ChapTEr III.2.3 Voluntary Consensus Standards 1399

First human use is often performed outside the United States, since other countries typically have a shorter review and approval cycle, lower costs, and faster patient recruitment. In addition, in the event a start-up must make modifications to its device or protocol after these trials, there will often be less adverse publicity than if the trials occurred in the US.

Validation of Clinical Utility

Validation of clinical utility occurs upon early statistical confirmation of what had heretofore been anecdotal evi-dence of product and procedural value.

Trial results from the initial human use site provide the first data used for this validation. This data – including description of device, protocol, clinical outcomes, eco-nomics, post-procedure recovery, and other parameters of the trial – is measured, captured, and made available for others to review. While early clinical adopters may be willing to use devices that have limited human use, the average practitioner will wait for test results from numerous users at several institutions. And the more serious the indication, the more conservative the average practitioner will be.

The difficulty is that some devices – especially biomaterials-based ones – can require extensive time and large numbers of patients for true validation. A new drug-eluting stent will take at least 6–12 months (perhaps more) of patient follow-up in hundreds or thousands of patients before most clinicians will have confidence in its performance. A new orthopedic implant may take many years before the true story is known.

approval for Use

This occurs upon clear and unequivocal receipt of notice from a regulator that the company is cleared for com-mercial launch. For more information, see the “Regula-tory Strategy” section above.

Expanded Clinical Use

The product is in general market release, in use by main-stream clinicians. It has been estimated that 5–10% of clinicians can be characterized as “early adopters” will-ing to use a product before it is widely accepted. But mainstream users need more. They rely on things such as testimonials from one or more early adopters, discussion at medical conferences, and journal articles. The product still requires user training and sales, but there is much less “missionary” selling; most potential users are aware of the new technology, and it requires just a little bit of persuasion to give them the confidence to try it.

Standard of Care

By this phase, the product is in widespread use by main-stream clinicians as part of their standard patient practice. By the time a product has achieved this market-leading milestone, it usually will have large competitors mak-ing knock-offs with incremental or substantial improve-ments. One sure indication that a device or technology has reached this milestone is when the device and related procedures are taught in medical schools and residency programs. But by then, the start-up is no longer a start-up. It will have typically sold the business or licensed the product to a large medical device company or in rare cases will be a large company itself.

The Next phase

A new idea or invention! And the cycle begins anew.

BIBLIOGRAPHY

Zenios, S., Makower, J., Yock, P., Editors (2010). Biodesign: The Process  of  Innovating  Medical  Technologies (1st ed.). MA, USA: Cambridge University Press.

CHAPTER III.2.3 VOLUNTARY CONSENSUS STANDARDS

Jack E. LemonsUniversity Professor, Schools of Dentistry, Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, USA

WHAT ARE STANDARDS?

Consensus standards are documents that have been developed by committees to represent a consensus opin-ion on test methods, materials, devices or procedures. Most standards organizations review their documents within five years to ensure that they are up-to-date. The mechanisms by which they are developed are described in subsequent sections. Development of standards is an

ongoing process, and the latest publications should be consulted for new standards.

A test method standard describes the test specimen to be used, the conditions under which it is to be tested, how many specimens and what controls are to be tested, and how the data are to be analyzed. Many methods are validated by “round-robin testing,” meaning that several laboratories have followed the method and their results are analyzed to determine the degree to which they agree to a specified degree of precision and accuracy. Once a test method has been standardized, it can be used in any other laboratory; the details are sufficient to ensure that different facilities will obtain similar results for the same samples. Stating that a test was “conducted in accordance with…” ensures that the results can be duplicated. Some representative test methods are listed in Table III.2.3.1.

1400 SECTION III.2 Voluntary Standards, Regulatory Compliance, and Non-Technical Issues

A material or specification standard describes the chemical, mechanical, physical, and electrical proper-ties of the material. Any test method standards cited are to be used to ensure that a significant sample meets the requirements of the standard. Some representative material standards are listed in Table III.2.3.2.

