Re iew a icle
O al ad e se e en epo ing in smoking cessa ion ials using
non-combus ible nico ine p oduc s: A quali y assessmen
Giusy Ri a Ma ia La Rosa
a,*
, Cinzia Del Gio ane
b,c,1
, Sil ia Minozzi
d,1
, Jan Kowalski
e
,
Iain Chapple
, a
, Amaliya Amaliya
g
, Dewi Zakiawa i
h
, F ancesco Sa e io Ludo iche i
i
,
Baek Il Kim
j
, Wanninayake Mudiyanselage Tilaka a ne
k
, Kons an inos Fa salinos
l
,
Ricca do Polosa
a,m
a
Depa men o Clinical and Expe imen al Medicine, Uni e si y o Ca ania, Ca ania, I aly
b
Depa men o Medical and Su gical Sciences o Child en and Adul s, Uni e si y-Hospi al o Modena and Reggio Emilia, Modena, I aly
c
Ins i u e o P ima y Heal h Ca e (BIHAM), Uni e si y o Be n, Be n, Swi ze land
d
Depa men o Epidemiology, Lazio Regional Heal h Se ice, Rome, I aly
e
Depa men o Pe iodon ology, Medical Uni e si y o Wa saw, Wa saw, Poland
Pe iodon al Resea ch G oup, Ins i u e o Clinical Sciences, College o Medical & Den al Sciences, The Uni e si y o Bi mingham, Bi mingham, UK
a
Bi mingham Communi y Heal hca e NHS Founda ion T us , Bi mingham, UK
g
Depa men o Pe iodon ology, Facul y o Den is y, Uni e si as Padjadja an, Wes Ja a, Indonesia
h
Depa men o O al Medicine, Facul y o Den is y, Uni e si as Padjadja an, Wes Ja a, Indonesia
i
Den is y sec ion, Depa men o Neu oscience, Uni e si y o Padua, Padua, I aly
j
Depa men o P e en i e Den is y & Public O al Heal h, Yonsei Uni e si y College o Den is y, Seoul, Republic o Ko ea
k
Depa men o O al and Maxillo acial Clinical Sciences, Facul y o Den is y, Uni e si i Malaya, Kuala Lumpu , Malaysia
l
Depa men o Public and Communi y Heal h, School o Public Heal h, Uni e si y o Wes A ica, A hens, G eece
m
Cen e o he Accele a ion o Ha m Reduc ion, Uni e si y o Ca ania, Ca ania, I aly
ARTICLE INFO
Keywo ds:
CONSORT ha ms
E-ciga e e
Nico ine eplacemen he apy
Non-combus ible nico ine p oduc s
O al ad e se e en s
Snus
Sa e y
Smoking cessa ion
ABSTRACT
Objec i es: To assess he comple eness and quali y o epo ing o o al ad e se e en s (OAEs) in andomized
con olled ials (RCTs) ha e alua ed non-combus ible nico ine p oduc s (NCNPs) and whe he epo ing
p ac ices ha e imp o ed o e ime.
Da a sou ces and s udy selec ion: This seconda y da a analysis was based on 36 RCTs included in a p e ious
sys ema ic e iew. T ials in ol ed adul smoke s and included nico ine eplacemen he apy, elec onic ciga-
e es, hea ed obacco, and smokeless obacco. The OAE epo ing was e alua ed using an adap ed CONSORT
Ha ms checklis . An Adjus ed Checklis Sco e (ACS), ep esen ing he p opo ion o c i e ia me , was calcula ed.
Uni a ia e linea eg essions explo ed he associa ion be ween ACS and s udy-le el a iables (publica ion yea ,
coun y, unding, blinding and p oduc ype).
Resul s: OAE epo ing was agmen ed, wi h a mean ACS o 0.52 (0.11–0.74). O e 80 % o s udies (n=30)
p o ided some quan i a i e da a, bu only 53 % (n=19) p esen ed esul s in a abula ed, a m-speci ic o ma .
De ini ions o OAEs and se e i y measu emen we e a ely epo ed (n=5, 14 % and n=6, 17 % espec i ely).
The me hod o OAEs collec ion was desc ibed in 50 % o he s udies (n=18). OAEs we e a ely men ioned in i les
(n=4, 11 %) and conclusions (n=13, 36 %). Less han hal o he s udies epo ed he easons o pa icipan
wi hd awal due o AEs (n=16, 44 %). Only 28 % (n=10) and 44 % (n=16) o he s udies epo ed he analysis
app oach and s a is ical me hods o AEs, espec i ely. A weak, non-signi ican posi i e co ela ion was ound
be ween ACS and yea o publica ion ( =0.288, p =0.09). No s udy-le el a iable showed a s a is ically sig-
ni ican associa ion wi h ACS.
Conclusions: Repo ing o OAEs in clinical ials o NCNPs emains limi ed and inconsis en , o en lacking clea
de ini ions, s anda dized se e i y assessmen s, de ailed da a collec ion me hods, and p ede ined s a is ical plans.
* Co esponding au ho a : Depa men o Clinical and Expe imen al Medicine, Via San a So ia, 89, 95123, Uni e si y o Ca ania, Ca ania, I aly.
E-mail add ess: [email p o ec ed] (G.R.M. La Rosa).
1
These au ho s con ibu ed equally as second au ho s.
Con en s lis s a ailable a ScienceDi ec
Jou nal o Den is y
jou nal homepage: www.else ie .com/loca e/jden
h ps://doi.o g/10.1016/j.jden .2025.106057
Recei ed 28 July 2025; Recei ed in e ised o m 21 Augus 2025; Accep ed 24 Augus 2025
Jou nal o Den is y 162 (2025) 106057
A ailable online 24 Augus 2025
0300-5712/© 2025 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license ( h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/ ).
