A large range of medical devices access the vasculature in a minimally invasive manner, usually percutaneously. Rigorous testing is required for design verification, CE-marking and US FDA submissions of these products. As an example, an overview is provided of the requirements for design validation of an intravascular stent and its delivery system.
Share [4]
Product classification
Food and Drug Administration (FDA) guidance describes intravascular stents as Class III devices that require pre-market approval (PMA).1 This involves a clinical study prior to marketing and a postmarketing surveillance study. This article considers only the non-clinical test requirements. In addition, specific FDA guidance is published for drug eluting stents,2 which is not discussed here. Under the revised European Medical Device Directive (93/42/EEC) devices designed for use in the central circulatory system are classified as Class III products.Non-clinical testing can be broadly divided into biological evaluation and functional testing. Functional testing includes how the device works and its durability and packaging, and sterility studies.
Biological evaluation
The guidance provided in the ISO 10993 series, Biological Evaluation of Medical Devices, is broadly accepted worldwide.3 ISO 10993 Part 1 details the types of test that should be considered, but manufacturers intending to market in the United States (US) where requirements can be more stringent should also be aware of the useful guidance provided in ASTM F748-04.4
Biological evaluation should be considered in terms of the toxicological risk to patients and draw on the nature of the materials, the literature, the biological data and the clinical purpose and environment. Toxicological risk assessment should be performed in accordance with the guidance provided in ISO 14971.5 This can be applied to reduce the amount of biological testing required if a predicate device exists or the material(s) have a documented history of use in other medical devices.
Parts 18 and 19 of the ISO 10993 series address the chemical and physico-chemical characterisation of medical device materials, including potentially hazardous extractables and leachables. It is recommended that manufacturers using new or novel materials or manufacturing processes perform a thorough characterisation at an early stage of the research and development process and use the information in a first toxicological risk assessment.
Biological evaluation plans for two devices are presented: a (European regulated) Class III intravascular stent and its Class IIa delivery system, as defined by FDA. Manufacturers should be aware that if the two products are marketed in Europe as a single device then the whole system becomes Class III, which means that the delivery system must also be treated as a Class III device and undergo more stringent testing.
ISO 10993 Part 1 recommends that a Class IIa device is subjected to cytotoxicity, acute systemic toxicity and irritation testing. These address the short-term biocompatibility of the materials because the stent delivery system is in contact with the patient only for a short period of time (circulating blood contact, under 24 hours). In addition, because the delivery system comes into contact with circulating blood, a haemocompatibility test is recommended. The test data can then be fed into a further round of toxicological risk assessment. ISO 10993 Part 4, regarding haemocompatibility, lists 25 different categories of test and therefore manufacturers should consider their strategy carefully and are advised to discuss it first with their regulatory agency. A typical set of tests for a stent delivery system may include thrombosis, coagulation, platelet count, haematology (two tests) and a complement activation panel for immunology.
As a Class III, long-term implant device that contacts circulating blood, the intra-vascular stent should be subjected to
additional tests that address the potential longer term effects: sensitisation, geno-toxicity, chronic toxicity, local and systemic toxicity and carcinogenicity. In Europe, two in vitro genotoxicity tests (ISO 10993 Part 3) are usually performed; in the USA, FDA also requires an in vivo study to assess the mutagenic potential of stent extracts.
additional tests that address the potential longer term effects: sensitisation, geno-toxicity, chronic toxicity, local and systemic toxicity and carcinogenicity. In Europe, two in vitro genotoxicity tests (ISO 10993 Part 3) are usually performed; in the USA, FDA also requires an in vivo study to assess the mutagenic potential of stent extracts.
It should not be necessary to perform both subchronic and chronic studies, but the more appropriate one should be chosen and justified. Local effects after implantation should also be evaluated.
Functional testing of a delivery system
| TABLE I: Summary of functional test requirements for an intravascular stent delivery system. | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
The majority of the functional assessments for a delivery device are described in ISO 25539-1:2003, Cardiovascular Implants, Endovascular Devices.6 This standard provides a guide to design verification. The tests encompass strength and durability, dimensional characteristics, and forces to deploy and remove. Important strength factors are tensile strength of all joints, circumferential strength, kink resistance in bending and rotational rigidity. Other more subtle characteristics are the acceptability and robustness of user ergonomics and the low trauma requirements of components passing through vessels.
Test benches are available that simulate different vascular geometries and allow insertion and removal forces of the delivery systems being analysed. These benches can simulate blood flow within the vasculature and a variety of vessel wall compliances. Also, linear force transmission, torque transmission and resistance to kinking can be evaluated this way. The test requirements are summarised in Table I.
Functional testing of a stent
Implanted devices such as stents are required to function for a long period (usually as a permanent implant) in a hostile environment. Durability testing is critical in proving that performance does not decay in vivo. To provide evidence of this within a reasonable time scale, testing is performed at an accelerated rate. This testing involves pulsing a number of stents (within artificial vessels at body temperature) at a higher frequency that is above the biological rate. This simulates conditions in the body and provides quicker feedback on performance.
