (3) other (i.e., protocols, guidelines, workshop reports). For publications within categories one and three, we abstracted the following study level details: objective, funding source, databases, included study types, and eligibility criteria. If an article was categorized as consensus development, then consensus methodology was also captured. We abstracted data about the characteristics of the included studies, as well as characteristics of the stakeholder groups involved in consensus development if applicable. Finally, for all publications, we abstracted data on the outcomes and associated instruments when available, along with whether they were deemed a prioritized or non-prioritized outcome or instrument.

Data Synthesis
Following abstraction, the data was synthesized to create a prioritized list of outcome domains and instruments that included any abstracted subdomains or items. Outcomes were organized by the four core areas of Life Impact, Pathophysiological Manifestations, Resource Use/Economical Impact, and Death, borrowed from the OMERACT Filter 2.0 guidelines on core outcome measurement set development. (Boers M et al., 2014) An additional Other area was used to house outcomes that did not fit under any of the specified core areas. Within each area, outcomes were further organized by whether they were prioritized or non-prioritized based on the literature. Prioritized outcomes were defined as those designated as either mandatory, critical, core, or major by the majority of included publications. In contrast, non-prioritized outcomes were deemed as important but optional, non-core, minor or received no designation. Outcomes that were classified as research agenda warranting further exploration were excluded from the synthesis. Instruments in the synthesis table were organized hierarchically by the number of citations received amongst the included publications, with the most used instruments at the top.

The synthesis table also captures additional information obtained through targeted literature searches on minimal important differences (MID) and its variations (i.e., minimal clinically important differences (MCID), the minimal clinical difference (MCD), minimal clinically important improvement (MCII), minimal important change (MIC), and minimum detectable change (MDC)), as well as validation data. This information was only retrieved if it pertained to knee or knee/hip OA within the outcome domain of assessment. Every attempt was made to find validation and minimal difference studies conducted in the United States or other English-speaking countries where knee OA patients received surgical or other device therapies. Furthermore, instrument-specific characteristics that could potentially contribute to decision-making during multi-stakeholder discussions were captured, such as feasibility (e.g., number of items, time to complete), recall period, reporter, dimensions assessed, the intent of development, and access.

Quality Assessments
To assess the quality of the consensus methodology employed in the consensus development publications, the COMET COS-STAD recommendations were applied. (Kirkham J et al., 2017) These recommendations involve consideration of the following factors: scope specification, stakeholders involved, and consensus process rigor. The methodological quality of included SLRs was first determined using U.S. Preventive Services Task Force (USPSTF) criteria for assessing the internal validity of systematic reviews, (USPSTF, 2017), including the areas of comprehensiveness of sources considered/search strategy used, standard appraisal of included studies, validity of conclusions, and recency and relevance.

Results
Literature
Using the search terms specified in Appendix A within the PubMed/MEDLINE and Embase/Science Direct databases, we retrieved 799 records. Of these, 38 were included after title screening, and nine were retained following abstract screening. After full-text articles for the nine records were obtained and screened, five papers met the eligibility criteria for this review. Two of the full-text articles were excluded because they were neither a systematic review nor a consensus statement, and the remaining two articles were excluded because they did not adequately describe a prioritization of outcomes or instruments necessary for the project scope. Notably, we observed that many of the papers discussed knee and hip OA outcomes concurrently, and thus, articles were included if they addressed either solely knee OA outcomes or both knee and hip OA outcomes collectively.

Searches within the Cochrane Library and CMSG about surgical or other device interventions for knee OA or knee/hip OA, published 2012 onwards, yielded two relevant protocols and four systematic reviews. A search within AHRQ using the same criteria retrieved one relevant comparative effectiveness review. Searches targeted at knee or knee/hip OA core outcome sets or consensus statements within the COMET Initiative, OMERACT, OARSI, EULAR, and ICHOM platforms produced ten relevant articles, five of which were duplicates from the PubMed and Embase searches. A webpage was also included from OARSI, which detailed the most important indices to evaluate the algofunctional status of patients with musculoskeletal diseases. Queries for relevant publications within the FDA and NIH platforms yielded one relevant document, a draft guidance on structural endpoints for the development of drugs, devices, and biological products for OA. A search for summaries from Voice of the Patient or Patient-Focused Drug Development meetings provided an additional record a report from a Voice of the Patient meeting hosted by the Arthritis Foundation and attended by the FDA. See Appendix A for further details on these supplementary scans.

