Ó 2015 Eur J Oral Sci
Eur J Oral Sci 2015; 123: 61–64 DOI: 10.1111/eos.12175 Printed in Singapore. All rights reserved
European Journal of Oral Sciences
Focus
Animal research as a basis for clinical trials
Clovis M. Faggion Jr Department of Periodontology, Faculty of €nster, Mu €nster, Dentistry, University of Mu Germany
Faggion CM Jr. Animal research as a basis for clinical trials. Eur J Oral Sci 2015; 123: 61–64. © 2015 Eur J Oral Sci Animal experiments are critical for the development of new human therapeutics because they provide mechanistic information, as well as important information on efficacy and safety. Some evidence suggests that authors of animal research in dentistry do not observe important methodological issues when planning animal experiments, for example sample-size calculation. Low-quality animal research directly interferes with development of the research process in which multiple levels of research are interconnected. For example, high-quality animal experiments generate sound information for the further planning and development of randomized controlled trials in humans. These randomized controlled trials are the main source for the development of systematic reviews and meta-analyses, which will generate the best evidence for the development of clinical guidelines. Therefore, adequate planning of animal research is a sine qua non condition for increasing efficacy and efficiency in research. Ethical concerns arise when animal research is not performed with high standards. This Focus article presents the latest information on the standards of animal research in dentistry, more precisely in the field of implant dentistry. Issues on precision and risk of bias are discussed, and strategies to reduce risk of bias in animal research are reported.
Animal experiments are critical for the development of new human therapeutics because they provide mechanistic information, as well as important information on efficacy and safety. Although the number of animals used in research seems to decrease over the years, there are currently millions of animals being used for experimental purposes (1). In dental specialties, such as implant dentistry, new materials and techniques are regularly tested on animals, and the number of publications describing animal experiments in implant dentistry has increased considerably in recent years (Fig. 1). Therefore, it is necessary to evaluate whether these experiments are performed rigorously. The aims of this Focus article were to describe the concept of research hierarchy (a process in which multiple levels of research are conducted to increase efficacy and efficiency) and to report and discuss the current animal research standards in the field of implant dentistry.
Quality and risk of bias It is important to differentiate between quality and risk of bias (ROB). Quality refers to the level of rigor in research studies, whereas ROB refers to the extent to which the results should be believed (2). Even carefully planned studies performed at a high level can still present ROB. For example, it would be unfair to judge
Clovis M. Faggion Jr., Faculty of Dentistry, €nster, Waldeyerstraße 30, University of Mu €nster, Germany 48149 Mu E-mail: [email protected] Key words: animal experimentation; clinical trials; systematic review; meta-analysis; systematic review Accepted for publication January 2015
a randomized controlled trial in which it is technically impossible to blind personnel (surgeon and patient) owing to the evaluated therapies being heterogeneous, as low quality. Nevertheless, this type of study may still present ROB if the inability to blind interferes with the final outcome. Therefore, ROB levels, rather than quality scores, should be used to determine the magnitude of effectiveness of treatments.
Hierarchy in the research process Several types of research methods are used to evaluate different outcomes in dental research within a hierarchical research process (Fig. 2). Ideally, the findings at each level guide subsequent phases of research; for example, research output from animal experiments guides clinical research. Therefore, research performed at each level should be of the highest quality possible and have a low level of bias to ensure high accuracy. As shown in Fig. 2, the final step of the research process is the development of clinical guidelines to improve the quality of clinical treatments. By improving all phases of research, including animal research, the most accurate information will be used to develop these guidelines and consequently improve treatment quality. In the hierarchical research process, evidence-based guidelines, which help clinicians make decisions, are
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10 20
20
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-0
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-7 70
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0
Fig. 1. Number of animal experiments in implant dentistry published from 1970 to 2014. Publications were retrieved from the PubMed database using the keyword ‘dental implants’ and the filter ‘other animals’. The vertical axis represents the total number of publications, and the horizontal axis represents the year of publication. This information was retrieved on 11 December 2014.
