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CLINICIAN'S CORNER

Adverse clinical events reported during


Invisalign treatment: Analysis of the
MAUDE database
Veerasathpurush Allareddy,a Romesh Nalliah,b Min Kyeong Lee,c Sankeerth Rampa,d
and Veerajalandhar Allareddye
Iowa City, Iowa, Ann Arbor, Mich, Los Angeles, Calif, and Omaha, Neb

Introduction: 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. Methods:
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.
Results: A total of 173 medical device reports were reported in the Manufacturer and User Facility Device Expe-
rience 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). Conclusions: 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. (Am J Orthod Dentofacial
Orthop 2017;152:706-10)

A
ccording to a survey conducted by the American resulted in reduction of treatment duration, changes in
Association of Orthodontists, close to 5.9 insurance reimbursement policies, flexible spending ac-
million patients were treated for malocclusions counts, and improved oral health have contributed to
in the United States during 2012.1 There was a 20% in- more people seeking orthodontic care,1 and one should
crease in orthodontic patients from 2010 to 2012, with not discount the impact of innovative technologies such
more adults seeking orthodontic treatment.1 This points as the Invisalign system (Align Technology, San Jose,
to a healthy trend for our specialty. Although a multi- Calif) in contributing to this trend. With the growing
tude of factors, such as improved technology have 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.
a
Department of Orthodontics, College of Dentistry and Dental Clinics, University Whereas prior studies have examined treatment out-
of Iowa, Iowa City.
b
comes and patient satisfaction associated with the Invis-
College of Dentistry, University of Michigan, Ann Arbor.
c
Children's Hospital of Los Angeles, Los Angeles, Calif. align system, there is a paucity of studies that have
d
Department of Health Services Research, Administration and Policy, University examined systemic adverse events associated with it.2-6
of Nebraska Medical Center, Omaha.
e
Only a few studies have examined the cytotoxic effects
Stead Family Department of Pediatrics, Carver College of Medicine, University of
Iowa, Iowa City. of the Invisalign system7,8; these 2 studies were in-
All authors have completed and submitted the ICMJE Form for Disclosure of Po- vitro investigations, and their effects cannot be extrapo-
tential Conflicts of Interest, and none were reported. lated to humans. Consequently, there is a need for
Address correspondence to: Veerasathpurush Allareddy, College of Dentistry,
University of Iowa, Iowa City, IA 52242; e-mail, Veerasathpurush-Allareddy@ further research exploring potential side effects the In-
uiowa.edu. visalign system on humans. To our knowledge, there
Submitted, March 2017; revised and accepted, June 2017. are no published reports on adverse clinical events after
0889-5406/$36.00
! 2017 by the American Association of Orthodontists. All rights reserved. the use of the Invisalign system. In this study, we at-
http://dx.doi.org/10.1016/j.ajodo.2017.06.014 tempted to address this gap in the literature. Our
706
Allareddy et al 707

