(322 days)
Not Found
Not Found
No
The device description and performance studies focus on the enzymatic breakdown of fats using immobilized lipase. There is no mention of AI or ML in the intended use, device description, or performance evaluation.
Yes.
Explanation: The device is described as mimicking the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase, and is intended to improve fat absorption and utilization by the body. This addresses a medical condition and provides a medical benefit.
No
Explanation: The RELIZORB™ device is designed to hydrolyze fats in enteral formula, mimicking the function of lipase to aid absorption and utilization in the body. This is a therapeutic function, not a diagnostic one. It does not provide information about a patient's health status or condition.
No
The device description clearly states that RELIZORB™ is a physical device comprised of a cylindrical, hollow port, an outlet port connection, and polymeric beads with immobilized lipase enzyme. It is an accessory designed to fit in series with enteral feeding circuits. This is a hardware device with a biological component (enzyme).
Based on the provided information, the RELIZORB™ device is not an In Vitro Diagnostic (IVD).
Here's why:
- Intended Use: The intended use is to "hydrolyze fats in enteral formula." This is a treatment or therapeutic function, directly acting on the enteral formula before it enters the patient's body to aid in digestion and absorption.
- Device Description: The device is described as a "point-of-care accessory designed to fit in series with currently used enteral feeding circuits." It contains an enzyme (lipase) that chemically breaks down fats. This is a physical/chemical process applied to a substance intended for administration to the body, not a test performed on a sample taken from the body.
- Mechanism of Action: The device mimics the function of the enzyme lipase in patients who lack sufficient levels. This is a replacement or augmentation of a physiological process, not a diagnostic test.
- Performance Studies: The performance studies focus on the device's ability to break down fats (fat hydrolysis bench test), improve fat absorption in animal models (%CFA, plasma omega-3 fats), and its mechanical integrity and safety. These are all related to its therapeutic function, not its ability to diagnose a condition or provide information about a patient's health status.
In Vitro Diagnostics (IVDs) are devices intended for use in the collection, preparation, and examination of specimens taken from the human body (such as blood, urine, tissue) to provide information for the diagnosis, monitoring, or treatment of a disease or condition. The RELIZORB™ does not perform any of these functions. It acts on the enteral formula outside the body to modify it before it is administered.
N/A
Intended Use / Indications for Use
RELIZORB™ is indicated for use in adults to hydrolyze fats in enteral formula.
Product codes
PLQ
Device Description
The RELIZORB™ device is a point-of-care accessory designed to fit in series with currently used enteral feeding circuits. During the submission process, the device was also known as the Enteral Feeding In-Line Cartridge (EFIC). Therefore, the subject device may be referred to as EFIC in some figures within this document. RELIZORB™ is designed to hydrolyze (break down) fats present in enteral formulas from triglycerides into fatty acids and monoglycerides to allow for their absorption and utilization by the body. This breakdown of fats by the RELIZORB™ is intended to mimic the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase. The RELIZORB™ is comprised of a cylindrical. hollow port and a single outlet port connection.
RELIZORB™ is packed with polymeric beads that have lipase enzyme immobilized on the surface. This lipase enzyme is Generally Regarded as Safe (GRAS). The chemical action of the lipase enzyme is shown in Figure 2, where triglyceride molecules are broken into constituent monoglycerides and fatty acids. The food contacting substance (FCS) of beads manufactured using the RELIZORBTM are. The lipase enzyme is chemically bound to the FCS and is intended to remain within the cartridge.
RELIZORB™ is an intermediary between an enteral feeding source (infusion pump) and an implanted feeding tube, as shown in Figure 3. The distal end of compatible infusion pump administration sets (Figure 3A) should have a stepped connector (Christmas tree). This connector plugs into the proximal end of the RELIZORB™ device (Figure 3B). The distal end of the RELIZORB™ (Figure 3C) connects to the enteral funnel of an extension set (Figure 3D). This extension set connects to an enteral feeding tube on the patient, such as a nasogastric or gastrostomy tube.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Patient's gastrointestinal tract
Indicated Patient Age Range
adults
Intended User / Care Setting
clinical care setting with trained operators and the home care setting with lay users.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
SUMMARY OF NON-CLINICAL/BENCH STUDIES
Bench tests were conducted to demonstrate mechanical integrity, package integrity, enzyme activity, and that RELIZORB™ can be integrated into existing enteral feeding circuits.
- Torque strength: To determine the torque necessary to separate the small bore connectors from the cartridge body at both the distal and proximal ends of RELIZORB™. Results: RELIZORB™ met the acceptance criteria.
- Tensile strength: To determine the force required to separate the device small bore connectors from the cartridge using a linear tensile force. Results: RELIZORB™ met the established acceptance criteria.
- Air leakage test: To establish that the RELIZORB™'s material bonds would not fail or leak when challenged with pressurized air. Results: RELIZORB™ did not leak when pressurized with air. The device met the acceptance criteria.
