The Spine Journal 14 (2014) 560–565
Review Article
Postmarketing safety of biologics and biological devices Emily Jane Woo, MD, MPH* Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, HFM-222, 1401 Rockville Pike, Rockville, MD 20852, USA Received 6 August 2012; revised 27 August 2013; accepted 27 September 2013
Abstract
BACKGROUND CONTEXT: Regardless of study design, the approval process of biologics and biological devices cannot identify every possible safety concern. Postmarketing safety surveillance can provide information based on real-world use of medical products in heterogeneous populations and is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials. PURPOSE: To review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals. METHODS: This is an overview of postmarketing safety surveillance. RESULTS: Review of adverse event reports has resulted in safety notifications, label changes, and publications regarding the safety of biologics and biological devices, such as the risk of airway compromise after the use of recombinant human bone morphogenetic protein in cervical spine fusion, the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, and infections after allograft transplantation of human tissues. CONCLUSIONS: In light of the rapid development of new biologics, postmarketing surveillance is imperative for ensuring that these products are as safe as possible. By reporting adverse events, surgeons and other health care professionals play a key role in improving and refining our understanding of the safety of biologics. Published by Elsevier Inc.
Keywords:
Postmarketing safety; Adverse events; FDA; Medical devices; Biological products; Surveillance; FAERS; MAUDE
Introduction Biologics and biological devices regulated by the Food and Drug Administration (FDA) reach the United States market by starkly different paths [1]. Some are approved or cleared based on a review of their mechanical, chemical, and technological characteristics, whereas others are evaluated in randomized, controlled trials in humans. Even FDA device/drug status: The products mentioned in this article are approved for some indications but not approved for others:Infuse Bone Graft (rhBMP-2): indicated for (1) treatment of acute, open, stabilized tibial shaft fractures, within 14 days after the initial fracture; (2) sinus augmentation and localized alveolar ridge augmentation for defects associated with extraction sockets; and (3) spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L2 to S1. It is not approved for use in cervical spine fusion. Tisseel and Evicel (fibrin sealants): indicated as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques is ineffective or impractical. Artiss (fibrin sealant): indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than or equal to 1 year 1529-9430/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.spinee.2013.09.056
when clinical data are available, the trials may be underpowered to show a statistically significant difference in adverse events; failure to demonstrate such a difference does not mean that the risks in the experimental and control groups are equal, that is, ‘‘absence of proof’’ does not equal the ‘‘proof of absence’’ (Box 1). Moreover, long-term follow-up may be limited and information about a product’s
of age, and to adhere tissue flaps during facial rhytidectomy surgery. It is not indicated as an adjunct to hemostasis. Human tissues (e.g., bone, tendons, and dura): intended for implantation, transplantation, infusion, or transfer into a human recipient; no premarket approval is required. Author disclosures: EJW: Nothing to disclose. No potential conflict of interest exists, nor any funding source. Disclaimer: This article reflects the views of the author and should not be construed to represent the FDA’s views or policies. * Corresponding author. Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, HFM-222, 1401 Rockville Pike, Rockville, MD 20852, USA. Tel.: (301) 827-6088; fax: (301) 827-5218. E-mail address: [email protected] (E.J. Woo)
E.J. Woo / The Spine Journal 14 (2014) 560–565
Box 1. Statistical significance: an example. In each of the following scenarios, 53% of the experimental group and 40% of the control group experienced an adverse event. However, when applying the conventional cutoff of p!.05, one draws different conclusions because the second study is larger and has greater statistical power than the first.
Adverse event observed
Experimental group
Control group
Yes No Total
32 (53%) 28 (47%) 60 (100%)
24 (40%) 36 (60%) 60 (100%)
p5.14 (chi-square).
The evidence is insufficient to say that the risk of the adverse event is different in the two groups, but the results do not prove that the risk is the same. Adverse event observed
Experimental group
Control group
Yes No Total
320 (53%) 280 (47%) 600 (100%)
240 (40%) 360 (60%) 600 (100%)
p!.0001 (chi-square).
It is very unlikely that these results are due to chance alone. One concludes that the risk in the two groups is not the same.
use in specific subpopulations (eg, children, elderly patients, immunocompromised individuals, and women who are pregnant or lactating) might not be available. Because of these limitations, postmarketing safety surveillance is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials. The objective of this article is to review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals.