Clinical signi icance: S anda dized OAE epo ing is c i ical o ole abili y da a in e p e a ion. We p opose
p ac ical ecommenda ions o guide esea che s in imp o ing he epo ing o OAE and s eng hening he ole o
den al p o essionals in suppo ing pa ien s h ough smoking cessa ion s a egies.
1. In oduc ion
Non-combus ible nico ine p oduc s (NCNPs) - including nico ine
eplacemen he apies (NRTs) such as gums, lozenges, mou h sp ays,
and inhale s [1], as well as smokeless obacco (e.g., snus) [2] and
elec onic nico ine deli e y sys ems (ENDS) like e-ciga e es (e-cigs) and
hea ed obacco p oduc s (HTPs) [3,4] - ha e eme ged as key ools in
smoking cessa ion s a egies. These p oduc s o e he po en ial o
educe ha m by elimina ing combus ion- ela ed oxican s; howe e ,
because hey a e adminis e ed ia he o al ou e, he o al ca i y is he
i s si e exposed o hei chemical cons i uen s [5]. As such, o al ad e se
e en s (OAEs) such as d y mou h, aph hous ulce s, gingi al i i a ion,
and o he mucosal eac ions a e pa icula ly ele an when assessing he
ole abili y and sa e y o NCNPs [6,7].
Despi e he g owing clinical and public heal h in e es in OAEs
associa ed wi h NCNPs, much o he exis ing e idence de i es om
obse a ional s udies, which a e inhe en ly p one o con ounding and
epo ing biases [8]. Randomized con olled ials (RCTs) emain he
gold s anda d o e alua ing he e icacy and sa e y o medical in-
e en ions [9,10], bu he eliabili y o OAE da a eme ging om RCTs
depends c i ically on he quali y and comple eness o ha ms epo ing.
His o ically, RCTs ha e p io i ized e icacy endpoin s, o en ele-
ga ing sa e y da a, pa icula ly o ad e se e en s no deemed se ious o
li e- h ea ening, o seconda y s a us. In esponse o widesp ead conce ns
o e unde epo ing and inconsis en ha m da a, he Consolida ed
S anda ds o Repo ing T ials (CONSORT) g oup issued a dedica ed
Ha ms ex ension in 2004, p o iding de ailed guidance on how ad e se
e en s should be epo ed in RCTs [11]. This ex ension has since un-
de gone a ecen upda e in 2022 o u he s eng hen and cla i y ec-
ommenda ions [12]. These e o s ha e con ibu ed o imp o ed sa e y
epo ing p ac ices ac oss clinical esea ch domains. Howe e , as p e-
iously highligh ed in oncology and o he ields, ad e se e en epo ing
emains he e ogeneous and o en incomple e, especially o e en s o
mode a e se e i y o unce ain causali y [13,14]. In pa icula , o al
symp oms - al hough no li e- h ea ening - can signi ican ly a ec
adhe ence, use sa is ac ion, and long- e m e ec i eness o NCNP-based
cessa ion s a egies [15–17].
This comp omises bo h he e alua ion o p oduc ole abili y and he
abili y o in o m clinical guidelines and use decision-making. To
add ess his, we aimed o assess he comple eness and quali y o OAE
epo ing in RCTs e alua ing o al ad e se e ec s linked o NCNP use by
using an adap ed 19-i em checklis based on he CONSORT Ha ms
ex ension [12]. This ool allows he e alua ion o indi idual epo ing
componen s and he gene a ion o an Adjus ed Checklis Sco e (ACS), a
con inuous summa y index anging om 0 o 1. Simila sco ing ap-
p oaches ha e been used in p io me a- esea ch on ha m epo ing [13],
bu ha e no ye been applied o he con ex o NCNPs. Th ough a
comp ehensi e analysis o he quali y o OAE epo ing in cu en RCTs,
we aimed o p opose a se o p ac ical ecommenda ions o imp o e
epo ing in u u e ials. We also examined whe he epo ing quali y
has imp o ed o e ime.
2. Me hods
2.1. Sea ch and s udy selec ion
Ra he han conduc ing a new independen sea ch, his analysis d ew
upon RCTs p e iously iden i ied in a ecen sys ema ic e iew and
ne wo k me a-analysis [7], which in es iga ed he o al ole abili y o
NCNPs o smoking cessa ion. Tha e iew included RCTs published in
English and e ie ed h ough a sys ema ic sea ch o PubMed, Scopus,
and he Coch ane Lib a y, upda ed o Feb ua y 2025.
Eligible ials included adul pa icipan s and in es iga ed a wide
ange o NCNPs, speci ically: NRTs adminis e ed ia local deli e y sys-
ems (including gum, mou h sp ay, able , lozenge and inhale ); ENDS,
including bo h e-cigs and HTPs; and SMT such as snus.
Fo de ailed in o ma ion ega ding he o iginal eligibili y c i e ia,
sea ch e ms, and s udy selec ion p ocedu es, eade s a e e e ed o he
me hods sec ion o he p ima y e iew [7].
2.2. Da a ex ac ion
Fo each included s udy, we ex ac ed basic s udy cha ac e is ics
including i s au ho , yea o publica ion, ype o in e en ion in each
a m, blinding s a us, geog aphic egion whe e he RCT was conduc ed,
and a ge popula ion. We also documen ed whe he OAEs we e e-
po ed and, i so, whe he hey we e p esen ed in abula o na a i e
o m, and whe he he in o ma ion appea ed in he main a icle o in he
supplemen a y ma e ial.
2.3. Quali y epo ing assessmen
In his s udy, OAEs we e b oadly de ined as any o al symp oms
po en ially a ibu able o he in es iga ional p oduc o i s adminis-
a ion. Based on he da a epo ed in he included RCTs, i e main
ca ego ies o OAEs we e iden i ied: aph hous ulce s, d y mou h, mou h
i i a ion, pe iodon al/den al issues, and empo omandibula diso de s
(TMDs).
