the terms  phase iii  and  multiple sclerosis  were used for a pubmed search with no time restriction in march 2014 .
studies were eligible for inclusion if they ( 1 ) were phase iii trials of dmds in pwrms and ( 2 ) reported the rate of neoplasms and cancers observed .
conference abstracts were excluded as were studies investigating only an acute dose effect or follow - up studies of previously published phase iii trials .
the proportion of pwrms who developed cancer was extracted from each study . in trials where multiple doses were tested ,
given the relatively short and very similar duration of analyzed studies , the proportion of pwrms in whom cancer occurred was used as an estimate of the  rate  of cancer .
the cancer rate in the treatment group of clarity was first compared to the combined cancer rate of all treatment groups of placebo - controlled phase iii trials of other dmds .
the cancer rate in the placebo group of clarity was then compared to the combined cancer rate of the placebo groups of all other phase iii trials .
study heterogeneity was calculated using  test and publication bias was assessed using a funnel plot .
statistical analysis was performed using graphpad prism , revman , and stata 13.1 ( statacorp , college station , tx ) .
analysis was similarly done using the cancer rates reported in a recently completed phase iii trial on the effect of oral cladribine on time to conversion to clinically definite ms in patients with a first demyelinating event ( oracle ms ) .
furthermore , meta - analysis pooling using a random - effects model was performed based on risk difference to assess any excess risk from cladribine .
risk difference was selected as a measure rather than the more commonly used measures of relative risk or relative odds because when incidence rates are low and the comparator arm has zero cases ( as in clarity ) , these latter measures are not reliably estimated .
the terms  phase iii  and  multiple sclerosis  were used for a pubmed search with no time restriction in march 2014 .
studies were eligible for inclusion if they ( 1 ) were phase iii trials of dmds in pwrms and ( 2 ) reported the rate of neoplasms and cancers observed .
conference abstracts were excluded as were studies investigating only an acute dose effect or follow - up studies of previously published phase iii trials .
the proportion of pwrms who developed cancer was extracted from each study . in trials where multiple doses were tested ,
given the relatively short and very similar duration of analyzed studies , the proportion of pwrms in whom cancer occurred was used as an estimate of the  rate  of cancer .
the cancer rate in the treatment group of clarity was first compared to the combined cancer rate of all treatment groups of placebo - controlled phase iii trials of other dmds .
the cancer rate in the placebo group of clarity was then compared to the combined cancer rate of the placebo groups of all other phase iii trials .
study heterogeneity was calculated using  test and publication bias was assessed using a funnel plot .
statistical analysis was performed using graphpad prism , revman , and stata 13.1 ( statacorp , college station , tx ) .
analysis was similarly done using the cancer rates reported in a recently completed phase iii trial on the effect of oral cladribine on time to conversion to clinically definite ms in patients with a first demyelinating event ( oracle ms ) .
furthermore , meta - analysis pooling using a random - effects model was performed based on risk difference to assess any excess risk from cladribine .
risk difference was selected as a measure rather than the more commonly used measures of relative risk or relative odds because when incidence rates are low and the comparator arm has zero cases ( as in clarity ) , these latter measures are not reliably estimated .
including clarity , a total of 11 phase iii trials in pwrms were eligible for inclusion in the analysis .
dmds investigated in these studies were cladribine , dimethyl fumarate , fingolimod , teriflunomide , natalizumab , alemtuzumab , and glatiramer acetate .
the combirx trial ( interferon [ ifn]--1a plus glatiramer acetate ) was excluded because malignant and nonmalignant neoplasms were not reported separately .
seven of the included studies compared dmd with placebo ; 4 compared dmd with ifn--1a .
one trial compared natalizumab as an add - on to ifn--1a with placebo added to ifn--1a .
study characteristics , references , and annualized cancer rate of dmds included in the analysis are provided in table e-1 at neurology.org/nn .
the cancer rate in the clarity treatment group was 0.34% and thus not different from all other treatment groups of placebo - controlled trials ( 0.6% , p = 0.4631 ) . among these treatment groups ,
the cancer rate in clarity was the third lowest observed ( figure 1 ) . among placebo groups ,
the cancer rate of zero in clarity was the lowest observed and significantly lower than the combined cancer rate of all other placebo groups ( 1.19% , p = 0.0159 ; figure 2 ) .
forest plot of malignancy rates in treatment groups from phase iii trials with a placebo group .
forest plot of malignancy rates in placebo groups of phase iii trials . comparing all trials ( i.e.
