- Email: [email protected]
Harms and adverse events in clinical research
13
Readers' forum
paradigms, which gave us the opportunity to express once more the importance of how to interpret our short-term studies on physiologic craters, orthodontic root resorption, and repair. Braydon M. Patterson Oyku Dalci Alexandra K. Papadopoulou Suman Madukuri Jonathan Mahon Peter Petocz Axel Spahr M. Ali Darendeliler Sydney, Australia, and Thessaloniki, Greece Am J Orthod Dentofacial Orthop 2017;152:12-3 0889-5406/$36.00 Ó 2017 by the American Association of Orthodontists. All rights reserved.
http://dx.doi.org/10.1016/j.ajodo.2017.04.015 REFERENCES 1. Henry JL, Weinmann JP. The pattern of resorption and repair of human cementum. J Am Dent Assoc 1951;42:270-90. 2. Chan E, Darendeliler MA. Physical properties of root cementum: part 5. Volumetric analysis of root resorption craters after application of light and heavy orthodontic force. Am J Orthod Dentofacial Orthop 2005;127:186-95. 3. Harris D, Jones A, Darendeliler MA. Physical properties of root cementum: part 8. Volumetric analysis of root resorption craters after application of controlled intrusive light and heavy orthodontic forces: a microcomputed tomography scan study. Am J Orthod Dentofacial Orthop 2006;130:639-47. 4. Deane S, Jones AS, Petocz P, Darendeliler MA. Physical properties of root cementum: part 12. The incidence of physiologic root resorption on unerupted third molars and its comparison with orthodontically treated premolars: a microcomputedtomography study. Am J Orthod Dentofacial Orthop 2009; 136:148-9. 5. Oh C, T€ urk T, Elekdag-T€ urk S, Jones AS, Petocz P, Cheng LL, et al. Physical properties of root cementum: part 19. Comparison of the amounts of root resorption between the right and left first premolars after application of buccally directed heavy orthodontic tipping forces. Am J Orthod Dentofacial Orthop 2011;140:e49-52. 6. Cheng LL, T€ urk T, Elekda g-T€ urk S, Jones AS, Petocz P, Darendeliler MA. Physical properties of root cementum: part 13. Repair of root resorption 4 and 8 weeks after the application of continuous light and heavy forces for 4 weeks: a microcomputed-tomography study. Am J Orthod Dentofacial Orthop 2009;136:320.e1-10. 7. Cheng LL, T€ urk T, Elekda g-T€ urk S, Jones AS, Yu Y, Darendeliler MA. Repair of root resorption 4 and 8 weeks after application of continuous light and heavy forces on premolars for 4 weeks: a histology study. Am J Orthod Dentofacial Orthop 2010;138:727-34. 8. Smale I, Artun J, Behbehani F, Doppel D, van't Hof M, KuijpersJagtman AM. Apical root resorption 6 months after initiation of fixed orthodontic appliance therapy. Am J Orthod Dentofacial Orthop 2005;128:57-67. 9. Artun J, Van 't Hullenaar R, Doppel D, Kuijpers-Jagtman AM. Identification of orthodontic patients at risk of severe apical root resorption. Am J Orthod Dentofacial Orthop 2009;135:448-55.
10. Brudvik P, Rygh P. Transition and determinants of orthodontic root resorption-repair sequence. Eur J Orthod 1995;17:177-88. 11. Patterson BM, Dalci O, Papadopoulou AK, Madukuri S, Mahon J, Petocz P, et al. Effect of piezocision on root resorption associated with orthodontic force: a microcomputed tomography study. Am J Orthod Dentofacial Orthop 2017;151:53-62.