For implant materials, there is also a requirement that the materials meet general biocompatibility test criteria. There are two formats for the biocompatibility language

in the material standards of the American Society for Testing and Materials (ASTM). For materials that can be well-characterized by chemical, mechanical, and physical tests, and have demonstrated a well-characterized biologi-cal response, reference to the published biological testing data and clinical experience is often sufficient. For materi-als that are not well-characterized, for example, the wide class of materials called epoxy resins, biological test meth-ods are cited, and each particular formulation must be tested independently. This area is evolving for combina-tion biological and synthetic (tissue-engineered) products.

A device standard describes the device and its laboratory-based performance. General design aspects, dimensions, and dimensional tolerances are given using schematic drawings. The materials to be used are described by refer-ence to materials standards. Methods for testing the device are also cited. Since test methods only describe how to do a test, it is in the device-related standards that performance is addressed. For example, the fatigue life requirements of biocompatibility requirements of the device and its materi-als would be stated in a device standard. Some representa-tive device standards are listed in Table III.2.3.3.

TaBLE I I I .2.3.2 Some Typical ASTM Materials Standards (4)

ASTM F75 Cast cobalt-chromium-molybdenum alloy for surgical implant applications

ASTM F139 Stainless steel sheet and strip for surgical implants (special quality)

ASTM F451 Acrylic bone cementsASTM F603 High-purity dense aluminum oxide for surgical implant

applicationsASTM F604 Silicone elastomers used in medical applicationsASTM F641 Implantable epoxy electronic encapsulants

ASTM: American Society for Testing and Materials

TaBLE I I I .2.3.3 Some Representative AAMI and ASTM Device Standards

AAMI CVP3 Cardiac valve prosthesesAAMI VP20 Vascular graft prosthesesAAMI RD17 Hemodialyzer blood tubingAAMI ST8 Hospital steam sterilizersASTM E667 Clinical thermometers (maximum self-registering,

mercury-in-glass)ASTM F367 Holes and slots with spherical contour for metric cortical

bone screwsASTM F703 Implantable breast prosthesesASTM F623 Foley catheters

AAMI: Association for the Advancement of Medical InstrumentationASTM: American Society for Testing and Materials

TaBLE I I I .2.3.4 Some Representative AAMI (1) and ASTM (4) Procedure Standards

AAMI ROH-1986 Reuse of hemodialyzersAAMI ST19 Biological indicators for saturated steam sterilization

process in healthcare facilitiesAAMI ST21 Biological indicators for ethylene oxide sterilization

processes in healthcare facilitiesASTM F86 Surface preparation and marking of metallic surgical

implantsASTM F561 Retrieval and analysis of implanted medical devices and

associated tissuesASTM F565 Care and handling of orthopedic implants and

instrumentsASTM F983 Permanent marking of orthopedic implant components

AAMI: Association for the Advancement of Medical InstrumentationASTM: American Society for Testing and Materials

TaBLE I I I .2.3.1 Some Representative ASTM Standard Test Methods

A. Mechanical testing standardsASTM D412 Test methods for rubber properties in tensionASTM D638 Test method for tensile properties of plasticsASTM D695 Test method for compressive properties of rigid plasticsASTM D790 Test methods for flexural properties of unreinforced

and reinforced plastics and electrical insulating materialsB. Metallographic methods

ASTM E3 Preparation of metallographic specimensASTM E7 Terminology relating to metallographyASTM E45 Determining the inclusion content of steelASTM E112 Determining the average grain size