- Filter integrity: To ensure that the FCS/enzyme beads are retained within the cartridge. Results: RELIZORB™ allowed for five particles to leave the cartridge in three repetitions in the forward flow direction and one particle in reverse flow direction. This was deemed acceptable as the particles were considered not systemically toxic based on biocompatibility and GRAS status of lipase.
- Fat hydrolysis: To determine the amount of free fatty acids (FFA) that RELIZORB™ produces by enzymatic hydrolysis. Results: The sponsor submitted bench testing data demonstrating that RELIZORB™ breaks down ≈90% of fats in most enteral formulas.
- Unconjugated lipase analysis: To evaluate the potential leaching of the lipase enzyme from the beads. Results: Using several lots, the sponsor observed leaching by the BCA assay and leaching by absorbance. No safety concerns with this small amount of enzyme released due to biocompatibility and GRAS status.
- Assessment of impact to other nutrients: To ensure that RELIZORB™ does not adversely affect other nutrients in enteral formula. Results: After exposure to RELIZORBTM, there was no meaningful difference for any vitamins or minerals.
- Flow rate: To ensure that RELIZORB™ does not restrict the flow of formula using an enteral feeding pump. Results: There were no statistical differences between the flow rate with or without RELIZORB™ in the enteral feeding line.
- Liquid leakage test: To determine if the device leaked during priming or flow rate testing. Results: In all cases, the sponsor did not observe any leaking from any material joints.
- Pump alarm verification: To verify that the flow error alarm works both before and after RELIZORB™ when the tubing is kinked. Results: The sponsor verified that the flow alarm sounds if the tubing becomes occluded before or after the RELIZORB™.
SHELF LIFE/STERILITY
- RELIZORB™ is provided non-sterile in a foil package. Single use only device. Identified shelf life is six months.
- Several tests were completed using real-time aged devices after simulated shipping.
- Tests: Fat hydrolysis, Tensile strength, Filter integrity, Flow rate, Package integrity (Visual inspection, Peel strength, Bubble leak test).
- Results: Fat hydrolysis conversions were in agreement with baseline data (TwoCal HN: 51% (t=0), 47% (t=6 months); Peptamen: 85% (t=0), 92% (t=6 months)). No meaningful difference between baseline and aged product. Tensile strength, filter integrity, and flow rate were not compromised. Clean barrier was not compromised. Six-month shelf life is acceptable.
PERFORMANCE TESTING - ANIMAL
Four animal tests using exocrine pancreatic insufficient pig models.
1. Chronic Porcine Study
- Protocol: Purpose was to determine if the absorption of long-chain polyunsaturated fatty acids (LCPUFAs) is enhanced when formulas were prehydrolyzed with soluble microbial lipase. Pigs were monitored for reduction of total and PUFA fecal fats, change in coefficient of fat absorption (% CFA), and increase in arachidonic acid (AA) and docosahexaenoic acid (DHA) in plasma and tissues. Necropsy performed to harvest specified tissues.
- Results: No adverse clinical effects or pathologic macroscopic findings. Both RO and CV pre-hydrolyzed formulas increased the absorption of LCPUFA as reflected by reduced total stool fat, fecal AA, and DHA. Enriched diets enhanced fat absorption with an improvement in %CFA of 20-30% in comparison to controls. %CFA (MEAN ± SD) for Control group was 67±5.8 and for Treatment group was 86.6±4.3* (CV lipase) and 87.1±3.5* (RO lipase) with p values of 0.002 and 0.003 respectively.
2. Chronic Porcine Study
- Protocol: Safety and effectiveness of continuous feeding of the RO lipase enzyme in the porcine model over six weeks using the same lipase bound beads packed into the final device. Measured total and PUFA fecal fats, %CFA, and AA and DHA levels in plasma and tissue. Gross postmortem examination and blinded GLP histopathology examination.
- Results: Food intake and body weight were reported. A 38% and 53% reduction in omega-3 and omega-6 fecal LCPUFA, respectively. 66% and 50% respective reduction in fecal AA and DHA levels. Reversed inability to absorb fat. Improved consumption of LCPUFA and improved Vitamins A and E absorption. Histopathology found no safety signals relative to lipase enzyme consumption. Observations included increased periportal fat, inflammatory lesions in liver, stomach, tongue (in affected animals, not healthy controls). Findings were related to the pigs' pre-existing status and not the treatment group, with some findings showing milder and less frequent issues in treatment animals.
3. 12 Day Efficacy study with Gastrostomy Tube Feeding
- Protocol: Simulated use study of RELIZORB™ with nightly gastrostomy tube feeding over 12 days. Collected 24-hour stool and urine samples during the last three days. Collected blood samples for protein and fat profiles, DHA and eicosapentaenoic acid (EPA) measurements.
- Results: No adverse events reported. Statistically significant decrease in stool weight for the treatment group (p=0.014). Statistically significant increase in %CFA, with PepAF+EFIC having approximately 60% CFA compared to PepAF's 42%.
4. 24 Hour Pharmacodynamics Study
- Protocol: 24-hour, randomized, cross-over study in 11 pigs to assess pharmacodynamics of gastrostomy tube feeding using a prototype of the RELIZORBTM device. Collected baseline samples and at several time points after tube feeding began.