Harms and adverse events in clinical research arm is “the totality of possible adverse consequences of an intervention or therapy.”1 An adverse event is any unfavorable or harmful occurrence in a patient, temporarily related to a medical intervention, but without any judgment about causality.1 Although many biological and mechanical risk factors have been associated with external apical root resorption (EARR), a causal relationship has not yet been established.2 Thus, EARR is an adverse event occurring in orthodontic patients, and its research is a harm-related issue. Barros et al, in their article in the February 2017 issue, reported the EARR related to anterior retraction with miniscrews (Barros SE, Janson G, Chiqueto K, Baldo VO, Baldo TO. Root resorption of maxillary incisors retracted with and without skeletal anchorage. Am J Orthod Dentofacial Orthop 2017;151:397-406). However, comparing this technique with the extraoral anchorage, using historical controls, and measuring the outcome with periapical radiographs, were not the right choices, since the target was not to evaluate efficacy or effectiveness but, rather, harms.3 Kokich2 raised clinical questions related to EARR: “What causes root resorption? Is it due to heavy orthodontic forces placed on the teeth? What is the incidence of root resorption among orthodontic patients? Is the tendency for root resorption inherited? What is the prognosis for teeth that have had significant root resorption?” The answers to these questions are important for achieving optimal management of EARR during orthodontic treatment and appropriately informing patients about the risk with this treatment alternative. In clinical research, however, more important than elaborating appropriate questions, is choosing the right methodology to arrive at useful, valid answers.4 The randomized controlled trial is not the gold standard in the search of the evidence related to harm, since it may be unfeasible, unethical, or ineffectual.4 Thus, observational methods may be valid alternatives.4 As Rothman5 said: “The type of study should not be taken as a guide to a study’s validity.” The development of new orthodontic techniques will affect the occurrence of EARR and other adverse events, and so the assessment of the risk of harm will become more important.
H
American Journal of Orthodontics and Dentofacial Orthopedics
July 2017 Vol 152 Issue 1
14
Readers' forum
Florian Benicio Chauca Lima, Peru Am J Orthod Dentofacial Orthop 2017;152:13-4 0889-5406/$36.00 Ó 2017 by the American Association of Orthodontists. All rights reserved.
http://dx.doi.org/10.1016/j.ajodo.2017.04.017 REFERENCES 1. Ioannidis JP, Evans SJ, Gøtzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extensi on of the CONSORT statement. Ann Intern Med 2004;141: 781-8. 2. Kokich VG. Orthodontic and nonorthodontic root resorption: their impact on clinical dental practice. J Dent Educ 2008; 72:895-902. 3. Levine M, Ioannidis J, Haines T, Guyatt G. Harm (observational studies). In: Guyatt G, Rennie D, Meade MO, Cook DJ, editors. Users' guides to the medical literature: a manual for evidence-based clinical practice. 3rd ed. Valley Stream, NY: Mc-Graw Hill Medical; 2008. p. 363-81. 4. Feinstein AR. The clinician as scientist. In: Vig PS, Ribbens KS, editors. Science and clinical judgment in orthodontics. Monograph 19. Craniofacial Growth Series. Ann Arbor: Center for Human Growth and Development; University of Michigan; 1986. p. 1-14. 5. Rothman KJ. Six persistent research misconceptions. J Gen Intern Med 2014;29:1060-4.