objectives were to examine adverse clinical events after


Table I. Reports submitted to MAUDE by patients and
the use of Invisalign and to provide an overview of ac-
health care professionals using products from Invisa-
tions taken by the manufacturer to address these events.
lign Technology
Treating doctor thought
MATERIAL AND METHODS that event was serious
MDR (n) or life threatening
This was a retrospective analysis of the Manufacturer Year (total 5 173) (n 5 45) P value
and User Facility Device Experience (MAUDE) database 2016 (until 27 7 (25.9%) 0.02
of the United States Food and Drug Administration November 30)
(FDA).9 Since we used a publicly available database of 2015 30 14 (46.7%)
the United States Department of Health and Human Ser- 2014 18 9 (50%)
2013 16 0
vices, as per the Office of Human Subjects Protection of 2012 16 6 (37.5%)
the University of Iowa (protocol #201612726), the study 2011 50 9 (18%)
did not meet the regulatory definition of human subjects 2010 10 0
research and did not require institutional review board Before 2010 6 0
approval, because it was limited to analysis of publicly
available, deidentified data. Statistical analysis
The MAUDE database houses all medical device reports
(MDRs) reported to the FDA. Mandatory reporters to the After the search, data records were downloaded into
MAUDE include manufacturers, importers, and device- an Excel spread sheet (Microsoft, Redmond, Wash) and
user facilities, and voluntary reporters include health imported into SPSS software (version 23.0; IBM, Ar-
care professionals, patients, and consumers.9 The MAUDE monk, NY).
is a Web-based search engine (https://www.accessdata. Qualitative content analysis was performed on all
fda.gov/scripts/cdrh/cfdocs/cfmaude/Search.cfm) that event description narratives and manufacturer narra-
provides information on MDRs reported by both manda- tives. Two investigators (R.N. and M.K.L.) independently
tory and voluntary reporters. Detailed information on performed qualitative content analyses of 20 recent
the MAUDE database is available at https://www.fda. MDRs to identify recurring themes. These themes were
gov/MedicalDevices/DeviceRegulationandGuidance/Post discussed with the first author to identify adverse clinical
marketRequirements/ReportingAdverseEvents/ucm127891. events (based on event description and manufacturer
htm. narratives) to be reported in this study. After this, 2 au-
The MAUDE database is a passive surveillance system thors (R.N and V.A.) independently reviewed all 173
of MDRs. It can be searched by several variables MDRs and coded each clinical adverse event as a bino-
including product problem, product class, event type, mial variables (“yes” for occurrence and “no” for nonoc-
manufacturer, model number, report number, brand currence). Simple descriptive statistics were used to
name, and product code. Only MDRs reported within report the clinical adverse events. A chi-square test was
the past 10 years are included in the MAUDE database. conducted to examine whether the proportion of adverse
It is updated monthly. The information available from events that were deemed serious or life threatening was
the MDRs typically includes brand name, model number, different across study years. Statistical analysis was con-
event date, event type, manufacturer narrative, event ducted using the SPSS software.
description, source type, reporter occupation, report
RESULTS
date, adverse event report, device operator, device avail-
ability for evaluation, event location, device evaluation During the observation period (November 1, 2006, to
by manufacturer, type of device usage, and so on. November 30, 2016), a total of 173 MDRs were reported
Certain types of information in the event descriptions in the MAUDE database. These included 138 MDRs re-
and manufacturer narratives are protected from public ported by manufacturer (Align Technology) and 35
disclosure. In this study, we have used “XXX” to desig- MDRs reported voluntarily by either patients, family
nate protected information. members of patients, or health professionals (including
The following search terms were used in the MAUDE dentists, physicians, and so on); 169 (97.7%) MDRs
database Web-based query system to identify MDRs per- were designated as adverse event reports. Trends in the
taining to Invisalign systems: manufacturer, Align Tech- reporting of MDRs are given in Table I. Between
nology and Align Technology Inc.; report date, November 1, 2006, and December 31, 2010, only 6
November 1, 2006, to November 30, 2016; and no re- MDRs were reported. Most MDRs were reported in
strictions placed on any of the other queries. 2011 (50 reports). From 2012 through 2015, there

American Journal of Orthodontics and Dentofacial Orthopedics November 2017 ! Vol 152 ! Issue 5
708 Allareddy et al

patients reported visiting emergency rooms, and several


Table II. Frequency of reported clinical adverse events
others reported being hospitalized.
by patients and health care professionals using prod-
The event description and the manufacturer narra-
ucts from Invisalign Technology (number of events is
tives of the 10 most recent MDRs in which the treating
at least 5)
doctor mentioned feeling that it was a “serious or life-
Clinical adverse threatening event” are provided in Appendix 1, along
Type of clinical adverse event events (n) with the source links. The following common themes
Difficulty breathing 56 were evident from the content analysis of the manufac-
Sore throat 35
Swollen throat 34
turer's narratives of all 45 MDRs in which a serious or
Swollen tongue 31 life-threatening event was mentioned.
Hives and itchiness 31
Anaphylaxis 30
1. No test methods were performed because the prod-
Swollen lips 27 uct performed according to specifications, and the
Feeling of throat closing/tight airway/ 24 device was used according to labeled indications.
airway obstruction/laryngospasm 2. No conclusive evidence was provided that supports
Chest pain 19 or opposes that the Invisalign system aligners
Cough 19
Nausea 18
caused or contributed to the patient's symptoms.
Difficulty swallowing 12 3. Devices were not returned to the manufacturer.
Dry mouth 11
Headaches 10
Thirty-five MDRs were reported voluntarily by either
Swelling of eyes 9 patients, family members of patients, or health profes-
Blisters or sores of lips 9 sionals (including dentists, physicians, and so on). Of
Fatigue 8 these, 28 were reported by patients themselves. The nar-
Burning/tingling/sore tongue 7 ratives of event descriptions of the 2 most recent
Blisters or ulcerations on tongue 6
Swelling of gums 5
patient-reported MDRs are presented in Appendix 2.
Content analysis of the event description of all
patient-reported MDRs indicated that the patients
appeared to be an increasing trend toward more MDRs believed that they experienced their reported symptoms
reported. In 45 (26%) MDRs, it was mentioned that the after use of Invisalign trays; the symptoms minimized or
treating doctor thought that the event was serious or disappeared after discontinuation of aligners. Patients
life threatening. The highest proportion of MDRs that re- would have liked to have more information on complica-
ported a serious or life-threatening event was in 2014 tions or adverse events associated with Invisalign sys-
(50%) followed by 2015 (46.7%). Overall, there were sig- tems and more information on product safety from the
nificant increases in the proportion of MDRs that were manufacturer.
considered serious or life threatening from 2014 to
2016 when compared with earlier years (P 5 0.02). DISCUSSION
The frequencies of individual adverse clinical events We used the MAUDE database to examined adverse
are summarized in Table II. The most frequently reported clinical events reported by the manufacturer (Align Te-
adverse event was difficulty breathing (56 events) fol- chonology) and volunteers after use of Invisalign sys-
lowed by sore throat (35 events), swollen throat (34 tems. While a prior study reported on adverse events
events), swollen tongue (31 events), hives and itchiness during use of orthodontic aligners, none to our knowl-
(31 events), anaphylaxis (30 events), swollen lips (27 edge have documented adverse clinical events specif-
events), feeling of throat closing/tight airway/airway ically while using the Invisalign system and the actions
obstruction/laryngospasm (24 events), chest pain (19 taken by manufacturer to address these adverse
events), cough (19 events), nausea (18 events), difficulty events.10 Thsee results show that adverse events do
swallowing (12 events), dry mouth (11 events), head- occur with Invisalign. As with any medical device, pro-
aches (10 events), swelling of eyes (9 events), blisters viders and patients should be fully informed about all re-
or sores of lips (9 events), fatigue (8 events), burning/ ported adverse events and any potential health risks with
tingling/sore tongue (7 events), blisters or ulcerations the Invisalign system. Our study showed that the most
on tongue (6 events), and swelling of gums (5 events). MDRs were reported in 2011. On November 17, 2010,
Adverse events that were reported in fewer than 5 reports the FDA issued a warning letter to Align Technology
included lymph node enlargement, rashes on face or based on an inspection conducted in the summer of
body, sinus tachycardia, palpitations, numbness of 2010 for failing to report serious adverse events associ-
tongue, chest congestion, and joint pains. Several ated with the Invisalign system.11 Reports of adverse

