There are many products containing hyaluronic acid (HA) in its various forms and concentrations at the modern market of health products. We will name only some of these products - synovial fluid prostheses for intra-articular injection, cosmetic fillers, viscoprotectors (viscoelastics) for ophthalmology. All these products are traditionally classified as medical device, both in our country, and in Europe and the USA. The State Register of Medical Devices of the Russian Federation contains a sufficient number of examples of registered products (http://www.roszdravnadzor.ru/services/misearch).
The reason for this classification is the special mechanical viscoelastic properties of HA, which is its main mechanism of action. When injected into the cavity of the joint affected by osteoarthritis, the synovial fluid prostheses mechanically “pushes” the affected articular surfaces from each other, allowing them to recover. A cosmetic filler mechanically fills skin folds (wrinkles), smoothing the surface. A viscoprotector becomes a barrier that mechanically protects the sensitive cellular layers of the eye from a potential injury. Thus, these products fall under the definition given in Article 38 of the Federal Law Basics of Health Protection of the Citizens in the Russian Federation: “... whose functionality is not implemented via pharmacological, immunological, genetic or metabolic effects on the human body.”
Is this classification correct? Arguments continue since its occurrence.
Studies on the properties of HA are far from complete. What is the primary mechanism of action of hyaluronic acid – mechanical or metabolic action? The scope of application of products containing hyaluronic acid is rather wide, and its positive effects are diverse and sometimes unexpected. References to a number of studies of the mechanism of action and effects of HA are provided at the end of this article.
On December 17, 2018, the US Food and Drug Administration (FDA) published on its website a statement of intent to review the classification of HA products for intra-articular administration in osteoarthritis. They propose to “reclassify” these products from medical devices into medicinal products. The respective statement is posted on the website (https://s3.amazonaws.com/public-inspection.federalregister.gov/2018-2735...).
In the USA, these products have been classified for almost 23 years as medical devices of risk class III, and have the appropriate product code: “MOZ”, and the description “Acid, Hyaluronic, Intraarticular”.
According to the FDA, the latest scientific publications confirm the hypothesis that the primary mechanism of action of HA on pain syndrome in knee osteoarthritis is its “chemical effect on the body” (in the terminology of Section 210 (h) FD&C Act). Moreover, the anesthetic and anti-inflammatory effect of the synovial fluid prosthesis with HA persisted for a long period after administration, which, according to the FDA, is also not related to the mechanical action.
Since pain syndrome in osteoarthritis is considered by many leading experts to be the primary one, all the efforts of doctors should be aimed first of all to relieve pain syndrome. Consequently, a synovial fluid prosthesis containing HA and relieving pain syndrome due to the currently confirmed “chemical” rather than mechanical action, automatically loses the status of a medical device.
This FDA statement arouse a storm of indignation among industry experts and confused many registration applicants (PMA - Premarket Approval) of these products. Experts are outraged by the FDA’s voluntaristic approach, the absence of any public discussion and the violation of the formal procedure for making such a decision. The issue with classification of HA products is not new, and discussions have been going on for a long time, but the unexpected FDA statement caused, at a minimum, complete bewilderment.
As a solution to the problem, the FDA offers applicants to reconsider the purpose of the product, indications and composition, as well as obtain a preliminary decision on the classification by submitting a corresponding application (Pre-RFD) before submitting the dossier.
What should we expect? Synovial fluid prostheses for intraarticular injection have always been a challenge for state registration in the Russian Federation, and it has always been necessary to present facts confirming their mechanical, rather than metabolic mechanism. It is possible that such a "reclassification" will also affect us. In this case, I would like to hear the opinion of the Federal Service on Surveillance in Healthcare (Roszdravnadzor).
At the same time, everyone should keep in mind that technical, normative and operational documentation cannot be simply updated from a “medical device” to a “medicinal product”, and the legal status of a product cannot be changed that easy. This is a complicated and lengthy process that can take up all the time of regulatory departments of manufacturing companies. Accordingly, the launch of new products on the market may be delayed, and their prime cost may increase.
Mikhail Vinogradov, Senior Manager Regulatory Affairs (Medical Devices).
The list of scientific works to which FDA refers:
1. Vasi, A.M., M. Popa, M. Butnaru, et al., "Chemical Functionalization of Hyaluronic Acid for Drug Delivery Applications." Materials Science and Engineering, 38: 177-185, 2014.
2. Altman, R.D., V. Dasa, and J. Takeuchi, "Review of the Mechanism of Action for Supartz FX in Knee Osteoarthritis." Cartilage, 9: 11-20, 2018.
3. Greenberg, D.D., A. Stoker, S. Kane, et al., "Biochemical Effects of Two Different Hyaluronic Acid Products in a Co-Culture Model of Osteoarthritis." OsteoArthritis and Cartilage, 14: 814-822, 2006.
4. Jahn, S., J. Seror, and J. Klein, "Lubrication of Articular Cartilage." Annual Review of Biomedical Engineering, 18: 235-258, 2016.
5. Trouvin, A.-P. and S. Perrot, "Pain in Osteoarthritis. Implications for Optimal Management." Joint Bone Spine, 85: 429-434, 2018.
6. Balazs, E.A., "The Physical Properties of Synovial Fluid and the Special Role of Hyaluronic Acid." In Disorders of the Knee, A. Helfet, pp. 63-75. Philadelphia: Lippincott Company, 1974.
7. Liao, Y.-H, S.A. Jones, B. Forbes, et al., "Hyaluronan: Pharmaceutical Characterization and Drug Delivery." Drug Delivery, 12: 327-342, 2005.
8. Moreland, L.W. "Intra-Articular Hyaluronan (hyaluronic acid) and Hylans for the Treatment of Osteoarthritis: Mechanisms of Action." Arthritis Research and Therapy, 5: 54-67,
9. Altman, R.D., A. Manjoo, A. Fierlinger, et al., "The Mechanism of Action for Hyaluronic Acid Treatment in the Osteoarthritic Knee: A Systematic Review." BMC Musculoskeletal Disorders, 16: 321, 2015.
10. Richards, M., J. Maxwell, L. Weng, et al., "Intra-Articular Treatment of Knee Osteoarthritis: From Anti-inflammatories to Products of Regenerative Medicine." The Physician and Sportsmedicine, 44: 101-108, 2016.
11. Nicholls, M., A. Fierlinger, F. Zaizi, et al., "The Disease Modifying Effects of Hyaluronan in the Osteoarthritic Disease State." Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders, 10: 1-10, 2017.
12. Migliore, A. and S. Procopio, "Effectiveness and Utility of Hyaluronic Acid in Osteoarthritis." Clinical Cases in Mineral and Bone Metabolism, 12: 31-33, 2015.
13. Schaible, H.-G., F. Richter, A. Ebersberge, et al., "Joint Pain." Experimental Brain Research, 196: 153-162, 2009.
14. Chen, L., J. Xue, Z. Zheng, et al., "Hyaluronic Acid, an Efficient Biomacromolecule for Treatment of Inflammatory Skin and Joint Diseases: A Review of Recent Developments and Critical Appraisal of Preclinical and Clinical Investigations." International Journal of Biological Macromolecules, 116: 572-584, 2018.
15. Strauss, E., J. Hart, M. Miller, et al., "Hyaluronic Acid Viscosupplementation and Osteoarthritis: Current Uses and Future Directions." The American Journal of Sports Medicine, 37: 1636-1644, 2009.