, placebo - controlled and active comparator ifn--1a  controlled ) , no difference was detected in the cancer rate of clarity treatment arms vs all other trial arms ( 0.67% , p = 0.3669 ; figure 3 ) . no difference in cancer rate
was detected between treatment arms of clarity and oracle ms ( 0.34% vs 0.49% , p = 0.6546 ) ; both trials used identical doses of cladribine .
comparison of the total neoplasm rate ( including both malignant and nonmalignant neoplasms ) in clarity treatment arms ( 1.13% ) vs oracle ms treatment groups ( 0.98% ) did not reveal any difference ( p = 1 ) .
the clarity placebo group had a lower neoplasm rate ( 0% ) than the oracle ms placebo group ( 2.91% , p = 0.0012 ) .
random - effects pooling based on risk difference indicated a cancer risk profile from the clarity trial comparable to that of other dmds ( cladribine had a lower risk difference compared to 4 other trials ; figure 4 ) .
we further noted that the clarity trial did not indicate a higher risk difference than the other 
induction  dmd , alemtuzumab , in previously untreated pwrms in the cohen 2012 trial . given the heterogeneity of treatments , significant heterogeneity between trials was detected ( i = 56.3% , p = 0.009 ) .
alem = alemtuzumab ; ci = confidence interval ; clad = cladribine ; dime = dimethyl fumarate ; fing = fingolimod ; nata = natalizumab ; teri = teriflunomide .
the main findings of this study are that ( 1 ) the rate of cancer was similar between the only phase iii trial of cladribine and all other phase iii trials of dmds in pwrms , and ( 2 ) a significant difference emerged when comparing the placebo groups of clarity ( no cancers ) with the placebo arms of all other phase iii trials included in this study .
these findings were corroborated by a cancer rate difference in clarity that was comparable to that of all other phase iii trials for dmds for pwrms .
focusing on cancers observed in pwrms treated with cladribine in clarity ( and oracle ms ) might lead to the suspicion that cladribine plays a causative role , given the fact that 3 pwrms on cladribine developed cancer whereas none on placebo did .
however , comparison with other dmds shows that the number of malignancies in clarity was not increased .
indeed , the cancer rate in clarity was among the lowest observed for any treatment group , suggesting that the cancers developed on cladribine are a reflection of the background risk in the population
. moreover , the short latency between initiation of treatment and cancer diagnosis in clarity ( 18 months ) renders a causal relationship unlikely .
we also note that in contrast to the trials of alemtuzumab , cladribine was compared with placebo ( rather than an active comparator ) .
investigations of the general risk of cancer among pwrms in large cohorts reported conflicting results . in a danish study using population - based registers of ms and cancer
, there was no evidence of an overall increased risk of cancer after a diagnosis of ms ; however , they did report a small excess risk of breast cancer among women .
a recent systematic review of the incidence and prevalence of cancer in ms reported substantial variation in reported estimates between studies .
overall , the risk of  any  cancer was most commonly reported to be lower in pwrms compared to the general population .
cancer risk appeared to be higher for malignant brain tumors and for cancers affecting the urinary tract system .
however , potential surveillance bias and variation of age and sex of pwrms across studies stand in the way of more definitive conclusions .
the data from our meta - analysis of dmds in pwrms are supported by the long - term outcome of people with leukemia treated with cladribine . in a 20-year follow - up
report of 88 patients diagnosed with hairy cell leukemia before the age of 40 , no increase in the incidence of secondary malignancies was detected . according to the preliminary report of the 96-week phase ii 
oral cladribine as add - on to ifn- therapy in patients with active multiple sclerosis 
( onward ) trial , in which oral cladribine ( dose 3.5 mg / kg ) was compared vs placebo as an add - on to interferon - beta treatment , 1 of 124 patients , a 57-year - old woman with a 25-year smoking history , developed squamous cell carcinoma about 2 years following first cladribine exposure .
