Baldwin, M.

Buckley, F.

Cope, S.

Jansen, J.

Keininger, D.

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 VA L U E  I N  H E A LT H  1 6  ( 2 0 1 3 )  A 3 2 3 – A 6 3 6  A575
Objectives: There is a growing interest from health technology assessment agen-
cies in determining the clinical outcomes assessments and endpoint strategies 
that can establish treatment benefits. We describe a systematic literature review 
of endpoints and outcomes used in schizophrenia trials to determine treatment 
benefit. MethOds: The therapies selected in the search strategy included pharma-
cological interventions, cognitive-behavioural therapies, family intervention, and 
music therapy. These were chosen to reflect the range of interventions in current 
use, and to allow comparison between outcomes reported for different therapies. 
The search terms were designed to include all outcomes for each therapy area, and 
were used to search four electronic databases for published English language stud-
ies. Randomised controlled trials (RCTs) were retrieved if they included patients 
with schizophrenia treated with the chosen therapies, and clinical outcomes from 
a predefined list (e.g. symptom improvement, functionality, quality of life, remission 
rates, response rates, and recovery). Results: Of 2,221 RCTs identified, 271 pro-
gressed to data extraction; 225 assessed pharmacological interventions and 46 non-
pharmacological interventions. Approximately 76 outcomes were measured across 
the trials. The most common scale used in pharmacological trials was the Positive 
and Negative Syndrome Scale (PANSS) total score (76.9%), and the PANSS positive 
subscale in non-pharmacological trials (50%). However, even within the common 
outcomes, the specified level of reduction to define a relevant response varied; 
among trials reporting PANSS total, five different levels of reduction were defined 
(≥ 20%, ≥ 25%, ≥ 30%, ≥ 40%, ≥ 50%). Common outcomes were also measured differ-
ently in terms of improvement from baseline and proportion achieving response/
remission, with little consensus on clinical meaningfulness. cOnclusiOns: The 
RCTs included in this review reported a broad range of outcomes, making com-
parison of different therapies a complex task. The disparity in outcomes between 
pharmacological and non-pharmacological outcomes scales highlights the chal-
lenges in designing trials to demonstrate clinical benefit.
PRM5
Multi-DiMensional CaPtuRe of Patient-Relevant enDPoints 
in RegulatoRy tRials anD HealtH teCHnology assessMents in 
onCology two yeaRs afteR intRoDuCtion of tHe geRMan aMnog 
HealtH CaRe RefoRM
Dintsios C.M.1, Knoerzer D.2, Duenne A.A.2, Schwartz F.W.3, Ruof J.2
1German Association of Research-based Pharmaceutical Companies (vfa), Berlin, Germany, 2Roche 
Pharma, Grenzach-Wyhlen, Germany, 3Hannover Medical School, Hannover, Germany
Objectives: With the introduction of AMNOG in January 2011, an early benefit 
assessment (EBA) was required for new medicines in Germany. EBAs are based on 
the additional therapeutic benefit of a drug on patient-relevant endpoints (PREs). 
We compared the acceptance of PREs for oncology in regulatory trials, and in EBAs 
conducted by German health technology assessment (HTA) bodies. MethOds: EBAs 
on oncology drugs and the respective regulatory trials were reviewed. The Federal 
Joint Committee (G-BA) website was used to obtain manufacturers’ value dossiers, 
Institute for Quality and Efficiency in Health Care (IQWiG) assessments, and G-BA 
resolutions. Acceptance of endpoints in the dimensions of mortality, morbidity 
and quality of life (QoL) by HTA bodies, IQWiG and G-BA, were compared to those 
accepted for regulatory trials. Data on endpoints used in regulatory trials were 
obtained from the manufacturers’ value dossiers. Results: Overall survival (OS) 
and measures of disease morbidity, such as progression-free survival (PFS), were 
generally accepted in regulatory trials. OS was accepted by IQWiG and G-BA as a 
mortality endpoint for evaluating additional benefit. Widely accepted morbidity 
endpoints such as PFS were not deemed patient-relevant by IQWiG and G-BA. In 
general, QoL questionnaires used in regulatory trials were accepted by the HTA 
bodies, although minor variability between questionnaires led to some exclusions 
from the HTA evaluations and the obtained QoL data revealed a number of missing 
values. cOnclusiOns: HTA and regulatory bodies largely agree on the accept-
ance of mortality and QoL endpoints typically evaluated in oncology. Considerable 
