Why insurance rarely covers orthobiologic procedures

Insurance rarely covers orthobiologic procedures because coverage is a contractual decision a payer makes against its own written policy, and that decision answers a different question than the one asked in an examination room. The payer is deciding whether a claim matches a policy. Your physician is deciding whether a treatment is reasonable for the person in front of him. Those two judgments can point in opposite directions without either one being wrong.

That is not an interpretation imposed from outside. One large national plan’s current medical coverage policy for platelet-rich plasma says in its own instructions for use that its coverage policies are “not recommendations for treatment and should never be used as treatment guidelines” [2]. A denial is a statement about policy language, coding, and documentation. It is not a finding about your joint.

A coverage decision and a clinical decision answer different questions

A payer approves a claim against inputs it decided on in advance: a covered indication, a procedure code that maps to it, documentation the reviewer can audit, and an evidence standard the plan adopted before your case existed. Orthobiologic injections frequently fail to line up with one or more of those inputs even when the clinical rationale is sound.

A 2025 review of the economics of orthobiologics describes platelet-rich plasma and concentrated bone marrow aspirate as exempt from stringent regulatory pathways, and identifies that exemption — together with off-label use and a lack of standardized pricing — as what leads to insurance coverage issues and financial burdens for patients [1]. The same review reports sparse literature on the economic landscape of orthobiologics and limited cost transparency across the country [1]. When a payer cannot compare one claim to another with confidence, the default answer is no.

Payers do not agree with one another either

Researchers took the 47 medical devices addressed in Medicare national coverage determinations issued between February 1999 and August 2013 and compared each one against the publicly available policies of the 16 largest private payers. The national determinations were equivalent to the corresponding private policies roughly half the time, more restrictive about a quarter of the time, and less restrictive about a quarter of the time [3]. The authors concluded that patients may have variable access to medical technology across Medicare and private plans, and that private plans do not necessarily follow the lead of the Centers for Medicare & Medicaid Services [3].

If a coverage decision were a measurement of whether something works, sixteen organizations reading the same literature would converge on the same answer. They do not, because they are not measuring the same thing.

The regulatory gap behind PRP and BMAC

Orthobiologics fall under the Food and Drug Administration’s Center for Biologics Evaluation and Research, which regulates human cells, tissues, and cellular and tissue-based products. Many cell therapies are held to strict guidelines from that center, while platelet-rich plasma and concentrated bone marrow aspirate are exempt from the more stringent pathways [1].

The payer policy describes the same structure from the billing side. It characterizes platelet-rich plasma as a minimally manipulated autologous blood product, and notes that the systems used to prepare it are approved under the 510(k) process, generally to prepare platelet-rich plasma from the patient’s own blood at the point of care or in a clinical laboratory [2]. What carries a clearance is the equipment that separates the blood. There is no premarket approval of an injection for a joint indication, so there is no approval document a claim can attach itself to, and the use is classified as off-label [1].

The same product, different answers by indication

Medicare’s own record on autologous platelet-rich plasma shows how indication-bound this is. Effective for services performed on or after April 13, 2021, the Centers for Medicare & Medicaid Services covers autologous platelet-rich plasma for the treatment of chronic non-healing diabetic wounds for a duration of 20 weeks, when it is prepared by devices whose FDA-cleared indications include the management of exuding cutaneous wounds [4]. In the same determination, autologous platelet-rich plasma applied directly to a closed incision after acute surgery, or used for dehiscent wounds, remains nationally non-covered [4]. Coverage beyond 20 weeks, and coverage for every other chronic non-healing wound, is left to the local Medicare Administrative Contractors [4].

The revision history attached to that determination is more instructive than the determination itself. The policy reflected non-coverage in 1992. In 2004 it remained non-covered, with an exception for routine costs inside federally sponsored or approved clinical trials. In 2008 non-coverage was extended to additional wound categories. In 2012 it became covered only when provided under a clinical research study meeting specific requirements. In 2021 it became covered outright for one indication [4].