C. Corrosion testingASTM G3 Conventions applicable to electrochemical

measurements in corrosion testingASTM G5 Reference test method for making potentiostatic and

potentiodynamic anodic polarization measurementsASTM G59 Conducting potentiodynamic polarization resistance

measurementsASTM F746 Pitting and crevice corrosion of surgical alloysASTM F897 Fretting corrosion of osteosynthesis plates and screwsASTM F1875 Practice for fretting corrosion testing of modular

implant interfaces: Hip femoral head-bore and cone taper interface

ASTM F2129 Conducting cyclic potentiodynamic polarization measurements to determine the corrosion susceptibility of small implant devices

D. Polymer testingASTM D2238 Test methods for absorbance of polyethylene due to

methyl groups at 1378 cm−14

ASTM D3124 Test method for vinylidene unsaturation in polyethylene by infrared spectrophotometry

ASTM: American Society for Testing and Materials

ChapTEr III.2.3 Voluntary Consensus Standards 1401

WHO USES STANDARDS?

The term “voluntary standards” implies that the docu-ments are not mandatory; anyone can use them. This terminology also refers to the way that standards are developed. Standards are used by manufacturers, users, test laboratories and, in many instances, college profes-sors and their students. One’s use or compliance with a standard is voluntary. Using them is often to everyone’s advantage. At this time, standards can also be utilized as a part of the regulatory (US Food and Drug Administra-tion (FDA)) approval process.

Manufacturers often use standards as guidelines in making and testing their materials and devices. Manufac-turers also cite standards in their sales literature as a con-cise way of describing their product. Stating that a device is made from cast cobalt-chromium-molybdenum alloy in accordance with ASTM F75 tells the user precisely what the material is. Conformance to standards is also a way to expedite device review by the FDA.

On a more personal level, for example, after purchas-ing a piece of plastic pipe at the hardware store labeled with “ASTM D1784,” one could go to ASTM Volume 8.02 and find that this is a specification for rigid poly (vinyl chloride) compounds. If you have “DIN” stamped on the bottom of your ski boots, you know they conform to the standards of the Deutsches Institut für Normung, and the ski shop will have standards for adjusting your bindings.

As an example of why one would want device stan-dards used for medical devices, consider screws for fix-ing bone fractures. There are device standards for bone screws, plates, taps, and screwdrivers. The physician can purchase a screw and a screwdriver, and be confident that the components will fit as intended. A surgeon about to remove a plate implanted at another hospital can evalu-ate radiographs and see that the device has 4.5 mm bone screws of a specific design. Knowing this, a standard 4.5 mm screwdriver can be used to remove the screws.

Standardized test methods should simplify life. For example, many who teach undergraduate and gradu-ate biomedical engineering courses use standards. In a mechanical testing laboratory, several ASTM standard test methods for mechanical testing, such as D790, “Flexural properties of plastics and electrical insulating materials,” might be used. This method describes the samples, test apparatus, test speeds, and equations used to calculate the results. During a laboratory session, the students follow the test directions. In writing the meth-ods section of their reports, all they had to write is “the test was done according to D790.”

WHO WRITES STANDARDS?

In the United States, voluntary consensus standards are developed by a number of organizations. In the medical electronics, sterilization, vascular prosthesis, and cardiac

valve areas, most standards are developed by committees within the Association for the Advancement of Medical Instrumentation (AAMI). In the implant materials and implants area, most standards are set by ASTM Committee F04 on Medical and Surgical Materials and Devices. These documents may then be reviewed and accepted by the American National Standards Institute (ANSI). ANSI is the official US organization that interacts with other national organizations in developing international standards within the International Standards Organization (ISO), such as TC 150 on Medical Materials and Devices, and TC 194 on Biological Evaluation of Medical Devices. The USP pro-vides information on minimal biocompatibility testing for materials intended to be used in medical devices.

Dental material standards are written by the Ameri-can Dental Association (ADA). Similar committees exist in other countries: the Canadian Standards Association (CSA); the British Standards Institute (BSI); the Associa-tion Française de Normalisation (AFNOR) in France; and the Deutsches Institut für Normung (DIN) in Germany, which is a voluntary organization.