Twenty records were included in this review (Appendix B).

Data Abstraction and Data Management
Seven papers were abstracted under the Systematic and Comparative Effectiveness Review category. Three papers focused solely on knee OA. (Palmet J et al., 2019; Dulvenvoorden T et al., 2015; Brouwer R et al., 2014) One included knee rheumatoid arthritis, (Hofstede S et al., 2015), one covered other musculoskeletal knee conditions in addition to OA, (Howe T et al., 2012), and the remaining two papers focused on both knee and hip OA. (Konnyu K et al., 2021; Lange T et al., 2017) Five of the reviews were within the context of interventions that included surgery or other devices (Palmet J et al., 2019; Dulvenvoorden T et al., 2015; Brouwer R et al., 2014; Hofstede S et al., 2015; Lange T et al., 2017) while one focused on (p)rehabilitation for TKA or THA, (Konnyu K et al., 2021) and the last did not specify. (Howe T et al., 2012) The number of studies included in each review ranged from 5 to 100, in which the number of patients ranged from 566 to 14,533. Most reviews did not specify a mean age; however, Duivenvoorden et al. (2015) reported a mean of 62 years (range: 48 to 75), and Brouwer et al. (2014) reported a mean of 60 years (range: 42 to 67). Outcomes from the CMSG reviews were designated as either major or minor, and similarly, outcomes were pre-specified as important/prioritized in the AHRQ comparative effectiveness review. Lange et al. (2017) explored uptake of the OMERACT-OARSI knee/hip OA COS, reflecting the relative importance researchers placed on these outcomes. Six of the seven review papers discussed instruments that corresponded with their outcomes of interest.

Among the eight Consensus Development papers, two addressed knee OA solely (Christensen R et al., 2015; McAlindon T et al., 2015) while the remaining papers focused on both knee and hip OA. Six papers centered around interventions that included surgery or other devices (McAlindon T et al., 2015; Smith T et al., 2019; Hoang A et al., 2017; Singh J et al., 2017; Singh J et al., 2015) and the remaining two papers did not specify an intervention type. (Christensen R et al., 2015; Rolfson O et al., 2016) Of note, two benchmark papers developed sets of core or mandatory outcome domains that four other included consensus development papers corroborated. Smith et al. (2019) discussed an update of the OMERACT-OARSI COS developed for knee and hip OA clinical trials that McAlindon et al. (2015) supported. Likewise, Singh et al. (2015) introduced an OMERACT-endorsed core set of outcome domains for knee and hip OA patients undergoing total joint replacement, which Hoang et al. (2017) and Singh et al. (2017) substantiated in various stakeholder groups. There was evidence of diverse stakeholder participation in the consensus processes, with patients involved in five of the panels. Four of the processes utilized a Delphi or modified Delphi approach to reach consensus (McAlindon T et al., 2015; Smith T et al., 2019; Singh J et al., 2015; Rolfson O et al., 2016), whereas others involved a single round of voting or roundtable discussion.

Under Other Publication Types, we abstracted data from the following records: one webpage containing instrument data, an FDA draft guidance document, a Voice of the Patient report, and two CMSG systematic review protocols. Both review protocols were specific to arthroplasty for the treatment of knee OA. (Jolles B et al., 2013; Singh A & K Vinay, 2013) The remaining records were geared toward OA in general (FDA, 2018; Arthritis Foundation, 2017) or chronic musculoskeletal diseases, including OA. (OSARI, 2022) The authors indicated prioritized outcomes by use of phrasing such as significant, major, and meaningful. Abstracted data for all publications mentioned above can be found in Appendix B.

Data Synthesis
Out of the 26 identified outcome domains in the included literature, 11 were classified as prioritized: joint pain, physical function, health-related quality of life (HRQoL), patient satisfaction, function/functional ability, joint structure, stiffness, treatment failure, mortality, serious adverse events (SAEs), and adverse events (AEs) (Table 2). Representation from each of the four core areas is present, and recommended instruments per the literature are listed correspondingly for five of the outcome domains. Instruments were considered prioritized if the number of citations met at least 50% of the highest cited instruments total citations within an outcome domain for example, under physical function, the Western Ontario and McMaster University OA Index (WOMAC) global score was the highest cited instrument with six citations; thus, any instrument under this domain that had at least three citations was prioritized. Synthesized data can be found in Appendix C.

