Shire Pharmaceuticals/Johnson & Johnson 16 December 2005 Comments on Addenda to MRC report on clinical efficacy and NICE Technical Report 2; Drugs for the Treatment of Alzheimer s Disease (review)
Executive Summary Shire Pharmaceuticals/Johnson & Johnson have reviewed the documents sent by NICE on 08 December 2005 and in the short review time available have assembled the response detailed below. The evidence provided in the addendum to Technical Report no. 2 does not present substantive new information that should have a bearing on reimbursement of AChEIs in the NHS, above data already provided to the committee in the earlier reports and responses. In common with almost all clinical trials, placebo effects are present in clinical trials of galantamine however galantamine has demonstrated statistically significant effect vs. placebo in all relevant trials identified by NICE. Placebo effects are most apparent in mild AD patients, while galantamine s effect is consistently observed across mild, moderate and advanced moderate AD patients The placebo response in the Nordic study reflects the particular issues in that trial. New evidence from two other 12-month placebo-controlled trials in AD showed a smaller proportion of placebo patients responding according to NICE guidance criteria (20% vs. 34%), a lower magnitude of effect at six months, and a less sustained long-term profile (both responder groups below baseline by month 12). Scenario G is ill conceived and unrealistic as a policy option for the NHS, while the economic modelling is inadequate both in conception and implementation, reducing only drug benefits for placebo effect but assuming that such placebo effect, including monitoring and assessment by the NHS, is costless.
1. Introduction The original submission to NICE (June 2004) 1 and additional data submitted on 21 October 2005 2 provide a transparent and comprehensive exploration of the clinical efficacy of galantamine across 7 placebo-controlled trials and 3389 patients. The data re-confirm significant treatment effect in patients with mild, moderate and advanced moderate Alzheimer s disease (AD). On 09 December 2005 Shire and Johnson & Johnson submitted a response to NICE to the MRC report on clinical efficacy and NICE Technical Report no. 2, presenting additional commentary on the clinical effectiveness and a series of new costeffectiveness estimates for galantamine. NICE have issued, at short notice on 08 December 2005, addenda to the MRC report on clinical efficacy and NICE Technical Report no. 2. In order to be as transparent and responsive as possible, Shire and Johnson & Johnson detail their further comments below on these addenda for consideration by the appraisal committee. New data are supplied to support claims made in the text below. 2. Placebo responses It is well established that placebo responses occur in clinical trials and that such responses can be substantial within the CNS and pain therapeutic areas 3;4. In the large galantamine database, responses to placebo treatment in terms of recognised efficacy parameters were observed across the range of clinical trials - but such responses were significantly exceeded in magnitude by treatment with galantamine in all trials. Various authors have debated the occurrence and ethical issues of the placebo response in Alzheimer s and other CNS diseases. Goldney and Stoffel reviewed the use of placebo in clinical controlled trials in AD and have raised ethical issues regarding use of placebo against active AChEIs in such trials 5. Placebo effects are thought to be related to expectation of clinical benefit; and mechanisms of placebo response involving modulation of neurotransmitter activity have been explored. Investigations in Parkinson s disease in particular have suggested inducement of dopamine release to explain a placebo effect 6. In common with other disease areas placebo patients in AD demonstrate a response. This reflects both trial based effects on clinical care such as the treatment of psychiatric or cardiovascular symptoms or even simple interventions such as the removal of earwax. In addition a placebo effect also exists where patients respond to the treatment. The placebo response is most typically observed in patients with milder AD at study baseline. Such patients may experience an improvement in anxiety and depression that had affected cognitive performance as well as being capable of producing learning effects on study instruments. In more advanced patients where diagnosis and disease course are better established, the relative placebo effect is much lower.
The addendum to Technical Report no 2 implicitly attributes much of the improvement observed in AChEIs to a placebo effect. If this was the case then a decrease in the proportion of responders would be expected in both drug and treatment groups at more advanced disease levels. While the expected reduction in response is observed for placebo treatment, the response to galantamine is consistent and the drug vs. placebo effect is more apparent in more advanced patients, as demonstrated by additional analyses (figure 1 & 2 attached excel file) from GAL-INT1, GAL-USA-1, GAL-USA-10 and GAL-INT-10). Figure 1: Probability of Response (NICE Definition) by Baseline MMSE Score (Logistic Regression Model) AD Trials: INT-1, INT-10, USA-1, USA-10 GAL 24 mg Placebo 3. The Nordic Study and long-term placebo responses - alternative evidence The new data presented in the addendum to Technical Report no. 2 were inspired by the Donepezil Nordic Study 7. However, the placebo response observed in this single study may not be typical of the longer-term placebo response in AD. We note that the placebo responders were on average milder (higher MMSE at baseline) compared to the remainder of the placebo group. The response observed in placebo responders therefore reflects in part the slower natural decline in AD at this disease stage as well as milder patients increased propensity to show trial-related and placebo-related improvements in cognition. Evidence from two other large-scale 12-month placebo controlled trials 8 in AD that used the ADAS-Cog rather than the MMSE did not replicate the placebo response observed in the Nordic Study (figure 3 & 4 attached excel file).