f) Clinical guidelines e) Systematic reviews with metaanalysis of clinical trials d) Clinical trials c) Systematic reviews with metaanalysis of animal experiments
b) Animal experiments a) In vitro experiments
Fig. 2. The hierarchical research process in which multiple levels of research are interconnected. This process optimizes research output and generates reliable information for the development of evidence-based clinical guidelines.
primarily based on systematic reviews (3). Ideally, systematic reviews should generate a ‘summary of treatment effect’ meta-analysis to guide clinical treatments. The reliability of a meta-analysis depends upon the degree of heterogeneity among the trials included in the systematic review. The higher the heterogeneity, the lower the confidence that the meta-analytic approach will generate reliable treatment-effect estimates. Similarly, the inclusion of trials with high or unclear ROB in a meta-analysis increases deviations from the treatment-effect estimates to more- or less-inflated meta-analytic estimates (2). Thus, trials with a low ROB performed in animals or humans should be included in meta-analyses of animal studies and clinical trials, respectively.
approaches. Because, in implant dentistry, animal experiments are primarily focused on testing the efficacy of new therapeutic approaches (4), studies with low ROB are essential to guide the development of clinical trials. Nevertheless, most ROB can be categorized as unclear (4). An unclear ROB means that the level of bias may be high risk, low risk, or in between. This inability to determine ROB translates into a lack of confidence in the research findings. Another important parameter to consider when designing a research study is the calculation of sample size and power (5). Sample size contributes to the reliability of precision measurements rather than to bias (2), and evidence suggests that authors of animal experiments in implant dentistry often do not calculate the sample size (4, 6). For experiments aiming to determine quantitative differences between groups or therapies, an a priori calculation of sample size is recommended to avoid type II errors. Type II errors occur when the experiment has insufficient power to detect a difference between different interventions. In other words, the experiment failed to reject the null hypothesis (7). Improper sample sizes raise doubts about the validity of results and may interfere with the development of further clinical research. Sample size is included in the ARRIVE (Animals in Research: Reporting of In Vivo Experiments) guidelines, a checklist for reporting animal experiments (8). Although this checklist was published a few years ago, it does not appear to have improved the reporting and conducting of animal research (9). The lack of similarity between animal and human research protocols is another methodological limitation in implant dentistry. The data show that researchers change their protocols significantly when they move from animal experiments to clinical trials. Consequently, it becomes challenging (if not impossible) to determine whether results were replicated (6). Replication is the process of confirming previous results in an independent study and is one of the cornerstones of the scientific method (10). Publication bias, a form of reporting bias, may also affect basic animal research. This type of bias occurs when studies presenting significant differences between treatment arms are published more frequently than are studies that report no significant differences (2). A recently published survey evaluated the responses from 454 researchers on questions regarding the magnitude, drivers, consequences, and potential solutions for publication bias (11). Their responses indicated that only approximately 50% of animal experiments performed are published.
Strategies to reduce ROB in animal research Limitations in implant dentistry animal research Animal research is used to develop models to study disease and to test the safety and efficacy of therapeutic
Researchers should adhere to procedures that consistently reduce the chances of ROB in animal research in order to improve efficiency in all phases of the research process. For example, animal experiments should be
Animal research
planned and performed taking into account domains of bias that could affect the internal validity of the trial. A good reference would be the Cochrane approach for evaluating ROB in randomized controlled trials (RCTs) (2), but it should be adjusted to different research environments. For example, the SYRCLE0 s (SYstematic Review Centre for Laboratory animal Experimentation) ROB tool (12) comprises 10 items based on the Cochrane ROB tool (2). The tool has been adjusted for particular bias that may play an important role on the internal validity of an animal experiment (12). Furthermore, to improve the quality of reporting, researchers should adhere to guidelines, such as ARRIVE (8). The development of this guideline was based on the CONSORT (Consolidated Standards of Reporting Trials) checklist for reporting RCTs (13); it comprises 20 items describing essential information that should be included in any publication based on animal research (8). To improve precision in animal experiments, appropriate sample sizes should be used. The challenges of increasing the number of animals in experiments are higher costs and the logistics of maintaining large colonies of animals. One possible solution would be the development of multicenter animal studies, involving the collaboration of two or more centers with animal facilities in order to obtain adequate sample sizes of animals. Alternatively, small laboratories with limited vivarium space may collaborate with larger research institutions that can accommodate large groups of animals, or researchers may perform a large study through a series of replications with small cohorts. To minimize publication bias, editors of scientific journals could insist on submission of original animal research protocols along with manuscripts. Furthermore, a public database for animal research protocols should be developed, like those already created for human clinical trials (14). The registration of animal experiment protocols would probably reduce the incidence of outcome reporting bias (when the report of outcomes is based on the direction and nature of results) (15).