Authors' response
W
e are pleased that our article has stimulated comments because they are an opportunity for further discussion on this challenging orthodontic subject: root resorption. We are not convinced that external apical root resorption (EARR) could be considered an adverse event because the concept of adverse events suggested in the letter does not admit any judgment about causality.1 However, the cause-and-effect relationship between induced tooth movement and EARR has been demonstrated for many decades. This relationship is known as orthodontically induced inflammatory root resorption (OIIRR)2 and is frequently described as an adverse side effect of orthodontic treatment because it presents causality and is undesirable.3-5 This causal relationship between induced tooth movement and EARR is the justification for our study and many other studies comparing different orthodontic treatment protocols regarding OIIRR,6-9 since different biomechanics can produce distinct degrees, types, and directions of induced tooth movement. Regardless of our will, this fact may have a direct impact on OIIRR and treatment effectiveness. Thus, our study was mainly focused on OIIRR evaluation using periapical radiographs. Although this evaluation method can be criticized because of its
July 2017 Vol 152 Issue 1
inherent limitations, it has been demonstrated that the percentages of correct diagnosis of EARR degree using periapical radiographs and cone-beam computed tomography (CBCT) were 71.3% and 80.9%, respectively.10 Other studies have demonstrated that a periapical radiograph is almost as accurate and reliable as CBCT to evaluate root length and lesions.11,12 Since CBCT delivers a significantly greater radiation dose than conventional dental x-ray examinations,13 the biologic cost and the clinical impact of this choice should be carefully weighed by clinicians and researchers in the light of CBCT guidelines before deciding for a CBCT examination only to obtain a bit more accuracy to evaluate EARR.14-16 Furthermore, the limitations of periapical radiographs are prone to similarly affect the experimental groups. Thus, what would be a “right methodological choice”? In a brief Shakespearean analogy, we could say that sometimes the choice of a gold standard evaluation may be as tempting and logical as choosing the gold instead of the silver or lead caskets, which were enigmatically offered by Portia’s father to her potential suitors. But when they opened the gold casket, they discovered that the “golden choice” was not the right choice to win Portia’s hand, leaving them surprised and disappointed (William Shakespeare's The Merchant of Venice). Probably, these are the main reasons that nowadays authors of a randomized controlled study (RCT), which is essentially prospective, still choose periapical radiographs to evaluate EARR.2 In our study, we collected prospective data that were compared with the data of a retrospectively selected control group. Although most EARR studies are only based on retrospective data,17 the RCT is a feasible research design to compare EARR associated with different orthodontic treatment protocols.2,9 Furthermore, if orthodontists more and more seek a clinical practice based on evidence, the answers to the questions related to EARR should come from systematic reviews, which greatly depend on prospective data and RCTs, because these types of scientific information are at the top of the pyramid of evidence18 and they can produce more consistent systematic reviews. Thank you for your comments. Sergio Estelita Barros Porto Alegre, Brazil Guilherme Janson Bauru, Brazil Kelly Chiqueto Porto Alegre, Brazil
American Journal of Orthodontics and Dentofacial Orthopedics
Readers' forum
paradigms, which gave us the opportunity to express once more the importance of how to interpret our short-term studies on physiologic craters, orthodontic root resorption, and repair. Braydon M. Patterson Oyku Dalci Alexandra K. Papadopoulou Suman Madukuri Jonathan Mahon Peter Petocz Axel Spahr M. Ali Darendeliler Sydney, Australia, and Thessaloniki, Greece Am J Orthod Dentofacial Orthop 2017;152:12-3 0889-5406/$36.00 Ó 2017 by the American Association of Orthodontists. All rights reserved.
http://dx.doi.org/10.1016/j.ajodo.2017.04.015 REFERENCES 1. Henry JL, Weinmann JP. The pattern of resorption and repair of human cementum. J Am Dent Assoc 1951;42:270-90. 2. Chan E, Darendeliler MA. Physical properties of root cementum: part 5. Volumetric analysis of root resorption craters after application of light and heavy orthodontic force. Am J Orthod Dentofacial Orthop 2005;127:186-95. 3. Harris D, Jones A, Darendeliler MA. Physical properties of root cementum: part 8. Volumetric analysis of root resorption craters after application of controlled intrusive light and heavy orthodontic forces: a microcomputed tomography scan study. Am J Orthod Dentofacial Orthop 2006;130:639-47. 4. Deane S, Jones AS, Petocz P, Darendeliler MA. Physical properties of root cementum: part 12. The incidence of physiologic root resorption on unerupted third molars and its comparison with orthodontically treated premolars: a microcomputedtomography study. Am J Orthod Dentofacial Orthop 2009; 136:148-9. 5. Oh C, T€ urk T, Elekdag-T€ urk S, Jones AS, Petocz P, Cheng LL, et al. Physical properties of root cementum: part 19. Comparison of the amounts of root resorption between the right and left first premolars after application of buccally directed heavy orthodontic tipping forces. Am J Orthod Dentofacial Orthop 2011;140:e49-52. 6. Cheng LL, T€ urk T, Elekda g-T€ urk S, Jones AS, Petocz P, Darendeliler MA. Physical properties of root cementum: part 13. Repair of root resorption 4 and 8 weeks after the application of continuous light and heavy forces for 4 weeks: a microcomputed-tomography study. Am J Orthod Dentofacial Orthop 2009;136:320.e1-10. 7. Cheng LL, T€ urk T, Elekda g-T€ urk S, Jones AS, Yu Y, Darendeliler MA. Repair of root resorption 4 and 8 weeks after application of continuous light and heavy forces on premolars for 4 weeks: a histology study. Am J Orthod Dentofacial Orthop 2010;138:727-34. 8. Smale I, Artun J, Behbehani F, Doppel D, van't Hof M, KuijpersJagtman AM. Apical root resorption 6 months after initiation of fixed orthodontic appliance therapy. Am J Orthod Dentofacial Orthop 2005;128:57-67. 9. Artun J, Van 't Hullenaar R, Doppel D, Kuijpers-Jagtman AM. Identification of orthodontic patients at risk of severe apical root resorption. Am J Orthod Dentofacial Orthop 2009;135:448-55.