Adverse event reporting systems The FDA maintains the Manufacturer and User Facility Device Experience [2] (MAUDE) database that contains reports of adverse events involving medical devices, such as those cleared through the 510(k) process (eg pedicle screws; biphasic calcium phosphate granules) and those evaluated under a Premarket Approval (eg, bovine serum albumin surgical sealant; recombinant human bone morphogenetic
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protein 2 or rhBMP-2). The Manufacturer and User Facility Device Experience database includes mandatory reports from manufacturers, distributors, and user facilities and voluntary reports from health care professionals and consumers [2]. The FDA Adverse Event Reporting System (FAERS) is a passive surveillance system that collects reports through the MedWatch system [3–5] and contains reports of adverse events involving licensed blood and cellular products (eg, recombinant coagulation factor VIIa; fibrin sealants; and autologous cultured chondrocytes), human tissues (eg, cancellous bone chips; dura mater; and cornea), drugs, and other products. The FDA Adverse Event Reporting System contains mandatory reports from pharmaceutical manufacturers and voluntary reports from health care professionals and patients [4–8]. To help distinguish which products are regulated by the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health, the FDA’s website provides a list [9] of human cells, tissues, cellular- and tissue-based products, devices composed of human tissues, and combination products (such as demineralized bone combined with handling agents). For voluntary reporting, health care professionals and consumers may use MedWatch to report adverse events associated with drugs, biologics, and medical devices [3,5]. Strengths of MAUDE and FAERS include the detection of rare adverse events, timely availability of data, national coverage, and the ability to generate hypotheses. However, passive surveillance systems are subject to many limitations, including under-reporting, incomplete information in many reports, and the inability to calculate incidence rates. In addition, diagnoses are not medically confirmed and there is no direct, unbiased comparison group. In general, it is not possible to determine causal associations between devices/biologics and adverse events based on MAUDE or FAERS reports. Nevertheless, the data can be used to describe the range of adverse events and look for unexpected patterns in demographics and clinical characteristics that might lead to hypotheses about a relationship between a given product and adverse events. Analysis and interpretation of adverse event data Physicians, nurses, pharmacists, and other safety evaluators monitor adverse events that have been reported to the FDA. This process is accomplished through numerous complementary approaches that can include manual review of individual case safety reports, patient registries, periodic benefit-risk evaluation reports submitted by manufacturers, data from postmarketing studies, and data mining. Active surveillance for a given adverse event may also be considered depending on the frequency, severity, expectedness (ie, whether the event is listed in the package insert), and potential to reduce the risk of the event or its complications. Safety evaluators review these data in the context of their experience in postmarketing surveillance and in consideration of formal epidemiologic criteria [10] (Box 2), also
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Box 2. Hill criteria [10] for assessing causality. Strength of association. Does the risk appear to be slightly higher or many times higher? How reliable is the estimate? Consistency. Has an increased risk been reported in only one study or numerous studies? Do any studies report a decreased risk? Specificity. Do people ever experience the adverse event without having been exposed to this product? Temporal relationship. Does the time sequence make sense? If the adverse event began before the exposure, then the product is not the instigator. Dose-response relationship. Is the severity or duration of the adverse reaction greater when patients are exposed to a larger dose? Has anyone experienced the same adverse event after repeated exposures? Biological plausibility. In light of what is already known about the chemical, biological, and mechanical properties of the product, does an association with the adverse event seem possible and likely? Coherence. Based on the product’s characteristics and known safety profile, current knowledge of the patient’s condition and its natural history, and the treatment of that medical condition in general, does a causal association seem reasonable? Experiment/reversibility. If the device is removed, does the problem disappear or at least improve? Alternative explanation. Could the adverse event be due to a different exposure? Could it be a reflection of the disease process itself? Are the studies biased?
