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Sequential analysis applied to clinical trials in

dentistry: a systematic review

Introduction

Sequential

researched in medicine, particularly for use

in the design and analysis of clinical trials.1

In general, sequential methods involve ana-

lysing data as it becomes available, either

continuously or in groups. As soon as suf-

ficient information is received, the trial can

be terminated.2 The two main types are

‘fully’ (or continuous) sequential and ‘group’

sequential.2 Other types include sequential

treatment allocation3 and control charts.4

The earliest known formal application of

sequential analysis was the development

of control charts in the 1920’s for statisti-

cal process control.4 Control charts aim to

detect unnatural variation caused by some

change in a process.5 Data are presented lon-

gitudinally on graphs along with lower and

upper control limits.5 Types of control charts

include Shewhart charts, p-charts, u-charts,

and cumulative sum (CUSUM) charts.

Fully sequential analysis, in its modern

form, was developed during World War II for

quality control in manufacturing.2,4 In the

context of clinical trials, the data are ana-

lysed after the inclusion of each patient, or

pair of patients if the data are paired.2 The

main fully sequential methods are graphical

in nature (the sequential probability ratio test

and the triangular test, in its original form).2

analysis has been widely

These tests, in most cases, have expected

sample sizes (average stopping times) smaller

than the equivalent fixed sample sizes.2,4,6

Group sequential procedures were devel-

oped in response to alleged shortcomings of

fully sequential procedures, such as frequen-

cy of analysis.1,2,4 In general, analyses are

performed either after a certain number of

patients are recruited or according to a spe-

cific timeframe.2 Common group sequential

procedures involve correction of probability

(p) values for interim analyses, including the

fixed and flexible boundaries approaches,

as well as modifications of graphical fully

sequential methods.2 Some group sequential

procedures also offer expected sample sizes

that are smaller than the fixed sample sizes

of equivalent nonsequential designs.2,6

Another form of sequential methodology,

somewhat disparate in nature, is sequential

treatment allocation. Sequential allocation

aims to balance treatment groups in terms

of the number of patients as well as any

important prognostic factors.1 The simplest

version is the so-called biased coin design,

where the probability of assignment chang-

es as treatment groups become unbalanced.

This concept can be extended to balance

treatment groups over multiple stratify-

ing variables.3 These methods of allocation

do not necessarily affect the sample size.3

A further class of allocation procedures

introduces an adaptive element depend-

ing on previous outcomes. Here the objec-

tive is to minimise the number of patients

receiving a placebo or inferior treatment.1

Conventional methods, on the other hand,

require a fixed sample size and, in general,

make no formal provisions to allow for early

stopping. Stopping a trial early is beneficial

to patients receiving a control or inferior

treatment, and may also free up resources to

be used in other experiments.2,4,7–9 This is

particularly important for research involv-

ing expensive treatments, and for treat-

ments extending over long periods of time.

Clinicians are hence increasingly employing

sequential methods in clinical trials.7

In the field of dentistry, clinical trials are

characterised by repeated measures over

time, often for multiple endpoints.10 Trials

frequently proceed for many years, with data

collected at annual visits.10 It is of interest

to terminate such a trial as early as possible,

given ethical concerns for those involved.10–

12 When dentistry trials are stopped, other

scientific endeavours may benefit from the

freed resources.11 In the hope of attaining

these benefits, several researchers have there-

fore suggested that techniques of sequential

analysis be applied in dentistry.10–15

The aim of this systematic review was to

assess and characterise the extent to which

sequential analysis has been applied in den-

tistry and its subfields. This information will

be used to provide guidance in the imple-

mentation of this useful statistical method

for other dental researchers.

Methods

The Cochrane Handbook16 was used as a

basic template for the methodology. The

types of studies included in this systematic

review were clinical trials, excluding review

articles and meta-analyses. In particular,

trials were restricted to those in the field of

dentistry or its subfields, and which applied

sequential methods. There were no restric-

tions on the types of participants, interven-

tions, and outcome measures.