To assess he comple eness and quali y o OAE epo ing, we
employed a ailo ed e sion o he CONSORT Ha ms ex ension checklis
[12]. Ou app oach was ini ially inspi ed by he s uc u ed amewo k
p oposed by Xie e al. [13] in hei e alua ion o immune- ela ed
ad e se e en s in oncology ials. While Xie’s model was i sel based
on he CONSORT Ha ms ecommenda ions, we u he adap ed i o
be e e lec he speci ici y o o al ad e se e en s in ials in es iga ing
NCNPs. The adap ed checklis (Table 1) includes 10 co e i ems, each
co esponding o a speci ic domain o ha ms epo ing. Each co e i em
was subdi ided in o one o mo e speci ic subi ems, esul ing in a o al o
19 i ems.
The domains co e ed a e he ollowing: men ion o ad e se e en s
(AEs) in he i le o abs ac ; s a emen o ha ms in he in oduc ion;
de ini ion and se e i y o AEs; me hods and iming o da a collec ion;
plans o ha ms analysis; epo ing o ha m- ela ed wi hd awals; a ail-
abili y o denomina o s; quan i a i e and abula ed da a p esen a ion;
speci ica ion o s a is ical me hods o AEs; and in eg a ion o AEs in he
discussion and conclusions.
Each i em was sco ed as 1 (Yes) i he c i e ion was adequa ely me ,
and 0 (No) i he in o ma ion was absen o unclea . Sco es we e hen
summed and used o calcula e he ACS o each s udy as he numbe o
i ems adequa ely epo ed di ided by he o al numbe o applicable
i ems in he adap ed checklis . I anges om 0 o 1, whe e 0 indica es
ha none o he checklis i ems we e me and 1 indica es ull adhe ence
o all p ede ined epo ing c i e ia. The checklis was independen ly
applied by wo e iewe s (GRMLR and RP). In cases o disag eemen ,
disc epancies we e discussed un il consensus was eached.
2.4. S a is ical analysis
Gene al cha ac e is ics o he included s udies we e summa ized as
equencies and pe cen ages. In e - a e ag eemen be ween he wo
G.R.M. La Rosa e al.
Jou nal o Den is y 162 (2025) 106057
2
e iewe s was assessed o each checklis -i em using bo h aw pe cen -
age ag eemen and Cohen’s kappa coe icien . The quali y o OAE
epo ing was quan i ied using he ACS. Mean, s anda d de ia ion,
minimum, and maximum alues o ACS we e calcula ed. Fo each i em,
he equency and pe cen age o s udies ha me he i em we e also
epo ed. To explo e changes in OAE epo ing quali y o e ime, we
gene a ed a sca e plo illus a ing he dis ibu ion o ACS sco es ac oss
publica ion yea s. We calcula ed he Spea man’s co ela ion coe icien
o assess he co ela ion be ween he ACS and he s udy publica ion
yea . Uni a ia e linea eg ession analyses we e conduc ed o examine
he associa ion be ween ACS and each o he ollowing s udy-le el
co a ia es, adop ed om Xie e al. [13]: yea o publica ion, unding
sou ce, geog aphic egion, blinding s a us and p oduc ype. S a is ical
signi icance was se a p <0.05. All analyses we e pe o med using S a a
S a is ical So wa e: Release 17 (S a aCo p LLC, College S a ion, TX,
USA).
3. Resul s
3.1. Gene al cha ac e is ics
The low o s udy selec ion has been p e iously epo ed [7]. A o al
o 36 RCTs, in ol ing 12,454 pa icipan s, we e included in he p esen
analysis [18–53]. Gene al cha ac e is ics and desc ip i e s a is ics o he
included s udies a e p esen ed in Table 2 and Appendix 1 and u he
de ailed in he p e ious publica ion [7]. Eigh ypes o NCNPs we e
included: e-cigs (n =6, 17 %), HTPs (n =1, 3 %), snus (n =4, 11 %), and
a ious o ms o NRTs, including gum (n =19, 53 %), mou h sp ay (n =
3, 8 %), able (n =3, 8 %), lozenge (n =1, 3 %), and inhale (n =4, 11
%). The yea s o publica ion anged om 1982 o 2024. Six een s udies
(44 %) we e unded by pha maceu ical o obacco companies, while 13
(36 %) ecei ed unding om non-p o i o ganiza ions o ins i u ional
sou ces. One s udy (3 %) epo ed no unding, and he emaining six (17
%) did no p o ide any in o ma ion abou unding. The mos equen ly
epo ed o al ad e se e en s we e mou h i i a ion (n =23, 64 %),
aph hous ulce s (n =13, 36 %), d y mou h (n =10, 28 %), and
empo omandibula join diso de s (n =10, 28 %). Pe iodon al o den al
issues we e documen ed in 7 s udies (19 %).
3.2. Assessmen o he epo ing o OAEs
The wo e iewe s demons a ed subs an ial ag eemen in he
applica ion o he checklis , wi h aw ag eemen exceeding 90 % ac oss
Table 1
Adap ed ha ms ex ension o CONSORT checklis o o al ad e se e en s (OAE)
assessmen .
Co e Co e desc ip ion I em I ems desc ip ion
1I he s udy collec ed da a on
ha ms and bene i s, he i le
o abs ac should so s a e
1a AEs men ioned in i le.
1b AEs men ioned in abs ac .
2I he s udy collec ed da a on
ha ms and bene i s, he
in oduc ion should so s a e
2a AEs add essed in in oduc ion.
3Lis add essed AEs wi h
de ini ions o each
3a Does he me hods sec ion
speci y ha AEs ha e been
assessed?
3b Does he me hods sec ion
p o ide a de ini ion o he AEs?
3c Was he se e i y o AEs
assessed?
3d Was he me hod o assessing
AEs se e i y clea ly desc ibed?