10. Brudvik P, Rygh P. Transition and determinants of orthodontic root resorption-repair sequence. Eur J Orthod 1995;17:177-88. 11. Patterson BM, Dalci O, Papadopoulou AK, Madukuri S, Mahon J, Petocz P, et al. Effect of piezocision on root resorption associated with orthodontic force: a microcomputed tomography study. Am J Orthod Dentofacial Orthop 2017;151:53-62.
Harms and adverse events in clinical research arm is “the totality of possible adverse consequences of an intervention or therapy.”1 An adverse event is any unfavorable or harmful occurrence in a patient, temporarily related to a medical intervention, but without any judgment about causality.1 Although many biological and mechanical risk factors have been associated with external apical root resorption (EARR), a causal relationship has not yet been established.2 Thus, EARR is an adverse event occurring in orthodontic patients, and its research is a harm-related issue. Barros et al, in their article in the February 2017 issue, reported the EARR related to anterior retraction with miniscrews (Barros SE, Janson G, Chiqueto K, Baldo VO, Baldo TO. Root resorption of maxillary incisors retracted with and without skeletal anchorage. Am J Orthod Dentofacial Orthop 2017;151:397-406). However, comparing this technique with the extraoral anchorage, using historical controls, and measuring the outcome with periapical radiographs, were not the right choices, since the target was not to evaluate efficacy or effectiveness but, rather, harms.3 Kokich2 raised clinical questions related to EARR: “What causes root resorption? Is it due to heavy orthodontic forces placed on the teeth? What is the incidence of root resorption among orthodontic patients? Is the tendency for root resorption inherited? What is the prognosis for teeth that have had significant root resorption?” The answers to these questions are important for achieving optimal management of EARR during orthodontic treatment and appropriately informing patients about the risk with this treatment alternative. In clinical research, however, more important than elaborating appropriate questions, is choosing the right methodology to arrive at useful, valid answers.4 The randomized controlled trial is not the gold standard in the search of the evidence related to harm, since it may be unfeasible, unethical, or ineffectual.4 Thus, observational methods may be valid alternatives.4 As Rothman5 said: “The type of study should not be taken as a guide to a study’s validity.” The development of new orthodontic techniques will affect the occurrence of EARR and other adverse events, and so the assessment of the risk of harm will become more important.
