Verteporfin photodynamic therapy for neovascular age-related ...

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30 Key changes to the protocolFor item 1, the primary outcome was the number of applications of VPDT in years 1 (≤ 350 days)and 2 (> 350 and ≤ 715 days). Treatment frequencies were cross-tabulated with TAP eligibilityand tested for significance using chi-squared statistics. We also compared treatment frequenciesin year 1 with treatment frequencies reported for the TAP trials. 30 For item 2, we calculated thetime until the first treatment episode was completed (see Classification of treatment as active orcompleted) or 350 days, whichever was later. These times were described as a Kaplan–Meier curve(see Figure 6), estimating the duration of follow-up when 50% of participants had completedtheir treatment.In order to make the comparison with the TAP trials, the cohort for this analysis was restricted topatients with a CNV lesion diagnosed as nAMD and who had completed their treatment or whohad completed follow-up for 1 or 2 years after the first treatment. The analysis was also limited toone eye per patient.B: Is ‘outcome’ the same in the NHS as in randomised trials?Objective B focused on patients who would have been EFT. We aimed to address this objective byestimating BCVA 1 year after the first treatment in patients classified as having completed theirtreatment for year 1. We fitted a mixed regression model to estimate the BCVA trajectory duringthe first year, using data up to 2 years where available. This method of analysis allowed all visitdata for an eligible eye to be included irrespective of adherence to the data collection schedule.The duration of follow-up (‘time’) was a covariate in the model; interactions of other covariateswith time represented non-parallel trajectories.A single model was used to answer objectives B and C and included the following covariates:age, gender, baseline BCVA, TAP eligibility, CNV composition, smoking status and whether ornot the fellow eye was the better-seeing eye. Coefficients from the model were used to estimateBCVA at 1 year for the EFT [objective (B)], IFT [objective (C)] and UNC subgroups. Inclusionof covariates was necessary because they were potential confounding factors when comparingoutcome across the EFT, IFT and UNC subgroups. The influence of the covariates in such a largecohort was also intrinsically of interest; inclusion of the UNC subgroup increased the precision ofthe analysis with respect to estimating the influence of the covariates.Because of substantial loss to follow-up in year 2, we again restricted our main analysis toestimating BCVA at 12 months for the cohort of patients described above for objective A (see A:Is verteporfin photodynamic therapy in the NHS provided as in randomised trials?).C: Is ‘outcome’ the same for patients ineligible from randomised trials?Objective C focused on patients who would have been IFT. A single model was used to addressobjectives B and C (see B: Is ‘outcome’ the same in the NHS as in randomised trials?).D: Is verteporfin photodynamic therapy safe when provided in the NHS?Adverse reactions and AEs were not classified as required for good clinical practice, althoughsuch events were promptly notified to the Data Management Centre at the LSHTM in accordancewith good clinical practice. Attribution of ocular AEs to VPDT is difficult because such eventsmay occur as part of the natural history of nAMD. An AR was defined as an ocular or systemicreaction at the time of treatment which was recorded on the same day as the treatment with
DOI: 10.3310/hta16060Health Technology Assessment 2012; Vol. 16: No. 631other clinical data for that visit. An AE was defined as any other ocular or systemic AE reportedat the next visit after a treatment or retreatment visit. The association of an AE with the previoustreatment visit was coded during data management and, therefore, was associated with thecorresponding treatment visit, not the visit on which it was reported.The probability of a treatment visit giving rise to an AR or AE by site and visit was estimatedusing a logistic regression model, fitting participating site as a random effect. The distributionsof centre-specific probabilities were examined carefully because of concern about the extentto which sites had adhered to the instructions for collecting data about ARs and AEs. Tocontextualise the overall probability of an AR or AE, we also described the probabilities for asite which had the largest number of treated patients and which we believed had collected suchdata better than average. We also investigated whether any site had a site-specific upper 95%confidence limit below the lower 95% confidence limit for the entire cohort; where this was thecase, a sensitivity analysis was rerun omitting the site.E: How effective and cost-effective is verteporfin photodynamic therapy?Different approaches to estimate effectiveness were proposed in the manual of operations (seeChapter 3, Estimating the effectiveness and cost-effectiveness of verteporfin photodynamic therapy).For reasons outside our control, we were able to use only the second of these methods, that is toinvestigate associations between the use of resources and visual function and other outcomes inthe study. This method is described in more detail in How effective is verteporfin photodynamictherapy?, below. This method also underpinned the second element of objective E, that isestimation of the cost-effectiveness of VPDT.The first method depended on obtaining individual patient data from other researchers,including the TAP triallists. We were able to obtain some data for studies which had academicor public sponsors, but were unable to obtain the data for the key RCTs of VPDT (TAP and VIPtrials 3,5 ), even though the manufacturer of verteporfin (Novartis) was represented on the SteeringCommittee. Without these data, we judged that the first method was not feasible.The third method depended on being able to characterise an untreated control group in thecohort of patients recruited for the study. However, it quickly became apparent that we werenot capturing adequate data for patients who were not treated (either by choice or because ofineligibility) and that untreated patients represented in the database were not similar across sitesbecause of the varied arrangements in place for triaging patients before referral to VPDT clinics.How effective is verteporfin photodynamic therapy?The estimates of BCVA outcome at 1 year were used to derive indirect estimates of theeffectiveness of VPDT by comparing the estimates with the reported BCVA outcomes at 1 year inthe treatment and sham treatment groups of the TAP trials.The strategy for estimating the HRQoL benefit from VPDT was as follows:1. to estimate the extent to which HRQoL changes per unit change in BCVA2. to ‘translate’ the observed difference in BCVA in the TAP trials into HRQoL, based on theassociation quantified by step 13. to ‘translate’ the observed change in BCVA in the VPDT cohort study over time minus thechange in BCVA observed in the sham treatment arms of the TAP trials into HRQoL, basedon the association quantified by step 1.© Queen’s Printer and Controller of HMSO 2012. This work was produced by Reeves et al. under the terms of a commissioning contract issued by theSecretary of State for Health.
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84 References16. Stelmack J. Qualit
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86 References49. Guymer RH, Chiu AW
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88 References83. Margrain TH. Minim
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90 Appendix 1THE VERTEPORFIN PHOTOD
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92 Appendix 11. Overview of Manual
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94 Appendix 1And, if also collectin
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96 Appendix 1more patients in the v
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98 Appendix 12.4 Limitations of the
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100 Appendix 1Box 2 Key advantages
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102 Appendix 14. Study population4.
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104 Appendix 15. Recruitment to the
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106 Appendix 16. Background data co
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108 Appendix 1Table 1: Schedule of
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110 Appendix 1The Verteporfin Photo
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112 Appendix 1• Additional clinic
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114 Appendix 18. Recording adverse
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116 Appendix 1level of benefit from
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118 Appendix 1• comparison of num
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120 Appendix 110.6 Sub-group analys
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122 Appendix 112. Data issues12.1 D
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124 Appendix 113. Organisation13.1
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126 Appendix 114. References[1] Ref
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128 Appendix 1Barnes RM, Gee L, Tay
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130 Appendix 1Appendix 1: Classifyi
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132 Appendix 1Liverpool re-treatmen
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134 Appendix 1Service StructurePlea
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136 Appendix 1Has your photographer
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138 Appendix 1There are many differ
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140 Appendix 1testing on vision tes
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142 Appendix 1something to do with
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144 Appendix 1College of Ophthalmol
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146 Appendix 1Appendix 5:Protocol f
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148 Appendix 16.2 Subjective Refrac
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150 Appendix 1• The patient shoul
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152 Appendix 1Appendix 6:Protocol f
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154 Appendix 18. It is customary to
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156 Appendix 1Early or Transit Phas
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166 Appendix 1Appendix 9:Site imple
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168 Appendix 1Option 2 - units inte
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170 Appendix 1Dos and Don’tsDosDo
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172 Appendix 1Resource use question
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174 Appendix 1Appendix 11: Recommen
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176 Appendix 1ADVERSE REACTION AND
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178 Appendix 1acute Trust; note tha
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180 Appendix 1Ophthalmologistrespon
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192 Appendix 3manufacturer’s pers
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FeedbackThe HTA programme and the a
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