The initiation, development, and process for the com-pletion of national ASTM F04 consensus standards for medical and surgical materials and devices has evolved significantly within recent years. In part, this has been a result of multiple interactions among those involved with the basic sciences, applied research and development, business marketing and sales, clinical applications, regu-latory agencies, professional societies, legal and insurance professions, device recipients, and associated advocacy groups. To establish consensus opinions satisfactory to all of these interest groups is far from a simple process.

history and Current Structure of aSTM F04

The ASTM was organized in 1898, whereas Commit-tee F04 on Medical Devices and Surgical Materials and Devices was founded in 1962. The committee has grown to include a current membership of approximately 600 individuals, representing a variety of disciplines and inter-ests. The ASTM F04 Committee has more than 100 active standards, and is structured into more than 30 techni-cal subcommittees. The overview structure includes five divisions divided according to responsibilities specific to organizational activities (process) or the development of specific types of standard document e.g., full consensus standards include six types: (1) classification; (2) guide; (3) practice; (4) specification; (5) terminology; and (6) test methods, plus a provisional status. The divisions are: (I) resources; (II) orthopedic devices; (III) medical/surgical devices; (IV) tissue engineered products; and (V) administration. Each division is subdivided into subcom-mittees and task groups according to areas of interest and activities. This structure is intended to be flexible and can be rearranged to suit new or more efficient operations at any scheduled meeting of the executive committee. The divisions, subcommittees, and task groups have an

1402 SECTION III.2 Voluntary Standards, Regulatory Compliance, and Non-Technical Issues

appointed chair and vice-chair, whereas the executive is nominated and elected on a two-year cycle.

Standards Development process

After a request for a new standard is received by a member or group (task group or subcommittee) and accepted by the executive committee, a task group activity is initiated. An appropriate chair is recommended and approved by the administrative committees, and the process is started. Consensus standards development follows a reference document for content, form, and structure. An assign-ment of an appropriate document number is made for records purposes, and a staff manager confirms that the committee and subcommittee representation associated with this activity is classified and balanced with respect to producers and non-producers. A first draft of the pro-posed document is reviewed (usually three to five times) before the task force reaches a consensus.

Critical to these proceedings is the necessity that ade-quate information is available within the public domain in order to substantiate the requirements listed with the final standard. If data are limited or unknown, round-robin tests or new test methods must be developed, and then confirmed to be applicable and valid. Sometimes, documents are held until basic (necessary) information for the standard is developed. Again, a standard must be based on known results, and documents are not intended to represent areas of new research.

As a part of the process, once a draft document has been circulated within the task group and consensus is reached, the task group chair may recommend initial voting at the task group level. At this time, the opin-ions gained could lead to further improvements and no formal voting rules are required within the task group interactions. At the next stages, the subcommittees and main committees of ASTM F04 must ensure a balance among the various voting interests, with adequate repre-sentation from the general interest, user, consumer, and producer segments of the membership. The total of the user, consumer, and general interest votes must equal or exceed the number of producer votes. To prevent domi-nation by any one interest group, only one vote per vot-ing interest is permitted. The ASTM staff confirms the numerical status (adequate response and balance) for each formal vote, and all members are permitted to vote on any ballot within their committee and membership. If approved or approved with editorial (no substantive) changes at the subcommittee level, the document pro-ceeds to main committee ballot and society review. If, however, a negative vote is received during formal vot-ing, the task group and subcommittee chairs must resolve the negative to the satisfaction of the negative voter or must provide rational and justification to find the nega-tive voter nonpersuasive. This opinion must be accepted by the task force and approved at the subcommittee and main committee levels by a formal recorded vote based

on written documentation and associated discussions. The staff manager works with the committee to confirm the validity of the vote, and to document the action.

