National Institute for Health and Clinical Excellence. Glaucoma. Guideline Consultation Comments Table. 29 September November 2008

Transcription

1 National Institute for Health and Clinical Excellence Glaucoma Guideline Consultation Comments Table 29 September November 2008 Stat us Organisa tion Order no. Version Page no Line no/se ction no Alcon UK 1 Full Comment The tables regarding Monitoring intervals for patients with OHT and COAG suspects (Pages 52, 57, 104, and 110), Monitoring intervals for patients with COAG (Page 53, 58, 108, and 111), and Treatment of OHT and COAG suspects (Page 53, 59, 155 and 158) only relate to treatment naïve patients, and recommend that untreated IOP of less than or equal to 21 mmhg are acceptable. Even though monitoring and treatment changes are suggested clinical assessment outcomes for these patient populations (Pages 52, 53, 57, 58, 104, 108, 110, 111) the guidance is relatively silent on the choice of therapeutic options available, other than to mention change treatment may include change to topical medication (footnote *** to tables on pages 53, 58, 108, and 111) We believe that guidance is incomplete without including within this section some specific clinical guidance on topical medication treatment options, including monotherapy, and/or concomitant and Response Thank you for your comments. 1. With regard to giving specific clinical guidance on topical medication options we have amended the recommendations so that combination treatments are offered as an alternative pharmacological treatment where intraocular pressure is uncontrolled. We also believe that beyond the recommendations made in the guidance properly trained clinicians are expected to make clinical judgement regarding the topical treatments prescribed for patients. A description of the available pharmacological treatments is adequately covered in section 7.1 of the full version of the guideline. 2. We disagree with the comment regarding our IOP thresholds. The references quoted by the stakeholder 1 of 226

2 fixed combination interventions. In Section Recommendations on treatment for patients with OHT and suspected COAG (Page 58, Line 24), it is not until Page 59 (Line 8) that an alternative medication is mentioned to treat OHT and COAG suspect patients with unacceptable IOP, and even then this is qualified by the suggestion of an alternative monotherapy (PGA, BB, others) (Page 59, Lines 10-11). There has been no consideration or mention of alternative effective therapeutic options which are not monotherapy treatments, and which are approved for use as first line treatment options for patients with OHT and OAG.(For example: brinzolamide (TCAI) + PGA). refer to patients with glaucoma, not to those with ocular hypertension or those patients with suspected glaucoma by our guideline definition. 3. With regard to setting target IOP for COAG, we believe this is based on clinical judgement. This term will be covered in the revised glossary of terms. The section quoted on page 180 refers specifically to the paper described and not to a guideline recommendation. The guidance makes no comment on how the IOP threshold values quoted in the tables were chosen. We have some reservations regarding recommendations using below 21 mmhg as an IOP threshold since published clinical studies report that as many as 61% of patients with IOP s < 22 mmhg have disc and visual field changes. [Reference 1: Dielemans et al. The Prevalence of Primary Open-angle Glaucoma in a Population-based Study in The Netherlands, The Rotterdam Study Ophthalmology 1994: 101 (11) ] [Reference 2: Sommer et al. Relationship Between Intraocular Pressure and Primary Open Angle Glaucoma Among White and Black Americans Arch Ophthalmology 1991: 109; ] 2 of 226

3 [Reference 3: Varma et al. Prevalence of Open-Angle Glaucoma and Ocular Hypertension in Latinos Ophthalmology 2004: 111 (8); ] [Reference 4: Iwase et al. The Prevalence of Primary Open-Angle Glaucoma in Japanese: The Tajimi Study Ophthalmology 2004: 111(9) ] The generally accepted standard relating to IOP threshold values comes from the AGIS research, which documents that reducing IOP at a much lower IOP threshold value of below 18mmHg (at all visits) is associated with no detectable visual field loss. [Reference 5: The AGIS Investigators The Advanced Glaucoma Intervention Study (AGIS): 7. The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. American Journal of Ophthalmology 2000: 130(4); ] Additional peer-reviewed data from the CNTG study recommends targeting a 30% IOP reduction, while CIGTS research recommends a 35% IOP reduction. [Reference 6: CNTG Collaborative Normal- Tension Glaucoma Study Group (Report II) The Effectiveness of Intraocular Pressure Reduction in the Treatment of Normal-Tension Glaucoma American Journal of Ophthalmology 1998: 126(4); ] [Reference 7: CNTG Collaborative Normal- Tension Glaucoma Study Group (Report I). 3 of 226

4 Comparison of glaucomatous progression between untreated patients with normal tension glaucoma and patients with therapeutically reduced intraocular pressures American Journal of Ophthalmology 1998: 106(4); ] Based upon this body of scientific research, we feel that the IOP threshold documented in the guidance of less than 21mmHg is too high, and recommend that the threshold value for treatment of OHT and suspected COAG is decreased from this documented value to less than 18 mmhg in line with current research. The draft recommendations do not mention an IOP threshold for treatment of COAG, and that this is contradictory to data presented on Page 180, Line 8, Paragraph 3 in which IOP of < 18mmHg at 6 months follow up is described as an acceptable IOP. We consider that an IOP threshold for both OHT and COAG patient group is required, as research demonstrates that considerable ganglial cell loss occurs before permanent vision loss is noticed or clinically detectable, and that structural alterations of the optic nerve or nerve fibre layer typically occur prior to visual field abnormalities or visual defects [Reference 8: Keltner et al. The Association between Glaucomatous Visual Fields and Optic Nerve Head Features in the Ocular Hypertension Treatment Study Ophthalmology 2006: 113(9); ] Alcon UK 2 Full Treatment discussions for COAG patients with Thank you for your comment. Glaucoma is a blinding disease and 4 of 226

5 ) visual field progression and/or progression of disc damage in one or both eyes, despite treatment, (Page 60, Lines 9-11) recommend surgical intervention with pharmacological augmentation (MMC of 5FU). We believe that there should be additional specific guidance included within this section on Pharmacotherapeutic options that should be tried before surgery intervention is considered, including detail on possible concomitant and fixed combination pharmacotherapy options available. The statement on surgical intervention should also be qualified by providing specific details on the number of ocular surgical interventions for COAG treatment that fail or only provide temporary alleviation of the condition, and provide a balance by detailing common surgical complications and risks. the decision to operate in a timely fashion is made on an individual basis. Whilst we accept that surgery has risks, the incidence of adverse effects resulting from delaying surgery by multiple switches of medication is common and regrettable. We were concerned that multiple switches were not cost effective and could delay sight saving surgery. Ensuring adherence to medication was the better option. If despite good adherence to two pharmacological treatments the risk to progression to sight loss remains high then surgery should be offered at this stage. Our opinion was that adding a third medication rarely produced much additional IOP lowering As per comment (1), even though monitoring and treatment changes are suggested clinical assessment outcomes for this population (Pages 52-53, 57-58) the guidance is relatively silent on the choice of therapeutic options, other than to mention change treatment may include change to topical medication laser or (Footnote *** to tables on pages 53 and 58). It is expected that this section of the guidance will be expanded to provide more specific details on Pharmacotherapeutic options available for treatment, prior to undertaking an invasive surgical intervention. 20- Later in the document (page 60, lines 1-4) it is stated that COAG patients whose intraocular 5 of 226

6 22 pressure is unacceptable after using pharmacological treatment or for COAG patients intolerant to a prescribed medication (page 59 line and page 60, lines 13-14), should be offered alternative monotherapy (PGA, BB, others), laser or surgery. The recommendation is then that after trying 2 alternative monotherapies consider offering surgery. We believe that there is strong clinical evidence for considering alternative monotherapies (PGA, BB, and TCAI s), concomitant/adjunctive therapies (TCAI + PGA, PGA + BB) or fixed dose combination (PGA + BB) options before undertaking an invasive surgical intervention. Early surgery with pharmacological augmentation (MMC or 5FU) is also presented as the only option for patients presenting with severe COAG. Again, we believe that there is a substantial evidence base to support the consideration of pharmaceutical intervention including a vast array of monotherapies (PGA, BB, and TCAI s), concomitant therapies (TCAI + PGA, PGA + BB) or fixed dose combination (PGA + BB) options that could offer fast, IOP lowering efficacy in some patients with severe COAG, before opting for invasive surgical intervention. Especially as some questions remain about the effectiveness, duration of effect, cost-effectiveness, and complications of surgical interventions, as is noted later in the guideline. The range of pharmaceutical alternatives is not mentioned within this section on treatment of patients presenting with severe COAG, and we believe that the guidance is not complete without expansion and additional detail of alternative 6 of 226

7 therapeutic treatment options being added to this section of the guidance, alongside the surgical alternatives. Alcon UK 3 Full Only 5 studies were found comparing laser surgery to pharmacological therapy, or laser and drug therapy to drug therapy. All 5 studies described as having serious limitations in terms of reporting or masking outcome assessments, and/or allocation concealment, and/or randomisation methods. In our opinion, the data supporting recommendations for both laser surgery and/or conventional surgery as the primary treatment option for COAG are weak. Alcon UK 4 Full The guidance provides results of trabeculectomy studies. However, without exception they are described as having serious limitations in terms of reporting or masking outcome assessments, and/or allocation concealment, and/or randomisation methods. Again, in our opinion the data supporting recommendations for this surgical procedure as the primary treatment option for the treatment of COAG are weak. Thank you for your comment but we disagree. All the trials for the treatment of COAG have limitations, including pharmacological treatment. Our economic model supports early surgery for people with advanced disease but otherwise surgery is not the primary treatment for COAG. Laser treatment is recommended only after pharmacological treatment or surgery have failed. Thank you for your comments. We agree that the evidence is of low quality. However, in glaucoma management eye drops are routinely used as a treatment to prevent visual field loss even though the evidence to support this is also of low quality. A lack of evidence does not mean a lack of effectiveness. Our economic model supports early surgery for people with advanced disease but otherwise surgery is not the primary treatment for COAG. Please see our recommendations as follows: Patients newly diagnosed with early or moderate COAG should be offered treatment with a prostaglandin analogue. 7 of 226