4Cla i y how ha ms- ela ed
in o ma ion was collec ed
4a Is he e a desc ip ion o he
me hod o collec ion o OAEs
da a?
4b A e he OAEs epo ed wi h a
clea indica ion o he
co esponding ime poin ?
5Desc ibe plans o p esen ing
and analyzing in o ma ion on
ha ms
5a Does he me hods sec ion
p o ide a desc ip ion o he
me hods o analysis o AEs (i.
e., ITT o pe p o ocol)?
6Desc ibe o each a m he
pa icipan wi hd awals ha
a e a esul o ha ms and hei
expe iences wi h he
alloca ed ea men
6a Does he s udy epo whe he
any pa icipan wi hd awals
we e due o po en ial OAEs?
7P o ide he denomina o s o
analyses o ha m
7a Does he s udy epo he
numbe a baseline o each
a m?
7b Does he s udy epo he
numbe included in any
analysis o OAEs?
8P esen he absolu e isk pe
a m and pe OAE ype, and
p esen app op ia e me ics
8a Does he s udy p esen
quan i a i e da a o OAEs?
8b Does he s udy abula e esul s
o OAEs?
8c Does he s udy epo he
numbe o pa icipan s
expe iencing each OAE in each
ea men a m?
9Desc ibe s a is ical analysis 9a Was a s a is ical analysis
me hod speci ied o AEs?
10 P o ide a balanced
discussion o bene i s and
ha ms
10a A e AEs add essed in he
discussion?
10b Do he s udy conclusions
explici ly e e o he AEs
indings?
Legend: AEs: Ad e se E en ; ITT: In en ion o T ea ; OAEs: O al Ad e se E en s.
Table 2
Desc ip i e summa y o gene al cha ac e is ics o he included
s udies.
Cha ac e is ics RCTs (n =36)
No. ( %)
Yea o publica ion
1980–1990 12 (33)
1991–2000 6 (17)
2001–2010 4 (11)
2011–2020 12 (33)
≥2021 2 (6)
Coun y
A ica 1 (3)
Asia 2 (6)
Eu ope 15 (42)
No h Ame ica 17 (47)
Sou h Ame ica 1 (3)
In e en ion
NRT 27 (75)
ENDS 7 (19)
SMT (i.e., snus) 4 (11)
Sample size
<100 3 (8)
100–500 27 (75)
500–1000 3 (8)
>1000 3 (8)
Blindness
Open-label 12 (33)
Double o iple blind 24 (66)
No. in e en ion a ms
Single 27 (75)
Mul iple (dosage) 4 (11)
Mul iple ( ype) 5 (14)
Funding
Indus y 16 (44)
Academy/ ounda ion 13 (36)
None 1 (3)
No epo ed 6 (17)
Legend. NRT: nico ine eplacemen he apy; ENDS: elec onic
nico ine deli e y sys ems; RCT: andomized con olled ial; SMT:
smokeless obacco.
G.R.M. La Rosa e al.
Jou nal o Den is y 162 (2025) 106057
3
all i ems. The mean Cohen’s kappa coe icien was 0.938 (SD =0.166),
indica ing e y high in e - a e ag eemen ac oss checklis i ems. I em-
speci ic ag eemen da a a e shown in Appendix 2.
The mean ACS was 0.52 (SD =0.19), wi h alues anging om 0.11
- epo ed by one s udy [46] - o 0.74, epo ed by se en s udies [20,29,
31,45,47,51,52]. I em-by-i em e alua ions and o e all ACS sco es o all
s udies can be ound in Appendix 3. All included RCTs epo ed he
baseline numbe o pa icipan s pe a m (i em 7a) and 86 % o ials (n =
31) explici ly men ioned OAEs in he me hods sec ion (i em 3a) (Fig. 1).
Six y-se en pe cen o he s udies (n =24) speci ied he numbe o
pa icipan s included in he analysis o ad e se e en s (7b). Quan i a i e
da a on OAEs (i em 8a) and abula ed esul s (8b) we e p o ided in 83 %
(n =30) and 53 % (n =19) o he s udies, espec i ely. OAEs we e e-
po ed sepa a ely o each ial a m (8c) in 61 % o he s udies (n =22).
Only 14 % o he s udies (n =5) p o ided a de ini ion o ad e se e en s
(3b), and jus 17 % (n =6) o he 22 s udies (61 %) ha ci ed se e i y o
AEs (3c) explained how se e i y was assessed (3d). The me hod and
iming o da a collec ion (i ems 4a and 4b) we e clea ly speci ied in 50 %
(n =18) and 58 % (n =21) o ials, espec i ely. Six een s udies (44 %)
speci ied he easons o pa icipan wi hd awal due o AEs (i em 6a).
OAEs we e men ioned in he discussion and conclusion sec ions in 64 %
(n =23) and 36 % (n =13) o he s udies, espec i ely (i ems 10a and
10b). Less han hal o he s udies (n =16, 44 %) men ioned OAEs in he
in oduc ion (2a), while 11 % (n =4) and 67 % (n =24) did so in he i le
(1a) and abs ac (1b), espec i ely. Finally, i ems ela ed o he analysis
plan (5a) - such as in en ion- o- ea (ITT) o pe -p o ocol app oaches -
and he use o s a is ical analysis o AEs (9a) we e epo ed in only 28 %
(n =10) and 44 % (n =16) o he s udies, espec i ely.
3.3. Changes in ACS o e ime and p edic i e co a ia es
Changes in ACS alues o e ime a e p esen ed in Fig. 2. A weak,
non-signi ican posi i e co ela ion was ound be ween ACS and yea o
publica ion ( =0.288, p =0.09). We did no ind any signi ican as-
socia ion be ween each s udy- a iable and he ACS (Table 3).