Table 2. Prioritized Outcome Domains and Instruments

Abbreviations: EQ-5D-5L: EuroQol in 5 dimensions 5 levels; HSS: Hospital for Special Surgery; KOOS: Knee Injury and Osteoarthritis Outcome Score; NR: not reported; SF-12: Short Form 12; SF-36: Short Form 36; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster University Osteoarthritis Index

Five outcome domains were prioritized under life impact: joint pain, physical function, HRQoL, patient satisfaction, and function/functional ability. There was noticeable heterogeneity in the instruments used to measure joint pain, physical function, and HRQoL. The VAS, WOMAC pain subscale, Lequesne global score, and WOMAC global score were the most commonly used instruments to measure joint pain. Each instrument is patient-reported and has been validated within the knee or knee/hip OA patient population as having acceptable reliability and validity, though an MCID for pain could not be found for the Lequesne index. They have a relatively low respondent burden, ranging from a completion time of less than one minute for the VAS to up to ten minutes for the WOMAC global index. The WOMAC and Lequesne scales were developed specifically within the knee and hip OA population, whereas the VAS was not. While the VAS is publicly available, a fee is required for use of the WOMAC. It is unknown whether the Lequesne index is freely available. Importantly, the WOMAC and Lequesne scales are multidimensional assessments of pain whereas the VAS a unidimensional assessment of pain intensity. It has been suggested that a multidimensional measure may better evaluate pain status and responsiveness to interventions since a patients experience of pain is not a simple construct. (McAlindon T et al., 2015)

The WOMAC global score, Knee Injury and OA Outcome Score (KOOS), Hospital for Special Surgery (HSS) Knee Score, Lequesne global score, and WOMAC function subscale were commonly used to measure physical function. Similar to joint pain, physical functions multidimensional nature was reflected in the types of instruments cited. All instruments were developed in a knee or knee OA-specific population and have been validated within this population with acceptable reliability and validity, although the validity data presented for the KOOS was derived from its short form, the KOOS-PS. MCIDs were found for all but the Lequesne index. It is worth noting here that calculations of minimal differences are highly contextual, a reality reflected in the wide MCID range for the WOMAC global score, which spans from 4.2 for osteotomy to 10.5 to 36.0 for total knee arthroplasty (TKA). Of these recommended instruments, only the KOOS was confirmed to be publicly available. Each instrument is patient-reported, apart from the HSS Knee Score, and possesses a relatively low respondent burden. The HSS Knee Score is clinician reported and consists of a patient interview and physical exam. Although no performance-based measures reached the threshold set for prioritization, incorporating them may have benefits. A study conducted by Mizner et al. (2011) comparing the responsiveness of patient-reported versus performance-based outcome measures after unilateral TKA for end-stage knee OA found that physical performance decreased acutely after surgery per objective measures, but PROs did not concurrently capture these initial functional declines. Acknowledging the importance of objectivity in measuring physical function, OARSI, a leading international organization for scientists and healthcare professionals dedicated to OA research, developed a minimum core set of performance-based tests to assess physical function in knee/hip OA patients. This core set includes the Timed Up and Go (TUG) test, 30-second chair stand test, and 6-minute walk test (6MWT). (Dobson F et al., 2013) Validation data and instrument properties for these tests can also be found in Appendix C.