Animal research and ethics There has been discussion over the years regarding the necessity of animal research before clinical trials (16). In specialties such as implant dentistry, animal experiments play an important role in determining the behavior of new therapeutic approaches. For example, BRANEMARK’s discovery of osseointegration (i.e. the direct contact between living bone and the dental implant surface at the light microscopic level) (17) was made in the 1950s by the insertion of titanium implants into the bone of rabbits (18). It took several years of animal testing before dental implants started to be used in humans (18). Accordingly, it would be unrealistic to think that the sound current knowledge on the clinical use of dental implants would exist without this preclinical phase of animal research. It is nevertheless a sine qua non condition that these experiments are adequately conducted.
63
The evidence presented in this article demonstrates that standards in animal research can be improved. Three ethical concerns arise when animal research is not performed with high standards: (i) the misuse of animals; (ii) the waste of resources; and (iii) the possibility of testing dangerous or ineffective therapies in humans.
Conclusions The quality of animal research in implant dentistry is in urgent need of improvement. Inaccurate findings from basic animal research may directly interfere with clinical trials. Tools are available that can assist researchers to perform animal research with higher standards; researchers and journal editors should avail themselves of these tools and should adhere to them. Conducting animal research with limited methodologies may raise ethical concerns regarding the usefulness of animal experiments. Because animal research data were evaluated in only one specialty in dentistry, implantology, the applicability of these conclusions to other fields of dentistry cannot be taken for granted. However, because there tends to be homogeneity among research methods and reporting in dentistry as a whole, similar findings are likely to be obtained in other fields of dentistry. Notwithstanding, the performance and reporting of animal experiments should be evaluated in other fields. Conflicts of interest – The author declares no conflicts of interest.
References 1. VON AULOCH S. Number of animals used for experimental purposes lower in the European Union. ALTEX 2014; 31: 1. 2. HIGGINS JPT, ALTMAN DG, STERNE JAC (editors). Chapter 8: assessing risk of bias in included studies. In: HIGGINS JPT, GREEN S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org. 3. GUYATT G, OXMAN AD, AKL EA, KUNZ R, VIST G, BROZEK J, NORRIS S, FALCK-YTTER Y, GLASZIOU P, DEBEER H, JA€ ESCHKE R, RIND D, MEERPOHL J, DAHM P, SCHUNEMANN HJ. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–394. 4. FAGGION CM Jr, GIANNAKOPOULOS NN, LISTL S. Risk of bias of animal studies on regenerative procedures for periodontal and peri-implant bone defects – a systematic review. J Clin Periodontol 2011; 38: 1154–1160. 5. LACHIN JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981; 2: 93–113. 6. FAGGION CM Jr, SCHMITER M, TU YK. Assessment of replication of research evidence from animals to humans in studies on peri-implantitis therapy. J Dent 2009; 37: 737–747. 7. GUYATT G, JAESCHKE R, HEDDLE N, COOK D, SHANNON H, WALTER S. Basic statistics for clinicians: 1. Hypothesis testing. CMAJ 1995; 152: 27–32. 8. KILKENNY C, BROWNE WJ, CUTHILL IC, EMERSON M, ALTMAN DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8: e1000412. 9. BAKER D, LIDSTER K, SOTTOMAYOR A, AMOR S. Two years later: journals are not yet enforcing the ARRIVE guidelines
64
10. 11.