4. Discussion
This s udy o e s he i s s uc u ed e alua ion o OAE epo ing in
NCNP ials, highligh ing pe sis en sho comings. Ac oss 36 RCTs, he
mean ACS was 0.52, indica ing ha only hal o he ecommended
epo ing c i e ia we e me . Key gaps included missing de ini ions o
OAEs, limi ed in o ma ion on se e i y assessmen , and sca ce epo ing
Fig. 1. P opo ion o andomized con olled ials (RCTs) epo ing o al ad e se e en s (OAEs) in compliance wi h he adap ed CONSORT Ha ms checklis .
Ba cha showing he pe cen age o included ials (N =36) mee ing each o he 19 i ems o he adap ed epo ing checklis o OAEs.
Fig. 2. Va ia ion in adjus ed checklis sco e (ACS) by yea o publica ion.
Table 3
Findings om uni a ia e linea eg ession analysis.
Uni a ia e linea eg ession
analysis
Reg ession
coe icien
S anda d
E o
p
alue
Co a ia e
Yea o publica ion
(con inuous)
.004 .002 0.115
Coun y (Re . No h Ame ica)
Eu ope 0.055 .070 0.431
Asia 0.166 .146 0.265
A ica −0.018 .200 0.927
Sou h Ame ica −0.124 .200 0.542
Funding (Re . No unded)
Academy/ ounda ion −0.092 .088 0.303
Indus y 0.028 .085 0.746
Blinding (Re . Yes)
No −0.073 .066 0.274
P oduc (Re . NRT)
ENDS .08 .089 0.374
SMT .028 .120 0.820
NRT+ENDS/SMT .107 .143 0.464
Legend. ENDS: elec onic nico ine deli e y sys ems; NRT: nico ine eplacemen
he apy; SMT: smokeless obacco; Re .: Re e ence.
G.R.M. La Rosa e al.
Jou nal o Den is y 162 (2025) 106057
4
o s a is ical analysis plans. No signi ican imp o emen s we e obse ed
o e ime, no associa ions wi h s udy-le el cha ac e is ics. These
widesp ead inconsis encies comp omise he abili y o syn hesize e i-
dence on p oduc ole abili y, a c i ical ac o o bo h use adhe ence
and clinical decision-making.
As he i s si e o exposu e o NCNPs, he o al ca i y is cen al o
assessing ole abili y. Commonly epo ed OAEs, such as mou h i i a-
ion and aph hous ulce s, a e equen ly unde - epo ed, possibly due o
limi ed a en ion om non-den al ialis s. Ye , hese symp oms can
comp omise key o al unc ions like chewing and swallowing, a ec ing
nu i ional in ake and quali y o li e [54–56]. In he con ex o smoking
cessa ion, ole abili y issues may comp omise adhe ence and pe cep-
ions o sa e y. F om a public heal h pe spec i e, consis en OAE
epo ing is essen ial o e alua ing he isk-bene i p o ile o NCNPs and
suppo ing pe sonalized counselling. This s udy assessed he quali y o
OAE epo ing in RCTs and p oposed ecommenda ions o imp o e
u u e epo ing p ac ices.
Nea ly 90 % o he included ials did no men ion OAEs o ela ed
e ms in he i le. In addi ion, only 14 % o s udies p o ided an explici
de ini ion o ad e se e en s (i.e., o al o o he wise) and <20 %
desc ibed how se e i y was measu ed. In he con ex o clinical ials,
s anda dized classi ica ion sys ems o ad e se e en s, such as he
Common Te minology C i e ia o Ad e se E en s (CTCAE) [57], Med-
ical Dic iona y o Regula o y Ac i i ies (MedDRA) [58] o he Wo ld
Heal h O ganiza ion Ad e se Reac ion Te minology (WHO-ART) [59]
ha e been used o ensu e he eliabili y and ep oducibili y o epo ed
ou comes. Howe e , mos o he s udies elied on subjec i e,
sel - epo ed assessmen s o o al symp oms wi hou cla i ying wha
cons i u ed an ad e se e en , no how such e en s we e explained o
pa icipan s. This lack o cla i y a ec s he in e p e abili y o indings
and may comp omise da a eliabili y. In addi ion, exis ing ad e se e en
classi ica ion sys ems a e o en gene ic and ail o cap u e he speci ic
clinical nuances o o al ad e se e en s. This limi a ion may lead o
inconsis en epo ing o unde es ima ion o hei ele ance. No ably,
he e is cu en ly no s anda dized, den al-speci ic classi ica ion sys em
o OAEs, highligh ing he need o ailo ed amewo ks ha can be e
suppo accu a e iden i ica ion, g ading, and communica ion o hese
ou comes in smoking cessa ion esea ch.
Hal o he s udies epo ed how o al ad e se e en s we e collec ed.
Ye , his in o ma ion emains highly ele an , as da a collec ion may
ely on subjec i e me hods (e.g., sel - epo ques ionnai es) o objec i e
assessmen s (e.g., clinical examina ion). Beyond he issue o measu e-
men eliabili y - which has al eady been add essed in p e ious bias
assessmen s [7] - anspa en epo ing o da a collec ion me hods is
impo an o in e p e ing esul s and unde s anding hei alidi y.
Gi en he complexi y o o al ou comes, in ol ing den al p o essionals in
ial design may help ensu e ha OAEs a e p ope ly iden i ied and
consis en ly epo ed, enhancing he quali y o sa e y da a wi hou
shi ing he ial’s ocus. Simila ly, epo ing he iming o assessmen is
equen ly o e looked, wi h only 58 % o s udies speci ying when OAEs
we e e alua ed. In smoking cessa ion ials, ad e se e en s a e ypically
moni o ed h oughou he s udy, bu his can span an ac i e in e en ion
phase and a longe main enance phase in which p oduc use may
con inue ad libi um. A clea indica ion o when symp oms occu is
essen ial o dis inguish be ween eac ions igge ed by ini ial exposu e
and hose ha pe sis o eme ge o e ime. This dis inc ion is no only
c i ical o e alua ing he long- e m sa e y p o ile o he p oduc , bu
also o assessing he plausibili y o a causal ela ionship be ween he
in e en ion and he epo ed e en [14]. Wi hou p ecise empo al in-
o ma ion, a ibu ing symp oms o he p oduc - a he han o wi h-
d awal e ec s, como bidi ies, o un ela ed causes -becomes inhe en ly
unce ain [60,61].