The most cited instruments that measure HRQoL were the EuroQol in 5 dimensions and 5 levels (EQ-5D-5L), 12-item Short Form (SF-12), and 36-item Short Form (SF-36). Though these tools were developed as patient-reported generic measures for describing health, they have undergone validation studies within the knee or knee/hip OA population and were found to have acceptable reliability and validity. Minimal difference data was available for all three instruments; however, the values presented for the SF-12 separate the scale into its physical and mental component subscales. Researchers have historically advocated for using these component subscales in the Short Forms, stating that there is little evidence to support the relevance of the aggregate score within the knee and hip OA population. (Rannou F et al, 2007) Disaggregated MCIDs were not found for the SF-36. All three prioritized instruments have relatively low to moderate respondent burden. The SF-12 is a condensed version of the SF-36, containing a third of the items. Yet, it assesses the same eight dimensions and highly correlates with the SF-36 in OA patients undergoing knee replacement surgery (Webster K & J Feller, 2016), which might confer upon it an advantage over its longer counterpart. Additionally, all three instruments exist in the public domain, though a licensed version of the SF-36 distributed by Optum has scoring differences compared to the freely available version from RAND.

Patient satisfaction with treatment results and/or procedures can be measured via a patient-reported VAS or Likert scale. Evidence of validation for assessing satisfaction among knee OA patients was not found in the literature for either tool, and no validated, standard question nor point scale was observed. Five-and ten-point scales appeared to be commonly used, ranging from very/completely/extremely dissatisfied to very/completely/extremely satisfied. Though no MCID values could be found, a systematic review assessing measures of patient satisfaction with outcomes post-TKR defined satisfaction as a score of ≥ 7 on a 10-point scale and ≥ four on a 5-point scale VAS. (Klem N et al., 2020) Both scales can be administered without a fee.

The final outcome domain that includes suggested instruments is joint structure, measured by radiographic imaging. Other suggested measurement methods were magnetic resonance imaging (MRI) and sonography, though these needed to meet the threshold set for prioritization. Evaluation of joint structure can include changes in joint structure or observations of disfigurement. Validation was not applicable. Joint structure might be an outcome domain relevant only in specific types of clinical trials, such as those assessing structure-modifying technologies.

Specific instruments for the remaining outcome domains of function/functional ability, stiffness, treatment failure, mortality, SAEs, and AEs were not identified in the included literature. Several domains, such as mortality, treatment failure (e.g., revision surgery, reoperation), SAEs, and AEs, may not warrant a validated instrument. Moreover, stiffness and function/functional ability (e.g., ability to function in society or at work, employability, productivity) may be captured in algofunctional instruments used in other prioritized outcome domains, including the WOMAC, SF-12, and KOOS.

Quality Assessments
The quality of the consensus methodologies implemented across the eight consensus development publications was variable. Scope specification was generally acceptable, with all studies identifying at least three out of the following four factors: health condition, population, intervention, and setting intended for COS use. Robust stakeholder involvement that included knee OA patients as a comparable percentage of the overall panel was apparent in only two studies. (Smith T et al., 2019; Hoang A et al., 2017) All but one study had more than one type of stakeholder group relevant to the COS scope, though the participation of industry representatives who will implement the COS in clinical trials was limited to two studies. (McAlindon T et al., 2015; Smith T et al., 2019) Regarding the consensus process itself, a clearly defined scoring process was provided in four studies. (McAlindon T et al., 2015; Smith T et al., 2019; Hoang A et al., 2017; Singh J et al., 2017) A clear definition of consensus was also provided in four studies. (Smith T et al., 2019; Hoang A et al., 2017; Singh J et al., 2017; Rolfson O et al., 2016) There was not enough information to determine whether the initial list of candidate outcomes adequately incorporated healthcare provider and patient perspectives and avoided ambiguity of language. The quality of the systematic reviews was generally fair to good using the US Preventive Services Task Force (USPSTF) rating system. The main limitations of the reviews rated as fair were due to older search dates. One systematic review was rated as poor, as there were limited search databases, the searches were older, and there was a lack of risk of bias assessment of the included studies. (Lange T et al., 2017) However, for this assessment, the overall quality of the systematic reviews and included literature should not carry the same weight as the quality of the consensus papers. The evidence from the systematic reviews within the context of outcomes prioritization was used merely for retrieval and delineation of major versus minor outcomes and instruments. Hence, the quality of methods and confidence in conclusions drawn by the authors did not affect our findings.

Consensus Assessments

In the current review, professional consensus statements offered relatively homogenous recommendations regarding outcome measures for evaluating efficacy of treatments for knee osteoarthritis. In addition, four Cochrane reviews, one AHRQ comparative effectiveness review, and one FDA Voice of the Patient report were considered. We identified 11 outcome domains, and this report summarizes the instruments used within each domain, ranked by citation volume, and provides reference values for MDIC where they are available.