bearing in mind information that was evaluated during the premarketing approval or clearance process. Manufacturer and User Facility Device Experience data are not intended to be used to evaluate rates of adverse events or to compare adverse event occurrence rates across devices [2]. Similarly, FAERS data cannot be used to calculate the incidence of an adverse event [5]. The frequency and quality of reporting can vary widely, depending on the severity of an adverse event, temporal proximity to the administration of a pharmaceutical product or medical device, the practitioner’s level of concern about a possible causal association, public awareness and concern, and other factors. In all likelihood, health care professionals feel more compelled to report life-threatening adverse experiences (eg, respiratory distress) than minor side effects (eg, transient anorexia). Reporting by manufacturers may be influenced by trends in the medical literature and lay media coverage, the existence of litigation related to the product
(or products in the same class), a company’s own surveillance methods, and agreements made by the manufacturer and FDA at the time of product licensure or clearance. In addition, with passive surveillance data, there is no direct comparison group. For example, an analysis of pseudarthrosis cases reported to FAERS after the use of allograft bone in anterior cervical discectomy and fusion, compared with published reports of nonunion after anterior cervical discectomy and fusion with autogenous iliac crest bone graft, would not provide a reliable risk estimate of pseudarthrosis associated with allograft. Surgeons might systematically choose to use allograft in individuals in whom the risk of donor site morbidity after iliac crest bone graft harvest is unacceptably high; the incidence of nonunion might relate more to the patients’ baseline risk factors than the allograft itself. In very rare circumstances, the reporting rate of a specific adverse event can be estimated fairly precisely, particularly if the adverse experience is well-defined, a causal association has been established based on laboratory evidence, and the event has dire consequences for the patient. For instance, the reporting efficiency for paralytic poliomyelitis after the oral live attenuated polio vaccine is approximately 70% [11]. However, such examples are exceedingly uncommon. To the best of the author’s knowledge, no specific adverse event after the use of a biological product that is indicated for use in spine surgery has been scrutinized with the level of scientific and statistical rigor applied to the oral polio vaccine. Safety notifications and other public communication about potential risks Review of adverse event reports in MAUDE and FAERS has resulted in several important regulatory actions or other public communication regarding the safety of biologics or biological devices. Reviewers from multiple disciplines apply their specialized knowledge, judgment, and experience to determine whether an issue constitutes a safety signal and whether any regulatory action should be taken. The FDA issued a public health notification [12] about the risk of swelling, airway compromise, and compression of neurologic structures after the use of rhBMP-2 in cervical spine fusion. A Warning in the package insert [13] of rhBMP-2 states that edema and airway compromise have been reported after the use of this product in anterior cervical spinal fusion. Adverse experiences reported to the FDA after the use of rhBMP-2 in spine surgery [14] and nonspinal orthopedic procedures [15], as well as sealants used in dural repair [16], have been reviewed and analyzed. After the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, FDA took the following steps to alert surgeons to this rare but serious complication: ‘‘Dear health care professional’’ letters [17,18]; a safety notification [19] on the FDA’s website; and a class labeling change, that is, a statement about
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air embolism was added to the Warnings and Precautions in the package inserts of fibrin sealants [20]. In 2011, the FDA posted information [21] about potential signals of serious risks identified for fibrin sealants: graft failure in ophthalmological procedures and lack of efficacy in neurosurgical procedures for the repair of dural tears. Infections reported to the FDA after allograft transplantation of heart valves, tendons, bones, and other human tissues have been reviewed and summarized [22,23]. In accordance with the FDA Amendments Act of 2007 (FDAAA), the FDA performs formal postmarketing safety evaluations for products approved under New Drug Applications and Biologics License Applications [24] and conducts regular, bi-weekly screening of FAERS to identify potential signals of serious risks [25]. The results, which are posted on FDA’s website, are intended to improve public access to new safety information. Under FDAAA, the FDA may require the submission of a Risk Evaluation and Mitigation Strategy (REMS) to manage a known or potential serious risk associated with a drug or biological product if it finds that a REMS is necessary to ensure that the benefits outweigh the risks [26]. The FDAAA also authorizes the FDA to impose a Postmarketing Requirement (PMR) at the time of drug or biological product approval, or after approval if the FDA becomes aware of new safety information [27]. Specifically, the FDA may require manufacturers to conduct postmarketing studies and clinical trials for any or all of three purposes: to assess a known serious risk related to the use of the product, to assess signals of serious risk related to the use of the product, or to identify an unexpected serious risk when available data indicate the potential for a serious risk [27]. A PMR does not mandate reporting by health care professionals or consumers. For studies mandated as a condition of approval of a Premarket Approval application, Protocol Development Product application, or Humanitarian Device Exemption application, the FDA has established a tracking system of active Post-Approval Studies (PAS) ordered since January 1, 2005 to help ensure that all PAS commitments are fulfilled in a timely manner [28]. The FDA maintains a publicly available web page that displays general information pertaining to each PAS, study status, and the applicant’s reporting status for each submission [28]. The decision to impose a REMS, PMR, PAS, or other postmarketing study may involve clinical, statistical, epidemiologic, and other types of reviews within the FDA. An independent advisory committee may recommend enhanced postmarketing safety surveillance and additional clinical studies. The FDAAA also expanded the FDA’s authority regarding the active identification and analysis of postmarketing risks [29]. Notable achievements include the inception of the FDA’s Sentinel Initiative [30] to conduct active surveillance and monitor product safety in real time, using automated health care data from multiple sources; the establishment of collaborative agreements (eg, the Observational Medical Outcomes Partnership) to develop and
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implement strategies for integrating and analyzing data; increased scrutiny of pediatric medical devices; and the expansion of risk communication efforts, including the establishment of a dedicated advisory committee [29]. The collective goal of these endeavors is to improve the ability to identify and evaluate potential safety signals and communicate these concerns. Indeed, the Mini-Sentinel pilot project has generated important findings related to drugs [31,32], and the ultimate objective of Sentinel is to apply active surveillance methods to monitor all FDA-regulated products [30]. Conclusion There is no single threshold of safety that can be applied to all biologics and biological devices. For each product, the acceptable safety profile depends on the expected benefit, the underlying disease or indication, the target population, and the availability and tolerability of alternative therapies. That is, safety must be considered in the context of the risk-to-benefit ratio. Regardless of study design, the approval or clearance process cannot identify every possible safety concern. Postmarketing safety surveillance partially addresses this knowledge gap by providing information based on real-world use of medical products in heterogeneous populations and detecting adverse events that were not observed in the clinical trials—possibly because they occur infrequently in any population (eg, aplastic anemia) or because individuals in whom such events are most likely to occur were not enrolled in the trials (eg, spontaneous abortion, because pregnant women were excluded). At the time of application for FDA approval, clinical trial data may be published in peer-reviewed journals, but often remain proprietary. Studies conducted in the postmarketing period offer greater transparency because they are subject to peer review and because journals are increasingly requiring authors to make the data available on request. Negative results in the premarketing and early postmarketing studies may introduce a bias (ie, under-reporting); by reporting adverse events, spine professionals can help provide a more balanced picture, thereby improving and refining our understanding of the safety of biologics. Furthermore, the practice of medicine does not always reflect the approved indication(s) of a drug or device as listed in the manufacturer’s package insert. ‘‘Off-label’’ uses (eg, rhBMP-2 in cervical spine fusion, fibrin sealants for pterygium repair and duraplasty, and rhBMP-2 in pediatric orthopedic operations) may reveal safety issues that were not apparent during the premarketing clinical trials, because the studies were not designed to evaluate those uses. In light of the rapid development of new biologics, postmarketing surveillance of adverse events is imperative for ensuring that these products are as safe as possible. Participation by surgeons [33,34] and other health care professionals, consumers, academic institutions, industry, insurers, regulatory agencies, and professional societies [35] is indispensable. Their contributions may provide vital
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information and complementary perspectives [34] about known—and unknown—risks associated with the use of biologics and biological devices. Health care professionals and consumers can voluntarily report adverse events through the MedWatch system:
[14]
[15]
https://www.accessdata.fda.gov/scripts/medwatch/ medwatch-online.htm http://www.fda.gov/downloads/Safety/MedWatch/ HowToReport/DownloadForms/UCM082725.pdf 1-800-332-1088.
[16] [17]
Acknowledgment The author thanks Michael N. DiCuccio, MD, for critical review of the manuscript.