12.
13.
Faggion on reporting standards for pre-clinical animal studies. PLoS Biol 2014; 12: e1001756. MOONESINGHE R, KHOURY MJ, JANSSENS AC. Most published research findings are false-but a little replication goes a long way. PLoS Med 2007; 4: e28. TER RIET G, KOREVAAR DA, LEENAARS M, STERK PJ, VAN NOORDEN CJ, BOUTER LM, LUTTER R, ELFERINK RP, HOOFT L. Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions. PLoS One 2012; 7: e43404. HOOIJMANS CR, ROVERS MM, DE VRIES RB, LEENAARS M, RITSKES-HOITINGA M, LANGENDAM MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 43. SCHULZ KF, ALTMAN DG, MOHER D; CONSORT Group. CONSORT 2010 statement: updated guideliness for reporting parellel group randomised trials. BMJ 2010; 340: c332.
14. CLINICALTRIALS.GOV. https://clinicaltrials.gov. Accessed on 18 December 2014. 15. STERNE JAC, EGGER M, MOHER D (editors). Chapter 10: addressing reporting biases. In: HIGGINS JPT, GREEN S, eds. Cochrane Handbook for Systematic Reviews of 10.23 Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org. 16. LOEB JM, HENDEE WR, SMITH SJ, SCHWARTZ MR. Human vs animal rights. In defense of animal research. JAMA 1989; 262: 2716–2720. € J. 17. ALBREKTSSON T, BRANEMARK PI, HANSSON HA, LINDSTROM Osseointegrated titanium implants. Requirements for ensuring a long-lasting, direct bone-to-implant anchorage in man. Acta Orthop Scand 1981; 52: 155–170. 18. BRANEMARK R, BRANEMARK PI, RYDEVIK B, MYERS RR. Osseointegration in skeletal reconstruction and rehabilitation: a review. J Rehabil Res Dev 2001; 38: 175–181.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Eur J Oral Sci 2015; 123: 61–64 DOI: 10.1111/eos.12175 Printed in Singapore. All rights reserved
European Journal of Oral Sciences
Focus
Animal research as a basis for clinical trials
Clovis M. Faggion Jr Department of Periodontology, Faculty of €nster, Mu €nster, Dentistry, University of Mu Germany
Faggion CM Jr. Animal research as a basis for clinical trials. Eur J Oral Sci 2015; 123: 61–64. © 2015 Eur J Oral Sci Animal experiments are critical for the development of new human therapeutics because they provide mechanistic information, as well as important information on efficacy and safety. Some evidence suggests that authors of animal research in dentistry do not observe important methodological issues when planning animal experiments, for example sample-size calculation. Low-quality animal research directly interferes with development of the research process in which multiple levels of research are interconnected. For example, high-quality animal experiments generate sound information for the further planning and development of randomized controlled trials in humans. These randomized controlled trials are the main source for the development of systematic reviews and meta-analyses, which will generate the best evidence for the development of clinical guidelines. Therefore, adequate planning of animal research is a sine qua non condition for increasing efficacy and efficiency in research. Ethical concerns arise when animal research is not performed with high standards. This Focus article presents the latest information on the standards of animal research in dentistry, more precisely in the field of implant dentistry. Issues on precision and risk of bias are discussed, and strategies to reduce risk of bias in animal research are reported.
Animal experiments are critical for the development of new human therapeutics because they provide mechanistic information, as well as important information on efficacy and safety. Although the number of animals used in research seems to decrease over the years, there are currently millions of animals being used for experimental purposes (1). In dental specialties, such as implant dentistry, new materials and techniques are regularly tested on animals, and the number of publications describing animal experiments in implant dentistry has increased considerably in recent years (Fig. 1). Therefore, it is necessary to evaluate whether these experiments are performed rigorously. The aims of this Focus article were to describe the concept of research hierarchy (a process in which multiple levels of research are conducted to increase efficacy and efficiency) and to report and discuss the current animal research standards in the field of implant dentistry.