We searched PubMed (since 1966), Web of

Science (since 1900), the Cochrane Central

Register of Controlled Trials (CENTRAL) and

Scopus for articles published up until January

2008. We chose not to search Medline and

Embase as it is claimed that they are both cov-

Corresponding author: Dr Giseon Heo, Orthodontic

Graduate Program, Department of Dentistry, Faculty

of Medicine and Dentistry, University of Alberta,

Edmonton, Alberta T6G 2N8, Canada. Tel.:+1 780

492 1332; fax: +1 780 492 1624;

e-mail: gheo@ualberta.ca

RESEARCH

P Bogowicz, C Flores-Mir,2 PW Major1 and G Heo2

Faculty of Science, Department of Mathematical and Statistical Sciences, 1Craniofacial and Oral-health Evidence-based Practice Group,

Faculty of Medicine and Dentistry, 2Orthodontic Graduate Program, Faculty of Medicine and Dentistry

Clinical trials employ sequential analysis for the ethical and economic benefits it

brings. In dentistry, as in other fields, resources are scarce and efforts are made to

ensure that patients are treated ethically. The objective of this systematic review

was to characterise the use of sequential analysis for clinical trials in dentistry.

We searched various databases from 1900 through to January 2008. Articles were

selected for review if they were clinical trials in the field of dentistry that had

applied some form of sequential analysis. Selection was carried out independently

by two of the authors. We included 18 trials from various specialties, which

involved many different interventions. We conclude that sequential analysis seems

to be underused in this field but that there are sufficient methodological resources

in place for future applications.

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56 © EBD 2008:9.2

ered by Scopus (www.info.scopus.com/detail/

what/julie_arnheim.asp). The search terms

for PubMed, Web of Science, CENTRAL and

Scopus are summarised in Table 1 (where they

are partitioned into three columns for clar-

ity). The code for this search is provided in the

Addendum. A secondary search of trial refer-

ences was conducted in Scopus. As PubMed,

Web of Science and CENTRAL lack the capac-

ity to search article references, they were

not utilised at this stage. Besides the original

search terms, this further search was extended

to include the names of the main contributors

to sequential methods in medicine. They are

listed in Table 2. Code for this search is also

provided in the Addendum (available on the

journal's website www.nature.com/ebd/). The

computing limitations of the Scopus search

engine required splitting the search into

seven smaller searches. Each contained sev-

eral author names or title flag words, as well as

all the dentistry and clinical trial terms.

There were no constraints on dates,

other than the limitations of the search

engines themselves. There were also no

language restrictions.

Two authors (PB and GH) examined the

article abstracts independently to determine

which ones appeared to meet the inclusion

criteria. Articles were selected for review if

they were clinical trials in the field of dentist-

ry, and returned one or more of the sequen-

tial analysis keywords previously mentioned.

Disagreements were resolved by discussion

and, if necessary, retrieval of the full article.

Finally, the selected articles were accessed

online, or in original print form where neces-

sary. Thereafter the trials were assessed based

on the following criteria: experimental design,

whether or not the trial was randomised, the

type of sequential analysis used, and treat-

ment type. The corresponding speciality of

dentistry was also noted for each trial.

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Table 1. Search terms: primary search

For sequential analysisFor dentistry For clinical trials

“adaptive design”

“adaptive designs”

“c-chart”

“control chart”

“cumulative sum”

“EWMA chart”

“fully sequential”

“group sequential”

“ImR chart”

“interim analyses”

“interim analysis”

“interim look”

“interim looks”

“interim results”

“np-chart”

“p-chart”

“repeated significance test”

“repeated significance tests”

“sequential allocation”

“sequential analysis”

“sequential design”

“sequential designs”

“sequential method”

“sequential methodology”

“sequential methods”

“sequential probability ratio test”

“sequential probability ratio tests”

“sequential test”

“sequential tests”

“sequential t-test”

“sequential t-tests”

“shewhart chart”

“stage design”

“stage designs”

“triangular test”

“triangular tests”

“u-chart”

“XbarR chart”

“XbarS chart”

“XmR chart”

“z-chart”

CUSUM

EWMA

SPRT

dent*

dental

dentistry

endodont*

maxillofacial

“oral medicine”

“oral surgery”

orthodont*

pedodont*

periodont*

prosthodont*

teeth

tooth

“clinical trial”

“clinical trials”

“controlled clinical trial”

“controlled clinical trials”

trial

trial*

trials

CUSUM, cumulative sum charts

Table 2. Search terms: secondary search

Search term (authors)

Armitage, P.

Atkinson, A.

Begg, C. AND Iglewicz, B.

Bross, I.

