By Michael E. Trice, MD, with the AAOS Biological Implants Committee

Although the U.S. Food and Drug Administration (FDA) has established policies and procedures to ensure the safety and effectiveness of medical devices before they are marketed in the United States, some devices that make it to the marketplace are subsequently found to be unsafe or ineffective. Hence the need for adverse event reporting.

Orthopaedic biologic implants, which are rapidly entering the marketplace, may pose special challenges for both the FDA and clinicians, underscoring the need for early physician reporting of adverse events in biological-based treatments. This article covers the need for and importance of adverse event reporting, as well as the steps that should be taken if an adverse event is suspected.

What is an adverse event?
The FDA defines an adverse event as “any undesirable experience associated with the use of a medical product in a patient.” The event is deemed serious and reportable if it results in any of the following problems: death, life-threatening circumstances, hospitalization (initial or prolonged), disability, congenital anomaly, or necessity for additional medical or surgical intervention (to preclude permanent impairment or damage to the patient).

Although adverse events associated with orthopaedic biological products that prove to be life-threatening or cause permanent disability are rare, some have been reported, such as the life-threatening complications associated with recombinant human bone morphogenetic protein-2 in cervical spine fusions. Orthopaedic biologic products are more likely to produce adverse events resulting in prolonged hospitalizations or reoperation.

Why is physician adverse event reporting essential?
Manufacturers, institutions, clinicians, and patients may complete adverse event reports for FDA purposes. Adverse event reporting by physicians is especially important to the FDA both because it helps ensure the safety and efficacy of devices and because physicians may be best suited to identify an adverse event and provide valuable information about it.

Postmarket evaluation or surveillance is essential because premarket scrutiny cannot eliminate postmarket problems. (See “Getting to market,” this page). Postmarket surveillance allows for detection of a number of problems (Table 1).

Although the FDA may also conduct postmarket surveillance through epidemiologic studies of medical devices, scientific studies, and field inspection of facilities, the most relevant method for orthopaedic practices is adverse event reporting.

The direct contact that physicians have with patients enhances their integral role in ensuring the safety and efficacy of biologic implants. Physicians often have more information about the patient than do hospitals or manufacturers. As a result, the physician may be best suited to identify an adverse event. An informed physician can often provide more detailed and useful information when reporting an adverse event.

Adverse events have been historically under-reported. The best person to ensure that all potentially adverse events are reported may well be the orthopaedic surgeon because of his/her direct patient contact.

Finally, the inherent limitations in the FDA’s database make physician reporting crucial. Although the FDA can accumulate data confirming the number of adverse events attributed to a given biologic implant, it has difficulty obtaining data on the number of devices in question that are actually being implanted. Without that data, the FDA cannot quantify the actual rate of occurrence. Conscientious reporting of these events by orthopaedic clinicians may help the FDA to determine this rate of occurrence.

Why stress adverse event reporting for biologic implants?
Like all new device genres, biologic implants pose unique challenges for the FDA. The lack of long-term follow-up challenges the FDA’s ability to bring potential advances to the marketplace while ensuring patient safety. Because the premarket approval process may be different for some biologic implants, a potentially higher incidence of unsafe devices may reach the market.

Additionally, because biologic implants often function quite differently than their traditional mechanical counterparts, they may be predisposed to adverse outcomes that are unfamiliar and/or more difficult to discover. The relative newness of these devices may predispose them to unskilled and/or improper use, and the lack of long-term data may mean that unforeseen risks can be identified only after these products reach the market.

Even “predicate biologic devices” (the first commercially available devices or implant of a given genre) are relatively new to the market. The risks of these implants might, therefore, be difficult to quantify. Because many of the risks of other orthopaedic implants (such as metal-backed patellae) were seen only over time, the relative newness of biologic implants may be a cause of concern. Problems with implants may take years to become apparent. Early adverse event reporting may provide the earliest notice of impending widespread failures.

Biologic implants differ from other orthopaedic implants because they are often living implants or implants that have a pronounced influence on the metabolism of living tissues. Other implants are often unchanged structurally and functionally years after implantation, but biologic implants have the potential to be metabolically active as a result of ongoing evolution in their function and their effects on surrounding tissues.

Take, for example, infection transmission in allograft implantation. Allografts may pose a unique risk of transmission of infection caused by improper handling or from diseased donors. Adverse event reports of allograft-related infections might play an integral role in ensuring recipient safety.

The premarket approval process for biologic implants may predispose them to additional risk. For example, products that are “minimally manipulated” may be exempt from the premarket approval process normally mandated by the FDA. A “minimally manipulated” biologic implant is one in which the original structural or biologic features were not altered in the processing or development of the product. Without the traditional premarket approval process, postmarket surveillance may be even more important.

