1.1 Introduction

Platelet-rich preparations, especially platelet-rich plasma (PRP), have become an increasingly popular treatment for various musculoskeletal injuries. PRP is somewhat unique in that both the device used to concentrate platelets and the subsequent use of the PRP product fall under the purview of the United States Food and Drug Administration (FDA). With increased utilization of PRP, it is important for clinicians to understand the FDA’s regulatory role and stance on PRP. This can be challenging as the various methods of obtaining and processing PRP fall under different areas of FDA regulations.

The purpose of this chapter is to provide meaningful information to common points of confusion regarding the FDA and the use of PRP. A common clinical scenario is presented in an effort to convey the information in a clinically relevant manner.

1.2 Clinical Scenario: The Young Patient with Glenohumeral Arthritis

A 40-year-old manual laborer comes into the office complaining of shoulder pain and dysfunction. Plain radiographs are consistent with advance glenohumeral arthritis and magnetic resonance imaging reveals an intact rotator cuff. The patient has failed conservative management consisting of nonsteroidal anti-inflammatory drugs and formal physical therapy. Current treatment options for this patient include an arthroplasty procedure (hemi vs. total) or an intra-articular injection. Total shoulder replacement has been shown to provide pain relief in young adults, however, 10-year survival rates are low., ¹ Hemiarthroplasty in a young patient provides less predictable pain relief compared with total shoulder arthroplasty and may lead to increased glenoid erosion postoperatively. ² A corticosteroid injection may provide short-term relief, however multiple injections raises concern over damage to the rotator cuff. ^{3 ,​ 4 ,​ 5}

In these situations, the lack of a clear treatment choice often prompts an extended conversation regarding alternative treatment options. In most cases, the goal of treatment is to adequately manage the patient’s symptoms to allow a shoulder replacement to be delayed as long as possible. In this regard, PRP may be a viable treatment option. Although there are no studies to support the use of PRP in the treatment of glenohumeral arthritis, it has been used with some success in treating arthritis of the knee. ^{6 ,​ 7} Additionally, its benign nature as an autologous substance ⁸ and its potential from a biological perspective to reduce proinflammatory mediator production ^{9 ,​ 10} make it an attractive treatment option compared with corticosteroid injections or an arthroplasty procedure.

Following this conversation, the patient decides to try PRP and schedules a follow-up visit for an intra-articular injection. Before the patient’s return visit, numerous questions regarding the FDA and PRP surface. Is it the device or the PRP that is approved? How does the FDA regulate PRP? What does the language in 21 CFR 1271 of the Code of Regulations mean in terms of use of PRP?

1.3 Is It Platelet-Rich Plasma or the Platelet-Rich Plasma Device that Is Approved?

The first point of confusion is in regards to the FDA approval of PRP devices. There are many pathways in which a drug, biologic, or medical device can be brought to the market. The regulatory process in regards to the application of biologics in orthopedics is outlined in a recent review article by Anz et al. ¹¹ In general, drugs are approved via New Drug Applications (NDA) or Abbreviated New Drug Applications (ANDA), utilizing clinical data obtained from an Investigational New Drug (IND) application. Depending upon the type or classification, Biologics may be approved through NDAs, Biologics License Applications (BLA), or cleared via Premarket Notification (510(k)). NDA and BLAs require clinical data obtained from an IND or Investigational Device Exemption (IDE) application; a 510(k) may not require clinical data. Depending upon risk classification, medical devices may either be approved through Premarket Approval (PMA) or a 510(k) clearance. PMAs will require clinical data obtained from an IDE application; a 510(k) may not require the clinical data.

The 510(k) application is for devices that are considered lower risk devices, and determined to be “substantially equivalent” to a previously cleared device. A device under this application is given a 510(k) clearance. ^{12 ,​ 13} An approved device under this application is given a 510(k) clearance. The term “clearance” rather than “approval” is used to note that the device is similar to an existing device, or predicate, and the clearance is limited to the indications of the predicate device. The 510(k) application is the pathway typically used to bring PRP preparation systems to the market. While the 510(k) clearance is important as it allows clinicians access to PRP preparation systems, it can be confusing as to what the clearance actually signifies. In contrast to the IND, IDE, and PMAs, 510(k) applications focus primarily on the safety of a device as well as its performance characteristics and typically do not require supporting clinical data. In its simplest form, a device with 510(k) clearance is considered to be substantially equivalent to a predicate device for a specific indication. ^{12 ,​ 13}

There are numerous PRP preparation systems on the market today with FDA clearance; however, nearly all of these systems have 510(k) clearance for producing platelet-rich preparations intended to be mixed with bone graft materials to enhance bone graft handling properties in orthopedic practices. They are not intended for direct patient applications, such as injection or implantation without prior mixing with bone graft materials. The clearance applies only to the device and its intended use in an operative setting and makes no claim to its effectiveness for a particular indication. This clearance limits marketing of the device to the specific indication for which it was cleared, but it does not restrict or limit the practice of medicine by the clinician. Specifically, a PRP system with 510(k) clearance indicates that the device is (1) safe in that it does not create a platelet preparation that is hazardous or dangerous and (2) that its performance is substantially equivalent to a predicate PRP device meaning it has demonstrated the capability to isolate the platelets from whole blood. The 510(k) clearance applies to producing PRP for use with bone graft materials to enhance bone graft handling properties. In addition, 510(k) clearance is not synonymous with approval for a specific indication. Product approval for a given indication requires a BLA or PMA application, which is a more rigorous and clinically dependent process, centered on establishing safety and efficacy. ¹²

1.4 By Definition, Platelet-Rich Plasma Is a Biologic

Per their Web site, “the FDA is responsible for protecting the public health by regulating human and animal drugs, Biologics (e.g., vaccines and cellular and gene therapies), medical devices, food and animal feed, cosmetics, and products that emit radiation.” ¹⁴ It is natural to ask where does PRP fall among these items. In its simplest form, the term “Platelet-Rich Plasma” refers to a sample of autologous plasma with platelet concentrations above baseline values. ^{15 ,​ 16 ,​ 17} Under this definition, PRP is considered a biologic. Biologics are regulated by the FDA’s CBER.