- Results: Statistically significant improvement in fat absorption in the treatment arm. Statistically significant (p
§ 876.5985 Enzyme packed cartridge.
(a)
Identification. An enzyme packed cartridge is anex vivo prescription device that is used in enzymatic hydrolysis of macronutrients into their essential nutrient forms at the time of delivery. The device consists of an outer casing containing an inert polymer with a covalently bound enzyme through which nutritional formula is directed. The device fits in line with enteral feeding systems.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The patient contacting components of the device must be demonstrated to be biocompatible.
(2)
In vivo testing must be performed and must demonstrate that the device causes neither an adverse tissue response nor adverse performance.(3) Non-clinical testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
(i) Mechanical testing to demonstrate that the device can withstand clinical forces;
(ii) Flow rate and leakage testing to demonstrate that the device does not impede the flow of enteral formula;
(iii) Demonstration of enzymatic effect on intended macronutrient;
(iv) The amount of enzyme that exits the cartridge must be characterized;
(v) Validation that the device does not adversely impact the nutritional composition of enteral formula; and
(vi) Validation that the device does not impede flow alarms on enteral feeding pumps.
(4) Human factors testing must be performed to characterize use error risks.
(5) Performance data must support shelf life by demonstrating package integrity and device functionality over the identified shelf life.
(6) Labeling must include the following:
(i) A detailed summary of
in vivo testing pertinent to use of the device, including device-related adverse events;(ii) A detailed summary of compatible formulas that is supported by non-clinical testing, including the expected enzymatic conversion as a percentage;
(iii) Detailed instructions on how to place the device into an enteral feeding circuit;
(iv) A warning regarding the possibility for misconnections; and
(v) Expiration date or shelf life.
(7) Patient labeling must be provided and must include:
(i) Relevant warnings, precautions, adverse effects, and complications;
(ii) A description of the device and how it operates;
(iii) Instructions on how to correctly use the device; and
(iv) The benefits and risks associated with the use of the device.
0
DE NOVO CLASSIFICATION REQUEST FOR RELIZORB™
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Enzyme Packed Cartridge: The enzyme packed cartridge is an ex vivo prescription device that is used in enzymatic hydrolysis of macronutrients into their essential nutrient forms at the time of delivery. The device consists of an outer casing containing an inert polymer with a covalently bound enzyme through which nutritional formula is directed. The device fits in line with enteral feeding systems.
NEW REGULATION NUMBER: 21 CFR 876.5985
CLASSIFICATION: II
PRODUCT CODE: PLQ
BACKGROUND
DEVICE NAME: RELIZORBTM
SUBMISSION NUMBER: DEN150001
DATE OF DE NOVO: DECEMBER 17, 2014
CONTACT:
ALCRESTA, INC. One Newton Executive Park SUITE 202 NEWTON, MA 02462
INDICATIONS FOR USE
RELIZORB™ is indicated for use in adults to hydrolyze fats in enteral formula.
LIMITATIONS
The sale, distribution, and use of the device are restricted to prescription use in accordance with 21 CFR §801.109.
RELIZORB™ is for use with enteral feeding only. The "Feed Only" lettering on the RELIZORB™ purple outlet is there to identify that the RELIZORB™ cartridge is intended for connection to enteral feeding lines only.
Medications should not be administered through the RELIZORB™ cartridge. Do
1
not add medications to the enteral feed line in between the pump and RELIZORB™ (before RELIZORB™). The passage of medications through RELIZORB™ may adversely affect the medications or the ability of RELIZORB™ to hydrolyze fats.
Do not re-use RELIZORB™. RELIZORB™ is a single-use product. Re-use may result in contamination of the product. If re-used, RELIZORB™ may not effectively hydrolyze fats.
Enteral formulas containing insoluble fiber should NOT be used. Insoluble fiber may clog the RELIZORB™ cartridge.
The use of RELIZORB™ along with porcine pancreatic enzyme replacement therapy (PERT) has not been investigated. The appropriate dose and administration of PERT should be evaluated on an individual basis. Patients should continue to follow physician's guidance and PERT product labeling when used in conjunction with RELIZORB™.
The use of RELIZORB™ has not been studied in patients with exocrine pancreatic insufficiency (0) (4) RELIZORB™ has not been evaluated in pediatric populations.
PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS, AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The RELIZORB™ device is a point-of-care accessory designed to fit in series with currently used enteral feeding circuits. During the submission process, the device was also known as the Enteral Feeding In-Line Cartridge (EFIC). Therefore, the subject device may be referred to as EFIC in some figures within this document. RELIZORB™ is designed to hydrolyze (break down) fats present in enteral formulas from triglycerides into fatty acids and monoglycerides to allow for their absorption and utilization by the body. This breakdown of fats by the RELIZORB™ is intended to mimic the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase. The subject device is shown below in Figure 1. The RELIZORB™ is comprised of a cvlindrical. hollow port and a single outlet port connection.