Quality and risk of bias It is important to differentiate between quality and risk of bias (ROB). Quality refers to the level of rigor in research studies, whereas ROB refers to the extent to which the results should be believed (2). Even carefully planned studies performed at a high level can still present ROB. For example, it would be unfair to judge
Clovis M. Faggion Jr., Faculty of Dentistry, €nster, Waldeyerstraße 30, University of Mu €nster, Germany 48149 Mu E-mail: [email protected] Key words: animal experimentation; clinical trials; systematic review; meta-analysis; systematic review Accepted for publication January 2015
a randomized controlled trial in which it is technically impossible to blind personnel (surgeon and patient) owing to the evaluated therapies being heterogeneous, as low quality. Nevertheless, this type of study may still present ROB if the inability to blind interferes with the final outcome. Therefore, ROB levels, rather than quality scores, should be used to determine the magnitude of effectiveness of treatments.
Hierarchy in the research process Several types of research methods are used to evaluate different outcomes in dental research within a hierarchical research process (Fig. 2). Ideally, the findings at each level guide subsequent phases of research; for example, research output from animal experiments guides clinical research. Therefore, research performed at each level should be of the highest quality possible and have a low level of bias to ensure high accuracy. As shown in Fig. 2, the final step of the research process is the development of clinical guidelines to improve the quality of clinical treatments. By improving all phases of research, including animal research, the most accurate information will be used to develop these guidelines and consequently improve treatment quality. In the hierarchical research process, evidence-based guidelines, which help clinicians make decisions, are
62
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300
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10 20
20
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-0
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-0 00 20
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-8 85 19
-7
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80 19
-7 70
19
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75
4
0
Fig. 1. Number of animal experiments in implant dentistry published from 1970 to 2014. Publications were retrieved from the PubMed database using the keyword ‘dental implants’ and the filter ‘other animals’. The vertical axis represents the total number of publications, and the horizontal axis represents the year of publication. This information was retrieved on 11 December 2014.
f) Clinical guidelines e) Systematic reviews with metaanalysis of clinical trials d) Clinical trials c) Systematic reviews with metaanalysis of animal experiments
b) Animal experiments a) In vitro experiments
Fig. 2. The hierarchical research process in which multiple levels of research are interconnected. This process optimizes research output and generates reliable information for the development of evidence-based clinical guidelines.
primarily based on systematic reviews (3). Ideally, systematic reviews should generate a ‘summary of treatment effect’ meta-analysis to guide clinical treatments. The reliability of a meta-analysis depends upon the degree of heterogeneity among the trials included in the systematic review. The higher the heterogeneity, the lower the confidence that the meta-analytic approach will generate reliable treatment-effect estimates. Similarly, the inclusion of trials with high or unclear ROB in a meta-analysis increases deviations from the treatment-effect estimates to more- or less-inflated meta-analytic estimates (2). Thus, trials with a low ROB performed in animals or humans should be included in meta-analyses of animal studies and clinical trials, respectively.
approaches. Because, in implant dentistry, animal experiments are primarily focused on testing the efficacy of new therapeutic approaches (4), studies with low ROB are essential to guide the development of clinical trials. Nevertheless, most ROB can be categorized as unclear (4). An unclear ROB means that the level of bias may be high risk, low risk, or in between. This inability to determine ROB translates into a lack of confidence in the research findings. Another important parameter to consider when designing a research study is the calculation of sample size and power (5). Sample size contributes to the reliability of precision measurements rather than to bias (2), and evidence suggests that authors of animal experiments in implant dentistry often do not calculate the sample size (4, 6). For experiments aiming to determine quantitative differences between groups or therapies, an a priori calculation of sample size is recommended to avoid type II errors. Type II errors occur when the experiment has insufficient power to detect a difference between different interventions. In other words, the experiment failed to reject the null hypothesis (7). Improper sample sizes raise doubts about the validity of results and may interfere with the development of further clinical research. Sample size is included in the ARRIVE (Animals in Research: Reporting of In Vivo Experiments) guidelines, a checklist for reporting animal experiments (8). Although this checklist was published a few years ago, it does not appear to have improved the reporting and conducting of animal research (9). The lack of similarity between animal and human research protocols is another methodological limitation in implant dentistry. The data show that researchers change their protocols significantly when they move from animal experiments to clinical trials. Consequently, it becomes challenging (if not impossible) to determine whether results were replicated (6). Replication is the process of confirming previous results in an independent study and is one of the cornerstones of the scientific method (10). Publication bias, a form of reporting bias, may also affect basic animal research. This type of bias occurs when studies presenting significant differences between treatment arms are published more frequently than are studies that report no significant differences (2). A recently published survey evaluated the responses from 454 researchers on questions regarding the magnitude, drivers, consequences, and potential solutions for publication bias (11). Their responses indicated that only approximately 50% of animal experiments performed are published.