Across three decades the biology of centrifuged autologous blood did not change. The indication, the device clearance, and the accumulated evidence did. That is what a coverage decision tracks. Our overview of intra-articular, intraosseous, and intradiscal orthobiologic options describes the procedures themselves; how a given plan treats them is a separate question, and it is answered on separate grounds.

The evidence a payer asks for, and who was actually in it

Coverage policies rest on an evidence standard, and that standard has been getting higher. An analysis of Medicare national coverage determinations found that after adjusting for the strength of the evidence and other factors known to influence the agency, the evidentiary bar for coverage has risen: determinations issued from mid-March 2008 through August 2012 were twenty times less likely to be positive than those issued from February 1999 through January 2002 [5].

The question that follows is who the qualifying evidence was collected in. A systematic sampling review of 283 randomized controlled trials published in high-impact general medical journals between 1994 and 2006 found that common medical conditions formed the basis for exclusion in 81.3% of trials, that individuals receiving commonly prescribed medications were excluded in 54.1% of trials, and that only 47.2% of all exclusion criteria were graded as strongly justified in the context of the specific trial. Exclusion criteria were not reported at all in 12.0% of trials [6].

This matters for a specific reason. The patients this practice most often sees — metabolic dysfunction, insulin resistance, diabetes, autoimmune or inflammatory disease, several conditions at once, several medications at once, long symptom duration, prior treatment that did not hold — are the patients trial protocols are written to screen out, because screening them out protects internal validity. A result obtained in a population that excluded you is not a result about you. It is also not a result against you. It is silent.

RESTORE: platelet-rich plasma for knee osteoarthritis

This trial was null, and an honest account has to start there. In a randomized, placebo-controlled, participant-, injector-, and assessor-blinded trial, 288 community-based participants aged 50 or older with symptomatic medial knee osteoarthritis received three weekly intra-articular injections of leukocyte-poor platelet-rich plasma or saline placebo, and were followed for 12 months. Mean change in knee pain was −2.1 points with platelet-rich plasma versus −1.8 with placebo (difference −0.4; 95% CI, −0.9 to 0.2; P = .17). Mean change in medial tibial cartilage volume was −1.4% versus −1.2% (difference −0.2%; 95% CI, −1.9% to 1.5%; P = .81). Of 31 prespecified secondary outcomes, 29 showed no significant between-group difference. The authors concluded that the findings do not support use of platelet-rich plasma for the management of knee osteoarthritis [7].

Who was studied: adults 50 and older, recruited from broadcast, print and social media and from university volunteer databases in Sydney and Melbourne, with radiographic severity restricted to Kellgren and Lawrence grade 2 or 3 — mild to moderate disease [7].

Who was screened out: the reported exclusion criteria included systemic or inflammatory disease, ongoing anticoagulation therapy, a bleeding disorder, a platelet count of 150 × 10³/µL or lower, injection of a glucocorticoid in the past 3 months or hyaluronic acid in the past 6 months, past treatment with an autologous blood product or stem cell preparation, and radiographic lateral joint space narrowing greater than medial [7]. The published list is described as partial, with the full protocol in the trial supplement.

What the design could not capture, in the authors’ own words: results may not be generalizable to other platelet-rich plasma preparations, because preparations are heterogeneous and lack standardization; results may not be generalizable to more severe disease, because the trial deliberately enrolled mild to moderate radiographic osteoarthritis; and a community-based sample may not represent patients recruited from medical settings [7]. It also tested one modality, alone, on a fixed schedule. It did not test sequenced or combined care.

One finding cuts against reading too much into the exclusions, and it belongs here. Mean body mass index in the two groups was 29.0 and 29.6, obesity was not an exclusion, and the investigators found no evidence that body mass index, Kellgren and Lawrence grade, knee effusion, or knee alignment moderated the effect on either primary outcome [7]. Within the range this trial enrolled, a heavier participant did not do better. That is a real result and we do not discount it.