As seen in Table 3, citation volume for outcomes ranged from a low of 10% to a high of 95%. Lack of consensus around how to apply these outcomes consistently is a recognized deficiency of the literature. Greater consensus around how to apply the set would help improve consistency across studies. Having widely accepted measurement timepoints (e.g., every 3 or 6 months), methods of aggregation (e.g., mean), and specific metrics (e.g., change from baseline) will aid in reducing the heterogeneity currently seen in clinical trials and assist with conducting comparative effectiveness reviews.

Discussion

After a comprehensive review of the literature and other evidence-based sources for relevant, critical outcomes to consider when evaluating different technologies to treat knee OA, a list of eleven prioritized outcome domains and their commonly used instruments was identified. This list is comprised of the outcome domains joint pain, physical function, HRQoL, patient satisfaction, function/functional ability, joint structure, stiffness, treatment failure, mortality, SAEs, and AEs. It is important to note that this report does not designate these outcomes as core; instead, it suggests that per the included literature, they are perceived as most critical and perhaps most amenable to being part of a COS.

There are several considerations regarding this prioritized list and its related instruments. Though SAEs and AEs were acknowledged as critical outcomes in the included literature, researchers will sometimes exclude them from a final COS since they are inherently captured in clinical trials to fulfill regulatory requirements. This technique serves the dual purpose of eliminating redundant outcomes and decreasing the size of a COS to promote uptake. Additionally, the prioritized outcomes identified via data synthesis were partially influenced by the COS developed by OMERACT-OARSI for knee/hip OA clinical trials, as well as the OMERACT COS for knee/hip total joint replacement (TJR) clinical trials. The considerable overlap between the reported outcomes list and both COS evidences this. In total, eight papers six papers from the consensus development category and two from the SLR/CER category, which amounted to 40% of the included publications discussed or mentioned these two core sets. The consensus processes used to define and ratify both core sets involved diverse groups of stakeholders and structured Delphi methodology. Also, publications not linked to the existing COS appeared to reaffirm their choice of outcomes.

Concerning instruments, the values for minimal differences seen in Appendix C were calculated within highly contextual bases and should be interpreted as such. Although these values are relevant to knee or knee/hip OA mainly within the context of specific surgeries, they cannot be generalized to all surgeries or medical devices being evaluated for knee OA. The challenge with MCIDs is that they can be highly variable due to differences in the calculation, patient population, intervention, disease severity, timepoints of analysis, and study setting (e.g., clinical trial versus practice). Moreover, MCID is often erroneously used interchangeably with other related terms such as MID, MCD, MDC, and MIC. For example, MCID indicates the smallest clinically meaningful change that might suggest a change in care management. In contrast, MDC is a statistical term that denotes the smallest detectable change considering measurement error. (Maredupaka S et al., 2020) Understanding the distinctions between terms of minimal difference is crucial to utilizing these values appropriately.

Instruments were prioritized in this review based on the number of citations, which suggests general acceptability of use by researchers. Validation within the intended patient population was completed for most prioritized instruments except for the VAS and Likert scales for patient satisfaction, and some are available within the public domain. Not all validation studies reported were conducted in the US or other English-speaking countries, which might limit their applicability to US-based studies. Furthermore, despite our efforts to record instrument characteristics that could impact judgments around which ones should be used, there may be other characteristics or properties important to stakeholders that were not noted or difficult to find. For example, some participants may care about whether the development of instruments involved substantial patient input. The decision around which instruments to use can be swayed by the types of stakeholder groups and experiences involved in discussions.

CMS is developing this clinical endpoints guidance series to improve predictability and transparency of our evidence reviews. This review compiles a succinct list of outcomes and instruments that represent the most relevant, meaningful outcomes that may be used to evaluate knee osteoarthritis treatments. It also identifies available published evidence that defines clinically meaningful differences for each endpoint. This guidance is intended as a reference for clinical investigators who are developing knee osteoarthritis studies and for CMS staff who may review studies in this therapeutic area. As this is the first guidance document in the series, the format of these reviews may change over time. CMS is interested in public comment on this guidance document specifically, but also on how this series can deliver the greatest value to CMS and the public.