Finally, because some types of biologic implants are relatively new to the market, the rules about their use may be poorly understood and/or unclear. Unskilled or improper use of these devices may occur. Adverse event reporting can help identify potential risks in inadvertent or intentional “off-label use” (the use of products for purposes distinct from those approved or cleared by the FDA).

For example, certain bone plugs have been cleared by the FDA only for backfill of donor sites in osteochondral grafts. However, these devices have been implanted in recipient osteochondral defects with mixed outcomes.

The importance of adverse event reporting for orthopaedic biologic implants is underscored by the experiences of other clinicians. A sobering example is the case of FactorVIII concentrates tinged with human immunodeficiency virus (HIV). When given to patients with hemophilia, these concentrates resulted in a large number of HIV infections. Early adverse event reporting may be the clinician’s only defense against such a tragedy.

If you suspect an adverse event
Although manufacturer reporting of adverse events is mandatory, physician reporting is voluntary. Nonetheless, to ensure the safety and efficacy of biologic products for his or her own patients as well as those of others, if you suspect an adverse event, take the following steps.

Notify the manufacturer of the adverse event—First notify the manufacturer, who is uniquely positioned for early identification of potential problems. Notifying the manufacturer may provide important information that will help prevent future events. A diligent manufacturer might even find clusters of adverse events before the FDA does.

Report the adverse event to the FDA—Notify the FDA using the Med Watch reporting program. This user-friendly program allows reporting online, by telephone (800-FDA-1088), or by fax (800-FDA-1078). The report takes no more than 5 minutes to complete.

Ask the manufacturer if other similar events have been reported—Ask if other events involving the product have been reported. If the manufacturer confirms other reports, it may be sufficient cause for concern that this event may be a greater risk to your patients than was initially perceived. Additional information may help you to decide whether to continue to perform this procedure or wait until longer postmarket follow-up is available.

Search the FDA MAUDE database for similar events—The Manufacturer and User Device Experience (MAUDE) database houses reports of adverse events involving medical devices, including biologic implants. By entering information on the product in question into the database, you may be able to identify other adverse events, which will provide useful information about whether it is an isolated event or a manifestation of a larger problem.

Tell others as well—Although this document focuses on adverse event reporting as it relates to the FDA, your responsibility to report does not end with the FDA. You should also notify the hospital and any relevant committee (such as the hospital’s tissue service in the event of an infected allograft) of adverse events. This will enable the hospital to implement its own corrective actions to ensure patient safety.

Summary
The FDA relies on adverse event reporting to ensure the safety and efficacy of biologic implants. Although reporting is not mandatory, readers should be familiar with the rationale for and methods of reporting adverse events for biologic implants. Prompt reporting may result in improved patient safety and product effectiveness.

Michael E. Trice, MD, is a member of the AAOS Biological Implants Committee; assistant professor, department of orthopaedic surgery, The Johns Hopkins University and director of the Johns Hopkins Cartilage Restoration Center. He can be reached at ehenze1@jhmi.edu

This article was reviewed by the members of the AAOS Biological Implants Committee and Barbara Buch, MD, deputy director of the division of surgical, orthopaedic, and restorative devices in the FDA’s Center for Devices and Radiological Health.

Getting to market
The FDA must strike a delicate balance between serving as the custodian of patient safety and enabling products to get to market quickly so that patients can benefit from advances as soon as possible. Most devices enter the marketplace either by showing “substantial equivalence” or by confirming safety and effectiveness through a premarket approval process.

Substantial equivalence
The term “substantial equivalence” describes a new device that is medically similar to an established product used in the same medical application. Applications for clearance via the substantial equivalence route are termed “510(k)” applications. (See “The 510(k) pathway: Changes may be coming,” AAOS Now, December 2009.) These applications require confirmation that the relevant established devices are safe and effective and that the device purported to be substantially equivalent functions as claimed with respect to its physical properties specifically when tested in an animal model.

Products cleared through this pathway are usually considered medium-risk by the FDA. However, some biologic implants have reached the market through this pathway.

Premarket approval
The premarket approval application process is more rigorous and requires clinical data proving that the implant is safe and effective. Design and manufacturing information is carefully scrutinized, and most products reach the marketplace only after both clinical and nonclinical data is provided. Most devices considered high-risk by the FDA must be approved through this pathway.

Premarket evaluation, however, does not always identify all products or implants that are unsafe or ineffective. Only time and clinical experience can establish the ultimate safety of an implant; thus, the role of adverse event reporting is crucial in identifying potentially unsafe and ineffective devices.

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