The United Kingdom Achilles tendinopathy trial

Also null. A participant-blinded, multicenter randomized trial at 24 National Health Service hospital trusts assigned 240 adults with midportion Achilles tendon pain for longer than three months, confirmed on ultrasound or magnetic resonance imaging, to a single intratendinous platelet-rich plasma injection or a sham injection of a subcutaneous dry needle that did not enter the tendon. At six months, mean scores on the Victorian Institute of Sport Assessment–Achilles were 54.4 versus 53.4 (adjusted mean difference −2.7; 95% CI, −8.8 to 3.3), against a minimal clinically important difference of 12 points. The authors concluded that the findings do not support the use of this treatment for chronic midportion Achilles tendinopathy [8].

Who was studied: adults 18 and older screened from orthopedic foot and ankle clinics, referred for a surgical opinion and having already received other treatments; mean age 52 years, median symptom duration 24 months [8].

Who was screened out: the stated exclusion criteria included systemic conditions associated with tendinopathy, with diabetes and rheumatoid arthritis given as the examples; contraindications to receiving platelet-rich plasma including anticoagulation therapy, platelet dysfunction syndrome, active cancer, hemodynamic instability and septicemia; prior Achilles tendon surgery or rupture on the index side; previous major tendon or ankle injury; and previous receipt of platelet-rich plasma into a tendon [8]. Diabetes was named in the exclusion list. A patient with tendinopathy and diabetes was, by protocol, not in this trial.

What the design could not capture, again in the authors’ own words: the injections were not ultrasound guided; only a single injection was administered, and multiple injections might have had a different effect; 77 participants sought additional treatment during follow-up; and the quality of every sample injected was not independently assessed [8]. Follow-up ended at six months.

What these two trials establish, and what they do not

They establish something real and worth stating plainly. In the populations enrolled, using those specific preparations, targets, doses and schedules, single-modality platelet-rich plasma did not outperform placebo or sham on the chosen primary outcomes. Anyone who tells you otherwise is misreading the papers.

They do not establish what happens in a patient with type 2 diabetes and an inflammatory arthropathy on chronic anticoagulation, with grade 4 radiographic change and eight years of symptoms, treated with a different preparation at a different target in combination with metabolic management. Not because that patient did better, but because the protocols excluded him. That is the ordinary distinction between efficacy under trial conditions and effectiveness in practice, and it runs in both directions: the excluded patient might do better, worse, or the same. What cannot be claimed is that the question was answered.

Where the evidence is accumulating, and why it is still unsettled

A single null trial does not close a field, and this one has not closed. A 2025 systematic review and meta-analysis of 26 randomized controlled trials covering 1,650 knees compared platelet-rich plasma with hyaluronic acid viscosupplementation in knee osteoarthritis and found a significant benefit for platelet-rich plasma on the Western Ontario and McMaster Universities Osteoarthritis Index at both 6 and 12 months, and on the visual analogue scale for pain at both 6 and 12 months. In an analysis stratified by platelet dose at six months, the benefit appeared at specific concentration bands rather than uniformly across preparations. The authors classified the work as Level 1 and stated that the findings must be read in light of the many preparation protocols and classifications across the included trials [9].

Two honest qualifications belong with that. The comparator was hyaluronic acid, an active treatment whose own effect is contested, not an inert placebo. And the dose-stratified result is exactly the kind of finding that needs replication before it is treated as settled.

What happens next is the clearest illustration on this page of the difference between a coverage decision and a clinical one. The payer policy summarizes that same meta-analysis, reports the same statistically significant improvements, and then declines coverage — citing heterogeneity in preparation protocols, variation in the hyaluronic acid comparators, short follow-up, reliance on patient-reported outcomes, and the absence of regulatory standardization [2]. Its stated position is that autologous platelet-derived growth factors for any condition or indication are experimental, investigational, or unproven, and the same document provides that claims not accompanied by a covered code under the applicable policy are denied as not covered [2]. The evidence moved. The coverage did not. The stated reasons were about standardization and durability, not about whether patients improved.

Combination and sequence, in the population the trials excluded

The trials above tested one injection into one compartment. Practice does not work that way, and neither does the smaller literature on severe disease. In an observational study, 60 patients with severe knee osteoarthritis — Ahlbäck grade III and IV, ages 40 to 80 — received either three weekly intra-articular platelet-rich plasma infiltrations or a combination of two intraosseous infiltrations into subchondral bone plus three intra-articular injections. The intra-articular-only group did not improve on any score at any time point. The combination group improved significantly on all Knee injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index subscales at 2, 6 and 12 months. Minimal clinically important improvement was reached by 16 of 30 combination patients versus 8 of 30 intra-articular patients at 6 months, and 14 of 30 versus 5 of 30 at 12 months [10].

This study must be weighted for what it is. It was observational, not randomized: patients chose their preferred option after both were explained, which invites selection and expectation effects that a blinded trial is built to prevent. It was a single center, 30 patients per group, with no placebo arm. Its exclusion criteria were systemic autoimmune rheumatic disease, arthroscopy in the year before treatment, hyaluronic acid or corticosteroid infiltration in the past six months, and misalignment severe enough to require osteotomy [10]. It cannot carry the weight a randomized trial carries, and it does not show that anything regrows.

What it does add is a testable observation the large randomized trials were not designed to make: in radiographically severe disease, the compartment that was injected appeared to matter more than whether platelet-rich plasma was used at all. RESTORE enrolled grade 2 and 3 disease and injected the joint space [7]. This cohort was grade III and IV and reported that the joint space alone did nothing [10]. Those two results are compatible with each other, and neither one is a verdict on the other’s population.

Why “unsettled” is the accurate word

The disagreement in this literature is not mainly about honesty or rigor. It is about the fact that “PRP” names a category, not a product. Preparations differ in platelet concentration, leukocyte content, whether an activator is used, and injection frequency [9]. The payer policy makes the same point from the other side, noting that no standard procedure for production exists, which leads to varying platelet concentrations, varying growth factor content, and varying clinical results [2]. Add different anatomical targets, different schedules, small samples, and populations that range from screened volunteers to surgical referrals, and the trials are not measuring one intervention. Until preparation and dose are standardized and reported, pooled results will keep disagreeing, and every reader of them will be partly right.

What it would cost to produce the evidence payers are asking for

There is a practical reason the definitive trial keeps not happening. An analysis of the 138 pivotal efficacy trials that supported approval of 59 novel therapeutic agents by the Food and Drug Administration in 2015 and 2016 estimated a median trial cost of $19.0 million, with an interquartile range of $12.2 million to $33.1 million. Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million, and the highest-cost trials were those requiring larger populations to detect smaller treatment effects [11]. That figure describes drug approvals, not orthobiologics; it is a scale reference for what evidence of the grade payers now demand actually costs to generate.

Autologous blood drawn and returned to the same patient in a single visit has no premarket approval holder standing behind it, and the 2025 economics review identifies increased research funding, clear guidelines, standardized transparent pricing and regulated marketing as what the field still requires [1]. Until that funding exists, the evidence gap and the coverage gap will hold each other in place, and neither one is a statement about any individual patient.

What an ABN is, and what signing one actually means

If you have Original Medicare and a service is expected to be denied, you are given a specific document before the service is delivered: the Advance Beneficiary Notice of Noncoverage, Form CMS-R-131. Its statutory basis is the Limitation on Liability provision at section 1879 of the Social Security Act, and its function is to put the financial position in front of you in advance rather than after the fact [12].

A valid notice has to do specific things. It must identify the item or service. It must state, in plain language, at least one reason Medicare may not pay — the instructions give examples such as that Medicare does not pay for the test for your condition, or does not pay for experimental or research use. It must carry a good-faith estimate of what you would owe [13].

The form then presents three option boxes, and the difference between them is consequential. In summary, as Form CMS-R-131 sets them out [13]:

• Option 1 — you want the service and you want Medicare billed for an official decision, which comes back to you on a Medicare Summary Notice. You are responsible if Medicare does not pay, and you may appeal by following the directions on that notice.
• Option 2 — you want the service but you do not want Medicare billed. Because no claim is filed, there are no appeal rights.
• Option 3 — you decline the service. You owe nothing, and there is nothing to appeal.

Two further points about the form itself. The option box may not be filled in for you: pre-selection by the notifier invalidates the notice [13]. And a notice given voluntarily — for care Medicare never covers at all — should not ask you to pick an option box or sign [12].

What Regen.MD actually does

Regen.MD is enrolled in Medicare and does not submit claims. Not to Medicare, and not to any commercial insurer, for anything. That is the model, and it belongs on this page in plain words so that nothing on the form leaves you expecting a claim to be filed on your behalf.

The Advance Beneficiary Notice you are given here indicates that you may submit the claim form yourself — the CMS-1500, still widely called the HCFA form — if you choose to. Whether reimbursement follows is between you and your plan. It may come and it may not, and we do not tell patients which to expect, because we are not the party adjudicating it.

The practical consequence is worth being direct about: if you want a payment decision on the record, obtaining it is yours to pursue. That is a different thing from the clinical decision, and it is the whole argument of this page in miniature.

Where the ABN does not reach

An Advance Beneficiary Notice is a Medicare fee-for-service instrument [12]. If you are covered by a commercial plan, what you sign here is our own financial-responsibility agreement, and it does not carry Medicare appeal rights. Commercial plans set their own terms, and their coverage policies say so directly: in the absence of a controlling federal or state mandate, benefits are ultimately determined by the terms of your specific benefit plan document, which supersedes the general policy [2]. Two people can be handed the same clinical recommendation and get different answers because their employers bought different plan documents.

How we handle the coverage question at Regen.MD

Entry to care is a paid, physician-led Clinical Evaluation, and the coverage conversation happens inside it rather than after it. We separate two things deliberately: what a plan is likely to reimburse, and whether an orthobiologic is a reasonable option for your presentation. Those are different questions with different evidence behind them, and collapsing them into one does patients real harm in both directions.

We do not treat a denial as a clinical finding. We also do not treat a favorable trial as permission to promise you an outcome. Where a service is not covered, you are told before it is delivered, in writing, with the reason and the choices set out, and you decide. Where the evidence for something is thin or contested, we say which trial, in whom, and what it did not test — the same way this page does.

The corollary matters as much: if your metabolic terrain, your inflammatory burden, or your medication list is the reason a trial would have excluded you, that is not a reason to skip the work. It is usually the reason to address the terrain alongside the joint rather than instead of it. Our conservative-first sequence is described in how we evaluate and treat, and surgery remains available when conservative measures have been exhausted.

“My ethos is to treat all of my patients as I would my own family, with the goal of giving them back their quality of life.” — Dr. Gurpreet Singh Padda, MD, MBA, MHP

Frequently asked questions

Sources

1. Sachs JP, Mufti YN, Bi AS, Jesse JE, Cole BJ. Economic Realities of Orthobiologics. Clinics in Sports Medicine. 2025;44(4):827–840. https://doi.org/10.1016/j.csm.2024.10.011 (referenced for: FDA Center for Biologics Evaluation and Research oversight; PRP and concentrated bone marrow aspirate exempt from stringent regulatory pathways; off-label use and lack of standardized pricing driving coverage issues and financial burdens; sparse economic literature and limited cost transparency; the field’s need for clear guidelines, increased research funding, standardized transparent pricing and regulated marketing).
2. Cigna. Autologous Platelet-Derived Growth Factors (Platelet-Rich Plasma [PRP]). Medical Coverage Policy 0507, effective October 15, 2025. https://static.cigna.com/assets/chcp/pdf/coveragePolicies/medical/mm_0507_coveragepositioncriteria_autologous_plts.pdf (referenced for: coverage policies are not recommendations for treatment and should never be used as treatment guidelines; benefits ultimately determined by the terms of the applicable benefit plan document, which supersedes the policy; PRP for any condition or indication considered experimental, investigational or unproven, with claims denied as not covered; PRP characterized as minimally manipulated autologous blood product with preparation systems approved under the 510(k) process; no standard production procedure, producing varying platelet concentrations, growth factor content and clinical results; the policy’s summary of and stated reasons for declining coverage despite the 2025 PRP-versus-hyaluronic-acid meta-analysis).
3. Chambers JD, Chenoweth M, Thorat T, Neumann PJ. Private payers disagree with Medicare over medical device coverage about half the time. Health Affairs. 2015;34(8):1376–1382. https://doi.org/10.1377/hlthaff.2015.0133 (referenced for: 47 devices in CMS national coverage determinations issued February 1999–August 2013 compared with the 16 largest private payers; equivalent roughly half the time, more restrictive about a quarter, less restrictive about a quarter; variable patient access across Medicare and private plans).
4. Centers for Medicare & Medicaid Services. National Coverage Determination 270.3: Blood-Derived Products for Chronic Non-Healing Wounds. Effective April 13, 2021. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=217 (referenced for: national coverage of autologous PRP for chronic non-healing diabetic wounds for 20 weeks when prepared by devices whose FDA-cleared indications include management of exuding cutaneous wounds; national non-coverage for acute surgical wounds applied to a closed incision and for dehiscent wounds; coverage beyond 20 weeks and for all other chronic non-healing wounds left to local Medicare Administrative Contractors; the 1992, 2004, 2008, 2012 and 2021 revision history).
5. Chambers JD, Chenoweth M, Cangelosi MJ, Pyo J, Cohen JT, Neumann PJ. Medicare is scrutinizing evidence more tightly for national coverage determinations. Health Affairs. 2015;34(2):253–260. https://doi.org/10.1377/hlthaff.2014.1123 (referenced for: the evidentiary bar for coverage has risen after adjustment; determinations from mid-March 2008 through August 2012 twenty times less likely to be positive than those from February 1999 through January 2002).
6. Van Spall HGC, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA. 2007;297(11):1233–1240. https://doi.org/10.1001/jama.297.11.1233 (referenced for: 283 trials sampled; common medical conditions the basis for exclusion in 81.3%; individuals on commonly prescribed medications excluded in 54.1%; only 47.2% of exclusion criteria graded strongly justified; exclusion criteria not reported in 12.0%).
7. Bennell KL, Paterson KL, Metcalf BR, et al. Effect of Intra-articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial. JAMA. 2021;326(20):2021–2030. https://doi.org/10.1001/jama.2021.19415 (referenced for: n = 288, age 50+, Kellgren and Lawrence grade 2 or 3, community recruitment in Sydney and Melbourne, three weekly leukocyte-poor PRP or saline injections, 12-month follow-up; null primary pain and medial tibial cartilage volume results; 29 of 31 secondary outcomes null; the reported exclusion criteria; mean body mass index 29.0 and 29.6 and the absence of moderation by body mass index, radiographic grade, effusion or alignment; the authors’ stated limitations on generalizability to other preparations, to more severe disease, and from a community sample).
8. Kearney RS, Ji C, Warwick J, et al. Effect of Platelet-Rich Plasma Injection vs Sham Injection on Tendon Dysfunction in Patients With Chronic Midportion Achilles Tendinopathy: A Randomized Clinical Trial. JAMA. 2021;326(2):137–144. https://doi.org/10.1001/jama.2021.6986 (referenced for: n = 240 across 24 UK National Health Service trusts, screened from orthopedic foot and ankle clinics and referred for a surgical opinion, mean age 52, median symptom duration 24 months; single intratendinous PRP injection versus subcutaneous dry-needle sham; null VISA-A result at 6 months against a 12-point minimal clinically important difference; exclusion of systemic conditions associated with tendinopathy including diabetes and rheumatoid arthritis, anticoagulation therapy, platelet dysfunction syndrome and active cancer; the authors’ stated limitations on the absence of ultrasound guidance, the single injection, and additional treatments sought during follow-up).
9. Bagheri K, Shekhar A, Kwok E, Dungy D, Stewart SL, Jamali AA. Platelet rich plasma compared to viscosupplementation in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials with 6 month and 12 month follow-up. Journal of Experimental Orthopaedics. 2025;12(3):e70335. https://doi.org/10.1002/jeo2.70335 (referenced for: 26 randomized trials, 1,650 knees; significant benefit for PRP over hyaluronic acid on WOMAC and visual analogue scale at 6 and 12 months; the platelet-concentration-stratified analysis at 6 months; Level 1 designation; the authors’ caution that findings must be read in light of the many preparation protocols and classifications).
10. Sánchez M, Delgado D, Pompei O, et al. Treating Severe Knee Osteoarthritis with Combination of Intra-Osseous and Intra-Articular Infiltrations of Platelet-Rich Plasma: An Observational Study. Cartilage. 2019;10(2):245–253. https://doi.org/10.1177/1947603518756462 (referenced for: observational design with patient-chosen allocation, 60 patients aged 40–80 with Ahlbäck grade III–IV severe knee osteoarthritis in two matched groups of 30; no improvement in any score in the intra-articular-only group; significant improvement in all KOOS and WOMAC subscales at 2, 6 and 12 months in the combination group; minimal clinically important improvement in 16 of 30 versus 8 of 30 at 6 months and 14 of 30 versus 5 of 30 at 12 months; exclusion of systemic autoimmune rheumatic disease, arthroscopy in the prior year, hyaluronic acid or corticosteroid infiltration in the prior 6 months, and misalignment requiring osteotomy).
11. Moore TJ, Zhang H, Anderson G, Alexander GC. Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016. JAMA Internal Medicine. 2018;178(11):1451–1457. https://doi.org/10.1001/jamainternmed.2018.3931 (referenced for: 138 pivotal efficacy trials supporting 59 novel therapeutic agents; median estimated cost $19.0 million, interquartile range $12.2–$33.1 million; estimated mean cost $35.1 million for trials with placebo or active drug comparators; highest costs in trials requiring larger populations to detect smaller effects).
12. Centers for Medicare & Medicaid Services. Medicare Claims Processing Manual, Chapter 30, Section 50 — Form CMS-R-131 Advance Beneficiary Notice of Noncoverage (ABN). https://www.cms.gov/files/document/medicareclaimsprocessingmanualch30sec50abnpdf (referenced for: the ABN as a notice issued to Original Medicare fee-for-service beneficiaries in advance of items or services believed to be non-covered; Limitation on Liability under section 1879 of the Social Security Act; voluntary notices for never-covered care, for which the beneficiary should not be asked to choose an option box or sign).
13. Centers for Medicare & Medicaid Services. Form Instructions: Advance Beneficiary Notice of Noncoverage (ABN), Form CMS-R-131. https://www.cms.gov/medicare/medicare-general-information/bni/downloads/abn-form-instructions.pdf (referenced for: the requirement of at least one plain-language reason for non-coverage per item or service and the example reasons; the good-faith estimated cost requirement; the wording and consequences of Options 1, 2 and 3; the rule that pre-selection of an option by the notifier invalidates the notice).