variability was observed in the acceptance of PREs in morbidity. Evaluating addi-
tional benefit based only on mortality and QoL endpoints underestimate the poten-
tial value of new drugs. Multiple endpoints, which capture all three dimensions, 
should be evaluated in regulatory trials and accepted by IQWiG and G-BA to confirm 
patient-relevant additional benefit.
PRM6
tHResHolD seleCtion in BioMaRkeRs using Cox RegRession. an 
aPPliCation to non-sMall-Cell lung CanCeR
Luaces P.1, Sánchez L.1, Ballesteros J.2, García B.1, Rodríguez P.C.1, Viada C.1, Popa X.1,  
Crombet T.1, Lage A.1
1Center of Molecular Immunology, Havana, Cuba, 2University of the Basque Country UPV/EHU, 
Leioa, Spain
Objectives: To select thresholds for predictive biomarkers using Cox regres-
sion. MethOds: We used data from a Cuban trial designed to assess the efficacy 
of immunotherapy against the epidermal growth factor (EGF) to test our approach. 
The trial included 122 patients diagnosed with non-small-cell lung cancer (NSCLC) 
who had basal EGF concentration available. The EGF concentration was analysed as 
a predictor of immunotherapy success over the range of all possible values of the 
biomarker (w [a,b]). For each wi, patients with w > wi0 were selected and a Cox model 
adjusted to assess survival. We then identified the w0s with significant treatment 
results to find (a) the lowest biomarker threshold where the effect of treatment was 
significant and also to find (b) the biomarker threshold that reflected the highest 
difference between treatments. Results: For NSCLC we observed that EGF concen-
tration thresholds range from 870 pg/ml to 2000 pg/ml were significant. At the lowest 
threshold (870 pg/ml) the immunotherapy group showed a 6-month difference for 
the median survival (p = 0.022) whereas at the threshold that showed the maximum 
difference between treatments (EGF = 1750 pg/ml) the immunotherapy group pre-
sented a 10-month difference for the median survival (p = 0.004). cOnclusiOns: 
The evaluation of p-values of the effect of treatment for each w0 [a,b] allows the 
selection of the thresholds where the treatment result is significant. Whereas the 
intervals HPV-based screening was more effective than cytology alone, with a rela-
tive reduction in cervical cancer incidence of 49%-90% compared to 33%-80% with 
cytology alone (depending on screening intervals). In HPV- compared to cytology 
screening the incremental gain in effectiveness was higher with extended screening 
intervals and the increase in harms lower. Based on the BHF, 12 of 17 screening strate-
gies were dominated, including annual cytology, the current recommended standard 
in Germany. Biennial HPV-screening was similarly effective as annual cytology and 
reduced unnecessary treatment. Moving from biennial HPV- with cytological triage 
to annual HPV-screening alone results in an incremental harm-benefit ratio of 15-533 
unnecessary treatments per additional prevented cervical cancer case (depending on 
screening adherence rate). cOnclusiOns: The benefit-harm frontier is a useful tool 
to demonstrate the trade-off between expected gains and risks of different screening 
strategies. Based on our analyses, HPV-based cervical cancer screening is more effec-
tive than cytology alone, but has a higher risk of overtreatment when used in annual 
screening. In the German health care context, depending on screening adherence 
rates biennial or triennial HPV-screening for women ≥ 30 years is similarly effective 
as annual cytology with significantly reduced unnecessary treatments.
PRM2
evaluating wHetHeR inConsistenCies aRe PResent in a MixeD 
tReatMent CoMPaRison of tRougH foRCeD exPiRatoRy voluMe in  
1 seConD at 12 weeks
Buckley F.1, Baldwin M.2, Keininger D.3, Jansen J.1, Cope S.4
1Mapi, Boston, MA, USA, 2Novartis Pharmaceuticals UK Limited, Horsham, West Sussex, UK, 
3Novartis Pharma AG, Basel, Switzerland, 4Mapi, Toronto, ON, Canada
Objectives: To evaluate whether there are inconsistencies in the network of ran-
domized controlled trials (RCTs) used for a network meta-analysis (NMA) compar-
ing alternative long-acting bronchodilators among patients with moderate to severe 
chronic obstructive pulmonary disease (COPD) in terms of trough forced expiratory 
volume in 1 second (FEV1) at 12 weeks. MethOds: The change from baseline (CFB) 
in FEV as observed with placebo, tiotropium 18µg/5µg once daily (OD), salmeterol 
50µg twice daily (BID), formoterol 12µg BID, aclidinium 400µg BID, glycopyrronium 
50µg OD, indacaterol 75/150/300µg OD, formoterol 12µg+ tiotroipum 18µg BID/OD, 