[18]
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E.J. Woo / The Spine Journal 14 (2014) 560–565 fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugand CosmeticActFDCAct/SignificantAmendmentstotheFDCAct/Foodand DrugAdministrationAmendmentsActof2007/ucm184271.htm. Accessed August 23, 2013. [30] U.S. Food and Drug Administration. FDA’s Sentinel Initiative - Ongoing Projects. Available at: http://www.fda.gov/Safety/FDAsSentinel Initiative/ucm203500.htm. Accessed August 23, 2013. [31] Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013;368: 1272–4. [32] Toh S, Baker MA, Brown JS, et al, Mini-Sentinel Investigators. Rapid assessment of cardiovascular risk among users of smoking cessation
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drugs within the US Food and Drug Administration’s Mini-Sentinel program. JAMA Intern Med 2013;173:817–9. [33] Mihalko WM, Greenwald AS, Lemons J, Kirkpatrick J. Reporting and notification of adverse events in orthopaedics. J Am Acad Orthop Surg 2010;18:193–8. [34] Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J 2011;11:471–91. [35] FDA Public Health Notification: Life-threatening Complications Associated with Recombinant Human Bone. Morphogenetic Protein in Cervical Spine Fusion. Available at: http://www.spine.org/Documents/rhBMP_ cervical_7-08_rev%20_2_.pdf. Accessed August 23, 2013.
Review Article
Postmarketing safety of biologics and biological devices Emily Jane Woo, MD, MPH* Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, HFM-222, 1401 Rockville Pike, Rockville, MD 20852, USA Received 6 August 2012; revised 27 August 2013; accepted 27 September 2013
Abstract
BACKGROUND CONTEXT: Regardless of study design, the approval process of biologics and biological devices cannot identify every possible safety concern. Postmarketing safety surveillance can provide information based on real-world use of medical products in heterogeneous populations and is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials. PURPOSE: To review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals. METHODS: This is an overview of postmarketing safety surveillance. RESULTS: Review of adverse event reports has resulted in safety notifications, label changes, and publications regarding the safety of biologics and biological devices, such as the risk of airway compromise after the use of recombinant human bone morphogenetic protein in cervical spine fusion, the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, and infections after allograft transplantation of human tissues. CONCLUSIONS: In light of the rapid development of new biologics, postmarketing surveillance is imperative for ensuring that these products are as safe as possible. By reporting adverse events, surgeons and other health care professionals play a key role in improving and refining our understanding of the safety of biologics. Published by Elsevier Inc.
Keywords:
Postmarketing safety; Adverse events; FDA; Medical devices; Biological products; Surveillance; FAERS; MAUDE
Introduction Biologics and biological devices regulated by the Food and Drug Administration (FDA) reach the United States market by starkly different paths [1]. Some are approved or cleared based on a review of their mechanical, chemical, and technological characteristics, whereas others are evaluated in randomized, controlled trials in humans. Even FDA device/drug status: The products mentioned in this article are approved for some indications but not approved for others:Infuse Bone Graft (rhBMP-2): indicated for (1) treatment of acute, open, stabilized tibial shaft fractures, within 14 days after the initial fracture; (2) sinus augmentation and localized alveolar ridge augmentation for defects associated with extraction sockets; and (3) spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L2 to S1. It is not approved for use in cervical spine fusion. Tisseel and Evicel (fibrin sealants): indicated as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques is ineffective or impractical. Artiss (fibrin sealant): indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than or equal to 1 year 1529-9430/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.spinee.2013.09.056
when clinical data are available, the trials may be underpowered to show a statistically significant difference in adverse events; failure to demonstrate such a difference does not mean that the risks in the experimental and control groups are equal, that is, ‘‘absence of proof’’ does not equal the ‘‘proof of absence’’ (Box 1). Moreover, long-term follow-up may be limited and information about a product’s
of age, and to adhere tissue flaps during facial rhytidectomy surgery. It is not indicated as an adjunct to hemostasis. Human tissues (e.g., bone, tendons, and dura): intended for implantation, transplantation, infusion, or transfer into a human recipient; no premarket approval is required. Author disclosures: EJW: Nothing to disclose. No potential conflict of interest exists, nor any funding source. Disclaimer: This article reflects the views of the author and should not be construed to represent the FDA’s views or policies. * Corresponding author. Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, HFM-222, 1401 Rockville Pike, Rockville, MD 20852, USA. Tel.: (301) 827-6088; fax: (301) 827-5218. E-mail address: [email protected] (E.J. Woo)
E.J. Woo / The Spine Journal 14 (2014) 560–565
Box 1. Statistical significance: an example. In each of the following scenarios, 53% of the experimental group and 40% of the control group experienced an adverse event. However, when applying the conventional cutoff of p!.05, one draws different conclusions because the second study is larger and has greater statistical power than the first.
Adverse event observed
Experimental group
Control group
Yes No Total
32 (53%) 28 (47%) 60 (100%)
24 (40%) 36 (60%) 60 (100%)
p5.14 (chi-square).