2
Image /page/2/Picture/0 description: The image shows a filtration device with labels pointing to different parts. The labels indicate the inlet, filters, immobilized lipase, and outlet. The device is cylindrical in shape and appears to be made of plastic, with a white filter material visible inside.
Figure 1. Photograph of the RELIZORB™ device.
RELIZORB™ is packed with polymeric beads that have lipase enzyme immobilized on the surface. This lipase enzyme is Generally Regarded as Safe (GRAS) . The chemical action of the lipase enzyme is shown in Figure 2, where triglyceride molecules are broken into constituent monoglycerides and fatty acids. The food contacting substance (FCS) of (b) beads manufactured using the RELIZORBTM are (b) (4) . The lipase enzyme is process. The FCS was an effective notification chemically bound to the FCS and is intended to remain within the cartridge.
Image /page/2/Figure/3 description: This image shows the chemical reaction of a triglyceride being broken down by lipase. On the left side of the image, a triglyceride is shown with a glycerol backbone and three fatty acids attached. The lipase enzyme breaks down the triglyceride into a monoglyceride and two fatty acids, which are shown on the right side of the image.
Figure 2. The lipase enzyme breaks down triglycerides into monoglycerides and fatty acids.
RELIZORB™ is an intermediary between an enteral feeding source (infusion pump) and an implanted feeding tube, as shown in Figure 3. The distal end of compatible infusion pump administration sets (Figure 3A) should have a stepped connector (Christmas tree). This connector plugs into the proximal end of the RELIZORB™ device (Figure 3B). The distal end of the RELIZORB™ (Figure 3C) connects to the enteral funnel of an extension set (Figure 3D). This extension set connects to an enteral feeding tube on the patient, such as a nasogastric or gastrostomy tube.
3
Image /page/3/Figure/0 description: The image shows a final setup of a medical device with labels A, B, C, and D. The device includes a pump on the left side and a connection to the patient on the right side, labeled as 'Downstream'. A Y-connector extension set is present, and a note indicates that medications or other solutions may be added at point D.
Figure 3. Illustration showing a proposed enteral feeding circuit with RELIZORB™!
SUMMARY OF NON-CLINICAL/BENCH STUDIES
Non-clinical/bench studies conducted on the RELIZORB™ to demonstrate a reasonable assurance of safety and effectiveness of the device are summarized in the sections below.
BIOCOMPATIBILITY/MATERIALS
| The RELIZORBTM cartridge is constructed using a | (b) (4) housing, | (b) (4) |
|---|---|---|
| inlet connector, | (b) (4) outlet connector, and | (b) (4) filters. The |
| food contacting materials are the acrylic copolymer beads, lipase enzyme, and | ||
| (b) (4) stabilizer. |
All materials within the RELIZORB™ have indirect contact with the patient's gastrointestinal tract. The RELIZORB™ is categorized as a permanent (>30 days) contact device that is externally communicating. The following biocompatibility testing was conducted on the final RELIZORB™ device in Table 1.
| Test | Purpose | Results |
|---|---|---|
| Cytotoxicity – MEM Elution | ||
| Test (ISO 10993-5: 2009 | ||
| (b) (4) | To assess the biological activity of L-929 mouse fibroblast cells after exposure to extracts prepared from the final RELIZORB™ device. | Non-cytotoxic |
| Irritation – Intracutaneous | ||
| reactivity (ISO 10993-10: |
-
| To determine if extracts from the final RELIZORB™ device produce an irritation reaction when injected intracutaneously in the rabbit model. | Non-irritating |
| Sensitization – Guinea Pig
Maximization Test (ISO
10993-10: 2010) | To determine the potential for sensitization of extracts prepared from the final RELIZORB™ device using the guinea pig animal model. | Non-sensitizing |
| Acute systemic toxicity (ISO
10993-11: 2010) | To determine the potential for acute systemic toxicity of extracts prepared from the final RELIZORB™ device by injections into mice. | Not systemically toxic |
| Genotoxicity – In Vitro Gene
Mutations in Bacteria (Ames
Assay, ISO 10993-3: 2003
(b) (4) | To determine the potential mutagenic activity of extracts prepared from the final RELIZORB™ device by measuring reversion rates in bacteria. | Non-mutagenic |
| Genotoxicity – In Vitro
Mouse Lymphoma (ISO
10993-3: 2003 (b) (4) | To determine if extracts prepared from the final RELIZORB™ device induce forward mutations at the thymidine kinase locus | Non-mutagenic |
4
| Test | Purpose | Results |
|---|---|---|
| Genotoxicity – In Vivo | ||
| Mouse Micronucleus Assay | ||
| (ISO 10993-3:2003 (b) (4) ) | To determine the potential for extracts prepared from the | |
| final RELIZORBTM device induce micronuclei | ||
| formation in immature polychromatic erythrocytes in the | ||
| bone marrow of mice. | Non-mutagenic |
Table 1. RELIZORB™ Biocompatibility Testing.