Fo ins ance, aph hous ulce s ha e been equen ly epo ed a e
smoking cessa ion and may be in luenced by physiological changes
induced by obacco wi hd awal [62]. Se e al mechanisms ha e been
p oposed o explain his phenomenon: obacco smoke may p omo e
ke a iniza ion o he o al mucosa, which could p o ide mechanical
p o ec ion [63,64]; some o i s componen s migh exe an ibac e ial
e ec s [65]; and smoking cessa ion i sel may lead o immunological
al e a ions, possibly ela ed o wi hd awal-induced s ess o b oade
immune dys egula ion [66]. Gi en his complexi y, i would be aluable
o u u e ials o s a i y pa icipan s by abs inence s a us and depen-
dence le el, and o in es iga e he iming and pe sis ence o ulce s in
ela ion o p oduc use and cessa ion ou comes. In he cu en li e a u e,
OAEs a e o en a ibu ed gene ically o p oduc exposu e wi hou
conside ing hei po en ial in e ac ion wi h smoking cessa ion i sel , a
limi a ion ha wa an s u he explo a ion.
The choice o analy ical app oach (i.e., ITT o pe -p o ocol) plays an
impo an ole in shaping he in e p e a ion o sa e y da a [67,68].
While ITT emains he gold s anda d o e alua ing e icacy,
pe -p o ocol analysis can p o ide clea e insigh in o ad e se e en a es
among pa icipan s who ac ually used he p oduc [69]. Howe e ,
pe -p o ocol analysis is also subjec o bias, as i may ail o ully cap u e
he incidence o ad e se e en s - pa icula ly when pa icipan s dis-
con inue ea men due o ad e se e ec s. In such cases, excluding hese
indi iduals can lead o an unde es ima ion o ha ms and app op ia e
adjus men echniques a e equi ed o es ima e he e ec o ea men
[70]. Many o he included s udies did no clea ly speci y he s a is ical
me hods used o analyze o al ad e se e en s, making i di icul o
in e p e he obus ness o hei indings. In some cases, he numbe o
pa icipan s pe ea men a m was epo ed in a way ha allowed in-
di ec in e ence o he analy ical app oach, al hough his in o ma ion
was o en incomple e. Addi ionally, he easons o pa icipan wi h-
d awal due o ad e se e en s we e documen ed clea ly in less han hal
o he included ials, limi ing insigh s in o he sa e y p o ile o he es ed
p oduc s.
While mos s udies p o ided some o m o quan i a i e da a on
OAEs, he absence o s uc u ed and abula ed epo ing o ma s in
se e al ials comp omised he cla i y and ep oducibili y o he esul s.
This lack o s anda dized p esen a ion also impai ed he po en ial o
meaning ul seconda y da a analyses and e idence syn hesis. When such
in o ma ion is missing, i becomes mo e di icul o assess he compa -
a i e bu den o AEs ac oss in e en ions. This aspec is pa icula ly
impo an in he con ex o smoking cessa ion ials, whe e placebo
compa a o s a e no necessa ily ine [27,71,72]. Fo example, gums,
inhale s, o sp ays, e en when nico ine- ee, may independen ly
con ibu e o o al symp oms h ough mechanical o chemical i i a ion.
As no ed in he p e iously published ne wo k me a-analysis [7], he
highes odds o mou h i i a ion associa ed wi h speci ic deli e y o -
ma s including e-cigs and NRT gum we e obse ed when compa ed o
s anda d ca e (bu no o placebo). This inding sugges s ha he mode
o adminis a ion i sel , a he han he p esence o nico ine alone, may
play a mo e in luen ial ole in he onse o local ad e se e ec s.
Fu he mo e, epo ing he numbe o pa icipan s expe iencing a gi en
ad e se e en a he han simply lis ing he o al numbe o occu ences
is c i ical o a oid o e es ima ion. When mul iple e en s a e epo ed by
a single pa icipan and no clea ly disagg ega ed, he o e all bu den o
AEs may appea a i icially in la ed. Fu he mo e, a common p ac ice in
ad e se e en epo ing is o indica e only he numbe o pa icipan s
who expe ienced a leas one e en , wi hou p o iding in o ma ion on
he equency o du a ion o epea ed occu ences. While his simpli ies
p esen a ion, i obscu es impo an dis inc ions ele an o bo h pa ien
expe ience and heal h economic e alua ions [14]. Fo ins ance, a single
epo o o al i i a ion is no equi alen o pe sis en o ecu ing
symp oms o e ime; ye such di e ences canno be disce ned when
e en s a e simply epo ed as “a leas one occu ence” [73].
In se e al ials whe e quan i a i e da a on o al ad e se e en s we e
no clea ly p esen ed, sa e y was summa ized using gene ic s a emen s
such as “ he p oduc was well ole a ed” o “no majo side e ec s we e
obse ed.” These asse ions a e o en based on pos hoc compa isons o
on he absence o s a is ically signi ican di e ences be ween a ms [14].
Howe e , such in e p e a ions can be misleading, as a non-signi ican
G.R.M. La Rosa e al.