8 Patients with COAG who have visual field progression and/or progression of disc damage in one or both eyes, despite treatment, should be offered surgery with pharmacological augmentation (MMC or 5FU). Offer patients information on risks and benefits associated with surgery. Alcon UK 5 Full Few studies providing high quality clinical data and fixed end-points for viscocanalostomy, deep sclerectomy, and non-penetrating surgery were found, and those found demonstrated serious limitations in terms of reporting or masking outcome assessments, and/or allocation concealment, and/or randomisation methods. And again, in our opinion the data supporting recommendations for these surgical procedures as primary treatment option for the treatment of COAG are considered to be inconclusive and wholly unsubstantial. Alcon UK 6 Full There are several well controlled, masked, clinical studies and supporting publications involving fixed dose PGA+BB combinations Vs PGA and BB used as concomitant treatments in patients with OHT and/or suspected COAG. It is not clear as to why data on these studies has not been included Thank you for your comments. The best data we have is from trabeculectomy studies. As you are aware the absence of evidence does not mean the absence of effect. We agree that the evidence is of low quality. However, in glaucoma management eye drops are routinely used as a treatment to prevent visual field loss even though the evidence to support this is also of low quality. A lack of evidence does not mean a lack of effectiveness. Our recommendations do not state that surgery is the primary treatment for the treatment of all COAG. Rather that the offer of early surgery to people with advanced disease should be the first choice of treatment. Thank you for your comment. The additional studies referred to do not meet the inclusion criteria for consideration and we refer the stakeholder to the final paragraph of section 2.3. of the full version of the guideline. Some studies were 8 of 226

9 as part of this therapeutic review. Without including a full data set detailing all clinical evidence available, we believe that this guidance does not represent a full picture of all therapeutic options available to a treating physician. We strongly recommend that this section is revised to include information from the additional studies available (see response number 14 for additional information). identified covering these medications and were included in the review. There was no significant difference between the combination of PGA + BB compared to PGA alone. The GDG s conclusion from this is that there is no benefit in adding a beta-blocker to prostaglandins, particularly as there are worse side effects with betablockers. Alcon UK 7 Full The Introduction (page 30) says a plethora of topical medications and combinations of medications are available for treatment of COAG A number of studies involving fixed combination and concomitant treatment of COAG were reviewed. It is unclear as to why there is no corresponding recommendation within the guidance pertaining to these pharmacotherapeutic interventions. The evidence base must be ample since none of the research recommendations in the draft (pages 67 69) suggest more studies of fixed combination or concomitant treatments. We feel that the omission of these important treatments is striking in a document comprehensive enough to consider complementary therapies. Thank you for your comment. We have amended the recommendations to offer a wider choice of pharmacological treatments (which includes concomitant treatment) should the first choice not work. We disagree that the evidence base is ample for fixed combination therapies. None of the studies of fixed combination therapies were of sufficient quality to make a recommendation for or against their use. As a general principal when prescribing a drug, particularly one with a risk of side effects, the minimum effective dose should be used. Fixed combination therapies do not obey this principal. The panel were aware of one meta- analysis showing that carbonic anhydrase inhibitors and beta blockers are as effective in fixed combination as using the drugs separately but were concerned about patient safety as 9 of 226

10 using these drugs involves a dose of timolol above the necessary therapeutic dose. Meta-analysis of fixed combination prostaglandin agonist and timolol suggested that the fixed combination was not as effective as using the two drugs separately. It was noted that these combinations had not been licensed for use in the United States because they had not proved superior to using a prostaglandin agonist alone. There were also concerns that all fixed combinations contained timolol 0.5% and that the high dose of betablocker and that night time dosing could be potentially harmful to ocular blood flow although there was insufficient evidence to highlight this concern. It was noted that all trials of these therapies had excluded patients with a known risk factor for beta blocker side effects. Other studies have highlighted that predicting the risk of side effects in clinical practice is poor. We urge prescribers to take the risk of systemic side effects into account when offering treatments but have not been proscriptive. Alcon UK 8 Full It appears that the vast majority of beta-blocker data reviewed involved timolol (either 0.25% or 0.5% w/v). No guidance or rationale was provided for the non-inclusion of the other ophthalmic betablockers (betaxolol, levobunolol, cartelol, metipranol etc). Thank you for your comment. We have included all papers describing the use of beta blockers where they met our inclusion criteria (see section 2.3 of the full version of the guideline), but we have not considered intraclass comparisons for any of the glaucoma medications 10 of 226

11 No comment has been made in the guidance to differentiate between cardio-selective Beta-1 beta blockers (e.g. betaxolol) and the non-selective Beta-1 and Beta-2 beta-blockers (e.g. cartelol, levobunolol, metipranol, and timolol) which are important features of this class of product particularly related to safety. including beta blockers. Some of the Beta-1 selective beta-blockers have additional properties such as calcium channel blocking properties which are linked in studies and literature to the promotion of vasodilation increasing ocular blood flow, and neuroprotection of the optic nerve, which we also feel is important. [Reference 38: Osborne N et al, Brain Research 751 (1997) ] [Reference 39: Osborne N et al, The potential of neuroprotection in glaucoma treatment, Current Opinion in Ophthalmology 1999, 10:82-92] [Reference 40: Melena J. et al, Betaxolol, a B1- adrenoreceptor agonist, has an affinity for L- type Ca2+ channels, European Journal of Pharmacology 378 (1999) [Reference 41: Osborne N, Neuroprotection to the retina: relevance in glaucoma, Vascular Risk Factors and Neuroprotection in Glaucoma update 1996, pp ] [Reference 42: Osborne N., Comment Current Trends in Glaucoma: Pathology and Neuroprotection] Only three references are quoted for betaxolol, and given the wealth of clinical trials and 11 of 226