November 2017 ! Vol 152 ! Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics
Allareddy et al 709

events that were cited in the warning letter were received personnel should become wary about how to handle
between November 2007 and May 2010. In response, these unexpected events. We believe that the adverse
Align Technology released an update stating the events are grossly underreported. We recommend that
following: “It appears that at the time the FDA issued providers should provide information to the FDA via
the Warning Letter, it may not have fully reviewed the the MAUDE Web reporting system if they encounter in-
actions Align has completed and plans to complete to cidents of adverse events after the start of the Invisalign
address the observations contained in the Form 483 system. We strongly urge the manufacturer to conduct
Notice. We believe our response of November 8, 2010 product testing and take a more proactive approach to
may have crossed in the mail with the FDA's Warning disseminate findings pertaining to complications and
Letter and we are working with the FDA to quickly adverse events associated with Invisalign systems. As
resolve this matter with minimal impact on the Com- more “do-it-yourself” aligner companies set up shop,
pany.”12 One outcome of the FDA warning letter could we are concerned that patients who use over-the-
have been the increased number of MDRs reported counter aligners without a health care provider supervis-
in 2011. ing their treatment would be subjecting themselves to
Several adverse clinical events—eg, difficulty breath- increased risks for adverse events, some of which could
ing, swollen throat, anaphylactic reaction, swollen lips, be life threatening.
laryngospasm, blisters—were reported in the MDRs. In- This study is subject to several limitations, and the
visalign aligners are composed of polyurethanes, and results and conclusions should be interpreted keeping
isocyanate is a critical component required for polyure- these in perspective. The study is a retrospective qual-
thane synthesis.13 Health effects of isocyanate have been itative content analysis of the MAUDE database MDRs.
well documented in the literature, including but not A true cause-and-effect relationship cannot be estab-
limited to increased risk of asthma and contact derma- lished in this study. With a qualitative approach, we
titis.14-17 In an in-vitro cytotoxicity study, oral epithelial cannot establish causality, account for confounders,
cells exposed to Invisalign aligners eluate showed or provide true prevalence and incidence estimates.
increased cell death, compromised membrane integrity, External validity (generalizability) of findings is also
and reduced cell-to-cell contact and mobility, which questionable. We can identify, though, a problem
may be the mechanism for isocyanate allergy.8 that merits further investigation. Our study accom-
Forty-five MDRs reported a serious or life- plishes this objective. We believe that our findings
threatening event (per treating doctor). When we highlight areas (especially more product testings)
analyzed the manufacturer narratives of these MDRs, that can be the subject of future well-designed pro-
there was not a single instance when product testing spective clinical studies. We used a qualitative content
was done. The manufacturer mentioned that “product analysis approach to evaluate the event description re-
performed in accordance to specifications and the device ports and manufacturer narratives.19 Our interpreta-
was used in accordance with labeled indications”; “no tions are subject to our personal biases even though
conclusive evidence has been provided that supports or we made every attempt to minimize these by having
opposes that the Invisalign" system aligners caused or 2 researchers independently evaluate the MDRs. The
contributed to the patients symptoms”; and “devices MAUDE is a passive surveillance system, and its data
not returned to manufacturer.” It appears to us that are subject to limitations because of potential submis-
these reasons outlined by the manufacturer do not suf- sion of incomplete, inaccurate, unverified, or biased
ficiently address the serious concerns pertaining to life- data.20 Information on frequency of use of the Invis-
threatening events. A closeout letter issued by the FDA align systems is not available through the MAUDE;
dated July 2015 indicates that the violations mentioned hence, the true incidence and prevalence rates of
in the 2010 warning letter had been addressed.18 How- adverse events cannot be accurately quantified. The
ever, our results show that most life-threatening events MDR data cannot be used in isolation to establish
have occurred since 2014. event rates. Based on the information available for
Analysis of the event description reports in MDRs the MAUDE, we cannot conclude that a true causal
filed by patients highlighted a few issues that providers relationship exists between use of the Invisalign sys-
and the manufacturer should pay attention to. Providers tems and the side effects, especially if the product
must clearly communicate to patients about potential has not been directly evaluated. Submission of an
unexpected serious life-threatening events as well as MDR either by the manufacturer or a volunteer re-
less serious complications associated with Invisalign sys- porter does not necessarily indicate that use of the
tems so that patients can make an informed decision product contributed to the event reported.19 Despite
about using this product. Providers and their clinic these limitations, our findings are valuable, since