The evidence is insufficient to say that the risk of the adverse event is different in the two groups, but the results do not prove that the risk is the same. Adverse event observed
Experimental group
Control group
Yes No Total
320 (53%) 280 (47%) 600 (100%)
240 (40%) 360 (60%) 600 (100%)
p!.0001 (chi-square).
It is very unlikely that these results are due to chance alone. One concludes that the risk in the two groups is not the same.
use in specific subpopulations (eg, children, elderly patients, immunocompromised individuals, and women who are pregnant or lactating) might not be available. Because of these limitations, postmarketing safety surveillance is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials. The objective of this article is to review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals.
Adverse event reporting systems The FDA maintains the Manufacturer and User Facility Device Experience [2] (MAUDE) database that contains reports of adverse events involving medical devices, such as those cleared through the 510(k) process (eg pedicle screws; biphasic calcium phosphate granules) and those evaluated under a Premarket Approval (eg, bovine serum albumin surgical sealant; recombinant human bone morphogenetic
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protein 2 or rhBMP-2). The Manufacturer and User Facility Device Experience database includes mandatory reports from manufacturers, distributors, and user facilities and voluntary reports from health care professionals and consumers [2]. The FDA Adverse Event Reporting System (FAERS) is a passive surveillance system that collects reports through the MedWatch system [3–5] and contains reports of adverse events involving licensed blood and cellular products (eg, recombinant coagulation factor VIIa; fibrin sealants; and autologous cultured chondrocytes), human tissues (eg, cancellous bone chips; dura mater; and cornea), drugs, and other products. The FDA Adverse Event Reporting System contains mandatory reports from pharmaceutical manufacturers and voluntary reports from health care professionals and patients [4–8]. To help distinguish which products are regulated by the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health, the FDA’s website provides a list [9] of human cells, tissues, cellular- and tissue-based products, devices composed of human tissues, and combination products (such as demineralized bone combined with handling agents). For voluntary reporting, health care professionals and consumers may use MedWatch to report adverse events associated with drugs, biologics, and medical devices [3,5]. Strengths of MAUDE and FAERS include the detection of rare adverse events, timely availability of data, national coverage, and the ability to generate hypotheses. However, passive surveillance systems are subject to many limitations, including under-reporting, incomplete information in many reports, and the inability to calculate incidence rates. In addition, diagnoses are not medically confirmed and there is no direct, unbiased comparison group. In general, it is not possible to determine causal associations between devices/biologics and adverse events based on MAUDE or FAERS reports. Nevertheless, the data can be used to describe the range of adverse events and look for unexpected patterns in demographics and clinical characteristics that might lead to hypotheses about a relationship between a given product and adverse events. Analysis and interpretation of adverse event data Physicians, nurses, pharmacists, and other safety evaluators monitor adverse events that have been reported to the FDA. This process is accomplished through numerous complementary approaches that can include manual review of individual case safety reports, patient registries, periodic benefit-risk evaluation reports submitted by manufacturers, data from postmarketing studies, and data mining. Active surveillance for a given adverse event may also be considered depending on the frequency, severity, expectedness (ie, whether the event is listed in the package insert), and potential to reduce the risk of the event or its complications. Safety evaluators review these data in the context of their experience in postmarketing surveillance and in consideration of formal epidemiologic criteria [10] (Box 2), also
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Box 2. Hill criteria [10] for assessing causality. Strength of association. Does the risk appear to be slightly higher or many times higher? How reliable is the estimate? Consistency. Has an increased risk been reported in only one study or numerous studies? Do any studies report a decreased risk? Specificity. Do people ever experience the adverse event without having been exposed to this product? Temporal relationship. Does the time sequence make sense? If the adverse event began before the exposure, then the product is not the instigator. Dose-response relationship. Is the severity or duration of the adverse reaction greater when patients are exposed to a larger dose? Has anyone experienced the same adverse event after repeated exposures? Biological plausibility. In light of what is already known about the chemical, biological, and mechanical properties of the product, does an association with the adverse event seem possible and likely? Coherence. Based on the product’s characteristics and known safety profile, current knowledge of the patient’s condition and its natural history, and the treatment of that medical condition in general, does a causal association seem reasonable? Experiment/reversibility. If the device is removed, does the problem disappear or at least improve? Alternative explanation. Could the adverse event be due to a different exposure? Could it be a reflection of the disease process itself? Are the studies biased?