Strategies to reduce ROB in animal research Limitations in implant dentistry animal research Animal research is used to develop models to study disease and to test the safety and efficacy of therapeutic
Researchers should adhere to procedures that consistently reduce the chances of ROB in animal research in order to improve efficiency in all phases of the research process. For example, animal experiments should be
Animal research
planned and performed taking into account domains of bias that could affect the internal validity of the trial. A good reference would be the Cochrane approach for evaluating ROB in randomized controlled trials (RCTs) (2), but it should be adjusted to different research environments. For example, the SYRCLE0 s (SYstematic Review Centre for Laboratory animal Experimentation) ROB tool (12) comprises 10 items based on the Cochrane ROB tool (2). The tool has been adjusted for particular bias that may play an important role on the internal validity of an animal experiment (12). Furthermore, to improve the quality of reporting, researchers should adhere to guidelines, such as ARRIVE (8). The development of this guideline was based on the CONSORT (Consolidated Standards of Reporting Trials) checklist for reporting RCTs (13); it comprises 20 items describing essential information that should be included in any publication based on animal research (8). To improve precision in animal experiments, appropriate sample sizes should be used. The challenges of increasing the number of animals in experiments are higher costs and the logistics of maintaining large colonies of animals. One possible solution would be the development of multicenter animal studies, involving the collaboration of two or more centers with animal facilities in order to obtain adequate sample sizes of animals. Alternatively, small laboratories with limited vivarium space may collaborate with larger research institutions that can accommodate large groups of animals, or researchers may perform a large study through a series of replications with small cohorts. To minimize publication bias, editors of scientific journals could insist on submission of original animal research protocols along with manuscripts. Furthermore, a public database for animal research protocols should be developed, like those already created for human clinical trials (14). The registration of animal experiment protocols would probably reduce the incidence of outcome reporting bias (when the report of outcomes is based on the direction and nature of results) (15).
Animal research and ethics There has been discussion over the years regarding the necessity of animal research before clinical trials (16). In specialties such as implant dentistry, animal experiments play an important role in determining the behavior of new therapeutic approaches. For example, BRANEMARK’s discovery of osseointegration (i.e. the direct contact between living bone and the dental implant surface at the light microscopic level) (17) was made in the 1950s by the insertion of titanium implants into the bone of rabbits (18). It took several years of animal testing before dental implants started to be used in humans (18). Accordingly, it would be unrealistic to think that the sound current knowledge on the clinical use of dental implants would exist without this preclinical phase of animal research. It is nevertheless a sine qua non condition that these experiments are adequately conducted.
63
The evidence presented in this article demonstrates that standards in animal research can be improved. Three ethical concerns arise when animal research is not performed with high standards: (i) the misuse of animals; (ii) the waste of resources; and (iii) the possibility of testing dangerous or ineffective therapies in humans.