The sponsor justified that for non-polar extractions, sesame oil would be degraded by the lipase enzyme. Because the sponsor did leachability testing on the lipase enzyme from the beads, the sponsor used a surrogate bead for non-polar extractions. This approach was deemed acceptable by FDA.
PERFORMANCE TESTING - BENCH
The sponsor conducted bench tests to demonstrate mechanical integrity, package integrity, enzyme activity, and that RELIZORB™ can be integrated into existing enteral feeding circuits. Table 2 summarizes each of the bench tests.
| Test | Purpose | Acceptance Criteria | Results |
|---|---|---|---|
| Torque strength | To determine the torque | ||
| necessary to separate the | |||
| small bore connectors from | |||
| the cartridge body at both | |||
| the distal and proximal ends | |||
| of RELIZORB™ | The sponsor estimated the | ||
| clinical force that | |||
| RELIZORB™ may | |||
| encounter and built in a | |||
| three-fold safety factor. | |||
| The sponsor defined a | |||
| passing result as a torque | |||
| at separation higher (b) (4) | RELIZORB™ met the acceptance | ||
| criteria for this test. | |||
| Tensile strength | To determine the force | ||
| required to separate the | |||
| device small bore | |||
| connectors from the | |||
| cartridge using a linear | |||
| tensile force. | RELIZORB™ shall have | ||
| a linear tensile | |||
| (b) (4) | |||
| break. | RELIZORB™ met the established | ||
| acceptance criteria. | |||
| Air leakage test | To establish that the | ||
| RELIZORB™'s material | |||
| bonds would not fail or leak | |||
| when challenged with | |||
| pressurized air. | RELIZORB™ material | ||
| bonds shall not leak when | |||
| challenged with (b) (4) | |||
| compressed air. | RELIZORB™ did not leak when | ||
| pressurized with air. The device | |||
| met the acceptance criteria. | |||
| Filter integrity | To ensure that the | ||
| FCS/enzyme beads are | |||
| retained within the | |||
| cartridge. The sponsor | |||
| connected RELIZORB™ to | |||
| an enteral feeding circuit | |||
| and subjected the device to | |||
| the maximum pump flow | |||
| rate for five minutes. The | |||
| sponsor conducted this test | |||
| in both a forward and | RELIZORB™ should not | ||
| allow for beads (b) (4) | |||
| to pass the filter and leave | |||
| the cartridge. | RELIZORB™ allowed for five | ||
| particles to leave the cartridge in | |||
| three repetitions in the forward | |||
| flow direction. RELIZORB™ | |||
| allowed one particle to exit the | |||
| cartridge in the reverse flow | |||
| direction. Out of these six | |||
| particles, only one had a diameter | |||
| (b) (4) | |||
| The sponsor investigated the | |||
| Test | Purpose | Acceptance Criteria | Results |
| reverse flow orientation | |||
| The sponsor collected any | |||
| potential escaped particles | |||
| during this test using a (b)(4) | |||
| filter. | source of this particle using | ||
| spectroscopy and concluded that it | |||
| was a contamination from their | |||
| testing laboratory. The Agency | |||
| reviewed the sponsor's data and | |||
| agrees with their justification. | |||
| Because the sponsor did observe | |||
| some particles exiting the | |||
| cartridge, FDA considered clinical | |||
| or toxicological adverse events | |||
| resulting from escaped particles. A | |||
| clinical assessment determined that | |||
| so few escaped beads would likely | |||
| pass in a patient's stool. | |||
| Additionally, the sponsor | |||
| submitted acceptable | |||
| biocompatibility data and the FCS- | |||
| enzyme complex are acceptable | |||
| for use in foods. Based on these | |||
| assessments, this is an acceptable | |||
| result. | |||
| Fat hydrolysis | Using a simulated enteral | ||
| circuit, this test is to | |||
| determine the amount of | |||
| free fatty acids (FFA) that | |||
| RELIZORB™ produces by | |||
| enzymatic hydrolysis. The | |||
| sponsor used a | |||
| commercially available | |||
| colorimetric assay to | |||
| determine the amount of | |||
| free fatty acids produced by | |||
| RELIZORB™ after | |||
| simulated use. | RELIZORB™ should | ||
| produce (b)(4)FFA per | |||
| serving. | The sponsor submitted bench | ||
| testing data demonstrating that | |||
| RELIZORB™ breaks down ≈90% | |||
| of fats in most enteral formulas. | |||
| The sponsor added these results to | |||
| their labeling. This is an | |||
| acceptable result. | |||
| Unconjugated | |||
| lipase analysis | The sponsor evaluated the | ||
| potential leaching of the | |||
| lipase enzyme from the | |||
| beads. The sponsor | |||
| extracted the beads for (b)(4) | |||
| at room | |||
| temperature. | There were no formal | ||
| acceptance criteria for | |||
| this test. The sponsor | |||
| measured the lipase | |||
| concentration using a | Using several lots, the sponsor | ||
| observed (b)(4) leaching by the | |||
| BCA assay and (b)(4) leaching by | |||
| absorbance. Based on the | |||
| biocompatibility testing and the | |||
| GRAS status of lipase, there are no | |||
| safety concerns with this small | |||
| amount of enzyme released. | |||
| Assessment of | |||
| impact to other | |||
| nutrients | Using simulated use | ||
| conditions, the sponsor | |||
| flowed enteral formula | |||
| through their device. The | |||
| sponsor analyzed | There were no formal | ||
| acceptance criteria for | |||
| this bench test. The | |||
| sponsor conducted a | |||
| nutritional analysis of | After exposure to RELIZORBTM, | ||
| there was no meaningful | |||
| difference for any vitamins or | |||
| minerals. This is an acceptable | |||
| result. | |||
| Test | Purpose | Acceptance Criteria | Results |
| nutritional components | |||
| such as vitamins and | |||
| minerals to ensure that | |||
| RELIZORB™ does not | |||
| adversely affect other | |||
| nutrients in enteral formula. | vitamins and minerals. | ||
| Flow rate | The sponsor conducted this | ||
| test to ensure that | |||
| RELIZORB™ does not | |||
| restrict the flow of formula | |||
| using an enteral feeding | |||
| pump. | The presence of | ||
| RELIZORB™ in an | |||
| enteral feeding circuit | |||
| should not affect the flow | |||
| rate of formula. | There were no statistical | ||
| differences between the flow rate | |||
| with or without RELIZORB™ in | |||
| the enteral feeding line. This result | |||
| is acceptable. | |||
| Liquid leakage | |||
| test | After simulated feeding, the | ||
| sponsor inspected material | |||
| joints to determine if the | |||
| device leaked during | |||
| priming or flow rate testing. | RELIZORB™ should not | ||
| leak under normal and | |||
| worst-case conditions. | The sponsor used two formulas | ||
| and two different enteral feeding | |||
| pumps. In all cases, the sponsor | |||
| did not observe any leaking from | |||
| any material joints. | |||
| Pump alarm | |||
| verification | After performing flow rate | ||
| testing, the sponsor kinked | |||
| the tubing while the pump | |||
| was in run mode to verify | |||
| that the flow error alarm | |||
| works both before and after | |||
| RELIZORB™. | RELIZORB™ shall not | ||
| cause pump alarm failure. | The sponsor verified that the flow | ||
| alarm sounds if the tubing | |||
| becomes occluded before or after | |||
| the RELIZORB™. This is an | |||
| acceptable result. |
5
6
Table 2. RELIZORB™ Bench Testing.
In accordance with the recommendations outlined in the guidance document "Safety Considerations to Mitigate the Risks of Miscomnections with Small-bore Connectors Intended for Enteral Applications," mechanical misconnection testing was conducted and a warning is included in the labeling to reduce the risk of misconnection.
SHELF LIFE/STERILITY
RELIZORB™ is provided non-sterile in a foil package. RELIZORBTM is a single use only device that is disposed of after each use. The identified shelf life for RELIZORBTM is six months.
In support of the six-month shelf life, the sponsor completed several tests using real-time aged devices after simulated shipping. The shelf life tests have identical acceptance criteria to those identified in the Performance Testing - Bench section.
- Fat hydrolysis
- · Tensile strength
- · Filter integrity
- · Flow rate
- · Package integrity
- o Visual inspection
7
o Peel strength (ASTM F88)
o Bubble leak test (ASTM F2096)
The sponsor reported fat hydrolysis conversions that were in agreement with their baseline data:
| TwoCal HN | Peptamen | |
|---|---|---|
| t=0 | 51% | 85% |
| t=1 month | 44% | 89% |
| t=3 months | 49% | 84% |
| t=6 months | 47% | 92% |
Table 3. Fat hydrolysis results (% conversion of fats).
Because there was no meaningful difference between the baseline and aged product, the Agency determined that the fat hydrolysis results were acceptable. The tensile strength, filter integrity, and flow rate were not compromised after aging. After simulated shipping, the clean barrier for the RELIZORB™ was not compromised. The six-month shelf life is acceptable.
PERFORMANCE TESTING - ANIMAL
The sponsor completed four animal tests using exocrine pancreatic insufficient (0) ( (b) (4) pig models.
The four animal studies are summarized below.
1. Chronic Porcine Study
Protocol
The purpose of this study was to determine if the absorption of long-chain polyunsaturated fatty acids (LCPUFAs) is enhanced when formulas were prehydrolyzed with soluble microbial lipase.
Image /page/7/Picture/12 description: The image is mostly obscured by a gray block. The visible text says "hydrolyzed with soluble microbial lipase."
The pigs were monitored for a reduction of total and PUFA fecal fats, and change in coefficient of fat absorption (% CFA). The pigs were also monitored for an increase in arachidonic acid (AA) and docosahexaenoic acid (DHA) in plasma and tissues such as the liver, retina, heart, and fat. This result is consistent with increased absorption of LCPUFAs. After the study endpoint, the sponsor performed necropsy of study animals to harvest specified tissues, such as the liver, retina. heart, fat, red blood cells, hippocampus, cerebellum, and brain cortex.