Jou nal o Den is y 162 (2025) 106057
5
esul does no imply he absence o ha m, and mul iple unadjus ed
compa isons inc ease he likelihood o spu ious indings due o chance
[14]. S a is ical me hods o ad e se e en analysis we e equen ly
unde epo ed, educing he anspa ency and obus ness o sa e y
claims. Mo eo e , sa e y ou comes we e no consis en ly e lec ed in he
discussion and conclusion sec ions o he ials, sugges ing ha o al
ad e se e en s a e o en no ully in eg a ed in o he o e all in e p e-
a ion o indings. A mo e balanced app aisal o e icacy and sa e y,
ailo ed o pa ien cha ac e is ics, could imp o e he clinical ele ance
o u u e ials. The in ol emen o den al p o essionals in he OAE
in e p e a ion may o e a p ac ical way o enhance epo ing accu acy
and consis ency, suppo ing mo e pe sonalized and e idence-based
cessa ion s a egies [74].
The empo al analysis did no yield s a is ically signi ican esul s,
possibly due o he inconsis en adop ion o he CONSORT ex ension o
ha ms o e ime. The de elopmen and dissemina ion o s anda dized
ools a e expec ed o p omo e mo e consis en and comp ehensi e
epo ing o ad e se e en s [12]; howe e , hei use may emain limi ed
unless explici ly equi ed by jou nals. O no e, almos all ials e alua ed
p oduc s al eady app o ed and comme cially a ailable a he ime o
publica ion, wi h a p ima y ocus on con i ming e icacy a he han
sys ema ically assessing sa e y. This likely con ibu ed o he limi ed
a en ion gi en o OAEs in ial epo ing.
We did no analyze he associa ion be ween epo ing quali y (ACS)
and jou nal impac ac o , due o inconsis encies in indexa ion imelines
ac oss jou nals, especially hose published be o e 2000. Applying cu -
en me ics e ospec i ely could also in oduce bias, as impac ac o s
may ha e changed signi ican ly o e ime. Howe e , i is plausible ha
jou nals wi h highe impac ac o s - o en en o cing s ic e edi o ial
s anda ds - a e mo e likely o ensu e adhe ence o in e na ional
epo ing guidelines such as CONSORT.
The high in e - a e ag eemen obse ed in his s udy suppo s he
cla i y and ep oducibili y o he adap ed checklis . Disc epancies we e
a e and ypically due o unclea epo ing a he han checklis ambi-
gui y. Consensus was always eached h ough discussion, ein o cing he
ool’s eliabili y.
As p e iously no ed [7], he absence o ials on widely used p oduc s
like nico ine pouches e lec s he lack o eligible RCTs. Ou analysis was
limi ed o s udies published up o Feb ua y 2025; u u e ials a e ex-
pec ed o imp o e epo ing quali y h ough be e adhe ence o s an-
da dized guidelines.
Mos included s udies assessed sho - e m local ole abili y (e.g.,
d yness, i i a ion, ulce s), wi h no epo s o mucosal lesions o long-
e m ou comes, likely due o limi ed ollow-up (≤12 mon hs). The e-
o e, epo ing quali y e lec s he scope and design o hese ials.
Fu u e esea ch wi h ex ended ollow-up and dedica ed endpoin s is
needed o e alua e long- e m o al e ec s.
4.1. Recommenda ions o imp o ing OAE epo ing in smoking cessa ion
RCTs
Ou s udy con ibu es by adap ing he CONSORT Ha ms ex ension
checklis o e alua e he comple eness o OAE epo ing in smoking
cessa ion ials. Ra he han judging he alidi y o s udy p ocedu es -
which is he ocus o isk o bias ools - his checklis p o ides p ac ical
guidance on he essen ial sa e y in o ma ion ha should be disclosed o
ensu e anspa en , ep oducible epo ing.
Fig. 3 summa izes a se o ecommenda ions o enhance he epo ing
o OAEs in RCTs o smoking cessa ion by a p ac ical and use - iendly
amewo k o u u e esea ch. O ganized acco ding o each manu-
sc ip sec ion, he scheme ou lines key elemen s such as explici ly
men ioning sa e y in he i le and abs ac , de ining OAEs and se e i y
assessmen me hods, speci ying iming and s a is ical app oaches in he
me hods, disagg ega ing esul s by ea men a m, and e lec ing on
sa e y implica ions in he discussion and conclusions. This s uc u ed
guidance aims o p omo e anspa en , consis en , and clinically in o -
ma i e epo ing o OAEs. G ea e esea che awa eness is essen ial o
ensu e sys ema ic epo ing o o al ad e se e en s, which suppo s bo h
ongoing sa e y su eillance and he in eg a ion o den al p o essionals
in o smoking cessa ion ca e. Accu a e and anspa en epo ing en-
hances unde s anding o p oduc ole abili y and enables clinicians o
deli e pe sonalized, e idence-based guidance o indi iduals aiming o
qui smoking.
5. Conclusions
This s udy highligh s he agmen ed, inconsis en and o en insu -
icien epo ing o OAEs in RCTs e alua ing NCNPs o smoking
cessa ion. C i ical a eas include he absence o s anda dized de ini ions,
inconsis en epo ing o se e i y assessmen , and unclea iming and
me hods o da a collec ion. Fu he mo e, OAEs we e o en no epo ed
by ea men a m, no adequa ely discussed in he in e p e a ion o
Fig. 3. G aphical summa y o p ac ical ecommenda ions o imp o ing OAE epo ing, o ganized acco ding o he ypical s uc u e o a scien i ic manusc ip ( i le/
abs ac , in oduc ion, me hods, esul s, discussion/conclusions).
Legend. ITT: in en ion- o- ea ; OAE: o al ad e se e en ; PP: pe p o ocol; RCT: andomized con olled ial.
G.R.M. La Rosa e al.
Jou nal o Den is y 162 (2025) 106057
6
s udy indings. No signi ican associa ion was ound be ween yea o
publica ion and epo ing quali y, likely due o he inconsis en imple-
men a ion o he CONSORT ex ension o ha ms.