Efron, B.

Facey, K. AND Whitehead, J.

Freedman, L. AND White, S.

Jennison, C. AND Turnbull, B.

Kim, K. AND DeMets, D.

Lan, K. AND DeMets, D.

McPherson, C.

O’Brien, P. AND Fleming, T.

Peto, R.

Pocock, S.

Pocock, S. AND Simon, R.

Siegmund, D.

Slud, E. AND Wei, L.

Taves, D.

Tsiatis, A., Rosner, G. AND Mehta, C.

Whitehead, J.

Zelen, M.

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Results

The primary search (search terms in Table 1)

yielded 96 articles, 48 of which were unique.

The overlaps were eight articles appear-

ing in two databases, 14 appearing in three

databases, and four that appeared in all

four databases. The secondary, or references

search, yielded 131 articles. Scopus lacked

the computing capabilities to determine

the number of duplicates within the seven

smaller searches. The large, albeit minimised,

number of search terms overwhelmed the

server causing the search engine to time-out.

After eliminating articles that were duplicates

or not clinical trials, we had 53 unique arti-

cles. By retrieving and examining each trial,

it was ascertained through discussion that

there were a number of false positives. The

total number of relevant clinical trials was

thereafter narrowed to 18. A flow diagram

illustrating the selection process is found in

Figure 1.

The characteristics of the selected trials are

summarised below (see also Table 3). In terms

of experimental design, the majority17–29

were conventional parallel trials with either

two or three treatment arms. In addition,

there were some30–32 split-mouth trials. The

other33,34 trials employed crossover designs.

All trials except for three23,27,32 stated that

some form of randomisation was employed.

The prevalent form of analysis was graphi-

cal, with eight19,25,26,30–34 trials employing

some sort of sequential chart. Most19,25,30–34

charts involved plotting a sample path until

some rejection or nonrejection bound-

ary was crossed. Four25,30,33,34 trials used

Armitage’s method. Other methods used

included Wald’s,31 the triangular test19 and

the CUSUM.26 One32 trial did not specify

the methods used to produce its charts;

another27 used the CUSUM but no graphs

were presented. Several trials17,20,21,23,29

employed sequential treatment allocation.

Others18,22,24,28 used p value corrections for

interim analyses. The trials employing fully

or continuous sequential analyses25,30–34

were noted.

The sequential clinical trials employed

a variety of dental treatments, including

dental restorations,18,24,30

drugs,25,28,32,34 flap reflection during sur-

gery,31 intra-appointment

mechanical and electrical stimuli,26 oral

rinses,21,33 orthodontic appliances,22 oxy-

gen therapy,19 scaling and root planing27

dentrifices,23

dressings,20,29

Table 3. Results: trial characteristics

Reference number

(in date order,

most recent first)

Design typeRandomisationSequential analysis type Treatment typeDental speciality

17Parallel YesSequential treatment allocationVerbal advice Oral health

28Parallel YesInterim analysesDrugs Oral health

29Parallel YesSequential treatment allocationIntra-appointment dressing Endodontics

18Parallel YesInterim analyses Dental restorationsPaediatric Dentistry

19Parallel YesTriangular test Oxygen therapyOral surgery

33Crossover YesArmitage’s charts Oral rinseOral health

20Parallel YesSequential treatment allocationIntra-appointment dressingEndodontics

21 ParallelYes Sequential treatment allocation Oral rinse Oral health

30Split-mouthYes Armitage’s charts Dental restorationsGeneral dentistry

27ParallelNoCUSUMScaling and root planingPeriodontics

22 Parallel YesInterim analysesOrthodontic appliances Orthodontics

23 Parallel NoSequential treatment allocationDentrificesGeneral dentistry

31Split-mouthYes Wald’s charts Flap reflection during surgeryOral surgery

24ParallelYesInterim analysesDental restorationsProsthodontics

26ParallelYes CUSUMStimuliPeriodontics

34CrossoverYesArmitage’s chartsDrugsPaediatric Dentistry

32 Split-mouthNoCharts (type unspecified)DrugsOral surgery

25Parallel YesArmitage’s chartsDrugsOral surgery

Potentially relevant articles

identified for retrieval

(n=227*) *Raw score

including duplicates

Trials retrieved for a more

detailed evaluation (n=53)