Conclusions The quality of animal research in implant dentistry is in urgent need of improvement. Inaccurate findings from basic animal research may directly interfere with clinical trials. Tools are available that can assist researchers to perform animal research with higher standards; researchers and journal editors should avail themselves of these tools and should adhere to them. Conducting animal research with limited methodologies may raise ethical concerns regarding the usefulness of animal experiments. Because animal research data were evaluated in only one specialty in dentistry, implantology, the applicability of these conclusions to other fields of dentistry cannot be taken for granted. However, because there tends to be homogeneity among research methods and reporting in dentistry as a whole, similar findings are likely to be obtained in other fields of dentistry. Notwithstanding, the performance and reporting of animal experiments should be evaluated in other fields. Conflicts of interest – The author declares no conflicts of interest.
References 1. VON AULOCH S. Number of animals used for experimental purposes lower in the European Union. ALTEX 2014; 31: 1. 2. HIGGINS JPT, ALTMAN DG, STERNE JAC (editors). Chapter 8: assessing risk of bias in included studies. In: HIGGINS JPT, GREEN S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org. 3. GUYATT G, OXMAN AD, AKL EA, KUNZ R, VIST G, BROZEK J, NORRIS S, FALCK-YTTER Y, GLASZIOU P, DEBEER H, JA€ ESCHKE R, RIND D, MEERPOHL J, DAHM P, SCHUNEMANN HJ. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–394. 4. FAGGION CM Jr, GIANNAKOPOULOS NN, LISTL S. Risk of bias of animal studies on regenerative procedures for periodontal and peri-implant bone defects – a systematic review. J Clin Periodontol 2011; 38: 1154–1160. 5. LACHIN JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981; 2: 93–113. 6. FAGGION CM Jr, SCHMITER M, TU YK. Assessment of replication of research evidence from animals to humans in studies on peri-implantitis therapy. J Dent 2009; 37: 737–747. 7. GUYATT G, JAESCHKE R, HEDDLE N, COOK D, SHANNON H, WALTER S. Basic statistics for clinicians: 1. Hypothesis testing. CMAJ 1995; 152: 27–32. 8. KILKENNY C, BROWNE WJ, CUTHILL IC, EMERSON M, ALTMAN DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8: e1000412. 9. BAKER D, LIDSTER K, SOTTOMAYOR A, AMOR S. Two years later: journals are not yet enforcing the ARRIVE guidelines
64
10. 11.
12.
13.
Faggion on reporting standards for pre-clinical animal studies. PLoS Biol 2014; 12: e1001756. MOONESINGHE R, KHOURY MJ, JANSSENS AC. Most published research findings are false-but a little replication goes a long way. PLoS Med 2007; 4: e28. TER RIET G, KOREVAAR DA, LEENAARS M, STERK PJ, VAN NOORDEN CJ, BOUTER LM, LUTTER R, ELFERINK RP, HOOFT L. Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions. PLoS One 2012; 7: e43404. HOOIJMANS CR, ROVERS MM, DE VRIES RB, LEENAARS M, RITSKES-HOITINGA M, LANGENDAM MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 43. SCHULZ KF, ALTMAN DG, MOHER D; CONSORT Group. CONSORT 2010 statement: updated guideliness for reporting parellel group randomised trials. BMJ 2010; 340: c332.
14. CLINICALTRIALS.GOV. https://clinicaltrials.gov. Accessed on 18 December 2014. 15. STERNE JAC, EGGER M, MOHER D (editors). Chapter 10: addressing reporting biases. In: HIGGINS JPT, GREEN S, eds. Cochrane Handbook for Systematic Reviews of 10.23 Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org. 16. LOEB JM, HENDEE WR, SMITH SJ, SCHWARTZ MR. Human vs animal rights. In defense of animal research. JAMA 1989; 262: 2716–2720. € J. 17. ALBREKTSSON T, BRANEMARK PI, HANSSON HA, LINDSTROM Osseointegrated titanium implants. Requirements for ensuring a long-lasting, direct bone-to-implant anchorage in man. Acta Orthop Scand 1981; 52: 155–170. 18. BRANEMARK R, BRANEMARK PI, RYDEVIK B, MYERS RR. Osseointegration in skeletal reconstruction and rehabilitation: a review. J Rehabil Res Dev 2001; 38: 175–181.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