12 supporting clinical publications for both betaxolol and other beta-blockers, it is considered therefore that the characterization and guidance provided on the beta-blocker (BB) category is factually incomplete, and may mislead prescribers. There are betaxolol visual field (Flammer/Collignon-Branch) and safety (Diggory) studies that would be of interest, for example: [Reference 9: J. Flammer et al. - Long-term visual field follow-up in betaxolol- and timololtreated patients Proceedings of the Xth International Preimetric Society Meeting, Kyoto, Japan. October ] [Reference 10: J. Flammer et al. Influence of Carteolol and Timolol on IOP and visual fields in glaucoma: a multi-center, double-masked, prospective study - European Journal of Ophthalmology (4) ] [Reference 11: Diggory et al. Unsuspected Bronchospasm in Association with Topical Timolol a Common Problem in Elderly People: Can We easily identify Those affected and do Cardioselective Agents lead to Improvement? Age and Ageing 1994: 23; 17-21] [Reference 12: Diggory et al. Improved lung function tests on changing from topical timolol: Non-selective Beta-blockade Impairs 12 of 226

13 Alcon UK 9 Full Lung Function tests in Elderly Patients Eye 1993: 7; ] [Reference 13: Diggory et al. Randomised, controlled trial of spirometric changes in elderly people receiving timolol or betaxolol as initial treatment for glaucoma British Journal of Ophthalmology 1998: 82; ] [Reference 14: C. Messmer et al. Influence of Betaxolol and Timolol on the Visual Fields of Patients With Glaucoma American Journal of Ophthalmology 1991: 112 (5)] [Reference 15: Kaiser et al. Long-term Visual Field Follow-up of Glaucoma Patients Treated with Beta-blockers Survey of Ophthalmology 1994: 38 Supplement] [Reference 16 : Andreou et al. A randomised prospective double blind study of cardiac arrhythmias in elderly patients commencing topical betaxolol or timolol therapy. Presented as a poster at Oxford Ophthalmological Congress 1998] We recommend the inclusion of additional clinical data within this section, and expansion to include additional information on the specific characteristic of the topical beta-blockers available for treatment of OHT and COAG, as this level of detail is important consideration for prescribers, especially given the association between the prevalence of pre-existing medical conditions (such as asthma and COPD) and glaucoma in an elderly population. In the assumptions section (1.8) a statement says Thank you for your comment. We agree that absence of evidence is not 13 of 226

14 Alcon UK 10 Full there was no evidence of benefit from differentially treating patients with particular risk factors. Thus, all treatments were considered to be similarly effective in all patients. This may be an unfortunate assumption. There are no studies among the references that prospectively and specifically targeted treatment of patient groups defined by risk factors. We feel that absence of evidence is not a basis for the assumption, such as the one made here. There is clearly considerable evidence differentiating the glaucoma drug categories and combination therapies in terms of safety and efficacy performance. Perhaps most important, it is well known that different patients respond differently to different pharmaceutical alternatives. Thus, it is important to have access to a full range of alternatives so that treatments can be custom tailored to the individual patient. We have identified a contradiction between Pages 46 (Line 25) and 47 (Line 9) which states that economic studies were excluded from the economic paper review if the study was a non-uk cost-analysis; and Page 47 (Lines 17-18) indicating that We have included studies from all over the world in to our review. We recommend that this point is clarified in the recommendation. equivalent to absence of effect. We are aware that different patient groups may on average experience different outcomes as a result of variation in the natural history of certain sub-categories. This notion can be accounted for clinically in the setting of a target pressure which appropriately acknowledges the risk of sight loss for given situations. For increased clarity has been adjusted to read: Evidence of benefit from differentially treating patients with particular risk factors was not found. The rate of progression to vision loss may however vary between certain patient groups using standard treatment regimes and those perceived clinically to be at higher risk may need a lower target IOP Thank you for your comment. We do not agree with your comment and we have explained in the text that non-uk studies were included in the review; however non-uk cost analyses were deemed not useful to make recommendations and were excluded. Alcon UK 11 Full It is detailed on Page 48 (Lines 28-29) that When clinical and economic evidence was poor or Thank you for your comments. Indeed where the quality of the evidence was low or non-existent the 14 of 226

15 absent, the GDG proposed recommendation based on their expert opinions. The majority of the recommendations from Pages and Pages are associated with either clinical evidence of low quality or no evidence ; it is assumed that therefore expert opinion must have played a sizable role in the decision making process and guidance provided. It would be useful to indicate which of these recommendations were based in part or entirely on expert opinion. Guideline Development Group have had to use their clinical experience to formulate recommendations. We do not agree that we need to indicate which recommendations were based partly or wholly on expert opinion as this should be clear from the linking evidence to recommendation sections as well as the methodology section from which you quote. Alcon UK 12 Full None of the most frequently prescribed glaucoma products are available without preservative. For patients with allergy to preservatives, we feel additional specific guidance and recommendations should be provided including recommendations on the alternative therapeutic classes of preservative free therapy available (e.g. BB preservative free Betoptic Unit Dose or others, TCAI preservative free, TCAI+BB fixed dose combination, cholinergic and sympathomimetic preservative free,). [Reference 17: MIMS November 2008 Page ] [Reference 18: BNF September 2008 Section 11.6 Treatment of Glaucoma Pages ] Thank you for your comment. We believe our current recommendations regarding use of preservative free medications is adequate. These data are easily accessible in the public domain and are likely to change in the future. Alcon UK 13 Full Table: Treatment of OHT and COAG suspects (Page 53, Line 13, and Page 59, Line 3): Future consideration should be given to modifying Thank you for your comment. The life expectancy used in the model is based on the England and Wales life tables. Any changes in life expectancy will be addressed when 15 of 226

16 the ages shown in this table based on the increase in life expectancy being experienced in many countries. the Guideline is updated in the future. Alcon UK 14 Full These pages of the guidance do not provide any specific recommendation, comment or guidance on either, adjunctive/concomitant or fixed dose combination therapy; for either COAG patients or OHT/COAG suspects with elevated pressure where monotherapies have proven ineffective. Thank you for your comments. We have amended the recommendations so that combination treatments are an option as an alternative treatment when IOP is not controlled by monotherapy. It is our belief that this guidance is not fully comprehensive without inclusion of discussion on these therapeutic alternatives. Supporting data Kass et al in the OHTS study concluded that at 60 months, to control IOP (IOP <24 mmhg) and to obtain a 20% reduction in IOP from baseline: 60% of patients needed one medication to control IOP 40% of patients needed 2 or more topical medications (259 of 653) 9.3% (61 of 653) patients needed 3 or more medications [Reference 19: Kass et al, The Ocular Hypertension Treatment Study, Arch Ophthalmol/Vol. 120, June 2002] The volume of evaluable patients from these studies, demonstrates that in the course of therapeutic practice, multiple drug therapies are frequently tried before exposing patients to the uncertainties and risks of surgical intervention. Most of the papers cited do not meet the inclusion criteria for our guidance. We refer the stakeholder to section 2.3 of the full version of the guideline. The most important point of which is a six month duration of treatment to demonstrate the benefits and harms of treatment. With regard to surgical options for COAG, we do acknowledge the trade of between benefits and harm of surgery. This is mentioned in the section on link between evidence and recommendations for the surgical recommendations. We also allow for patient preference to continue using medications should they prefer to do so, and additional pharmacological treatment after surgery should it be required. The GDG are aware that special circumstances will apply to certain patients. This is covered generically in regard to side effects and complications of medications and we 16 of 226

17 Surgical Intervention Vs Pharmacotherapeutic Treatment It should be acknowledged that surgery is not a benign therapy. While there are data showing that early surgery may reduce long term loss of sight, the enthusiasm for surgery needs to be tempered with the reality of surgical shortcomings, including severe surgical complications that can include complete loss of vision at the time of surgery from haemorrhage or endophthalmitis. recommend switching to alternatives. As regards surgery in patients with only one eye, the GDG are of the view that consultant ophthalmologists are well placed to discuss risks and benefits in a manner which is tailored to the special circumstances of individual patients. It would be impossible to account for the multitude of possible special circumstances and we do not believe that such a prescriptive approach within a guideline would be helpful. Surgical intervention frequently involves only temporary relief at best. Given that OHT and/or COAG are chronic and progressive conditions, it becomes inevitable that after surgery, patients will still require pharmacotherapy. Consideration of, and suggestions for, inclusion of therapeutic alternatives to surgery for patients who prefer not to have surgery or who are not suitable for surgery The topic of pharmacological treatment in patients who prefer not to have surgery or who are not suitable for surgery only includes monotherapy treatments, and fails to include either adjunctive/concomitant or fixed combination therapies. Examples of alternative therapeutic treatments 17 of 226

18 There is a substantial amount of published clinical evidence which does not appear to have been reviewed to support additional therapeutic alternatives to single active monotherapy, including but not limited to: Adjunctive/concomitant therapy TCAI used as adjunctive therapy to a PGA brinzolamide + travoprost the synergistic effect of brinzolamide when used adjunctively with a travoprost adjunctive brinzolamide b.d. significantly reduced IOP compared with baseline, in patients uncontrolled on travoprost alone. P<0.001 vs. baseline week 4 change in IOP from baseline 3.9 mmhg (n=78) week 12 change un IOP from baseline 4.2 mmhg (n= 71) [Reference 20: Franks W et Al. Curr Med Res Opin 2006; 22(9): ] brinzolamide + latanoprost the synergistic effect of brinzolamide when used adjunctively with latanoprost brinzolamide b.d. significantly lowered IOP when added to latanoprost: mean decrease after 3 months = 5.3 mmhg (P<0.01, n=14) adjunctive brinzolamide b.d. consistently lowered IOP at all time points vs. latanoprost only baseline 18 of 226

19 [Reference 21: Shoji N et al. Curr Med Res Opin 2005; 21(4): 503-7] in patients already receiving latanoprost monotherapy, adding brinzolamide or timolol significantly lowered IOP during the diurnal period. only the brinzolamide adjunctive therapy had an IOP lowering efficacy during the nocturnal period [Reference 22: Liu et al. Comparing Diurnal and Nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy. Ophthalmology 2008] TCAI, BB, or Alpha2 agonist used as adjunctive therapy to PGA Vs PGA alone dorzolamide + latanoprost vs latanoprost Adjunctive therapy with dorzolamide provided a statistical significant IOP reduction at 1 year than latanoprost used alone When added to latanoprost, dorzolamide lowered IOP by an additional 3.9 mmhg (19.7%, P<0.001) 10% reduction in IOP from a latanoprost base line was seen in 84% of eyes 19 of 226

20 treated with dorzolamide (P= 0.012) [Reference 24: O Connor NJ et al, AM J Ophthalmol June 2002] dorzolamide + BB vs latanoprost dorzolamide + BB further reduced IOP by 2.0mmHg (12.3%, P < 0.001) 10% reduction in IOP from a latanoprost base line was seen in 61% of eyes treated adjunctively with BB (P= 0.012) [Reference 24: O Connor NJ et al, AM J Ophthalmol June 2002] dorzolamide + brimonidine vs latanoprost dorzolamide + brimonidine further reduced IOP by 2.0 mmhg (9.3%, P = ) 10% reduction in IOP from a latanoprost base line was seen in 44% of eyes treated adjunctively with brimonidine (P= 0.012) [Reference 24: O Connor NJ et al, AM J Ophthalmol June 2002] travoprost + brimonidine vs travoprost mean diurnal IOP at baseline were 21.7 mmhg vs travoprost monotherapy (P = 0.16) mean diurnal IOP at month 3 were 19.6 mmhg vs travoprost monotherapy (P = 0.019) travoprost + brinzolamide vs travoprost 20 of 226

21 mean diurnal IOP at baseline were 21.2 mmhg vs travoprost monotherapy (P = 0.16) mean diurnal IOP at month 3 were 18.4 mmhg vs travoprost monotherapy (P = 0.019) At month 3, mean diurnal IOPs were 19.3 in the brimonidine group and 18.6 in the brinzolamide group. [Reference 25: Feldman et Al Am J Ophthalmol : 2007] (travoprost + brinzolamide) or (travoprost + timolol) vs brimonidine Results of this trial suggest that brinzolamide 1% and timolol maleate 0.5% were more effective than brimonidine monotherapy when administered as nonfixed adjunctive treatment with travoprost 0.004% in treatment of patients with OAG or OHT whose IOP was not adequately controlled with travoprost monotherapy [Reference 26: Reis et al, Clinical Therapeutics/Volume 28, Number 4, 2006] 21 of 226

22 (travoprost + brinzolamide) or (travoprost + timolol) vs travoprost monotherapy travoprost + brinzolamide (n= 97), travoprost + timolol (n= 95), Diurnal mean at visit 4 (week 12) showed: travoprost + brinzolamide, mean IOP = 18.1 (p = 0.96), 3.4mmHg from baseline reduction (6.3% reduction, p = 0.55) travoprost + timolol, mean IOP 18.1 (p =0.96), 3.2 mmhg from baseline reduction (6.7% reduction, p = 0.55) [Reference 27: Hollo et al, EJO/Vol 18 no.6, 2006/pp ] PGA/BB Fixed Dose Combination benefits over monotherapy PGA travoprost/timolol fixed combination vs. travoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to travoprost used as monotherapy over 3 months of treatment, travoprost/timolol fixed combination, reduced mean IOP from baseline by up to 12 mmhg (38%) (n = 263, P< 0.001), compared with 9 mmhg reduction with travoprost alone. travoprost/timolol fixed combination showed a similar safety profile to concomitant therapy with travoprost and 22 of 226

23 180 8 timolol 0.5% or monotherapy with travoprost 0.004% or timolol 0.5% b.d. [References 28: Barneby HS et al. Am J Ophthalmol 2005; 140: 1-7] travoprost/timolol fixed combination was more effective than travoprost used as monotherapy 4.6mmHg change in IOP after switch to travoprost/timolol fixed combination (p=<0.001) additional 21.3% reduction in IOP after switch to travoprost/timolol fixed combination (n = 1131, p <0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination multi-centre study, open label, 6 weeks, involving 9,707 patients in this study, 94.4% of patients described tolerability of travoprost/timolol fixed combination as satisfactory, good, very good or excellent [References 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] no serious ophthalmic or systemic undesirable effects related to travoprost/timolol fixed combination were reported in clinical studies involving 721 patients [Appendix A.3: travoprost/timolol fixed combination summary of product characteristics (SmPC)] travoprost/timolol fixed combination vs. 23 of 226

24 latanoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to latanoprost used as monotherapy additional 21.1% reduction in IOP after switch to travoprost/timolol fixed combination from latanoprost n = 862, P< mmhg change in IOP after switch to travoprost/timolol fixed combination (p =<0.001) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 30: Hughes B et al. J Glaucoma 2005; No5, 14: ] travoprost/timolol fixed combination vs. bimatoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to bimatoprost used as monotherapy 3.9 mmhg change in IOP after switch to travoprost/timolol fixed combination additional 18.7% reduction in IOP after 24 of 226

25 switch to travoprost/timolol fixed combination (n= 285, P<0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] PGA/BB Fixed Dose Combination benefits over concomitant PGA + BB travoprost/timolol fixed combination vs. travoprost + timolol additional IOP reduction when using fixed combination travoprost-timolol compared to travoprost used concomitantly with b.d. timolol 0.5% 1.1 mmhg change in IOP after switch to travoprost/timolol fixed combination (p = <0.001) additional 6.2% reduction in IOP after switch to travoprost/timolol fixed combination (n= 339, p< 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] travoprost/timolol fixed combination vs. latanoprost + timolol 25 of 226

26 additional IOP reduction when using fixed combination travoprost-timolol compared to latanoprost used concomitantly with b.d. timolol 0.5% 2.2 mmhg change in IOP after switch to travoprost/timolol fixed combination (p = <0.001) additional 11.5% reduction in IOP after switch to travoprost/timolol fixed combination (n = 139, P < 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] travoprost/timolol fixed combination vs. bimatoprost + timolol additional IOP reduction when using fixed combination travoprost-timolol compared to bimatoprost used concomitantly with b.d. timolol 0.5% 1.4 mmhg change in IOP after switch to travoprost/timolol fixed combination (p=<0.001) additional 7.7% reduction in IOP after switch to travoprost/timolol fixed combination (n = 50, P< 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul 26 of 226

27 Pharmacol Ther 2008; 24(4): ] Therapeutic differences between fixed combination PG/BB Travoprost/timolol fixed combination vs. latanoprost/timolol fixed combination additional IOP reduction when using fixed combination travoprost-timolol compared to fixed combination latanoprost/timolol 3.0 mmhg change in IOP after switch to travoprost/timolol (p=<0.001) additional 14.9% reduction after switch to travoprost/timolol fixed combination (n= 608, P < 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] Therapeutic differences between fixed combination PGA/BB and fixed combination TCAI/ BB 27 of 226

28 Travoprost/timolol fixed combination vs. fixed combination dorzolamide/timolol additional IOP reduction when using fixed combination travoprost-timolol compared to fixed combination dorzolamide/timolol 4.2 mmhg change in IOP after switch to travoprost/timolol fixed combination (p = <0.001) additional 20.0% reduction in IOP after switch to travoprost/ timolol fixed combination (n = 452, P< 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] Therapeutic differences between fixed combination PG/BB and fixed combination Alpha2 agonist/bb fixed combination travoprost-timolol compared to fixed combination brimonidine/timolol additional IOP reduction when using fixed combination travoprost-timolol compared to fixed combination brimonidine/timolol 4.2 mmhg change in IOP after switch to travoprost/timolol fixed combination (p =<0.001) additional 19.5% reduction in IOP after switch to travoprost/timolol fixed combination (n= 12, P<0.05) IOP recorded at baseline (on previous 28 of 226

29 therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] ALOGRITHM 4 COAG PATHWAY ALOGRITHM 4 COAG PATHWAY depicted on Page 66 does not provide a treatment pathway or detail additional therapeutic options for patients who prefer not to have surgery or who are not suitable for surgery. We recommend the inclusion of an additional treatment pathway in this algorithm to show the suggested treatment pathway and alternative therapeutic therapies available for these types of COAG patient. Correction Please note that the guidance document states there is no significant difference between PGA monotherapy and a fixed combination of a PGA/ BB. This is factually incorrect, and we recommend the correction of this point. It was also of concern to us that only one 29 of 226

30 2 2 published paper reporting on concomitant travoprost + timolol therapy versus travoprost alone was considered during the therapeutic review, and we strongly recommend the review and inclusion of guidance from the following published material to provide a more comprehensive picture of the data available. The following clinical studies involving PGA/BB Fixed Dose Combination vs. concomitant PGA + BB demonstrated: travoprost used concomitantly with b.d. timolol 0.5% additional IOP reduction when using fixed combination travoprost-timolol compared to travoprost used concomitantly with b.d. timolol 0.5% 1.1 mmhg change in IOP after switch to travoprost/timolol fixed combination (p = <0.001) additional 6.2% reduction in IOP after switch to travoprost/timolol fixed combination (n= 339, p< 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] fixed combination travoprost-timolol compared to latanoprost used concomitantly with b.d. timolol 0.5% additional IOP reduction when using fixed 30 of 226

31 combination travoprost-timolol compared to latanoprost used concomitantly with b.d. timolol 0.5% 2.2 mmhg change in IOP after switch to travoprost/timolol fixed combination (p = <0.001) additional 11.5% reduction in IOP after switch to travoprost/timolol fixed combination (n = 139, P < 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] fixed combination travoprost-timolol compared to bimatoprost used concomitantly with b.d. timolol 0.5% additional IOP reduction when using fixed combination travoprost-timolol compared to bimatoprost used concomitantly with b.d. timolol 0.5% 1.4 mmhg change in IOP after switch to travoprost/timolol fixed combination (p=<0.001) additional 7.7% reduction in IOP after switch to travoprost/timolol fixed combination (n = 50, P< 0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul 31 of 226