The general experience has been that it requires three to five years (six to ten meetings) to go from a first draft to a full standard accepted at the main committee level. Several procedural steps are also required in the process, including approval of a rationale statement, use of stan-dardized units (SI) and terminology, and acceptance by the editorial and precision and bias subcommittees. At the stage of society acceptance, the final document is reviewed by the Committee on Standards prior to publi-cation by ASTM.

After approval, a given standard may remain “active as published” for up to five years. At five years, that standard must be reaffirmed or revised to suit the infor-mation available at that time. For records purposes, the date of last formal approval is included as a part of the standards designation.

BIOCOMPATIBILITY STANDARDS

There is a wide range of tests that may be used to determine the biological response to materials. Short-term uses require only short-term tests. Long-term uses require tests applicable to the particular device and tissue type. Since not all tests are necessary for all applications, national and international standards organizations have developed matrix documents that indicate what methods are appropriate for specific applications. These docu-ments can be used as guidelines in preparing a submis-sion to the US Food and Drug Administration (FDA) and other national regulatory agencies for approval of a new material or device. Similar matrix documents have been standardized by the CSA, BSI, and ISO. Test method documents have also been developed by the National Institutes of Health (NIH) and the US Pharmacopeia (USP). Guidelines for dental materials have been devel-oped by the ADA and ISO.

Much of the standards activity is now associated with the International Standards Organization (ISO) with biological evaluation of medical devices under the con-sideration of TC 194 and presented in the developing documents of ISO 10993. There are various parts to this document. Part 1 is definitions and the guidance on selec-tion of evaluation test categories that should be done. The other parts of ISO 10993 give more discussion and detail on the selection of individual tests that should be done for a particular biological interaction or biological effort (e.g., contact with blood, systemic toxicity, geno-toxicity). Often, the details of test methods are not given in the ISO documents, and reference is made to other documents such as ASTM and USP standards for proce-dures and methodology.

Material selection and evaluation of biological risk are integral components of the design process for medi-cal devices being considered by TC 194. This evaluation

ChapTEr III.2.3 Voluntary Consensus Standards 1403

is a component of the risk management plan in line with ISO/IEC 14971 – Application of Risk Management to Medical Devices, encompassing identification of all haz-ards and the estimation of their associated risks. Cri-teria to define the acceptable biological (toxicological) risk must be established at the start of the risk assess-ment and design management processes. The biological safety evaluation must be designed and performed to demonstrate the achievement of the specified criteria for safety. Adequate risk assessment requires characteriza-tion of toxicological hazards and exposures. Following the risk management structure described in ISO 14971, a major component in hazard identification is material characterization.

In the following section we review some of the steps taken to establish the biocompatibility of a new material for a specific application, in this case a long-term ortho-pedic implant. We use ASTM standard F748 “Practice for Selecting Generic Biological Test Methods for Mate-rials and Devices” as a guideline. The standard test methods described are those used within ASTM.

In Vitro Tests

F619. Practice for Extraction of Medical Plastics. A method for extraction of medical plastics in liquids that simu-late body fluids. The extraction vehicle is then used for chemical or biological tests. Extraction fluids include saline, vegetable oil (sesame or cottonseed), and water.

F813. Practice for Direct Contact Cell Culture Evalua-tion of Materials for Medical Devices. A cell culture test using American Type Culture Collection (ATCC) L929 mouse connective tissue cells. This method or this type of cell culture method can be used as the first stage of biological testing. It is also used for qual-ity control in a production setting. There are other ASTM standard cell culture methods, and others not standardized by ASTM that could also be used.

F756. Assessment of Hemolytic Properties of Materials. An in vitro test to evaluate the hemolytic properties of materials intended for use in contact with blood. Procedure A is static; procedure B is done under dynamic conditions.

Short-Term In Vivo Testing

F719. Testing Biomaterials in Rabbits for Primary Skin Irritation. A procedure to assess the irritancy of a bio-material in contact with intact or abraded skin. This test would be indicated for surgical glove material or skin dressing.