CMS has reviewed the consensus assessments described in the technology assessment (Section V) in this document and has concluded that this guidance can be proposed for public comment without need for a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC).[6]

In general, when making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of an illness or injury or to improve the functioning of a malformed body member under section 1862(a)(1)(A) of the Social Security Act. CMS encourages investigators to review our guidance documents on Clinical Evidence Review[7][8], as applicable, prior to designing clinical studies intended to satisfy the legal standard for national CMS coverage. Additionally, based upon the findings of the technology assessment on clinical endpoints for knee osteoarthritis, CMS can make the following recommendations for clinical studies for technologies in this therapeutic area:

Generalizability to the Medicare population:

CMS may have difficulty drawing conclusions regarding potential benefits and harms associated with an item or service if Medicare eligible beneficiaries are insufficiently represented in clinical studies.

• CMS recommends that investigators carefully consider the intended recipients of an item or service when designing clinical studies such that the findings may be credibly generalized to relevant Medicare beneficiaries, including important sub-populations.
• CMS recommends that studies avoid poorly justified exclusions based on age or common comorbidities that may limit generalizability of findings.
• CMS recommends that study investigators consider whether the context of care delivery within clinical studies may be reasonably generalized to the context where Medicare beneficiaries are expected to receive care.

Clinical Endpoints & Clinically Meaningful Differences:

Traditionally, CMS relies heavily on health outcomes data to make NCDs. Where there is limited evidence on the health outcomes for individuals in the Medicare beneficiary population, there may not be sufficient evidence to support favorable national Medicare coverage under section 1862(a)(1)(A) of the Act.

• CMS recommends that investigators consider the 11 prioritized outcome domains identified in Table 2 of this technology assessment when designing knee osteoarthritis clinical studies.
• CMS does not recommend any specific clinical endpoint or instrument that was identified in this review, but generally recommends that clinical studies include a range of outcomes that reflect multiple attributes of an item or service within a clinical study.
• When chosing among the available clinical endpoint options, CMS recommends that clinical studies prioritize validated endpoints / instruments and those with well-established/published minimal clinically important differences (MCID) values because study findings are more readily interpreted.

Duration of follow-up:

CMS may have difficulty reaching conclusions regarding potential risks and harms associated with an item or service if studies lack sufficient follow-up to demonstrate the durability of improved health outcomes.

• For osteoarthritis, CMS generally recommends that clinical studies include follow-up of at least one year for functional and/or patient reported outcomes.
• CMS generally recommends that clinical studies include follow-up of at last two years to establish the durability of implanted devices, though shorter or longer follow-up may be reasonable in some circumstances.

