The objectives of this study were to examine adverse clinical events after the use of the Invisalign system and to provide an overview of the actions taken by the manufacturer to address these events.
A retrospective analysis of the Manufacturer and User Facility Device Experience database of the United States Food and Drug Administration was used. All medical device reports reported to the United States Food and Drug Administration pertaining to products of Align Technology from November 1, 2006, to November 30, 2016, were analyzed. Qualitative content analysis was conducted of event descriptions and manufacturer narrative reports.
A total of 173 medical device reports were reported in the Manufacturer and User Facility Device Experience database: 169 (97.7%) were designated as adverse event reports, and 45 (26%) were deemed by the treating doctor to be serious or life threatening. The most medical device reports that reported a serious or life-threatening event were in 2014 (50%). The most frequently reported adverse event was difficulty breathing (56 events) followed by sore throat (35 events), swollen throat (34 events), swollen tongue (31 events), hives and itchiness (31 events), anaphylaxis (30 events), swollen lips (27 events), and feeling of throat closing/tight airway/airway obstruction/laryngospasm (24 events).
Serious or life-threatening events could be associated with use of Invisalign systems. Health care providers should be aware of these events and know how to handle them if they arise in their practices.
We found 173 medical device reports related to Invisalign in the MAUDE database.
169 were designated as adverse events, and 45 were serious or life-threatening events.
Difficulty breathing (56 events) was the most common event reported.
Sore (35) or swollen (34) throat and swollen tongue (31) were reported.
Hives and itchiness (31), anaphylaxis (30), and swollen lips (27) were reported.
Serious life-threatening events could be associated with the use of Invisalign.
According to a survey conducted by the American Association of Orthodontists, close to 5.9 million patients were treated for malocclusions in the United States during 2012. There was a 20% increase in orthodontic patients from 2010 to 2012, with more adults seeking orthodontic treatment. This points to a healthy trend for our specialty. Although a multitude of factors, such as improved technology have resulted in reduction of treatment duration, changes in insurance reimbursement policies, flexible spending accounts, and improved oral health have contributed to more people seeking orthodontic care, and one should not discount the impact of innovative technologies such as the Invisalign system (Align Technology, San Jose, Calif) in contributing to this trend. With the growing popularity of the Invisalign system, it is expected that more patients would be inclined to use it rather than traditional braces for correcting their malocclusions. Whereas prior studies have examined treatment outcomes and patient satisfaction associated with the Invisalign system, there is a paucity of studies that have examined systemic adverse events associated with it. Only a few studies have examined the cytotoxic effects of the Invisalign system ; these 2 studies were in-vitro investigations, and their effects cannot be extrapolated to humans. Consequently, there is a need for further research exploring potential side effects the Invisalign system on humans. To our knowledge, there are no published reports on adverse clinical events after the use of the Invisalign system. In this study, we attempted to address this gap in the literature. Our objectives were to examine adverse clinical events after the use of Invisalign and to provide an overview of actions taken by the manufacturer to address these events.
Material and methods
This was a retrospective analysis of the Manufacturer and User Facility Device Experience (MAUDE) database of the United States Food and Drug Administration (FDA). Since we used a publicly available database of the United States Department of Health and Human Services, as per the Office of Human Subjects Protection of the University of Iowa (protocol #201612726), the study did not meet the regulatory definition of human subjects research and did not require institutional review board approval, because it was limited to analysis of publicly available, deidentified data.
The MAUDE database houses all medical device reports (MDRs) reported to the FDA. Mandatory reporters to the MAUDE include manufacturers, importers, and device-user facilities, and voluntary reporters include health care professionals, patients, and consumers. The MAUDE is a Web-based search engine ( www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/Search.cfm ) that provides information on MDRs reported by both mandatory and voluntary reporters. Detailed information on the MAUDE database is available at www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/ucm127891.htm .