bearing in mind information that was evaluated during the premarketing approval or clearance process. Manufacturer and User Facility Device Experience data are not intended to be used to evaluate rates of adverse events or to compare adverse event occurrence rates across devices [2]. Similarly, FAERS data cannot be used to calculate the incidence of an adverse event [5]. The frequency and quality of reporting can vary widely, depending on the severity of an adverse event, temporal proximity to the administration of a pharmaceutical product or medical device, the practitioner’s level of concern about a possible causal association, public awareness and concern, and other factors. In all likelihood, health care professionals feel more compelled to report life-threatening adverse experiences (eg, respiratory distress) than minor side effects (eg, transient anorexia). Reporting by manufacturers may be influenced by trends in the medical literature and lay media coverage, the existence of litigation related to the product
(or products in the same class), a company’s own surveillance methods, and agreements made by the manufacturer and FDA at the time of product licensure or clearance. In addition, with passive surveillance data, there is no direct comparison group. For example, an analysis of pseudarthrosis cases reported to FAERS after the use of allograft bone in anterior cervical discectomy and fusion, compared with published reports of nonunion after anterior cervical discectomy and fusion with autogenous iliac crest bone graft, would not provide a reliable risk estimate of pseudarthrosis associated with allograft. Surgeons might systematically choose to use allograft in individuals in whom the risk of donor site morbidity after iliac crest bone graft harvest is unacceptably high; the incidence of nonunion might relate more to the patients’ baseline risk factors than the allograft itself. In very rare circumstances, the reporting rate of a specific adverse event can be estimated fairly precisely, particularly if the adverse experience is well-defined, a causal association has been established based on laboratory evidence, and the event has dire consequences for the patient. For instance, the reporting efficiency for paralytic poliomyelitis after the oral live attenuated polio vaccine is approximately 70% [11]. However, such examples are exceedingly uncommon. To the best of the author’s knowledge, no specific adverse event after the use of a biological product that is indicated for use in spine surgery has been scrutinized with the level of scientific and statistical rigor applied to the oral polio vaccine. Safety notifications and other public communication about potential risks Review of adverse event reports in MAUDE and FAERS has resulted in several important regulatory actions or other public communication regarding the safety of biologics or biological devices. Reviewers from multiple disciplines apply their specialized knowledge, judgment, and experience to determine whether an issue constitutes a safety signal and whether any regulatory action should be taken. The FDA issued a public health notification [12] about the risk of swelling, airway compromise, and compression of neurologic structures after the use of rhBMP-2 in cervical spine fusion. A Warning in the package insert [13] of rhBMP-2 states that edema and airway compromise have been reported after the use of this product in anterior cervical spinal fusion. Adverse experiences reported to the FDA after the use of rhBMP-2 in spine surgery [14] and nonspinal orthopedic procedures [15], as well as sealants used in dural repair [16], have been reviewed and analyzed. After the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, FDA took the following steps to alert surgeons to this rare but serious complication: ‘‘Dear health care professional’’ letters [17,18]; a safety notification [19] on the FDA’s website; and a class labeling change, that is, a statement about
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air embolism was added to the Warnings and Precautions in the package inserts of fibrin sealants [20]. In 2011, the FDA posted information [21] about potential signals of serious risks identified for fibrin sealants: graft failure in ophthalmological procedures and lack of efficacy in neurosurgical procedures for the repair of dural tears. Infections reported to the FDA after allograft transplantation of heart valves, tendons, bones, and other human tissues have been reviewed and summarized [22,23]. In accordance with the FDA Amendments Act of 2007 (FDAAA), the FDA performs formal postmarketing safety evaluations for products approved under New Drug Applications and Biologics License Applications [24] and conducts regular, bi-weekly screening of FAERS to identify potential signals of serious risks [25]. The results, which are posted on FDA’s website, are intended to improve public access to new safety information. Under FDAAA, the FDA may require the submission of a Risk Evaluation and Mitigation Strategy (REMS) to manage a known or potential serious risk associated with a drug or biological product if it finds that a REMS is necessary to ensure that the benefits outweigh the risks [26]. The FDAAA also authorizes the FDA to impose a Postmarketing Requirement (PMR) at the time of drug or biological product approval, or after approval if the FDA becomes aware of new safety information [27]. Specifically, the FDA may