American Journal of Orthodontics and Dentofacial Orthopedics November 2017 ! Vol 152 ! Issue 5
710 Allareddy et al

they highlight several areas in the care pathways (from 6. Hennessy J, Garvey T, Al-Awadhi EA. A randomized clinical trial
manufacturing to delivery of Invisalign trays to comparing mandibular incisor proclination produced by fixed
labial appliances and clear aligners. Angle Orthod 2016;86:
dealing with adverse events) that need to be improved
706-12.
for patients. 7. Eliades T, Pratsinis H, Athanasiou AE, Eliades G, Kletsas D. Cyto-
toxicity and estrogenicity of Invisalign appliances. Am J Orthod
CONCLUSIONS Dentofacial Orthop 2009;136:100-3.
8. Premaraj T, Simet S, Beatty M, Premaraj S. Oral epithelial cell reac-
1. Serious life-threatening events could be associated tion after exposure to Invisalign plastic material. Am J Orthod Den-
tofacial Orthop 2014;145:64-71.
with the use of Invisalign systems, and health care
9. U.S. Food and Drug Administration. Manufacturer and user
providers should be aware of these events and facility device experience (MAUDE). Available at: https://www.
know how to handle them if they arise in their prac- accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/Search.cfm. Ac-
tices. Providers should also communicate about cessed December 14, 2016.
these events to patients to enable them to make 10. Thavarajah R, Thennukonda RA. Analysis of adverse events with
use of orthodontic sequential aligners as reported in the manufac-
informed decisions.
turer and user facility device experience database. Indian J Dent
2. Health care providers should report adverse events Res 2015;26:582-7.
they encounter in their practices to the FDA through 11. FDA warning letter to Align Technology, November 17, 2010.
the MAUDE Web service system. Available at: https://www.fda.gov/ICECI/EnforcementActions/
3. Patients on the “do-it-yourself” orthodontics WarningLetters/ucm234578.htm. Accessed February 1, 2017.
12. Align Technology releases update regarding FDA warning letter,
pathway should be wary of adverse events and the
November 30, 2010. Available at: http://investor.aligntech.com/
risks of unsupervised treatment. releasedetail.cfm?ReleaseID5533831. Accessed February 1, 2017.
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ings and disseminate these findings widely in the in- Chemical and mechanical characteristics of contemporary
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14. Schyllert C, R€ onmark E, Andersson M, Hedlund U,
SUPPLEMENTARY DATA Lundb€ack B, Hedman L, et al. Occupational exposure to
chemicals drives the increased risk of asthma and rhinitis
Supplementary data related to this article can be observed for exposure to vapours, gas, dust and fumes: a
found online at http://dx.doi.org/10.1016/j.ajodo. cross-sectional population-based study. Occup Environ Med
2017.06.014. 2016;73:663-9.
15. Lefkowitz D, Pechter E, Fitzsimmons K, Lumia M, Stephens AC,
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November 2017 ! Vol 152 ! Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics

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