Articles excluded if

they were not trials in

the dentistry field, or if

they were duplicates

(n=174)

Number of useable trials

(n=18)

Trials excluded if no

reference to

sequential analysis

was made (n=35)

Figure 1. Results: selection flow diagram

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and verbal advice.17 The particular special-

ity of dentistry corresponding to each trial

was also noted. The trials corresponded to

endodontics,20,29 general dentistry,23,30 oral

health,17,21,28,33 oral surgery,19,25,31,32 ortho-

dontics,22 paediatric dentistry ,18,34 periodon-

tics26,27 and prosthodontics.24

Discussion

This systematic review was undertaken to

establish and characterise the extent to

which sequential analysis has been applied

in dentistry, and to provide guidance for use

in future dental research.

Present results In a thorough search

of PubMed, Web of Science, CENTRAL and

Scopus, we found 18 dental clinical trials

that applied sequential methods. In light

of the extensive theoretical considerations

of sequential analysis and the vast number

of clinical trials in dentistry, the number of

sequential dental trials seems relatively small.

The reader should note that this review may

not have identified all relevant studies, how-

ever, since the search terms might not have

been all-encompassing; there may be pub-

lished trials whose authors applied sequen-

tial analysis but did not disclose that this was

the case; and finally, there may be unpub-

lished trials which used sequential analysis.

The authors acknowledge that sequential

methods may not always be appropriate for

all dental trials.

There were eight trials19,25,26,30–34 employ-

ing graphical methods. The procedures were

successful in all cases, with no trials discon-

tinued for lack of conclusiveness. One trial,32

however, cited the nature of the charts as a

limitation. The authors lamented the lack of

a quantitative measure of differences in treat-

ment effect. These graphical trials included

all four of the oral surgery trials, as well as

one trial each from general dentistry, oral

health, paediatric dentistry and periodontics.

All but one32 mentioned randomisation.

The other trials in this review employed

p-value-corrected interim analyses (four

trials),18,22,24,28 sequential treatment allo-

cation (five trials)17,20,21,23,29 or CUSUM

tests27. Interim analyses, with p value cor-

rections for multiple looks , are a group

sequential method. The numbers of anal-

yses, including interim and final, were

two,24, three,28 five22 and seven.18 These tri-

als seemed to employ the group sequential

methods for correctness of statistical analy-

sis as opposed to the possibilities of early

stopping. Their corresponding subfields of

dentistry were oral health, orthodontics,

paediatric dentistry, and prosthodontics.

All were randomised.

Sequential treatment allocation facilitates

balance across treatments and prognostic

factors. Three studies17,23,29 used a version of

Pocock’s minimisation method. The other

two20,21 used a two-stage adaptive design.

Two of the studies were from endodontics,

one from general dentistry, and two from

oral health. All but one23 mentioned some

form of randomisation.

The last trial27 applied the CUSUM meth-

odology in a nongraphical form. The authors

made no mention of randomisation. The

trial was from the speciality of periodontics.

A note here is required concerning the

two general types of sequential analy-

sis, ie, fully and group sequential. It was

found that, of the trials that used sequen-

tial analysis, six25,30–34 were fully sequential

and five18,19,22,24,28 were group sequential.

The fully sequential trials were all graphi-

cal. All but one32 claimed to use some form

of randomisation. That same trial noted

that the lack of quantitative estimates was

a potential limitation of the trial design.

Three quarters of the trials involving drugs

and three quarters of the oral surgery tri-

als were fully sequential. By contrast, the

group sequential trials were distributed over

various areas of dentistry. The diminished

potential for early stopping under group

sequential trials did not seem to be a hin-

drance here. Indeed, most clinicians seemed

intent on letting their trials run to the

fullest extent.

There were also two trials35,36 that explic-

itly chose not to implement sequential

methodology in their trial designs. One35

involved a treatment period of 4 years and a

discontinuation period of 5 years thereafter.

The authors performed an interim analysis

after the first 4 years, and a final analysis

after 9 years had elapsed. They claimed that

the second, or final, measurement was the

only one that effectively measured their pri-

mary endpoint but noted that their conclu-

sions would have been unchanged by adjust-

ing significance levels. The other study36

included a halfway interim analysis as well

as a final analysis. These authors wrote that

the corrected boundaries would not have

been much less than 0.05, but they did not

calculate them explicitly. It was noted, how-

ever, that their reported p values were either

very small (P<0.001) or very large (P>0.15)

so that the adjustment would probably not

have altered their conclusions. These tri-

als were from general dentistry (use of seal-

ants and varnish)35 and orthodontics (use of

toothbrushes).36

Theoretical

PubMed, Web of Science, CENTRAL and

Scopus yielded some relevant theoretical

papers10–15 which are briefly reviewed here.