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Results
There were no adverse clinical effects or pathologic macroscopic findings in the gut or liver after seven days of administration. Both the RO and CV pre-hydrolyzed formulas increased the absorption of LCPUFA as reflected by reduced total stool fat, fecal AA, and DHA. The sponsor included a summary showing the %CFA for the control and treated groups. The sponsor's data supports their conclusion that the enriched diets enhanced fat absorption with an improvement in %CFA of 20-30% in comparison to controls.
| WEEK | CFA% (MEAN ± SD) | ||
|---|---|---|---|
| CONTROL | CV LIPASE | RO LIPASE | |
| CONTROL | 66.5±7.8 | 51.7±14.3 | 76.9±1.9 |
| TREATMENT | 67±5.8 | 86.6±4.3* | 87.1±3.5* |
| P value | 0.002 | 0.003 |
Shown is a mean (± SD) CFA values during Control and Treatment weeks for Control RO organe. Difference was consider sinnificant tocol 05 for company on helpers of and RO groups during treatment week, n=3/arm
Image /page/8/Figure/4 description: The image shows the title of a table. The title is "Table 4. Mean of 24 hour %CFA during 3 consecutive days (Study 1)". The table will likely contain data related to the mean percentage of CFA over a 24-hour period for three consecutive days.
2. Chronic Porcine Study
Protocol
The sponsor tested the safety and effectiveness of continuous feeding of the RO lipase enzyme in the b)(4) porcine model over six weeks. The sponsor used the same lipase bound beads that are packed into the final device in this study.
During the study, the sponsor measured total and PUFA fecal fats, %CFA, and AA and DHA levels in both plasma and tissue. At study termination, the sponsor completed a gross postmortem examination of tissue and a blinded GLP histopathology examination.
Results
The sponsor reported food intake and body weight of all pigs. The formula intake The spensor reported root make and body wergit of were its (b) (4) control pigs grew 2-4 kg per week. The sponsor observed a 38% and 53% reduction in omega-3 and omega-6 fecal LCPUFA in (0) pigs treated with the RO enzyme. Similarly, the sponsor reported a 66% and 50% respective reduction in fecal AA and DHA levels for (b)(0) pigs treated with RO enzyme. These data suggest that the inability for (0) (4) pigs to absorb fat was reversed by feeding with pre-hydrolyzed formula treated with the lipase enzyme. Additionally, the pigs fed a pre-hydrolyzed diet had a more normalized blood lipid profile, improved consumption of LCPUFA. and improved Vitamins A and E absorption.
The sponsor harvested the cranial alimentary. GI tract, and the liver to send the samples for a blinded, GLP histopathology examination. The sponsor included analyses on the tongue, esophagus, stomach, small intestines, large intestines, liver,
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and liver fat. The pathologist found no safety signals relative to the consumption of the lipase enzyme. The pathologist had the following observations:
- Increased periportal fat in the liver (all study animals). .
- Inflammatory lesions in the liver, stomach, and tongue of (b)(4) ● animals, but not healthy control animals.
- . An increase in distribution and severity of inflammatory lesions in EPI animals compared to healthy control animals.
The sponsor's findings seemed related to the pigs' 1010 status and not the 10/4/ treatment group. Some of the findings showed milder and less frequent issues in the treatment (4) animals in comparison to (1) controls. The observations noted in the (b)(4) treatment group were not related to the treatment itself and were of low incidence. The histopathological examination followed GLP regulations and was complete. Because the pathologist's findings were also peer reviewed, this study supported the accuracy of the sponsor's conclusions.
3. 12 Day Efficacy study with Gastrostomy Tube Feeding
Protocol
The sponsor conducted a simulated use study of RELIZORB™. The sponsor did nightly gastrostomy tube feeding over 12 days in the 014) porcine model.
During the last three days of the study, the sponsor collected two 24 hour stool and urine samples. On the last day after overnight fasting, the sponsor collected blood samples for protein and fat profiles, as well as DHA and eicosapentaenoic acid (EPA) measurements.
Results
The sponsor did not report any adverse events during this study. While the food intake between (8) (4) control and [8] treatment pigs was similar, the sponsor reported a statistically significant decrease in the stool weight for the treatment group (p=0.014). The sponsor reported a statistically significant increase in %CFA, as shown in Figure 4.
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Image /page/10/Figure/0 description: This bar graph compares the %CFA of PepAF and PepAF+EFIC. PepAF has a %CFA of approximately 42, while PepAF+EFIC has a %CFA of approximately 60. The error bars for PepAF+EFIC are larger than the error bars for PepAF. The y-axis ranges from 0 to 100.
Figure 4. Improved fat absorption expressed as %CFA for EFIC/RELIZORBIM (p=0.036, Study 3).
4. 24 Hour Pharmacodynamics Study
Protocol
The sponsor conducted a 24 hour, randomized, cross-over study in 11 pigs to assess the pharmacodynamics of gastrostomy tube feeding using a prototype of the RELIZORBTM device through a gastrostomy tube. While the sponsor used a device prototype for the treatment arm, this prototype was nearly identical in form and function to the finished device.