32 Pharmacol Ther 2008; 24(4): ] the beneficial additive effect of fixed dose dorzolamide-timolol combination vs concomitant therapy with timolol + dorzolamide [Reference 31: Boyle JE et al, Ophthalmology Dec 1999; 106 (12 Suppl): 10-6] travoprost/timolol combination produces greater IOP reducations than timolol 0.5% + travoprost concomitant therapy [Reference 32: Schuman et al, Am J Ophthalmology Vol 140 No 2; 242 August 2005] Other than the references reviewed in the guidance, there are additional clinical studies of interest involving PGA/BB Fixed Dose Combination benefits over monotherapy PGA: Travoprost/timolol fixed combination vs. travoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to travoprost used as monotherapy Over 3 months of treatment, travoprost/timolol fixed combination, reduced mean IOP from baseline by up to 12 mmhg (38%) (n = 263, P< 0.001), compared with 9 mmhg reduction with travoprost alone. [Reference 28: Barneby HS et al. Am J 32 of 226

33 Ophthalmol 2005; 140: 1-7] travoprost/timolol fixed combination was more effective than travoprost used as monotherapy 4.6mmHg change in IOP after switch to travoprost/timolol fixed combination (p=<0.001) additional 21.3% reduction in IOP after switch to travoprost/timolol fixed combination (n = 1131, p <0.05) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] travoprost/timolol fixed combination vs. latanoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to latanoprost used as monotherapy additional 21.1% reduction in IOP after switch to travoprost/timolol fixed combination from latanoprost n = 862, P< mmhg change in IOP after switch to travoprost/timolol fixed combination (p =<0.001) IOP recorded at baseline (on previous therapy) and after 4-6 weeks of therapy with travoprost/timolol fixed combination Multi-centre study, open label, 6 weeks, involving 9,707 patients 33 of 226

34 [Reference 30: Hughes B et al. J Glaucoma 2005; No5, 14: ] travoprost/timolol fixed combination vs. bimatoprost monotherapy additional IOP reduction when using fixed combination travoprost-timolol compared to Bimatoprost used as monotherapy [Reference 29: Arend K-O and Raber T. J Ocul Pharmacol Ther 2008; 24(4): ] Other than the references reviewed in the guidance, there are additional clinical studies of interest involving PGA/BB Fixed Dose Combination benefits over monotherapy BB: travoprost/timolol fixed combination demonstrated statistical significances in lowering IOP than timolol 0.5% mean IOP following treatment with travoprost/timolol fixed combination was statistically significantly lower than mean IOP following timolol 0.5% alone (p<0.003) [Reference 28: Barneby HS et al. Am J Ophthalmol 2005; 140: 1-7] 34 of 226

35 Clinical differentiation between TCAI s The guidelines should also consider differentiating the TCAI s based on published differences in comfort and tolerability which are thought to impact compliance and therapy persistence. Data from 2 randomised, prospective, multicentre, double masked, parallel group studies comparing brinzolamide t.i.d. with dorzolamide 2% in patients with POAG or OH demonstrated that brinzolamide caused less ocular discomfort than dorzolamide [Reference 33: Silver LH. Surv Ophthalmol 2000; 44 (suppl 2): 141-5] Switching from dorzolamide to brinzolamide resulted in an overall improvement in comfort and ocular hypotensive efficacy, and patients ratings of comfort were clinically and statistically significantly better with brinzolamide than with dorzolamide. [Reference 34: Barnebey H, Kwok SY. Clin Ther 2000: 22 (10): ] Fewer treatment failures with brinzolamide compared with dorzolamide The switch rate was significantly lower with brinzolamide treatment at both 6 months and 1 year, than with dorzolamide [Reference 35: Deschaseaux-Voinet C et al. J Med Economics 2003 ; 6 : 69-78] 35 of 226

36 In terms of ocular pressure reduction, brinzolamide 1% b.d. was equivalent to dorzolamide b.d (timolol baseline) brinzolamide produced significantly less ocular burning and stinging [Reference 36: Michaud et al, The international Brinzolamide adjunctive study group. Comparison of topical brinzolamide 1% and dorzolamide 2% eye drops given twice daily in addition to Timolol 0.5% in patients with Primary Open-angle glaucoma or ocular hypertension. American Journal of Ophthalmology 2001: 132 (2); ] Finally, we also believe that additional information is required on the cost implications to the NHS of surgical failures to make this section more balanced. Special Circumstance Patients The guidance does not take into account some special circumstance patients. Examples: Risks associated with a surgical intervention are significantly higher in patients with only one seeing eye. Added risk of PGA therapy in patients with cystoid macular oedema (CMO) We believe that for Special circumstance patients the guidance is insufficient and does not adequately demonstrate the breadth of alternative pharmacotherapeutic alternatives available. We recommend inclusion of additional information and guidance for the therapeutic treatment of these 36 of 226