In an early treatise, Smith and O’Mullane12

proposed the use of a two-sample sequential

t test for trials of caries prophylactic agents.

The t test was illustrated with an example

using annual incremental data. Armitage

et al.11 developed an alternative repeated

significance test for longitudinal data with

comparisons between interventions. The test

was illustrated with reference to a trial com-

paring the efficacy of two types of fluoride

dentrifice on dental caries.

In a general survey of the design and

analysis of periodontal clinical trials, Imrey

and Chilton13 noted that interim analyses

should be “undertaken systematically and...

compensated for by the method of establish-

ing statistical significance at each look.” Van

der Glas and colleagues15 proposed the use

of several CUSUM methods in reflex studies,

illustrated by teeth stimulation data. Petrie

et al.14 noted that sequential methods can

be applied in dentistry, both group and fully

sequential, but no specific examples were

given. Leroux et al.10 further advocated the

use of sequential methods for longitudinal

clinical trials in dentistry. They developed a

sequential test for trials with multiple end-

points and repeated measures over time. In

particular, they noted its applicability to tri-

als for caries prevention, and illustrated its

use in a trial to assess the safety of dental

amalgam fillings.

papers The searches of

General discussion There are a number

of advantages and disadvantages in using

fully and group sequential analysis. The

main benefits are ethical and economic,

arising from the possibility of early stop-

ping. As previously noted, stopping a trial

early may benefit those participants receiv-

ing inferior treatments and might free

up resources to be used elsewhere.2,4,7–9

Further, through early stopping under

the null hypothesis, clinicians may avoid

unknown side-effects.2 In general, early

stopping might engender substantial sam-

ple size reductions:2,4 ie, the expected sam-

ple size may be smaller than the sample size

of a nonsequential design. Lastly, ignoring

the inherently sequential nature of a clini-

cal trial can incur bias.9

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There are some disadvantages. For both

group and fully sequential analyses, the

data must be timely and highly accurate.7

There may be significant costs incurred by

this right-in-time organisation and statisti-

cal analyses.9 Indeed, the logistics are more

complicated than for conventional trials.2,9

It is possible that the length of a sequen-

tial trial may be longer than its single-stage

counterpart.9 Also, the maximum sample

size (truncation point) may be larger6,37 than

the sample size for a nonsequential trial, and

in some cases infinite.2 Reductions in patient

numbers only occur if the endpoint is avail-

able quickly enough relative to the patient

recruitment rate.2,37 Indeed, an extreme situ-

ation would have all patients included prior

to the first possible data analysis.2 Sometimes

it might not be unethical to continue a trial

to estimate a treatment effect or to achieve

higher power.2 Trials that stop early are prone

to exaggerating treatment effects8 and stop-

ping early also diminishes the probability of

uncovering adverse effects so that evidence

of harm does not emerge. Although the dis-

advantages are not trivial, Wegscheider9 sug-

gests that the ethical advantages dominate.

Sequential allocation is an alternative to

complete randomisation, where all treatment

assignments are equally likely and block-ran-

domised designs where patients are assigned

to treatments within groups (eg, male and

female).38 The main advantage of sequential

allocation is that allocations are balanced

across treatments and prognostic factors.

In addition, decreases in selection bias and

susceptibility to imbalance over permuted

block designs have been observed.3 Some

authors have suggested that it is ill-informed

not to incorporate accruing information into

the trial design.39 Although the method of

sequential allocation and its adaptive counter-

parts is not new, the techniques have seldom

been used in practice.39 According to Halpern

and Brown,3 these sequential designs may be

expensive and difficult to implement. They

noted that the gains in balance and efficiency

are negligible relative to complete randomisa-

tion. The reader may recall that randomisa-

tion is often said to validate statistical tests.40

In the case of sequential (nonrandom) alloca-

tion, conventional statistical analyses are not

valid.3 These problems are exacerbated by a

lack of clear examples in the literature.39 We

emphasise that nonrandom allocation meth-

ods are, in general, not advisable because they

may lead to overestimated treatment effects.41

Hence, the sequential allocation technique

should be applied with due caution.