cladribine administered as an injection or infusion has previously been investigated in placebo - controlled phase ii trials of varying dosages , with results demonstrating reduced disease activity ( clinically and on mri ) with no reported cancer signal
. limitations of our study include the inevitable variation between trials in terms of sample size , inclusion criteria , follow - up period , and dosing regimens ; the fact that not all phase iii trials for approved dmds in pwrms reported data on cancer rates ; and the fact that all cancers were considered together , i.e. , regardless of affected organ(s ) . furthermore , clarity was 2 months shorter than most of the other trials included , which lasted 2 years .
mathematically , a slightly lower number of cancers would therefore be expected in clarity due to the shorter observation period . however , there is no indication that this difference had any material impact on the results of our meta - analysis .
we also acknowledge that in a randomized trial such as clarity , if the cancer rate is truly  low , 
it should also have been low relative to the placebo group in its own trial .
however , the apparently high risk in clarity relative to placebo may be due to the use of the risk ratio rather than the risk difference ; the former is inappropriate in this context because of the zero cases in the clarity placebo group .
our meta - analysis of risk differences , which does not require arbitrary substitutions for the zeros , suggests that the risk difference for several other comparable drugs is higher than that in clarity .
our data suggest that although current evidence can not rule out an increased risk of cancer on cladribine , it also can not confirm that such a risk exists .
a more definitive assessment of cancer risk will only be feasible through long - term follow - up , be it of people treated with cladribine (  prospective observational long - term safety registry of multiple sclerosis patients who have participated in cladribine clinical trials 
the results of our meta - analysis should encourage further investigation into the potential use of cladribine as a dmd for pwrms .
k.s . has been supported by a higher education funding council for england ( hefce ) clinical senior lectureship .
altmann consulted for merck & co and received research support from multiple sclerosis society of great britain and northern ireland .
turner is on the scientific advisory board for biogen , novartis , and sanofi aventis .
m. marta received travel funding from biogen and abbott laboratories and received research support from merck - serono .
d. baker has a patent filed concerning the treatment of multiple sclerosis with cladribine and other compounds ; has consulted for canbex therapeutics ; received research support from genzyme sanofi , national multiple sclerosis society , and academic entities ; has stock options from canbex therapeutics ; and provided legal consult for teva .
j. chataway is on the scientific advisory board for novartis ; received travel funding and/or speaker honoraria from novartis , teva , and sanofi ; and received research support from novartis , uk mrc , and uk national institute of health research ( nihr ) university college london hospitals / ucl biomedical research centres funding scheme .
k. schmierer is a principal investigator of trials sponsored by novartis , roche , and teva .
he has received speaking honoraria from , and served on advisory boards for , biogen , novartis , teva , merck - serono , and merck inc ; and received research support from novartis , the multiple sclerosis society of great britain & northern ireland , the national ms society , the royal college of radiologists , and barts charity .
 objective : to compare the cancer risk of cladribine and other disease - modifying drugs ( dmds ) in trials of people with relapsing multiple sclerosis ( pwrms).methods : meta - analysis of phase iii trials of licensed dmds for pwrms and a phase iii trial of cladribine ( clarity ) . 
 cancer rates were compared using fisher exact test.results:eleven trials were included . investigated treatments included cladribine , dimethyl fumarate , fingolimod , teriflunomide , natalizumab , alemtuzumab , and glatiramer acetate . 
 the cancer rate in the clarity treatment group ( 0.34% ) was not increased compared to all other treatment groups , whether including placebo - controlled trials only ( 0.6% , p = 0.4631 ) or all trials , i.e. , including those with an active comparator arm ( 0.67% , p = 0.3669 ) . 
 no cancer was reported in the clarity placebo group , whereas the combined cancer rate of all other placebo groups was 1.19% ( p = 0.0159 ) . 
 the cancer rate of zero in the clarity placebo group was also lower than that in the phase iii trial of cladribine in people with clinically isolated syndrome ( oracle ms , 2.91% , p = 0.0012 ) . 
 in fact , no difference was detected between cancer rates in the treatment groups of clarity ( 0.34% ) and oracle ms ( 0.49% ) ( p = 0.6546).conclusions : our study does not support an increased cancer risk from cladribine in the doses used in clarity and oracle ms , which previously contributed to refusal of market authorization of cladribine in europe . longer - term follow - up is required to assess the safety profile of cladribine , as well as currently licensed dmds , to definitively assess cancer risk . 
METHODS
Literature search.
Statistical analysis.
RESULTS
DISCUSSION
Supplementary Material
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE