Appendix B- NTAP Review Template.docx

NTAP Review Template

Contents

07/15/2021

I. Preamble The Division of New Technology within the Technology, Coding, and Pricing Group of the Center for Medicare is requesting a clinical review of the attached new technology add-on payment (NTAP) application. This review of reference clinical trials, peer-reviewed articles, and other key evidence submitted with the application will be used to assess eligibility for one or more CMS programs.

Note that certain types of applications are not evaluated for substantial clinical improvement. This includes a technology that was:

· Granted review under the Breakthrough Device Designation at FDA,

· Designated by the FDA as a Qualified Infectious Disease Product (QIDP) or

· Approved under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD).

II. FDA Review

a. General information [Abstract from SSED Section I]

b. Description of Item/Service

[Abstract from SSED Section V]

c. Market history

[Abstract from SSED Section VII]

d. Panel meeting recommendation

[Abstract from SSED Section XII]

e. FDA post panel action

[Drawn from SSED Section XII]

f. Labelling

Indications

[Drawn from SSED Section II]

Contraindications

[Drawn from SSED Section III]

Potential adverse events, with frequency [Condense SSED Section VII]

III. CMS Review CMS pays acute care hospitals (with a few exceptions specified in the law) for inpatient stays under the Inpatient Prospective Payment System (IPPS). Under this payment system, which is updated annually, CMS sets base payment rates prospectively for inpatient stays based on a Medicare beneficiary’s diagnosis and severity of illness. Subject to certain adjustments, a hospital receives one payment for the case based on the payment classification assigned at discharge, the Medicare Severity Diagnosis-Related Group (MS-DRG). Prior to 2001, expensive new technology was bundled into MS-DRGs and paid as part of the single payment to the hospital. However, the high cost of new technologies may impact hospital’s willingness to adopt them. To promote uptake and expand beneficiary access to new technology, in 2001, Congress authorized the New Technology Add on Payment (NTAP) as a time-limited payment mechanism of 2-3 years to smooth market entry of new medical products, provided that the technology meets specific criteria.1 NTAP applications are due in October for the following fiscal year. CMS reviews the applications received in the annual IPPS rulemaking process to determine payment eligibility. In 2020, applications are due, Friday, October 16, 2020 for consideration for the FY 2022 rulemaking cycle.

a. CMS benefit category For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act [§1812 (Scope of Part A); §1832 (Scope of Part B); §1861(s) (Definition of Medical and Other Health Services)].

[Item or service] qualifies as:

· [Inpatient hospital services].

· [Physicians’ services].

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

b. CMS coverage history [There is no currently applicable national or local coverage decision.] [This item or service is addressed by an existing NCD titled [title, number, revision date], where it is [covered; left to MAC discretion; non-covered]].

c. General Methodologic Principles CMS evaluates relevant clinical evidence to determine whether or not an item or service falls within a coverable benefit category, and the evidence is of sufficient quality to find that it is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

1 Section 1886(d)(5)(K) of the Social Security Act authorizes the Secretary to establish a special payment methodology for new medical services and technologies used in inpatient procedures.

d. Background

[Paragraph(s): Treated condition; Incidence, prevalence; impact on patients. Style and brevity similar to UptoDate] [Paragraph(s): Therapeutic options; unmet need] [Paragraph: Description of device; intended application]

e. Summary of unpublished clinical evidence

[Succinct summary of SSED Section IX; do not overlap section 9 below; If not yet published, summarize unpublished FDA data in table form.]

f. Summary of published clinical evidence

i. Text summary of published clinical evidence

[Content and style consistent with Appendix D] [Description of studies submitted by the manufacturer] [Description of studies identified through a supplemental literature search] [Description of what was considered in the Evidence Preview vs. excluded] [Summary of overall body of evidence reviewed in Evidence Preview: number of studies, number of patients, duration of study] [Discussion of individual studies, multiple paragraphs] [Discussion risk of bias; note strategies that mitigate risk of bias] [Conclusion paragraph]

ii. Table 1 Characteristics of Included Studies

Reference: Akkanti et al. 2021{33786448} Country: USA Study Design: Retrospective case series Quality rating Poor Funding Source:

Partial support from the Ike Muslow, MD Endowed Chair for Healthcare Informatics, Louisiana State University Health Sciences Center, Shreveport, LA.

Senior author (Conrad) discloses receiving consulting fees from ALung Technologies, Inc.

Number of Patients:

Total: 31; 29 received treatment Diagnosis: COVID-19 Mean Age Years (SD):

54.7 (11.5) Female N (%):

11 (38) Inclusion/Exclusion Criteria:

Deidentified data for patients with known discharge status were obtained retrospectively from the Hemolung RAS device registry.

Single arm: Hemolung RAS

Patients were treated between March 4, and September 30, 2020

Follow-up Period: Hospital discharge

Mortality, LOS, duration of Hemolung support

Reference: Saavedra-Romero et al. 2021{34327027} Country: USA Study Design: Case report Quality rating Poor Funding Source:

ALung Technologies, Inc. ALung personnel provided editorial input Number of Patients: 1 Diagnosis: COVID-19 Age Years: “mid-60’s” Female N (%): 100

Single arm: Hemolung RAS

Follow-up Period: Hospital discharge

Duration of Hemolung support, de-escalation and weaning of invasive ventilation, LOS

Reference: Diehl et al. 2020{32990836} Country: France Study Design: Prospective case series Quality rating Poor Funding Source:

Sponsor: "Direction de la Recherche Clinique, Assistance Publique – Hôpitaux de Paris" “The study was founded by” ALung Technologies, Inc.

General Electric Healthcare provided non-financial technical support Number of Patients:

Total: 12 Diagnosis: AE-COPD Median Age Years (IQR):

65 (56.5 to 73.5) Female N (%):

4 (33) Inclusion/Exclusion Criteria:

Adult patients (>18 years) with AE-COPD; mechanical ventilation < 72 hrs; intubation (any reason); persistent respiratory acidosis and hyperinflation. Exclusion criteria: Body mass index > 35 kg/m2; PaO2/FiO2 <200 mm Hg, history of hemorrhagic stroke; history of heparin-induced thrombocytopenia; current severe bleeding Single arm: Hemolung RAS

All patients deeply sedated; all patients intubated after NIV failure

De-escalation and weaning of invasive ventilation, LOS, mortality at 28 days

Reference: Augy et al. 2019{31452899}

REXECOR

Country: France Study Design: Prospective registry study Quality rating Poor Funding Source:

None Number of Patients:

Total: 70 Total treated with Hemolung: 43

AE-COPD: 25

ARDS: 18

Diagnosis: AE-COPD or ARDS Median Age Years (IQR):

65 (61 to 74) * Female N (%):

30 (42.8) * Inclusion/Exclusion Criteria:

None reported *All patients, data for Hemolung not reported separately Single arm: Hemolung RAS

Other patients in the registry were treated with iLA Activve iLA kit (Xenios Novalung, Heilbronn, Germany)

Only data specific to Hemolung are tabulated within this report Duration of treatment, AEs, mortality

Reference: Bozkuş et al. 2018{30479235} Country: Turkey Study Design: Retrospective case series Quality rating Poor Funding Source:

NR

Number of Patients:

Total: 5 Diagnosis: COPD or ARDS Age Years, range:

36 to 71 Female N (%):

2 (40) Inclusion/Exclusion Criteria:

Case definition: Use of Hemolung RAS for partial respiratory support in subjects with hypercapnic respiratory failure Single treatment/all groups: Hemolung RAS

Duration of treatment, changes in clinical outcomes (dyspnea, use of other respiratory support)

Reference: Kalbhenn et al. 2017{28187047} Country: Germany Study Design: Prospective case series Quality rating Poor Funding Source:

Dr. Kalbhenn received speaker fees from Alung Technologies. Laboratory costs were financed by internal funding.

Number of Patients:

Total: 8 enrolled, 1 patient excluded after initiation of Hemolung because of death from multiorgan failure within 24-h of treatment Diagnosis: Hypercapnic respiratory failure Median Age Years (IQR):

55 (14) Female N (%):

5 (71) Inclusion/Exclusion Criteria:

Hypercapnic respiratory failure.

Indications: avoiding endotracheal intubation; facilitating extubation prior to lung transplant, providing lung protective ventilation in ARDS; preventing right-sided heart failure in persistent hypercarbia.

Single arm: Hemolung RAS

Follow-up Period: Hospital/ICU discharge

Mortality and AEs, duration of treatment, ICU LOS

Reference: Tiruvoipati, Buscher, et al. 2016{27903208} Country: Australia Study Design: Retrospective case series Quality rating Poor Funding Source:

None

One author (Buscher) was an invited speaker at an Alung Technologies-sponsored meeting Number of Patients:

Total: 15 Diagnosis: Hypercapnic respiratory failure Median Age Years (IQR):

61.5 (44.7 to 68.7) Female N (%):

3 (20) Inclusion/Exclusion Criteria:

All patients with acute or acute-on-chronic hypercapnic respiratory failure who were managed with ECCO2R in the three ICUs in Australia Single arm: Hemolung RAS

Survival and AEs, duration of Hemolung support

Reference: Burki et al. 2013{23460154} Hemolung CE Pre-market feasibility study Country: Germany and India Study Design: Prospective cohort Quality rating Poor Funding Source:

ALung Technologies, Inc.

Number of Patients:

Total: 20 Group 1: Failing NIPPV: 7 Group 2: Unable to wean from NIPPV: 2 Group 3: Unable to wean from IPPV: 11 Diagnosis: COPD with hypercapnia Median Age Years (IQR):

61.5 (44.7 to 68.7) Female N (%):

3 (20) Inclusion/Exclusion Criteria:

Age 21 to 80 years, with COPD and hypercapnic respiratory failure (PaCO 2 > 50 mm Hg, pH, 7.3) Single treatment/all groups: Hemolung RAS

Follow-up Period: Hospital discharge or 30 days after discontinuance of ECCO2R

Dyspnea, duration of treatment, clinical effects, mortality, and AEs

Abbreviations: AEs = adverse events; AE-COPD = acute exacerbation of COPD; ARDS: acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease; COVID-19 = coronavirus disease 2019; ECCO2R = extracorporeal carbon dioxide removal; ICU = intensive care unit; IPPV = invasive positive pressure ventilation; LOS = length of stay; MV = mechanical ventilation; NIPPV = noninvasive positive pressure ventilation; NIV = non-invasive ventilation; NR = not reported; RAS = Respiratory Assist System

iii. Table 2 Study Outcomes

Author, Year, Study

· Reduced mortality in intubated and invasively mechanically ventilated (IMV) patients

· Reduced mortality in non-invasively ventilated (NIV) patients

· De-escalation of mechanical ventilation settings (IMV patients)

· Avoidance of Intubation following NIV failure (NIV patients

· Improvement in activities of daily living

· Improvement in quality of life

· Reduced length of stay in IMV patients Adverse events

Akkanti et al. 2021{33786448}

Hemolung RAS Median (range) duration of treatment:

Survivors: 10.8 d (5-38 d) Nonsurvivors: 7.6 d (2-27 d) Survival to 48 hours post decannulation: 58% Survival to discharge: 38%

There was no difference between survivors and nonsurvivors on any baseline demographic variables

Baseline PCO2 (93 vs 71.2mm Hg; 0.03) and PAO2/FiO2 (176 vs 116mm Hg; 0.046): statistically higher in survivors Number transitioned to ECMO Survivors: 0 Nonsurvivors: 2

Hospital LOS, d, mean (SD) Survivors: 81.5 (52) Nonsurvivors: 35 (19) p=0.0014 Hospital LOS, d, median (IQR) Survivors: 69 (52.25 to 80.25) Nonsurvivors: 35 (19)

2 AE related to Hemolung use resulted in 2 patients not continuing Hemolung treatment Patient 1: 74-year-old with severe peripheral vascular disease sustained a vascular injury during cannulation attempt resulting in failed cannulation, patient experienced cardiac arrest Patient 2: “51-year-old who was successfully cannulated, but anticoagulation was unable to be started and the circuit clotted during initiation. The patient died the same day from inability to provide adequate gas exchange through mechanical ventilation”

First 24 hours:

PEEP (cmH2O): 14 Rate (/min): 26 Minute ventilation (L): 7.8 End of first 48 hours:

PEEP (cmH2O): 12 Rate (/min): 20 Minute ventilation (L): 5.0 Weaning from ECCO2R: 17 days Weaning from mechanical ventilation: 10 days after ECCO2R wean Hospital LOS: 47 d in ICU Transfer to ICU 5 d after admission to hospital “Patient developed thrombocytopenia and anemia one week into therapy, but plasma-free hemoglobin remained less than 30 mg/dL throughout. Platelets and red blood cell transfusion were provided accordingly to maintain adequate oxygen-carrying capacity and prevent hemorrhagic complications”

7-day treatment

3 patients died in ICU 1 hemorrhagic stroke during ECCO2R 2 sepsis (ventilator-related pneumonia) IMV total duration, d, median (IQR) 8 (6 to 18) IMV duration after ECCO2R duration, d, median (IQR) 6 (4 to 16.5)

WOB (during weaning) Median (IQR) Data from 5 patients

WOB (J/L)

With ECCO2R: 1.10 (0.8 to 1.40) Without ECCO2R: 1.50 (0.9 to 2.80) WOB (J/min) With ECCO2R: 11.70 (7.5 to 15.0) Without ECCO2R: 22.6 (13.9 to 34.7) WOB (J/breath) With ECCO2R: 0.59 (0.39 to 0.79) Without ECCO2R: 0.94 (0.56 to 1.29) RR (/min) With ECCO2R: 19 (19 to 20) Without ECCO2R: 24 (24 to 25) No differences on any measure Hospital LOS d, median (IQR) 39 (18.5 to 73)

ICU LOS d, median (IQR)

14.5 (8 to 22.5) Hemorrhagic complications 3, including one fatal stroke (noted as being absent of heparin overdosing or thrombocytopenia)

Thrombotic complications ECCO2R catheter thrombosis: 2 ECCO2R circuit thrombosis: 1

Ventilator-associated complications Pneumonia:4

Augy et al. 2019{31452899}

REXECOR

Hemolung RAS

ECCO2R-related death, n (%) Hemolung: 3 (6) 2 intra-cranial bleedings without heparin overdosing 1 cardiac tamponade following a right jugular vein catheterization ECCO2R treatment duration, d, median (IQR):

Hemolung 5 (3 to 8)

Catheterization failure: 2 (4) Biological hemolysis: 15 (28) Clinically significant hemolysis: 6 (11) Bleeding: 16 (30) Membrane clotting: 4 (8) Catheter infection: 0 (0) Device malfunction: 4 (8) 3/4 malfunctions were software-related, the other malfunction not investigated

0 to 72 ECCO2R treatment duration, hours, range:

30 to 144 hours

All patients saw improvement in ventilation and reductions in blood CO2

2 (29)*

* Does not include patient who died during first 24-hrs from multiorgan failure.

Duration of ECCO2R therapy (days), median (IQR) 8 (5.25)

Duration of ICU therapy (days), median (IQR) 19 (20.5) Clinical bleeding: 4/7 Platelet count: All patients, platelets decreased continuously during therapy (p < 0.001) Acquired von Willebrand Syndrome: 5/7 Factor XIII deficiency: 4/7 below 60% (2/4 below 50%) Transfusion: 6/7 received ~0.44 units/day packed RBC

Survival to ICU discharge: 73.3% Survival to hospital discharge: 66.6% “No patient died due to a complication from the Hemolung” ECCO2R treatment duration, d, median (IQR):

Hemolung 5 (3 to 7)

Patients saw reductions in blood CO2 (p<0.001)

5 patients on NIV avoided IMV, de-escalation of IMV successful in 10 patients

Packed RBC: 12/15; median (IQR) transfusion units: 2 (1 to 7) Thrombocytopenia: 4 requiring platelet transfusion Compartment syndrome: 1/15

Group 1: 0 Group 2: 0 Group 3: 1/11 (retroperitoneal bleed following catheterization)

Mortality 30 days post-ECCO2R treatment (non-device related) Group 1: 4/7 Group 2: 0 Group 3: 3/10 Authors comment “The overall mortality rate was very similar to that reported in comparable patients not receiving ECCO2R, and it could be argued that the absence of any significant improvement in mortality makes the value of this ECCO2R device questionable.”

Group 1: All patients avoided IMV Group 2: Both patients weaned from NIV Group 3: 3 patients weaned from IMV; 3 patients reduced IMV support

Deep venous thrombosis in cannulated vein: 1 Bleeding events requiring transfusion: 3 (1 case of acquired von Willebrand Syndrome)

Abbreviations: AEs = Adverse Events; cmH2O = centimeters of water; ECCO2R = extracorporeal carbon dioxide removal; ECMO = Extracorporeal Membrane Oxygenation; ICU = intensive care unit; IQR = interquartile range; LOS = length of stay; NR= not reported; PEEP = peak end-expiratory pressure; QoL = quality of life; RBC = red blood cells; SD = standard deviation; WOB = work of breathing measured as Joules per liter of minute ventilation (J/L) or as Joules per breath (J/breath)

g. References Reviewed

Akkanti B, Jagpal S, Darwish R, Saavedra Romero R, Scott LK, Dinh K, Hussain S, Radbel J, Saad MA, Enfield KB, Conrad SA. Physiologic Improvement in Respiratory Acidosis Using Extracorporeal Co2 Removal With Hemolung Respiratory Assist System in the Management of Severe Respiratory Failure From Coronavirus Disease 2019. Crit Care Explor. 2021 Mar 9;3(3):e0372. doi: 10.1097/CCE.0000000000000372. PMID: 33786448; PMCID: PMC7994071.

Akkanti B, Rajagopal K, Patel KP, Aravind S, Nunez-Centanu E, Hussain R, Shabari FR, Hofstetter WL, Vaporciyan AA, Banjac IS, Kar B, Gregoric ID, Loyalka P. Low-Flow Extracorporeal Carbon Dioxide Removal Using the Hemolung Respiratory Dialysis System® to Facilitate Lung-Protective Mechanical Ventilation in Acute Respiratory Distress Syndrome. J Extra Corpor Technol. 2017 Jun;49(2):112-114. PMID: 28638160; PMCID: PMC5474890.

Augy JL, Aissaoui N, Richard C, Maury E, Fartoukh M, Mekontso-Dessap A, Paulet R, Anguel N, Blayau C, Cohen Y, Chiche JD, Gaudry S, Voicu S, Demoule A, Combes A, Megarbane B, Charpentier E, Haghighat S, Panczer M, Diehl JL. A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area. J Intensive Care. 2019 Aug 20;7:45. doi: 10.1186/s40560-019-0399-8. PMID: 31452899; PMCID: PMC6701003.

h. References Excluded

[Excluded references, reason for exclusion]

IV. Newness

A technology is new if it does not meet one or more of the criteria below:

Does the product use the same or a similar mechanism of action as compared to existing technologies to achieve a therapeutic outcome?

Applicant Argument:

[Abstract from application]

CMS Response:

[CMS to complete]

Does the new use of the technology involve treatment of the same or similar type of disease and the same or similar patient population?

Applicant Argument:

[Abstract from application]

Does the technology meet the newness criterion? Do you have any remaining concerns?

Applicant Argument:

[Abstract from application]

V. Substantial Clinical Improvement

CMS analyzes the totality of the circumstances to determine whether a technology represents a substantial clinical improvement over existing technologies. After reviewing the applicant’s summary explaining why they believe their technology represents an SCI, please answer the following questions to evaluate the three SCI criteria below:

Does the applicant assert that technology offers a treatment option for patients unresponsive to or ineligible for currently available treatments?

Applicant Argument:

[Abstract from application]

CMS Response:

[With supporting information, explain why you agree and/or disagree with the applicant and/or have concerns regarding their assertion.] [State if this question is not applicable.]

Does the applicant assert that the technology can diagnose a medical condition in a population where the condition is currently undetectable, or does it offer the ability to diagnose earlier than what is currently available?

Applicant Argument:

[Abstract from application]

CMS Response:

[With supporting information, explain why you agree and/or disagree with the applicant and/or have concerns regarding their assertion.] [State if this question is not applicable.]

Does the applicant assert that use of the technology significantly improves clinical outcomes for a patient population as compared to currently available treatments?

Applicant Argument:

[Abstract from application]

[Include in your summary improvements regarding safety, efficacy and superiority. With supporting information, explain why you agree and/or disagree with the applicant and/or have concerns regarding their assertion.]

VI. Summary & Conclusions Provide a final recommendation with supporting information on whether the technology represents a substantial clinical improvement over existing technologies.

[Based on your review of reference clinical trials, peer-reviewed articles, and other key evidence submitted with the application, does the submitted evidence support the applicant’s conclusions?]

[Some examples of outcomes that are frequently evaluated in studies of technologies are the below:

· Reduced mortality rate with use of the device. (Y/N)

· Reduced rate of device-related complications. (Y/N)

· Decreased rate of subsequent diagnostic or therapeutic interventions (for example, due to reduced rate of recurrence of the disease process). (Y/N)

· Decreased number of future hospitalizations or physician visits. (Y/N)

· More rapid beneficial resolution of the disease process treatment because of the use of the device. (Y/N)

· Decreased pain, bleeding, or other quantifiable symptom. (Y/N)

· Reduced recovery time. (Y/N)]