require manufacturers to conduct postmarketing studies and clinical trials for any or all of three purposes: to assess a known serious risk related to the use of the product, to assess signals of serious risk related to the use of the product, or to identify an unexpected serious risk when available data indicate the potential for a serious risk [27]. A PMR does not mandate reporting by health care professionals or consumers. For studies mandated as a condition of approval of a Premarket Approval application, Protocol Development Product application, or Humanitarian Device Exemption application, the FDA has established a tracking system of active Post-Approval Studies (PAS) ordered since January 1, 2005 to help ensure that all PAS commitments are fulfilled in a timely manner [28]. The FDA maintains a publicly available web page that displays general information pertaining to each PAS, study status, and the applicant’s reporting status for each submission [28]. The decision to impose a REMS, PMR, PAS, or other postmarketing study may involve clinical, statistical, epidemiologic, and other types of reviews within the FDA. An independent advisory committee may recommend enhanced postmarketing safety surveillance and additional clinical studies. The FDAAA also expanded the FDA’s authority regarding the active identification and analysis of postmarketing risks [29]. Notable achievements include the inception of the FDA’s Sentinel Initiative [30] to conduct active surveillance and monitor product safety in real time, using automated health care data from multiple sources; the establishment of collaborative agreements (eg, the Observational Medical Outcomes Partnership) to develop and
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implement strategies for integrating and analyzing data; increased scrutiny of pediatric medical devices; and the expansion of risk communication efforts, including the establishment of a dedicated advisory committee [29]. The collective goal of these endeavors is to improve the ability to identify and evaluate potential safety signals and communicate these concerns. Indeed, the Mini-Sentinel pilot project has generated important findings related to drugs [31,32], and the ultimate objective of Sentinel is to apply active surveillance methods to monitor all FDA-regulated products [30]. Conclusion There is no single threshold of safety that can be applied to all biologics and biological devices. For each product, the acceptable safety profile depends on the expected benefit, the underlying disease or indication, the target population, and the availability and tolerability of alternative therapies. That is, safety must be considered in the context of the risk-to-benefit ratio. Regardless of study design, the approval or clearance process cannot identify every possible safety concern. Postmarketing safety surveillance partially addresses this knowledge gap by providing information based on real-world use of medical products in heterogeneous populations and detecting adverse events that were not observed in the clinical trials—possibly because they occur infrequently in any population (eg, aplastic anemia) or because individuals in whom such events are most likely to occur were not enrolled in the trials (eg, spontaneous abortion, because pregnant women were excluded). At the time of application for FDA approval, clinical trial data may be published in peer-reviewed journals, but often remain proprietary. Studies conducted in the postmarketing period offer greater transparency because they are subject to peer review and because journals are increasingly requiring authors to make the data available on request. Negative results in the premarketing and early postmarketing studies may introduce a bias (ie, under-reporting); by reporting adverse events, spine professionals can help provide a more balanced picture, thereby improving and refining our understanding of the safety of biologics. Furthermore, the practice of medicine does not always reflect the approved indication(s) of a drug or device as listed in the manufacturer’s package insert. ‘‘Off-label’’ uses (eg, rhBMP-2 in cervical spine fusion, fibrin sealants for pterygium repair and duraplasty, and rhBMP-2 in pediatric orthopedic operations) may reveal safety issues that were not apparent during the premarketing clinical trials, because the studies were not designed to evaluate those uses. In light of the rapid development of new biologics, postmarketing surveillance of adverse events is imperative for ensuring that these products are as safe as possible. Participation by surgeons [33,34] and other health care professionals, consumers, academic institutions, industry, insurers, regulatory agencies, and professional societies [35] is indispensable. Their contributions may provide vital
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information and complementary perspectives [34] about known—and unknown—risks associated with the use of biologics and biological devices. Health care professionals and consumers can voluntarily report adverse events through the MedWatch system:
[14]
[15]
https://www.accessdata.fda.gov/scripts/medwatch/ medwatch-online.htm http://www.fda.gov/downloads/Safety/MedWatch/ HowToReport/DownloadForms/UCM082725.pdf 1-800-332-1088.
[16] [17]
Acknowledgment The author thanks Michael N. DiCuccio, MD, for critical review of the manuscript.
[18]
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