H
American Journal of Orthodontics and Dentofacial Orthopedics
July 2017 Vol 152 Issue 1
14
Readers' forum
Florian Benicio Chauca Lima, Peru Am J Orthod Dentofacial Orthop 2017;152:13-4 0889-5406/$36.00 Ó 2017 by the American Association of Orthodontists. All rights reserved.
http://dx.doi.org/10.1016/j.ajodo.2017.04.017 REFERENCES 1. Ioannidis JP, Evans SJ, Gøtzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extensi on of the CONSORT statement. Ann Intern Med 2004;141: 781-8. 2. Kokich VG. Orthodontic and nonorthodontic root resorption: their impact on clinical dental practice. J Dent Educ 2008; 72:895-902. 3. Levine M, Ioannidis J, Haines T, Guyatt G. Harm (observational studies). In: Guyatt G, Rennie D, Meade MO, Cook DJ, editors. Users' guides to the medical literature: a manual for evidence-based clinical practice. 3rd ed. Valley Stream, NY: Mc-Graw Hill Medical; 2008. p. 363-81. 4. Feinstein AR. The clinician as scientist. In: Vig PS, Ribbens KS, editors. Science and clinical judgment in orthodontics. Monograph 19. Craniofacial Growth Series. Ann Arbor: Center for Human Growth and Development; University of Michigan; 1986. p. 1-14. 5. Rothman KJ. Six persistent research misconceptions. J Gen Intern Med 2014;29:1060-4.
Authors' response
W
e are pleased that our article has stimulated comments because they are an opportunity for further discussion on this challenging orthodontic subject: root resorption. We are not convinced that external apical root resorption (EARR) could be considered an adverse event because the concept of adverse events suggested in the letter does not admit any judgment about causality.1 However, the cause-and-effect relationship between induced tooth movement and EARR has been demonstrated for many decades. This relationship is known as orthodontically induced inflammatory root resorption (OIIRR)2 and is frequently described as an adverse side effect of orthodontic treatment because it presents causality and is undesirable.3-5 This causal relationship between induced tooth movement and EARR is the justification for our study and many other studies comparing different orthodontic treatment protocols regarding OIIRR,6-9 since different biomechanics can produce distinct degrees, types, and directions of induced tooth movement. Regardless of our will, this fact may have a direct impact on OIIRR and treatment effectiveness. Thus, our study was mainly focused on OIIRR evaluation using periapical radiographs. Although this evaluation method can be criticized because of its
July 2017 Vol 152 Issue 1
inherent limitations, it has been demonstrated that the percentages of correct diagnosis of EARR degree using periapical radiographs and cone-beam computed tomography (CBCT) were 71.3% and 80.9%, respectively.10 Other studies have demonstrated that a periapical radiograph is almost as accurate and reliable as CBCT to evaluate root length and lesions.11,12 Since CBCT delivers a significantly greater radiation dose than conventional dental x-ray examinations,13 the biologic cost and the clinical impact of this choice should be carefully weighed by clinicians and researchers in the light of CBCT guidelines before deciding for a CBCT examination only to obtain a bit more accuracy to evaluate EARR.14-16 Furthermore, the limitations of periapical radiographs are prone to similarly affect the experimental groups. Thus, what would be a “right methodological choice”? In a brief Shakespearean analogy, we could say that sometimes the choice of a gold standard evaluation may be as tempting and logical as choosing the gold instead of the silver or lead caskets, which were enigmatically offered by Portia’s father to her potential suitors. But when they opened the gold casket, they discovered that the “golden choice” was not the right choice to win Portia’s hand, leaving them surprised and disappointed (William Shakespeare's The Merchant of Venice). Probably, these are the main reasons that nowadays authors of a randomized controlled study (RCT), which is essentially prospective, still choose periapical radiographs to evaluate EARR.2 In our study, we collected prospective data that were compared with the data of a retrospectively selected control group. Although most EARR studies are only based on retrospective data,17 the RCT is a feasible research design to compare EARR associated with different orthodontic treatment protocols.2,9 Furthermore, if orthodontists more and more seek a clinical practice based on evidence, the answers to the questions related to EARR should come from systematic reviews, which greatly depend on prospective data and RCTs, because these types of scientific information are at the top of the pyramid of evidence18 and they can produce more consistent systematic reviews. Thank you for your comments. Sergio Estelita Barros Porto Alegre, Brazil Guilherme Janson Bauru, Brazil Kelly Chiqueto Porto Alegre, Brazil
American Journal of Orthodontics and Dentofacial Orthopedics