Memorandum of Understanding
The National Institute of Standards and Technology
The Food and Drug Administration
November 10, 1993
This memorandum of understanding (MOU) between the U.S. Department of Commerce, National Institute of Standards and Technology (NIST) and the U.S. Department of Health and Human Services, Food and Drug Administration (FDA) has been implemented to facilitate the development of Standard Reference Materials (SRMs) for materials used in medical implant applications. These materials are commonly referred to as biomaterials.
The National Institute of Standards and Technology has, as one of its long-standing programs, the development of and marketing of standard reference materials required for precision metrology in a variety of applications. The Food and Drug Administration is responsible for the regulation of medical devices made from biomaterials. For many of these biomaterials, it has been determined that subtle variations in chemical composition, trace element content, crystalline structure or morphology, homogeneity, surface topology and chemistry, and other material characteristics can significantly alter the response of living tissue (i.e. the body) to a material, either as an implant or by external contact. Thus the availability of well-characterized reference materials for use in generating baseline data on the biological performance of a biomaterial, is essential.
The parties to this MOU will collaborate in a program to develop (SRMs) for a variety of biomaterials. This collaboration will enable NIST to enhance its activities in the biomedical area and increase the utility of its SRM Program by addressing many critical measurement needs in the assessment of biomaterials and medical devices. The SRM Program at NIST will gain marketable SRMs for biomaterials, an area in which NIST has had no previous products. At the same time, FDA will be assuring the availability of well-characterized and uniform reference materials for the comparative evaluation of new materials and devices. Evaluation of biological performance data based on comparison to previously-used and successful products will be both facilitated and improved.
1. Selection of Materials — Candidate materials for SRM development will be selected by mutual agreement between FDA and NIST. The goal is to provide more realistic calibration standards for the determination of physical, chemical, electrical, and biological characteristics and/or properties of biomaterials. Criteria for selection will include magnitude of the current or potential utilization of the material in biomedical applications, documented or reasonably foreseeable variability in response from "off-the-shelf" materials, critically of the medical application, cost of developing and potential market for the SRM, and others mutually agreeable to both parties. At the time of selection, the properties and characteristics to be controlled and measured will be identified for each candidate SRM, as will be the proposed unit size for distribution.
1a. An initial listing of candidate materials proposed at the time of the initial agreement is given in Appendix A. Materials 1&2 were developed as a collaborative research iniative between FDA and the American Dental Association (ADA) at both the FDA and NIST laboratories. Material 1 has been provided to NIST for consideration as an SRM. Material 2 which is currently being synthesized will be provided on or about September 1993. No development work has been done on materials 3-8.
2. Production of Materials — SRMs will be developed by any of several laboratories, including NIST, FDA, NIH, commercial materials suppliers, device manufacturers, academic institutions, and others. A Material Safety Data Sheet (MSDS) will be required from the supplier of all component materials and precursor/catalyst/ancillary materials used in the production of SRMs developed under this MOU.
3. Certification — NIST will determine and specify what testing must be performed and be the sole reviewer of the adequacy of data used in the qualification of SRMs developed under this MOU. NIST reserves the right to refuse distribution of materials if the data are inadequate. All SRMs developed under this program will be supplied with NIST certification for the properties/characteristics deemed critical to the application.
4. Packaging — NIST will determine for each SRM the appropriate source of packaging, either in-house or contract. Contract packagers will seal the entire shipment in appropriate packages for shipment to NIST.
5. Replenishment — NIST agrees to assume the responsibility for replenishment of stocks for SRMs for which the market is at a level that is financially beneficial to the Standard Reference Materials Program.
6. Program Funding — FDA does not commit to providing any funding or equipment to NIST or any selected SRM producer, or to providing any laboratory effort in the development, characterization, or production of SRMs being developed under this program.
COSTS AND PRICING
1. Initially, FDA will provide 900 grams of hydroxyapatite (material 1, Appendix A) and 1000 grams of -Tricalcium Phosphate (material 2, Appendix A) to NIST for use as an SRM. No compensation to FDA is required for this initial supply of material. Monies collected from the sale of the SRMs which is over and above the cost to produce, characterize and package the materials will be used for additional SRM development.
2. NIST will have final authority over all matters pertaining to pricing policy and for setting the price of individual SRMs.
1. SRMs developed in whole or in part by FDA prior to or under this MOU, which remain unsold and are deemed by NIST, to be technologically obsolete or otherwise no longer acceptable as SRMs, may be removed from the NIST inventory without liability for reimbursement to FDA by NIST.
If FDA desires such products returned to FDA, NIST wil do so at FDA's expense after removal of SRM certification.
2. The official representatives of the respective organizations will be:
Division of Mechanics and Materials Science
Office of Science and Technology
Center for Devices and Radiological Health
Standard Reference Materials Program
Office of Measurement Services
1. This MOU will become effective 30 days after being signed by the appropriate authorities at both NIST and FDA. It will remain in effect until terminated.
2. Either NIST or FDA may unilaterally terminate this MOU by providing the other party written notice. It will become ineffective 60 days after such notice is delivered.
PURPOSE: Development of a series of Calcium-Phosphorous based SRMs for use in determining the composition of mixtures of calcium phosphate based biomaterials or biomaterial coatings.
Proposed Calcium Phosphate Reference Biomaterials
|1. Ca3(PO4)3OH||Hydroxyapatite||Ca/P = 1.67|
|2. Ca3(PO4)2||Tricalcium Phosphate||Ca/P = 1.50|
|3. Ca3(PO4)2||Tricalcium Phosphate (amorphous)||CA/P = 1.50|
|4. Ca4(PO4)2O||Tetracalcium Phosphate||CA/P = 2.0|
|5. Ca3(PO4)2||Tricalcium Phosphate||CA/P = 1.50|
|6. Ca2P2O7||Calcium Pyrophosphate||CA/P = 1.0|
|7. CaO||Calcium Oxide||NA|
|8. Ca10(PO4)5F2||Fluorapatite||CA/P = 1.67|
Approved and Accepted
Signed by: Peter L.M. Heydemann, Ph.D.
Date: January 14, 1994
Signed by: Thomas E. Gills
Date: January 14, 1994
Approved and Accepted
Signed by: D. Bruce Burlington, M.D.
Date: November 19, 1993