The MAUDE database is a passive surveillance system of MDRs. It can be searched by several variables including product problem, product class, event type, manufacturer, model number, report number, brand name, and product code. Only MDRs reported within the past 10 years are included in the MAUDE database. It is updated monthly. The information available from the MDRs typically includes brand name, model number, event date, event type, manufacturer narrative, event description, source type, reporter occupation, report date, adverse event report, device operator, device availability for evaluation, event location, device evaluation by manufacturer, type of device usage, and so on. Certain types of information in the event descriptions and manufacturer narratives are protected from public disclosure. In this study, we have used “XXX” to designate protected information.
The following search terms were used in the MAUDE database Web-based query system to identify MDRs pertaining to Invisalign systems: manufacturer, Align Technology and Align Technology Inc.; report date, November 1, 2006, to November 30, 2016; and no restrictions placed on any of the other queries.
After the search, data records were downloaded into an Excel spread sheet (Microsoft, Redmond, Wash) and imported into SPSS software (version 23.0; IBM, Armonk, NY).
Qualitative content analysis was performed on all event description narratives and manufacturer narratives. Two investigators (R.N. and M.K.L.) independently performed qualitative content analyses of 20 recent MDRs to identify recurring themes. These themes were discussed with the first author to identify adverse clinical events (based on event description and manufacturer narratives) to be reported in this study. After this, 2 authors (R.N and V.A.) independently reviewed all 173 MDRs and coded each clinical adverse event as a binomial variables (“yes” for occurrence and “no” for nonoccurrence). Simple descriptive statistics were used to report the clinical adverse events. A chi-square test was conducted to examine whether the proportion of adverse events that were deemed serious or life threatening was different across study years. Statistical analysis was conducted using the SPSS software.
During the observation period (November 1, 2006, to November 30, 2016), a total of 173 MDRs were reported in the MAUDE database. These included 138 MDRs reported by manufacturer (Align Technology) and 35 MDRs reported voluntarily by either patients, family members of patients, or health professionals (including dentists, physicians, and so on); 169 (97.7%) MDRs were designated as adverse event reports. Trends in the reporting of MDRs are given in Table I . Between November 1, 2006, and December 31, 2010, only 6 MDRs were reported. Most MDRs were reported in 2011 (50 reports). From 2012 through 2015, there appeared to be an increasing trend toward more MDRs reported. In 45 (26%) MDRs, it was mentioned that the treating doctor thought that the event was serious or life threatening. The highest proportion of MDRs that reported a serious or life-threatening event was in 2014 (50%) followed by 2015 (46.7%). Overall, there were significant increases in the proportion of MDRs that were considered serious or life threatening from 2014 to 2016 when compared with earlier years ( P = 0.02).
|Year||MDR (n) (total = 173)||Treating doctor thought that event was serious or life threatening (n = 45)||P value|
|2016 (until November 30)||27||7 (25.9%)||0.02|
The frequencies of individual adverse clinical events are summarized in Table II . The most frequently reported adverse event was difficulty breathing (56 events) followed by sore throat (35 events), swollen throat (34 events), swollen tongue (31 events), hives and itchiness (31 events), anaphylaxis (30 events), swollen lips (27 events), feeling of throat closing/tight airway/airway obstruction/laryngospasm (24 events), chest pain (19 events), cough (19 events), nausea (18 events), difficulty swallowing (12 events), dry mouth (11 events), headaches (10 events), swelling of eyes (9 events), blisters or sores of lips (9 events), fatigue (8 events), burning/tingling/sore tongue (7 events), blisters or ulcerations on tongue (6 events), and swelling of gums (5 events). Adverse events that were reported in fewer than 5 reports included lymph node enlargement, rashes on face or body, sinus tachycardia, palpitations, numbness of tongue, chest congestion, and joint pains. Several patients reported visiting emergency rooms, and several others reported being hospitalized.
|Type of clinical adverse event||Clinical adverse events (n)|
|Hives and itchiness||31|
|Feeling of throat closing/tight airway/airway obstruction/laryngospasm||24|
|Swelling of eyes||9|
|Blisters or sores of lips||9|
|Blisters or ulcerations on tongue||6|
|Swelling of gums||5|