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Medical Design and Outsourcing

Implanted Blood Access Devices for Hemodialysis – Draft Guidance for Industry and Food and Drug Administration Staff

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You should submit comments and suggestions regarding this draft document within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.  Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  Submit electronic comments to http://www.regulations.gov.  Identify all comments should with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this document, contact Jeffrey Cooper, DVM at (301) 796-5590 or via email at jeffrey.cooper@fda.hhs.gov. 

 

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Office of Device Evaluation
Division of Reproductive, Gastro-Renal, and Urological Devices

Preface

Additional Copies

Additional copies are available from the Internet.  You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to 301-827-8149 to receive a hard copy.  Please use the document number 1781 to identify the guidance you are requesting.

Table of Contents

  1. Introduction
  2. Background
  3. Scope
  4. 510(k) Submission Recommendations
    1. Device Description
    2. Device Materials
    3. Biocompatibility
    4. Performance Testing – Bench
    5. Sterility and Shelf-Life
    6. Labeling
    7. Animal and Clinical Testing
      • Performance Testing – Animal
      • Performance Testing – Clinical
    8. Special Considerations
      • Performance Testing – Subcutaneous Catheters
      • Coatings

Implanted Blood Access Devices for Hemodialysis – Draft Guidance for Industry and Food and Drug Administration Staff

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I. Introduction

This draft guidance document provides draft recommendations for complying with special controls being proposed to support reclassification of the Implanted Blood Access Devices for Hemodialysis into class II (special controls).  The device, as proposed, is intended to provide access to a patient’s blood for hemodialysis.  This draft guidance will be issued in conjunction with a Federal Register notice announcing the proposal to reclassify this device type.  This guidance is issued for comment purposes only.   

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. Background

FDA has issued a proposed administrative order to reclassify implanted blood access devices for hemodialysis, which are currently Class III devices, into Class II (special controls) and subject to premarket notification.  FDA is proposing this reclassification under the Federal Food, Drug and Cosmetic Act (FD&C Act) based on new information pertaining to the device.  This guidance is intended to provide recommendations on how to comply with the special controls proposed in 21 CFR 876.5540(b)(1) and indicate what information is suggested for submission to FDA in a 510(k) to demonstrate that the special controls have been met. 

This document supplements other FDA documents regarding the specific content requirements of a premarket notification [510(k)] submission. You should also refer to 21 CFR 807.87 and FDA’s guidance, “Format for Traditional and Abbreviated 510(k)s.”

III. Scope

An implanted blood access device for hemodialysis, as modified in 21 CFR § 876.5540(a)(1), is defined as:

(a) Identification. ***
(1) The implanted blood access device is a prescription device used for hemodialysis and consists of various flexible or rigid tubes, such as catheters, or cannulae, which are surgically implanted in appropriate blood vessels, may come through the skin, and are intended to remain in the body for 30 days or more. This generic type of device includes:  Single, double, and triple lumen catheters with cuffs, subcutaneous ports with catheters, shunts, cannula, vessel tips, and connectors specifically designed to provide access to blood.

The scope of this document is limited to the implanted blood access devices for hemodialysis regulated under 21 CFR § 876.5540(a)(1) and with product codes listed in the table below:

Product Code Name
FIQ A-V shunt cannula
FKW vessel tip
LFJ subclavian catheter
MSD implanted hemodialysis catheter
NIF implanted triple-lumen hemodialysis catheter
NYU implanted coated hemodialysis catheter

Implanted blood access devices outside of this aspect of this subpart of the classification regulation are not within the scope of this guidance. 

IV. 510(k) Submission Recommendations

The sections below provide recommendations on information to include in a 510(k) submission for implanted blood access devices for hemodialysis.  These recommendations include recommendations for compliance with special controls.

A. Device Description

The implanted blood access device for hemodialysis is described in 21 CFR § 876.5540 as a device intended to provide access to a patient’s blood for hemodialysis or other chronic uses. When used in hemodialysis, it is part of an artificial kidney system for the treatment of patients with renal failure or toxemic conditions and provides access to a patient’s blood for hemodialysis.

The implanted blood access device is a prescription device and consists of various flexible or rigid tubes, such as catheters, or cannula, which are surgically implanted in appropriate blood vessels, may come through the skin, and are intended to remain in the body for 30 days or more. This generic type of device includes single, double and triple lumen catheters with cuffs, subcutaneous ports with catheters, shunts, cannula, vessel tips, and connectors specifically designed to provide access to blood.

We recommend that you identify your device by the regulation and product code described in Section III.  “Scope.”  Per 21 CFR 807.87 you must also identify the common name of your device (e.g., double lumen hemodialysis catheter) as well as the trade or proprietary name.  We recommend you also provide the following information:

  1. classification name (e.g., blood access device);
  2. a listing of all model numbers (if known);
  3. a clear description of the proposed device’s intended use
  4. the CFR classification regulation number under which you believe the device and any components/accessories are regulated.

The device description should include a labeled diagram and the specifications (e.g., lengths, inner and outer diameters, French size, cuff positions, connectors1, extension lengths, hole diameters and positions) for each model included in the submission.  The physical description should include:

  1. a description of the overall device system including accessories, pictures, samples (if practical), and engineering diagrams;
  2. a functional description (including specifications, if applicable) of the individual components of the catheter system; and
  3. a description of the accessories that may be used to place the catheter or shunt.  Any accessory device that is labeled for use with the proposed catheter system should either be currently legally marketed or submitted as part of the 510(k) submission for the proposed catheter system.  Information on the accessory device to allow a determination of substantial equivalence should be provided.

The 510(k) should include a comparison of the proposed device to a legally marketed device, commonly referred to as the ‘predicate’ device.2 FDA recommends that all comparisons be provided in a manner that is clear and comprehensible, such as in tabular form that lists the similarities and differences between the proposed and predicate device in terms of intended use, technological features, performance specifications, and other important information necessary to determine substantial equivalence between the proposed and predicate device.

The 510(k) should identify the predicate device to which the proposed device will be compared.  The 510(k) should provide as much information as possible regarding the predicate device, such as, the proprietary and common name, manufacturer, model number, 510(k) reference number, preamendments status3 (i.e., marketed in the United States prior to May 28, 1976), etc. 

You should provide information to describe how your device is similar to and different from the predicate device (21 CFR 807.87(f)).  Side by side comparisons, whenever possible, are desirable. 

The comparison between the proposed and predicate device should include, at a minimum, the following information:

  1. Intended Use/Indications for use to include, as appropriate:
    1. general purpose of device (e.g., blood access for hemodialysis treatment)
    2. location of use (e.g., internal jugular, femoral, subclavian, transhepatic, translumbar);
    3. lengths and diameters of the catheters;
    4. duration of use (e.g., long-term [>30days]; and
    5. conditions of use (e.g., acute renal failure, chronic renal failure).
  2. Materials used, including the supplier, the material name, and the material designation numbers, for each device component, when applicable, including:
    1. catheter lumens and extensions;
    2. clamps;
    3. cuffs;
    4. luer adapters (bloodline connectors);
    5. hub;
    6. suture wing;
    7. caps;
    8. coatings;
    9. adhesives; and
    10. colorants or inks.
  3. Performance specifications
  4. Design parameters, including:
    1. catheter type;
    2. number of cuffs;
    3. outer and inner diameters;
    4. length; and
    5. tunneler information.

B. Device Materials

As specified in Section A. “Device Description” above, in the 510(k), you should provide the identification of all materials used to fabricate all components of the hemodialysis catheter, including any colorants (inks, dyes, markings, etc.), plasticizers (including di-(2-Ethylhexyl) phthalate or DEHP), lubricants, mold release agents, additives, or coatings (as further discussed in section I. “Special Considerations – Coatings”).  FDA is proposing to require as a special control that sponsors provide material names and specific designation numbers. We recommend you group these materials according to whether they have direct or indirect contact with the circulating blood. As also discussed in Section A. “Device Description,” you should provide a detailed comparison of your materials to those of the predicate device. 

C. Biocompatibility

FDA is also proposing to require as a special control that components of the device that come into human contact must be demonstrated to be biocompatible.  For all patient contacting materials, you should provide appropriate biocompatibility testing on finished, sterilized device(s) as recommended in the draft FDA guidance on biocompatibility testing, “Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing.”  When final, this guidance will represent the Agency’s current thinking on this topic. Hemodialysis catheters are considered “External communicating devices,” “Circulating blood,”  “Permanent contact – (Category C).”  Please also see Section 7 of the above-referenced draft biocompatibility guidance for specific information on the assessment of colorants, as when final, the guidance will represent our current thinking on that topic. 

If you are unable to identify a legally marketed predicate device with similar location/duration of contact and intended use that uses the exact materials as used in your device, we recommend you conduct the following biocompatibility tests:

  • Cytotoxicity
  • Sensitization (Guinea pig maximization with polar and non-polar extracts)
  • Irritation or intracutaneous reactivity
  • Systemic toxicity (acute)
  • Sub-chronic toxicity
  • Implantation4
  • Hemocompatibility
  • Genotoxicity

D. Performance Testing – Bench

FDA is proposing to require as a special control that performance data must demonstrate that the device performs as intended under anticipated conditions of use. The 510(k) should include adequate information describing the performance characteristics of the device.  At a minimum, this should include functional testing.

The performance testing outlined below should be conducted on a minimum of three (3) hemodialysis catheters of each model. If you choose to test one or more models to represent subsets of the product portfolio, you should provide a sample selection rationale detailing why this is appropriate. The proposed special controls would establish the following requirements for testing and performance characteristics:

  1. Pressure versus flow rates for both arterial and venous lines, from the minimum flow rate to the maximum flow rate in 100 ml/min increments must be established. The fluid and its viscosity used during testing must be stated.
    It is preferable that a fluid with a viscosity analogous to that of blood (e.g. 36%-40% glycerin in water) be used during the testing.
  2. Recirculation rates for both forward and reverse flow configurations compared to the predicate device, along with a description of the methodology used to perform the assay must be provided.
  3. Priming volumes5 must be established.
  4. Tensile testing of joints and materials as specified in the FDA currently recognized version of consensus standard ISO 10555-1, Sterile, single-use intravascular catheters – Part 1: General requirements must be conducted.6 
    The minimum acceptance criteria should be at least equal to the predicate device.  We recommend the minimum force at break should be 10 pounds for polyurethane joints and polyurethane materials that comprise the main lumens of the catheter excluding the catheter tip (due to the more frequent handling of hemodialysis catheters compared to general catheters).
  5. Air leakage testing as specified in the FDA recognized version of consensus standard ISO 10555-1 Annex D and Liquid leakage testing as specified in ISO 10555-1 Annex C must be conducted.
  6. Testing of the repeated clamping of the extensions of the catheter that simulates use over the life of the catheter must be conducted.
    Assuming that five clampings are done at each treatment, with an average of three treatments per week, an average catheter life of 26 weeks, and a three times safety factor, repeatedly clamping at least 1,200 times, followed by leakage testing, as described in  “e.” above, should provide assurance of extension durability.
  7. Mechanical hemolysis testing must be conducted.
    The data should be compared to that of the predicate device and demonstrate that no more red blood cell lysis occurs with the new design in comparison to the predicate device.  The testing should utilize the maximum recommended blood flow rates (see also Appendix A for considerations for testing).
  8. Chemical tolerance of the catheter to repeated exposure to commonly used disinfection agents (e.g., bleach, alcohol, iodine) must be established.

Results of performance testing should be compared to those obtained for the predicate device.  If test results for the proposed device are outside the range of the predicate device, the 510(k) should include an explanation of why this difference supports the substantial equivalence of the proposed device. The variances should be noted and any changes from those of the predicate device should be justified in the 510(k) submission.

E. Sterility and Shelf-Life

FDA is proposing special controls to require performance data to demonstrate sterility of the device and to support the shelf-life of the device for continued sterility, package integrity, and functionality over the requested shelf life, which that must include tensile, repeated clamping and leakage testing.  FDA’s draft guidance, “Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile,” provides basic information on sterility issues, and when final, will represent FDA’s current thinking on this topic.  All sterile devices intended for internal use are generally expected to meet the sterility assurance level (SAL) of 10-6.  Your submission should include the following information:

  1. sterilization method;
  2. radiation dose or the maximum residual levels of ethylene oxide and ethylene chlorohydrin that remain on the finished sterilized device, whichever is applicable. For ethylene oxide residuals, you may refer to the FDA currently recognized version of the consensus standard ANSI/AAMI/ISO 10993-7: Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide sterilization residuals);5
  3. validation method for the sterilization cycle and Sterilization Assurance Level (SAL);
  4. since the product should be labeled “non-pyrogenic,” a description of the method used to make the determination, e.g., limulus amebocyte lysate (LAL) and the sensitivity of the method in Endotoxin Units per milliliter (EU/mL);
  5. a description of the packaging system, and
  6. esting to demonstrate that the package remains sterile. 

FDA is proposing a special control to require that all labels for hemodialysis catheters must include an expiration date and, as stated above, that performance data must support the shelf life of the device.  The following test results or an appropriate rationale should be provided to substantiate the validity of the proposed expiration date:

  1. performance testing on aged samples to include, at a minimum, the performance testing as described in Section D. “Performance Testing – Bench” for tensile, repeated clamping, and leakage; and
  2. package integrity testing (to demonstrate sterility and non-­pyrogenicity over the labeled shelf life) as specified in the FDA currently recognized version of ASTM F1980-7: Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices.5

For devices with established materials and designs, accelerated conditions for establishing an expiration date may be used to support a 510(k). In such cases, it is typically acceptable to provide accelerated aging results for an initial time point such as “6-months equivalent” within a submission. Coatings or additives may make accelerated aging inappropriate. The labeled shelf life should reflect the initial test results provided in the 510(k), but may be increased by the manufacturer as subsequent accelerated aging results conducted under a protocol that FDA has found acceptable, which represent longer time points, become available. In addition, a scientific rationale should be provided to support the chosen conditions for the accelerated testing. Real-time testing results should be included in the device history record for subsequent review by FDA.7

F. Labeling

The 510(k) submission must include labeling in sufficient detail to satisfy the requirements of 21 CFR 807.87(e).  The following suggestions are provided to assist you in preparing labeling that satisfies the requirements of 21 CFR Part 801 and the special controls proposed by FDA.

As a prescription device, under 21 CFR 801.109, the device is exempt from having adequate directions for lay use.  Labeling must, however, include adequate information for practitioner use of the device, including indications, effects, routes, methods, and any relevant hazards, contraindications, side effects and precautions. (21 CFR 801.109(d)).

Proposed labels, labeling, and advertisements sufficient to describe the hemodialysis catheter, its intended use, and the directions for its use (21 CFR 807.87(e)) should be provided with a specific intended use statement and any warnings, contraindications, or limitations clearly displayed

Under 21 CFR 801.109, the instructions for use must include indications for use, and warnings, precautions, and contraindications associated with the use of the catheter.  The instructions for use should also include principle of operation, device description, features and/or accessories, directions for device use, implantation procedures, and troubleshooting.  Detailed instructions on catheter care should be provided, for example cleaning, site care, and disinfection.

The device label affixed to the hemodialysis catheter packaging must include the name and place of business of the manufacturer, packer, or distributor (21 CFR 801.1).  The label should also includethe device name, U.S. point of contact, storage conditions, priming volume, sterility status and method, sterilization date, lot number, and expiration date.

In addition to the general labeling recommendations and provisions above, we recommend the following labeling considerations specific to hemodialysis catheters:

  1. The intended use statement should include the specific indications and intended patient population.
  2. Device labeling for the hemodialysis catheter should address the following potential complications of the device related to insertion location:
    1. If a femoral catheter is indicated, the labeling should include:
      1. language to specify the placement site such as “Catheters greater than 40 cm are intended for femoral vein insertion”;
      2. potential complications specific to femoral placement (femoral artery bleed, femoral nerve damage, retroperitoneal bleed, and venous stenosis);
      3. suggestions to avoid infections such as tunneling the catheter to a pelvic area rather than an inguinal area; and
      4. a caution that increased infections are a possibility.
    2. If a trans-lumbar catheter is indicated, the labeling should include:
      1. language to specify the placement site; and
      2. potential complications specific to trans-lumbar placement, including migration of the catheter tip into subcutaneous tissues, retroperitoneum or iliac veins (causing hematoma or frank bleeding).
    3. If a subclavian catheter is indicated, the labeling should include:
      1. language to specify the placement site; and
      2. potential complications specific to subclavian placement, including pneumothorax and hemothorax.
  3. If applicable, the labeling should summarize the results of clinical performance data needed to demonstrate substantial equivalence.

FDA is also proposing to require as a special control that the labeling must bear all information required for the safe and effective use of the implanted blood access devices for hemodialysis, which has been defined to include the following:

  1. An arterial and venous pressure versus flow rate table or graph must be provided to communicate the performance capabilities of the catheter.
  2. The arterial and venous priming volumes must be included in the labeling and, if possible, printed directly on the catheter.  
  3. Forward and reverse recirculation rates along with the protocol used to perform the assay must be specified.
    It is recommended that catheters with greater than 50% recirculation in the reverse direction should include a caution in the labeling listing the percent reverse recirculation.
  4. An expiration date as established in Section E “Sterility and Shelf Life” must be specified.
  5. Any disinfecting agents that cannot be used to clean any components of the device must be identified in the labeling.
  6. Any contraindicated disinfecting agents due to material incompatibility must also be identified by printing a warning on the catheter. Alternatively, a label that can be affixed to the patient’s medical record with this information can be provided.
  7. The instructions for use must contain, the following information: comprehensive instructions for the preparation and insertion of the hemodialysis catheter, including recommended site of insertion, method of insertion, a reference on the proper location for tip placement, method for removal of the catheter, anticoagulation, guidance for management of obstruction and thrombus formation, and site care.
  8. Any coatings or additives must include a summary of the results of performance testing for any coating or material with special characteristics, such as decreased thrombus formation or antimicrobial properties.

G. Animal and Clinical Testing

Implanted blood access devices for hemodialysis will generally not be subject to animal or clinical testing if they are similar to legally marketed implanted blood access devices in design and technology.  However, modifications in the indication for use or different technological characteristics may require animal or clinical testing.

Performance Testing – Animal

Testing performed in animals may be needed to establish substantial equivalence. Some areas that animal testing has been useful are for demonstrating anti-thrombotic properties, testing for adequate flow, and assessing infection potential. Such testing must comply with 21 CFR Part 58, which prescribes Good Laboratory Practices for nonclinical studies.

Performance Testing – Clinical

Clinical evidence is generally not necessary for most implanted blood access devices for hemodialysis; however, such testing may be requested in situations such as the following:

  1. indications for use dissimilar from legally marketed devices of the same type;
  2. different technology, i.e., technology different from that used in legally marketed devices of the same type, yet does not raise different questions of safety or effectiveness; or
  3. cases where engineering and/or animal testing raise issues that warrant further evaluation with clinical evidence.

FDA will consider alternatives to clinical testing when the proposed alternatives are supported by an adequate scientific rationale. 

For hemodialysis catheters and shunts, any labeling claims about performance of the device in vivo should be supported with appropriate bench testing, in addition to either animal and/or clinical testing. 

FDA believes that implanted blood access devices for hemodialysis addressed in this guidance document are considered significant risk as defined in 21 CFR 812.3(m)(4). Hence, if a prospective clinical study is needed to demonstrate substantial equivalence, the study must be approved by FDA and conducted under the Investigational Device Exemptions (IDE) regulation, 21 CFR Part 812, if conducted in the United States.  In addition to the requirements of 21 CFR 812, sponsors of such studies must comply with the regulations governing institutional review boards (21 CFR Part 56) and informed consent (21 CFR Part 50).  Also, FDA’s “Guidance for Clinical Investigators, Industry,  and FDA Staff  Financial Disclosure by Clinical Investigators” provides recommendations to assist clinical investigators and sponsors in interpreting and complying with the regulations governing financial disclosure by clinical investigators, 21 CFR part 54.

A clinical study for implanted blood access devices should include endpoints that address both the safety and effectiveness of the proposed device that supports its substantial equivalence to the predicate device(s).  Effectiveness endpoints should focus on the ability of the device to properly function over a long period of time, such as 180 days.  Safety should focus on an evaluation of the adverse events that may be expected with implanted blood access devices.  FDA encourages that you utilize the opportunity to seek advice on prospective IDE clinical studies prior to the submission of an IDE application. FDA’s “Draft Guidance for Industry and FDA Staff, Medical Devices: The Pre-Submission Program and Meetings with FDA Staff” outlines the recommended procedures for seeking feedback from FDA on a clinical study design.  When final, this guidance will represent FDA’s current thinking on the topic.

H. Special Considerations

Performance Testing – Subcutaneous Catheters

Subcutaneous catheters refer to those catheters that are completely implanted below the skin surface and have no part of the device exposed to the outside of the body.  Subcutaneous catheters warrant more testing than described above in order to resolve issues of infection rates, adequacy of dialysis, maintenance of blood flow, and long-term patency. FDA is proposing to require as a special control that the recommended type of needle must be described in the submission and labeling (e.g., non-coring) and thattest results on repeated use of any ports must be provided.  Clinical data is generally necessary to establish the substantial equivalence of this type of device.

Coatings

Implanted blood access devices for hemodialysis may include coatings, additives, or have material properties that impart antithrombotic, antimicrobial, or lubrication properties to the device.  If there is a clinical benefit for such coatings, FDA is proposing to require as a special control that results of a clinical study must be provided in the labeling in support of these benefits. FDA is also proposing to require as a special control that the testing performed on the coated device must be reflected in the labeling.

Coatings intended for infection control generally require a clinical study to demonstrate that ability; although, coatings identical to previously cleared coatings for similar indications and anatomies may not need to provide new supportive clinical data.8

Coating information should include:

  1. a description of the coating material(s);
  2. the duration of effectiveness;
  3. how the coating is applied; and
  4. testing to show how well the coating performs.

Keep in mind that inclusion of a coating with a new drug entity or a coating that is released from the catheter will usually either change the intended use or raise different questions of safety and effectiveness.  An antimicrobial coating could create a combination product. In situations where you are proposing inclusion of a drug that is not included on a predicate device, we would strongly encourage the submission of a pre-submission.

Appendix A – Mechanical Hemolysis Testing of Hemodialysis Catheters

To evaluate the potential for hemodialysis catheters to cause blood damage, in vitro testing simulating clinical use is usually conducted using animal blood.  As animal blood is tested in an artificial in vitro environment and is more resilient to physical damage than the blood of hemodialysis patients, extrapolating the results of the bench testing to the clinical environment has limited value. However, by performing paired testing using blood from the same animal source, a relative comparison between a new and a predicate device can be made. 

The references included in this Appendix address many of the issues related to in vitro hemolysis testing, represent FDA’s current state of knowledge for performing this type of testing, and can be used as guides for the testing of hemodialysis catheters.9,10,11,12,13 The testing is composed of three sections: setting up the test, performing the test, and reporting and interpreting the results. 

Setting up the test:

1.  Standardized guidelines for the collection and preparation of blood to be used in the in vitro assessment of blood damage caused by a medical device under dynamic test conditions have been previously described.8  Briefly, the blood should be obtained from a healthy animal and immediately mixed with an appropriate anticoagulant (e.g., 4000-6000 USP units of heparin per liter of collected blood).  If not used immediately, the blood can be refrigerated at 2 to 8º C, but should be used within 48 hours of drawing.  Prior to testing, the blood should be filtered and the hematocrit adjusted to a standard level (e.g., 35 +/- 2%). 

2.  For performing paired testing, two separate and identical mock circulation blood loops should be assembled; one for the predicate device and one for the new device.  The components of the flow loops should include a blood pump, hemodialysis tubing with a side-port for drawing blood samples, luer connectors to attach the catheters, a system for measuring the pressure in both the arterial and venous catheter components, a calibrated method to measure blood flow rate, and a reservoir made of a hemocompatible material (which can be heated to physiologically relevant temperatures to hold the blood.  Due to the inherent variability in the blood from different animals, on each test date, the blood should be used from the same blood pool in both mock loops in a paired test configuration (operating under the same flow conditions and at the same time).

3.  Blood pumps used in hemodialysis are positive-displacement roller-occlusive pumps.  Following the User’s Manual, carefully check the occlusion setting of the blood pumps prior to the testing.  To match the flow resistance of the arterial and venous components, compressive clamps can be placed on the tubing to gradually decrease the flow path so that hemolysis is minimized.

4.  The total volume of blood in the two test circuits should be identical and minimized to increase the sensitivity of the testing.  However, the blood volume in the reservoirs must be sufficient that all of the inlet and exit ports of the catheters are completely submerged so that the blood is well-mixed, yet there is not significant mixing at the air-blood interface (e.g., cylindrical containers or blood bags should be considered for use as reservoirs).

5.  Using the paired testing scheme described above, the new devices are typically compared to the predicate device using a sample size of five devices for each cohort.  Testing should be performed at the maximum rated blood flow rate.

Performing the test:

6.  Prior to testing with blood, buffered saline should be circulated through the loop for five minutes to rinse the surfaces.

7.  The blood should be warmed and maintained at a physiological temperature (35– 38ºC) prior to and during the testing, while avoiding exposing the blood to temperatures (e.g., from a water bath) in excess of 39ºC.  The saline from the loop should be drained, the warmed blood should be introduced, and air bubbles should be cleared from the mock circuit.  The blood should be allowed to circulate in the loop for approximately three minutes before taking a baseline sample (time = 0).  The baseline sample should be evaluated for blood hematocrit, total blood hemoglobin concentration, and the plasma hemoglobin concentration.   A validated method should be used to assess the critical measurement parameter, the plasma hemoglobin concentration.12

8.  The in vitro testing with blood is usually conducted for as long as the device will be labeled for use.  For a four hour test, blood samples can be taken at time 0, 30, 60, 120, 180, and 240 minutes for plasma hemoglobin concentration analysis.

9.  To insure a well-mixed blood sample, blood can be gently withdrawn from the tubing Luer side-port.  As the use of small sampling needles may induce hemolysis, it is recommended you use needle-less syringes. Clear the port first by drawing out some fresh blood (1 mL) into a needle-less syringe.  Then, a new syringe should be used to draw out a fresh sample for analysis. It is recommended that two samples be drawn at each time period. You should avoid pulling the plunger of the syringe too rapidly, or pushing the collected blood forcefully into the blood sample collection tube, to avoid pressure or velocity-induced hemolysis.

10.  The catheter pressures, the blood temperatures, and the blood flow rates in each loop should be measured and recorded periodically throughout the testing.

Reporting the test results/ interpretation:

11.  A detailed protocol for performing the blood damage testing should be provided along with a diagram of the in vitro test circuit.  The date, time, and blood pool that were used in each testing circuit should be documented in the final report.

12. The data should be provided in both tabular and graphical format.  The plasma hemoglobin should be reported as a concentration (mg/dL) that increases over time using overlaying line plots for each of the different test circuits.  As these plots are generally linear over time, you can calculate the least squares fit for each of the test circuits.  The slope of the least fit line is the rate of plasma hemoglobin generation.

13. Mean (+/- SD) results should also be tabulated and graphed for each of the different catheter groups and mock circuits. 

14. Using paired statistical testing between the matched individual test circuits, you should compare the rate of plasma hemoglobin generation between the new and the predicate catheters. 

1 The currently FDA recognized versions of the following standards may apply to connectors for implanted blood access devices: ISO 80369: Small-bore connectors for liquids and gases in healthcare applications and ISO 594: Conical fittings with a 6 % (Luer) taper for syringes, needles and certain other medical equipment – Part 1: General requirements

FDA’s currently recognized version of standards and the extent of recognition can be located via FDA’s standards database.

2 A legally marketed device, as described in 21 CFR 807.92(a)(3), is a device that (i) was legally marketed prior to May 28, 1976 (preamendments device), for which a PMA is not required; or (ii) has been reclassified from Class III to Class II or I; or (iii) has been found SE through the 510(k) process. The legally marketed device for purposes of determining substantial equivalence is commonly referred to as the “predicate device.”
Section 513(i) of the FD&C Act states that for a new device to be considered substantially equivalent to a predicate device, the new device must have the same intended use as the (primary) predicate device and the same technological characteristics or different technological characteristics that do not raise different questions of safety and effectiveness than the predicate device.

3 See Preamendment Status.

4 Patients are exposed to hemodialysis catheter and shunt materials over a long period of time, and potentially with repeated use.  A long-term (90 to 120 days) implantation study with histopathology may replace sub-chronic toxicity.

5 The priming volume is the amount of fluid required to fill the inside of the catheter from the hubs to the tip.

6 FDA’s currently recognized version of standards and the extent of recognition can be located via FDA’s standards database.

7 21 CFR 820.184 Device History Record

8 CDRH has issued draft guidance on Premarket Notification [510(k)] Submissions for Medical Devices that Include Antimicrobial Agents.  When finalized, this guidance will represent the Center’s current thinking on this topic.

9 ASTM F1830-97: Standard practice for selection of blood for in vitro evaluation of blood pumps.  American Society for Testing and Materials (ASTM) International, West Conshohocken, PA.

10 ASTM F1841-97: Standard practice for assessment of hemolysis in continuous flow blood pumps.  American Society for Testing and Materials (ASTM) International, West Conshohocken, PA.

11 Guidance for cardiopulmonarybypass oxygenators 510(k) submissions; Final guidance for industry and FDA staff

12 Mueller, MR, Schima, H, et al.  In vitro hematological testing of rotary blood pumps: Remarks on standardization and data interpretation.  Artificial Organs, 17(2): 103-110, 1993.

13 Malinauskas, R.  Plasma hemoglobin measurement techniques for the in vitro evaluation of blood damage caused by medical devices.  Artificial Organs, 21(12): 1255-67, 1997.

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