In ligh o hese indings, we p opose a se o p ac ical ecommen-
da ions aimed a enhancing he epo ing o OAEs in smoking cessa ion
ials. The imp o emen o comple eness and consis ency in sa e y
epo ing is essen ial no only o suppo e idence-based clinical de-
cisions, bu also o empowe o al heal h p o essionals o play an ac i e
ole in ad ising pa ien s and ailo ing cessa ion s a egies based on
ole abili y p o iles.
Funding
This wo k is suppo ed by he Depa men o Clinical and Expe i-
men al Medicine (MEDCLIN), Uni e si y o Ca ania (UPB:
6C725202048/2024) and by he Tobacco Ha m Reduc ion Schola ship
P og amme (THRSP), deli e ed by Knowledge•Ac ion•Change (K•A•C)
as pa o he 2024/25 unding cycle. MEDCLIN speci ically con ibu ed
o co e ing publica ion ees. The THRSP awa ded a esea ch schola ship
o D . Giusy Ri a Ma ia La Rosa o suppo wo k in he ield o obacco
ha m educ ion. The THRSP is implemen ed by K•A•C wi h suppo
om a g an p o ided by Global Ac ion o End Smoking (also known as
he Founda ion o a Smoke-F ee Wo ld), an independen , U.S.-based
nonp o i 501(c)(3) g an -making o ganiza ion. The con en , selec ion,
and p esen a ion o in o ma ion in his wo k, as well as he iews
exp essed, a e he sole esponsibili y o he au ho s and should no be
in e p e ed as ep esen ing he iews o posi ions o he unde s.
CRediT au ho ship con ibu ion s a emen
Giusy Ri a Ma ia La Rosa: W i ing – e iew & edi ing, W i ing –
o iginal d a , So wa e, Resou ces, P ojec adminis a ion, Me hodol-
ogy, In es iga ion, Funding acquisi ion, Fo mal analysis, Da a cu a ion,
Concep ualiza ion. Cinzia Del Gio ane: W i ing – e iew & edi ing,
Me hodology, Fo mal analysis, Da a cu a ion. Sil ia Minozzi: W i ing –
e iew & edi ing, Me hodology, Fo mal analysis, Da a cu a ion. Jan
Kowalski: W i ing – e iew & edi ing, Valida ion. Iain Chapple:
W i ing – e iew & edi ing, Visualiza ion. Amaliya Amaliya: W i ing –
e iew & edi ing, Visualiza ion. Dewi Zakiawa i: W i ing – e iew &
edi ing, Visualiza ion. F ancesco Sa e io Ludo iche i: W i ing – e-
iew & edi ing, Da a cu a ion. Baek Il Kim: W i ing – e iew & edi ing,
Valida ion, Supe ision. Wanninayake Mudiyanselage Tilaka a ne:
W i ing – e iew & edi ing, Valida ion, Supe ision. Kons an inos
Fa salinos: W i ing – e iew & edi ing, Visualiza ion, Supe ision.
Ricca do Polosa: W i ing – e iew & edi ing, W i ing – o iginal d a ,
Supe ision, P ojec adminis a ion, Concep ualiza ion.
Decla a ion o compe ing in e es
GRMLR was awa ded a Schola ship P og amme o 2024/25 by
K•A•C Tobacco Ha m Reduc ion. The schola ship is speci ically in en-
ded o suppo he cu en p ojec .
CDG, SM, JK, IC, AA, DZ, FSL, BIK, WMT, and KF ha e no hing o
disclose.
RP is ull enu ed p o esso o In e nal Medicine a he Uni e si y o
Ca ania (I aly) and Medical Di ec o o he Ins i u e o In e nal Medi-
cine and Clinical Immunology a he same Uni e si y. He has ecei ed
g an s om U-BIOPRED and AIR-PROM, In eg al Rheuma ology &
Immunology Specialis s Ne wo k (IRIS), Global Ac ion o End Smoking
( o me ly known as Founda ion o Smoke-F ee Wo ld), P ize , Glax-
oSmi hKline, CV The apeu ics, Neu oSea ch A/S, Sandoz, Me k Sha p &
Dohme, Boeh inge Ingelheim, No a is, A bi G oup S l., Duska The a-
peu ics, Fo es Labo a o ies, Minis e o dell Uni e si a’ e della Rice ca
(MUR) Bando PNRR 3277/2021 (CUP E63C22000900006) and 341/
2022 (CUP E63C22002080006), unded by Nex Gene a ionEU o he
Eu opean Union (EU), and he minis e ial g an PON REACT-EU 2021
GREEN- Bando 3411/2021 by Minis e o dell Uni e si a’ e (MUR) –
PNRR EU Communi y. He is ounde o he Cen e o Tobacco P e-
en ion and T ea men (CPCT) a he Uni e si y o Ca ania and o he
Cen e o Excellence o he Accele a ion o Ha m Reduc ion a he same
uni e si y. He ecei es consul ancy ees om P ize , Boeh inge Ingel-
heim, Duska The apeu ics, Fo es Labo a o ies, CV The apeu ics, Se mo
Inc., GRG Heal h, Cla i a e Analy ics, Guidepoin Expe Ne wo k, and
GLG G oup. He ecei es ex books oyal ies om Else ie . He is also
in ol ed in a pa en applica ion o ECLAT S l. He is a p o bono scien i ic
ad iso o Lega I aliana An i Fumo (LIAF) and he In e na ional
Ne wo k o Nico ine Consume s O ganiza ions (INNCO); and he is Chai
o he Eu opean Technical Commi ee o S anda diza ion on “Re-
qui emen s and es me hods o emissions o elec onic ciga e es”
(CEN/TC 437; WG4).
Supplemen a y ma e ials
Supplemen a y ma e ial associa ed wi h his a icle can be ound, in
he online e sion, a doi:10.1016/j.jden .2025.106057.
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