indacaterol 150µg+ tiotropium 18µg OD, and indacaterol 110µg+ glycopyrronium 50µg 
OD in RCTs identified with a systematic literature review were synthesized with a 
NMA. Where possible, treatment estimates from fixed effect (FE) and random effects 
(RE) NMA models (assuming consistency between direct and indirect evidence) and 
independent means (IM) models (pooled direct evidence) were compared to assess 
whether any inconsistencies in the network were present. Results: Thirty-two 
RCTs identified through a systematic literature review were included in the analysis. 
Direct evidence was available for the monotherapies versus placebo, the combination 
therapies versus tiotropium, for indacaterol+ glycopyrronium versus placebo, and for 
tiotropium versus salmeterol. The largest differences between the estimated treatment 
effect estimates from the NMA and the IM models were observed for the compari-
sons between indacaterol 150µg versus tiotropium (FE difference= 0.025 [95% Credible 
Intervals (95%CrI): 0.002, 0.047]; RE difference= 0.027 [95%CrI: -0.007, 0.61]), indacaterol+ 
glycopyrronium versus placebo (FE difference= -0.022 [95%CrI: -0.053, 0.008]; RE differ-
ence= -0.018 [95%CrI: -0.059, 0.022]), and indacaterol+ glycopyrronium versus tiotro-
pium (FE difference= 0.011 [95%CrI: -0.014, 0.036]; RE difference= 0.015 [95%CrI: -0.024, 
0.053]). cOnclusiOns: Based on a comparison of the findings of a NMA and IM mod-
els, some minor inconsistencies in treatment effects for trough FEV1 at 12 weeks were 
identified that will be explored through additional sensitivity analyses.
PRM3
testing tHe eunetHta inteRnal valiDity of RanDoMizeD ContRolleD 
tRials guiDeline anD tool in HungaRy
Huszti Z., Juhasz J.
National Institute for Quality- and Organizational Development in Healthcare and Medicines, 
Budapest, Hungary
Objectives: The reliability of the results of a randomized trial depends on the extent 
to which potential sources of bias have been avoided. We tested the EUnetHTA Internal 
Validity guideline so that to harmonize our risk of bias assessments with the European 
standard and finally to improve the reliability of relative efficacy and cost effectiveness 
assessments for decision makers in Hungary. MethOds: We translated the risk of bias 
standardized assessment questions of the EUnetHTA Internal Validity (of randomized 
controlled trials) into Hungarian. We first chose ten studies for internal validity testing 
from the ones that were submitted for reimbursement at the beginning of 2012, and 
their results were used for health economy assessment. Results: We found adequate 
randomization sequence generation in seven studies and we marked it unclear in 
three trials (e.g.: lack of information, age related sequence generation). The allocation 
concealment was labeled suitable in six studies (e.g.: IVRS, IWRS) and unclear in four 
trials. All studies could be classified according the the type of blinding. We found 
selective reporting in one trial where the non-inferiority results in the per-protocol 
population were not published. We rated the risk of bias low for eight trials and high for 
two trials due to unclear sequence generation and publication bias. We also evaluated 
77 endpoints and we labelled 22 endpoints with high risk of bias. The most common 
reasons for high risk ratings were the not appropriately implemented ITT principle 
and selective reporting. cOnclusiOns: The EUnetHTA guideline gives an opportu-
nity to estimate the risk of bias of randomized controlled trials in a structured and 
harmonized way without leaving out any important considerations. The results of the 
internal validity evaluation can lead the focus of interest to those endpoints where 
the sensitivity analysis is requisite in the health economic models.
PRM4
CliniCal outCoMes assessMents in sCHizoPHRenia: a systeMatiC 
liteRatuRe Review
Cooke C.1, Heatley R.2, Galani Berardo C.3, Johnson K.I.2, Kasper S.4
1Complete Clarity, Macclesfield, UK, 2Complete Clarity, Macclesfield, Cheshire, UK, 3F. Hoffman La 
Roche, Basel, Switzerland, 4Medical University of Vienna, Vienna, Austria


PRM2 Evaluating Whether Inconsistencies Are Present in a Mixed Treatment Comparison of Trough Forced Expiratory Volume in 1 Second at 12 Weeks 

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PRM2 Evaluating Whether Inconsistencies Are Present in a Mixed Treatment Comparison of Trough Forced Expiratory Volume in 1 Second at 12 Weeks

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