Typically, 10 years use is simulated over 400 million cycles. The product under test is periodically examined under the microscope to identify any early signs of fatigue and any particles released are trapped for analysis. Following fatigue testing, a full examination of mechanical and surface properties is performed including electron microscope analysis. Mechanical testing includes a comparison of tensile strengths, burst resistance and crush resistance before and after use.
All testing should be performed on samples that are representative of the finished product. They should have undergone all production processes including maximum sterilisation and have any surface coatings in place.
| TABLE II: Summary of functional test requirements for a stent. |
||||||||||||||||||
|
||||||||||||||||||
The outward radial force delivered by a stent is also an important factor because it may damage a vessel wall or become dislodged if it is too loose. Sophisticated equipment is available for mapping this force against an array of pressure sensors. Equally, the vessel wall may collapse a stent and hence the stiffness and radial strength (defined as force to produce permanent distortion) are important. Similarly, flexural testing is important for stents and grafts. This information should be combined with a stress analysis.
In vitro testing should be combined with finite element, stress–strain analysis using data on the mechanical properties of materials combined with stent design and stress history during fabrication and use. The behaviour of stents during delivery is also critical. The retention force of the stent on its shaft should be detailed as well as any dimensional changes occurring during deployment (recoil and foreshortening). Test methods for dimensional changes are described in ASTM 20797 and ASTM 2081.8
Corrosion is of particular concern for metallic stents and there are a variety of standards recommending test methods. Significant among these is ASTM F2129-06.9
Magnetic resonance imaging compatibility, that is, force and heating should be demonstrated, including effects from damaged and overlapping stents as well as any heat effect on drug elution. ASTM F2213-0610 and ASTM F2052-06e111 give advice here. The test requirements are summarised in Table II.
Important points to remember
The biological and functional evaluation of a new medical device should be planned early during the research and development phase, bearing in mind prior history of the materials in medical devices, the chemical characterisation of the materials and the available literature. Companies should discuss their strategy with their regulatory agency; both parties will benefit. It is essential to bear in mind the regulatory differences of the target markets and to use a risk based approach. Also, be certain of the device classification and subject all biological data to toxicological risk assessment. As with any medical device, the testing requirements are dictated by the product claims and risk analysis. The degree of
novelty of designs, materials and production methods will have a considerable bearing on the risk analysis. Fatigue testing for implants is essential, as are a large range of dimensional and build quality tests.
novelty of designs, materials and production methods will have a considerable bearing on the risk analysis. Fatigue testing for implants is essential, as are a large range of dimensional and build quality tests.
The information provided in this article is not comprehensive and is supplied as an overview guide. Companies should consult with regulatory experts and the appropriate regulatory authorities to ensure that they have addressed all their requirements. More information on bench testing can be requested from the author.
References
1. Guidance for Industry and FDA Staff, Non-Clinical Tests and Recommended Labelling for Intravascular Stents and Associated Delivery Systems, 1 January 2005.
2. Guidance for Industry: Coronary Drug-Eluting Stents- Nonclinical and Clinical Studies,
27 March 2008.
27 March 2008.
3. ISO 10993, Biological Evaluation of Medical Devices.
4. ASTM F748-04, Standard Practice for Selecting Generic Biological Test Methods for Materials and Devices.
5. ISO 14971, Application of Risk Management to Medical Devices.
6. ISO 25539-1:2003, Cardiovascular Implants, Endovascular Devices.
7. ASTM F 2079, Standard Test Method for Measuring Intrinsic Elastic Recoil of Balloon-Expandable Stents.
8. ASTM F 2081, Standard Guide for Characterisation and Presentation of the Dimensional Attributes of Vascular Stents.
9. ASTM F2129-06, Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices.
10. ASTM F2213-06, Standard Test Method for Measurement of Magnetically Induced Torque on Medical Devices in the Magnetic Resonance Environment.
11. ASTM F2052-06e1, Standard Test Method for Measurement of Magnetically Induced Displacement Force on Medical Devices in the Magnetic Resonance Environment.
Other standards of interest
- ISO 11070: 1998, Sterile, Single Use Intravascular Catheter Introducers.
- ISO 10555-1:1995, Sterile, Single Use Intravascular Catheters, Part 1: General Requirements amended in 1999 and 2004.
- ASTM F 2004, Standard Test Method for Transformation Temperature of Nickel-Titanium Alloys by Thermal Analysis.
- ASTM F 2082-02, Standard Test Method for Determination of Transformation Temperature of Nickel-Titanium Shape Memory Alloys by Bend and Free Recovery.
- ASTM F746 – 04, Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant Materials.
- ASTM F2119 – 07, Standard Test Method for Evaluation of MR Image Artifacts from Passive Implants.
Mark Turner
is Sales Director at Medical Engineering
Technologies Ltd, Yew Tree Studios, Stone Street, Stanford North, Ashford TN25 6DH, UK tel. +44 8454 588 924
e-mail: m.turner@met.uk.com [5]
Technologies Ltd, Yew Tree Studios, Stone Street, Stanford North, Ashford TN25 6DH, UK tel. +44 8454 588 924
e-mail: m.turner@met.uk.com [5]
www.met.uk.com [6]