There is debate over whether it is best

to use fully sequential or group sequential

procedures. Fully sequential procedures

generally offer larger expected sample

size8 and time reductions.9 Further, fewer

patients are exposed to the poorer treat-

ment.8 On the other hand, group sequen-

tial methods are much simpler2,7 and more

flexible2 than their continuous counter-

parts. Group sequential trials are shortened

less often and are less biased.9 They are

desirable when the need arises to estimate

treatment effects and also to demonstrate

superiority.9 Both types have some short-

comings, however. Fully sequential analy-

sis is rarely applied in medicine because of

the frequency of data analysis.2 If the data

monitoring committee is unable to meet

at short notice, accrual continues. This is

inefficient compared with group sequen-

tial methods.37 There are also a number of

statistical issues in applying fully sequen-

tial analysis. First, conventional point

estimates and p values are incorrect.2,7,9

Secondly, adjustment of the final analysis

is more marked than for group sequential

procedures.8 Lastly, there is the possibil-

ity of incurring bias when pooling fully

sequential trials with others for meta-

analysis.9 Group sequential methods, in

contrast, delay the potential for early stop-

ping.7 Also, any unplanned interim analy-

ses, especially those that are data-provoked,

could cause data interpretation problems

and exaggerate treatment effects.2

The debate is far from resolved. Any deci-

sion to choose one over the other must

come with careful consideration of costs and

benefits. The solution may lie in new pro-

cedures such as that outlined by Gombay

and Hussein.6 They proposed a sequential t

test with no restrictions on the timing and

number of interim analyses. Indeed, the test

enables clinicians to switch from periodic

interim analyses to continuous monitoring.6

A simulation study of adaptive designs

demonstrated relative efficiencies of 100–

120% versus nonadaptive alternatives.39 This

corresponds to sample sizes for the adaptive

designs that are 83–100% of those of the

fixed sample size designs.39 In some clinical

trials, it might be useful for the investigators

to set the maximal sample size (truncation

point) and design sequential procedures to

achieve the best power and average stop-

ping time. In group and fully sequential pro-

cedures, the maximum sample size is about

105–130% of the fixed sample size and the

average stopping time is about 70–80% of the

fixed sample size in the case of independent

two sample t tests.4,6 Recall that the sample

size depends on the power, the significance

level and the parameters specified under the

alternative hypothesis. In group sequential

procedures, the number of interim analyses

must be set before the trial begins. The maxi-

mum sample size and the expected sample

size depend also upon the number of inter-

im analyses. One might argue, then, that

the possible increase in the maximum sam-

ple size is negligible relative to the benefits,

when group and fully sequential procedures

are applied.

Finally, we consider another version

of sequential analysis, which has been

recently proposed. The Pharmaceutical

Research and Manufacturers of America

Adaptive Design Working Group, estab-

lished in 2005, broadly defines an adaptive

design as one that, “... uses accumulating

data to decide on how to modify aspects of

the study without undermining the valid-

ity and integrity of the trial.”42 According

to the working group, the most desirable

sequential design should be flexible to:

(1) allocate the subjects to available arms;

(2) re-assess the sample size; (3) determine

when to stop the trial for efficacy, harm

and futility; and (4) make the interim and

terminal decisions.42 The adaptive design is

a generalisation of group sequential meth-

ods. It may be the most practical sequen-

tial technique for clinicians in dentistry,

because it permits redesigning of the next

stage with emphasis on one or more of the

aforementioned rules, (1)-(4). The inter-

ested reader is encouraged to seek out the

article by Bauer and Brannath.43

In summary, this systematic review has

examined the use of sequential analysis in

dentistry as well as its general advantages

and disadvantages. We found 18 clinical tri-

als which applied sequential methodology.

Conclusions

• The small number of relevant trials in

this review might suggest that sequential

analysis is underused in dental fields and

its subfields.

• Theoretical and methodological resources

are already in place to support future appli-

cations of sequential analysis in dentistry.

• The direction of future research may lie in

the flexible group sequential and adaptive

designs mentioned above.

Conflicts of interest The authors declare

that they have no conflicts of interest.