F720.  Practice  for  Testing  Guinea  Pigs  for  Contact  Allergens:  Guinea  Pig  Maximization  Test. A two-stage induction procedure employing Freund’s com-plete adjuvant and sodium lauryl sulfate, followed two weeks later by a challenge with the extract material. Ten animals per test material.

F749. Practice for Evaluating Material Extract by Intra-cutaneous Injection in the Rabbit. Extraction vehicles (as per F619) of saline and vegetable oil are injected intracutaneously and the skin reaction graded for erythema, edema, and necrosis. Two rabbits per extraction vehicle.

F750.  Practice  for  Evaluating  Material  Extracts  by  Systemic  Injection  in  the Mouse. Intravenous injec-tion of saline extracts and intraperitoneal injection of oil extracts. Animals are observed for evidence of toxicity. Five mice per extract and five mice per extract vehicle controls.

F763.  Practice  for  Short-Term  Screening  of  Implant Materials. This method provides for several implant types and sites for short-term screening in vivo. This method is essentially the first stage of animal testing of solid pieces of the implant material.

F1983.  Assessment  of  Compatibility  of  Absorbable/Resorbable  Biomaterials  for  Implant  Applications. This material type presents unique features for tissue evaluation, in that the materials are not inert, and a chronic inflammatory reaction may be observed dur-ing the degradation period. The time periods at which reactions are examined are based on the anticipated rates of degradation of the test material.

Additional tests for special issues are also included in ASTM standards, such as examination and reactions to particles, immunotoxicity, and retrieval and analysis of implants and tissues.

These are additional in  vivo tests that have not yet been standardized by ASTM:

Thrombogenicity. Tests for the propensity of materials to cause blood coagulation have not been standard-ized. Guidelines for such tests have been developed by the NIH Heart Lung and Blood Institute.

Mutagenicity. There are a number of in vitro and in vivo tests to determine if chemicals cause cell mutations. Although not specifically developed for implants, guidelines do exist as part of the OECD (Organisa-tion for Economic Co-operation and Development) guidelines for testing of chemicals, and within ASTM, e.g., E1262, Guide for the Performance of the Chinese Hamster Ovary Cell/Hypoxanthine Guanine Phos-phoribosyl Transferase Gene Mutation Assay; E1263, Guide for Conduct of Micronucleus Assays in Mam-malian Bone Marrow Erythrocytes; E1280, Guide for Performing the Mouse Lymphoma Assay for Mam-malian Cell Mutagenicity; E1397, Practices for the In  Vitro Rat Hepatocyte DNA Repair Assay; and E1398, Practices for the In Vivo Rat Hepatocyte DNA Repair Assay, which are in Vol. 11.05 of the ASTM Annual Book of Standards.

Pyrogenicity. A pyrogen is a chemical that causes fever. The USP rabbit test is a standard in vivo test. One can also test for bacterial endotoxins, which are pyro-genic, using the Limulus amebocyte lysate (LAL) test.

1404 SECTION III.2 Voluntary Standards, Regulatory Compliance, and Non-Technical Issues

The oxygen carrying cell (amebocyte) of the horse-shoe crab, Limulus polyphemus, lyses when exposed to endotoxin.

Long-Term In Vivo Testing

There are two aspects to the long-term testing issue. One is the response of tissue to the material; the other is the response of the material (degradation) to implantation.

F981. Practice for Assessment of Compatibility of Bioma-terials for Surgical Implants with Respect to Effects of Materials on Muscle and Bone. Long-term implan-tation of test materials in the muscle and bone of rats, rabbits, and dogs. Two species are recommended. For rabbit muscle implants the standard calls for four rabbits per sacrifice period, with one control and two test materials placed in the paravertebral muscles on each side of the spine. For bone implants in rabbits the standard calls for three implants per femur.