The sponsor collected baseline samples and at several time points after tube feeding began.
Results
Due to the short study duration, food consumption and body weight were not endpoints. The sponsor reported a statistically significant improvement in fat absorption in the treatment arm in comparison to the control. The plasma omega-3 fat (DHA and EPA) concentrations over 24 hours are shown in Figure 5. The sponsor reported a statistically significant (p In vivo testing Labeling |
| Mechanical failure Deprivation of care Device clogging Filter becomes dislodged and releases beads into enteral formula | Non-clinical testing Shelf life testing Labeling |
| Reduced enzymatic effect | Non-clinical testing In vivo testing Shelf life testing Labeling |
| Use error | Human factors testing Labeling |
| Infection | Shelf life testing Labeling |
SPECIAL CONTROLS:
In combination with the general controls of the FD&C Act, the Enzyme Packed Cartridge is subject to the following special controls:
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- The patient contacting components of the device must be demonstrated to be biocompatible.
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- In vivo testing must be performed and must demonstrate that the device causes neither an adverse tissue response nor adverse performance.
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- Non-clinical testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
- (A). Mechanical testing to demonstrate that the device can withstand clinical forces.
- Flow rate and leakage testing to demonstrate that the device does not impede the (B). flow of enteral formula.
- Demonstration of enzymatic effect on intended macronutrient. (C).
- The amount of enzyme that exits the cartridge must be characterized. (D).
- Validation that the device does not adversely impact the nutritional composition (E). of enteral formula.
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- (F). Validation that the device does not impede flow alarms on enteral feeding pumps.
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- Human factors testing must be performed to characterize use error risks.
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- Performance data must support shelf life by demonstrating package integrity and device functionality over the identified shelf life.
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- Labeling must include the following:
- (A). A detailed summary of in vivo testing pertinent to use of the device, including device-related adverse events.
- (B). A detailed summary of compatible formulas that is supported by non-clinical testing, including the expected enzymatic conversion as a percentage.
- (C). Detailed instructions on how to place the device into an enteral feeding circuit.
- A warning regarding the possibility for misconnections. (D).
- (E). Expiration date or shelf life.
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- Patient labeling must be provided and must include:
- (A). Relevant warnings, precautions, adverse effects, and complications.
- A description of the device and how it operates. (B).
- Instructions on how to correctly use the device. (C).
- The benefits and risks associated with the use of the device. (D).
BENEFIT/RISK DETERMINATION
The observed risks of the device are based on the animal studies described above. The sponsor did not include any clinical data. The sponsor presented safety data from four different porcine studies. The sponsor did not observe any adverse events in their animal studies. Since the sponsor's small bore connector is based on a legacy design, there is a risk for misconnection with devices from other healthcare applications.
The observed probable benefits of the device are also based on nonclinical laboratory and animal study data as described above. The sponsor demonstrated in laboratory testing that the device was able to hydrolyze >90% of fat in most enteral formulas. The four preclinical animal studies appeared to provide benefit to pigs displaying clinical signs of exocrine pancreatic insufficiency (b) (4) when fed a diet pre-hydrolyzed by the lipase enzyme manually or through the RELIZORB™ device. In their animal studies, the sponsor demonstrated that treating (9) (4) pigs using RELIZORB™ led to increases in total fat absorption, improved update of omega-3 fatty acids in plasma, and improved Vitamin D and E levels. FDA expects these benefits would also be seen using pre-hydrolyzed formula due to the nutritional benefits observed from fat hydrolysis in the literature.
Additional factors to be considered in determining probable risks and benefits for the RELIZORB™ include:
- The cumulative data from the animal studies were robust. Thev were designed logically, . systematically, and built on each other. The first two studies did not use the device. The
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pigs in the first study were fed soluble lipase enzyme, while the second study used the beads bound with lipase in a mesh bag. The final two studies used a device prototype that was functionally equivalent to the final device.
- . Study 2 had a safety endpoint and the histopathology was conducted at a GLP pathology lab under blinded conditions. Study results were peer-reviewed prior to release of final study report.
- Study 4 was a randomized, blinded, cross-over study.
- Patients can have abdominal cramps, steatorrhea (loose, greasy, foul-smelling . voluminous stools), and malnutrition with weight loss. The condition is currently treated with oral administration of pancreatic enzyme replacement therapy tablets (PERTs).
- . Human factors testing and clear labeling help mitigate risks.
- The device is beneficial because no enteral formulas currently contain pre-hydrolyzed fat. ●
In conclusion, given the available information above, the data support that the probable benefits for the RELIZORB™ device to hydrolyze fats in enteral formula outweigh the probable risks. The device provides probable benefits and the risks can be mitigated by the use of general and the identified special controls.
CONCLUSION
The De Novo request for the RELIZORB™ is granted and the device is classified under the following:
Product Code: PLQ Device Type: Enzyme Packed Cartridge Class: II Regulation: 21 CFR 876.5985