Abbreviations: AAOS: American Academy of Orthopedic Surgeons; AAOS-Outcome SIG: AAOS Outcome Special Interest Group; ADLS: Activities of Daily Living Scale; AHRQ: Agency for Healthcare Research and Quality; AIMS: Arthritis Impact Measurement Scales; AKPS: Anterior Knee Pain Scale; ALF: Aggregated Locomotor Function; AQoL: Assessment of QoL; ASES: Arthritis Self-Efficacy Scale; BOA: British Orthopaedic Association; CCT: controlled clinical trial; CER: comparative effectiveness review; CGA: Clinician Global Assessment; CMSG: Cochrane Musculoskeletal Group; COMET: Core Outcome Measures in Effectiveness Trials; COS: core outcome set; EPC: evidence-based practice center; EQ-5D: EuroQol in 5 dimensions; FDA: Food and Drug Administration; GP: general practitioner; HAP: Human Activity Profile; HAQ: Health Assessment Questionnaire; HOOS-PS: Hip Disability and Osteoarthritis Outcome Score short version; HRQoL: health-related QoL; HSS: Hospital for Special Surgery; CHOM: International Consortium for Health Outcomes Measurement; ICOAP: Intermittent and Constant Osteoarthritis Pain; ICTRP: International Clinical Trials Registry Platform; IKDC: International Knee Documentation Committee; IOS: International Orthopedic Societies and Surgeons; IOSK: Indices of severity for OA of the knee; IQR: interquartile range; J-MAP: Joint specific Multidimensional Assessment of Pain; JOA: Japanese Orthopedic Association; KOOS: Knee Injury and Osteoarthritis Outcome Score; KOOS-PS: KOOS short version; KSPS: Knee-Specific Pain Scale; KSS: Knee Society Score; LEFS: Lower Extremity Functional Scale; MACTAR: McMaster Toronto Arthritis score; MTA: meta-analysis; NA: not applicable; NHP: Nottingham Health Profile; NIHR: National Institute for Health Research; NR: not reported; NRCS: non-randomized controlled study; NRS: numerical rating scale; OA: osteoarthritis; OARSI: Osteoarthritis Research Society International; OKS: Oxford Knee Score; OMERACT: Outcome Measures in Rheumatoid Arthritis Clinical Trials; ORS: Outcomes Research Group of the Orthopedic Research Society; OT: occupational therapist; PFDD: patient-focused drug development; PGA: Patient Global Assessment; PRO: patient-reported outcome; PT: physiotherapist; QoL: quality of life; RA: rheumatoid arthritis; RCT: randomized controlled trial; R3: Round 3; SAE: serious adverse event; SF-36: Short Form 36; SD: standard deviation; SIP: Sickness Impact Profile; SLR: systematic literature review; SoC: standard of care; THA: total hip arthroplasty; TJR: total joint replacement; TKA: total knee arthroplasty; TKR: total knee replacement; TUG: Timed get Up and Go; UKA: unicompartmental knee arthroplasty; VAS: visual analogue scale; VR-12: Veterans Short Form 12 health survey; WHO: World Health Organization; WOMAC: Western Ontario and McMaster University Osteoarthritis Index; 6MWT: 6-minute walk test 

Abbreviations: ADL: activities of daily living; ADLS: Activities of Daily Living Scale; AE: adverse event; AIMS: Arthritis Impact Measurement Scales; AQoL: Assessment of QoL; ASES: Arthritis Self-Efficacy Scale; BOA: British Orthopaedic Association; CRO: clinician reported outcome; EQ-5D: EuroQol in 5 dimensions; EQ-5D-5L: 5 level version of EQ-5D; HAQ: Health Assessment Questionnaire; HRQoL: health-related QoL; HSS: Hospital for Special Surgery; ICC: intraclass correlation coefficient; ICOAP: Intermittent and Constant Osteoarthritis Pain; IKDC: International Knee Documentation Committee; JKOM: Japanese knee OA measure; JOA: Japanese Orthopedic Association; KOOS: Knee Injury and Osteoarthritis Outcome Score; KOOS-PS: KOOS short version; KSPS: Knee-Specific Pain Scale; KSS: Knee Society Score; LEFS: Lower Extremity Functional Scale; MACTAR: McMaster Toronto Arthritis score; MCD: minimal clinical difference; MCID: minimal clinically important difference; MCII: minimal clinically important improvement; MCS: mental component scale; MDC: minimum detectable change; MIC: minimal important change; MID: minimal important difference; NA: not applicable; NHP: Nottingham Health Profile; NR: not reported; NRS: numerical rating scale; OA: osteoarthritis; OARSI: Osteoarthritis Research Society International; OKS: Oxford Knee Score; OMERACT: Outcome Measures in Rheumatoid Arthritis Clinical Trials; PCS: physical component scale; PGA: Patient Global Assessment; PRO: patient-reported outcome; PROMIS: Patient-Reported Outcomes Measurement Information System; QoL: quality of life; RA: rheumatoid arthritis; RAND: Research and Development Corporation; RCT: randomized controlled trial; R3: Round 3; SAE: serious AE; SF-12: 12-item Short Form; SF-36: 36-item Short Form; SD: standard deviation; SE: standard error; SIP: Sickness Impact Profile; THA: total hip arthroplasty; TKA: total knee arthroplasty; TKR: total knee replacement; TUG: Timed get Up and Go; UK: United Kingdom; US: United States; VAS: visual analogue scale; VRS: verbal rating scale; VR-12: Veterans Short Form 12 item health survey; VR-36: Veterans 36 item health survey; WOMAC: Western Ontario and McMaster University Osteoarthritis Index; 6MWT: 6-minute walk test 

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