A general necropsy is performed at the time of sac-rifice. Muscle and bone implant sites are removed at sacrifice and the implants left in situ until the tissue has been fixed in formalin. Implants may be removed prior to embedding and sectioning.

No standards have been established for any long-term testing of devices. However, for a device intended for a particular application, it is essential to conduct a func-tional device test. For a fracture fixation plate, it could be proposed to use plates to fix femoral osteotomies in dogs. This study would consider the effects of the implant on the tissues, as well as the effect of implantation on the properties of the device, i.e., material degradation.

The methodology for long-term carcinogenicity test-ing of implants also has not yet been standardized by the ASTM, although F1439 (Standard Guide for Perfor-mance of Lifetime Bioassay for the Tumorigenic Poten-tial of Implant Materials) does provide guidelines for test selection. This is normally a life survival and tumor production test, typically in rats. ISO 10993-3 provides considerations for genotoxicity, carcinogenicity, and reproductive toxicity testing with reference to some test methods.

TISSUE-ENGINEERED MEDICAL PRODUCTS

A rapidly evolving area for standards has been tissue-engineered medical products (TEMPs). This area was identified early in the product development cycle, and focused initially on terminology and guidance standard-ization. Combination products, including synthetic and biologic origin biomaterials within bioactive and bio-degradable device designs, required very different types of test for product safety and efficiency. Key within this activity was testing of biocompatibility and meth-ods for sterilization of substances with biologic type

properties. Examples of some standards from the ASTM F04 Division IV documents are provided below.

NANOTECHNOLOGY

The continued expansion of nanotechnology-based medi-cal and dental devices has now evolved as an area in need of standardization. In this regard, higher resolution microscopy and spectroscopy instruments and methods are required, thereby resulting in a focus on test methods and round-robin testing to ensure precision and accuracy. It is anticipated that this area and the need for standard-ization will increase significantly over the next few years.

WORKSHOP AND SYMPOSIA

Planning for a new standard often results in identifica-tion of areas where data are needed prior to developing a consensus standard. As an example, the ASTM F04 annual meetings normally initiate with a workshop or symposium within a pre-identified focus topic. Work-shops include invited short papers with abstracts, usu-ally as half-day sessions where participants are asked to participate in the following subcommittee group meet-ing for standard development. Symposia often follow and require a two-year planning cycle. The meeting is based on peer-reviewed papers and the proceedings are published as a Standard Technical Publication (STP) as a component of the ASTM Journal (ASTMI) or a co-sponsoring professional society document.

Importantly, these meetings, which are open to all stakeholders, provide interactions for acceptance or not of basic data on existing or new surgical implant prod-ucts. Examples of some previous and scheduled ASTM F04 and co-sponsored workshop and symposia titles are listed in Table III.2.3.5.

Biomaterials Biomolecules, Cells, and Tissue-Engineered Constructs for Tissue-Engineered Medical products

Test Methods for F2131-02 In Vitro Biological Activity of Recombinant Human Bone

Morphogenetic Protein-2 (rhBMP-2) Using the W-20 Mouse Stromal Cell Line

F2260-03 Determining Degree of Deacetylation in Chitosan Salts by Proton Nuclear Magnetic Resonance (1H NRM) Spectroscopy

F2259-03 Determining the Chemical Composition and Sequence in Alginate by Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy

Guides for F2450-04 Assessing Microstructure of Polymeric Scaffolds for

Use in Tissue-Engineered Medical ProductsF2064-00 Characterization and Testing of Alginate as Starting

Materials Intended for Use in Biomedical and Tissue-Engineered Medical Products Application

ChapTEr III.2.4 Regulatory Overview for Medical Products Using Biomaterials 1405

F2150-02 Characterization and Testing of Biomaterial Scaffolds Used in Tissue-Engineered Medical Products

F2103-01 Characterization and Testing of Chitosan Salts as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications

F2347-03 Characterization and testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications

F2027-00 Characterization and Testing of Substrate Materials for Tissue-Engineered Medical Products

Test Methods for F2149-01 Automated Analyses of Cells – the Electrical Sensing

Zone Method of Enumerating and Sizing Single Cell Suspensions

Guides for F2212-02 Characterization of Type I Collagen as Starting Material

for Surgical Implants and Substrates for Tissue- Engineered Medical Products (TEMPs)

F2315-03 Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels

INTERNATIONALIZATION OF STANDARDS

The various USA-based standards organizations harmo-nize the consensus standards within the world commu-nities through a number of different interactions. The American National Standards Institute (ANSI) represents many of the standards groups, such as ASTM and AAMI, for the International Standards Organization (ISO). The various committees within the USA act through Tech-nical Advisory Groups (TAGs), and participate within the ISO committees as formal voting participants. Where applicable, considerable similarities exist between AAMI, ASTM, and ISO standards. Although processes are

different within ISO, the outcome is published standard documents.

Organizations such as the ASTM also maintain inter-national structures (ASTMI), where international partic-ipation results in an ASTMI standard and in some cases a memorandum of understanding (MoU) for utilization of the standard as applicable to specific products. In many situations, regulatory organizations such as the FDA seek and accept the most applicable standard(s) related to procedures for product acceptance.

TaBLE I I I .2.3.5 Examples of ASTM and Collaborative Workshop and Symposia Held Using a Consensus Standard Format

1. Porous Implants for Hard Tissue Application, ASTM STP 953, 1987.

2. Calcium Phosphate Coatings for Implants, ASTM STP 1196, 1994. 3. UHMW Polyethylene, ASTM STP 1307, 1998. 4. Synthetic Bioabsorbable Polymers for Implants, ASTM STP 1396,

2000. 5. Bone Graft Substitutes, ASTMI/AAOS, 2003. 6. Spinal Implants: Are We Evaluating Them Appropriately? ASTMI

STP 1431, 2003. 7. Cross-linked and Thermally Treated UHMWPE, ASTMI STP 1445,

2004 8. Titanium, Niobium, Zirconium and Tantalum for Surgical Appli-

cation, ASTMI, 1471, 2006. 9. Osteolysis and Implant Wear: AAOS/NIH, Nov. 2007. 10. Proposed Regulator Strategy for Neurotoxicity Testing, ASTMI/

FDA, Nov. 2009. 11. Fretting Fatigue of Metallic Medical Devices and Materials,

ASTMI E8/F04, Nov. 2009. 12. Symposium on Mobile Bearing Total Knee (MBK) Replacement

Devices, May, 2010. 13. Static and Dynamic Spinal Implants: Are We Evaluating Them

Appropriately? 2010. 14. Workshop on Metal on Metal Total Hip Replacement Devices,

ASTM F04/AAOS, May, 2011.

CHAPTER III.2.4 REGULATORY OVERVIEW FOR MEDICAL PRODUCTS USING BIOMATERIALS

Elaine DuncanPaladin Medical, Inc. Stillwater, MN, USA

INTRODUCTION

Assessment of the safety and effectiveness of new (and the ongoing evaluation of approved) medical devices is challenging. The US Food, Drug & Cosmetic Act amendment in 1976 extended the powers of the US Food and Drug Administration (FDA) over medical devices. The key areas of the FDA that are responsible for the

regulation of therapeutic medical products are the Cen-ter for Biologics Evaluation and Research, the Center for Devices and Radiological Health, and the Center for Drug Evaluation and Research. The FDA’s Center for Devices and Radiological Health (CDRH) is responsible for regulating firms who manufacture, repackage, rela-bel, and/or import medical devices sold in the United States. In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, X-ray systems, ultrasound equipment, micro-wave ovens, and color televisions. Thus, CDRH plays an essential role in promoting and protecting the public health by ensuring that medical devices marketed in the United States provide a reasonable assurance of safety and effectiveness and confer a favorable risk–benefit