The proportion of responders [following the NICE guidance definition was 19% in SAB-INT-12 and 20% in SAB-USA-25 was lower than that observed in the Nordic Study (34%). The magnitude of response at six months is also smaller than that observed in the Nordic study (taking into account of course the difference between ADAS and MMSE scaling) The response among placebo responders was also less sustained that in the Nordic study with the small group of placebo responders in both studies having fallen back below their baseline values by 12 months. 4. Scenario G is not a relevant option for NHS policy Scenario G does not present a valid clinical scenario for the committee. The reality of the choice facing the committee is whether patients with AD should continue to have access to AChEIs or whether such treatment be withdrawn from funding by the NHS. Scenario G is predicated upon the placebo responses observed in clinical trials but absent in usual clinical practice in the NHS. The scenario would require that the NHS distribute placebo pills to patients but that clinicians, pharmacists, caregivers and patients should be blinded to whether the pills were active or not. Beyond the clear practical and conceptual limitations of this proposed approach, the analyses from technical team is also inappropriate since on one hand they reduced drug benefits to take account of placebo effects, but on the other side of the equation fail to include the costs for the manufacture, distribution, prescription and clinical monitoring of placebo drug therapy to the NHS. Scenario G is therefore not a valid option upon which the committee should make a policy decision. The clear comparison is between current guidance that allows responders to continue on treatment versus patients remaining untreated (Scenario A). This option already has an element of placebo effect built in and can therefore be considered as conservative. We note that the costs of galantamine have been altered since the 25 th November 2005 Technical report but draw the committee s attention to the additional issue as yet unaddressed issue which is the use of the higher costs for the 24mg maintenance dose rather than the more appropriate weighted average of the costs for the 24mg and the less costly 16mg maintenance dose for long-term treatment costs. 5. Summary Shire Pharmaceuticals/Johnson & Johnson have reviewed the documents sent by NICE on 08 December 2005 and in the short review time available have assembled the response detailed below. The evidence provided in the addendum to Technical Report no. 2 does not present substantive new information that should have a bearing on reimbursement of AChEIs in the NHS, above data already provided to the committee in the earlier reports.
Placebo effects are present but galantamine s significant effect vs. placebo has been demonstrated in 8 trials. Placebo effect is most easily observed in mild AD patients, while galantamine treatment effect is consistently observed in mild, moderate and advanced moderate AD patients The placebo response in the Nordic study reflects the particular issues in that trial. New evidence from two other 12-month placebo-controlled trials in AD showed a smaller proportion of placebo patients responding according to NICE guidance criteria (20% vs. 34%), a lower magnitude of treatment effect at six months, and a less sustained long-term profile (with both responder groups below baseline by month 12). Scenario G is ill conceived and unrealistic as a policy option while the economic modelling is inadequate in conception and implementation. The scenario reduces only drug benefits for placebo effect but assumes that such placebo effects, including monitoring and assessment by the NHS, are costless.
Reference List 1. Shire Pharmaceuticals and Johnson & Johnson. Drugs for the treatment of Alzheimer's Disease: submission to the National Institute of Clinical Excellence. 1-6-2004. Ref Type: Report 2. Shire Pharmaceuticals and Johnson & Johnson. Response to the National Institute of Clinical Excellence (NICE) Request for Additional Analyses of July 2005: Additional Analyses Using Studies of galantamine in Subjects with Dementia of the Alzheimer's Type. 21-10-2005. Ref Type: Report 3. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25:10390-402. 4. Zubieta JK, Yau WY, Scott DJ, Stohler CS. Belief or Need? Accounting for individual variations in the neurochemistry of the placebo effect. Brain Behav.Immun. 2005;%19;.. 5. Goldney RD,.Stoffell BF. Ethical issues in placebo-controlled trials in Alzheimer's disease. Med J Aust. 2000;173:147-8. 6. Fuente-Fernandez R, Schulzer M, Stoessl AJ. Placebo mechanisms and reward circuitry: clues from Parkinson's disease. Biol.Psychiatry 2004;56:67-71. 7. Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-95. 8. Feldman HH, Van Baelen B, Kavanagh SM, Torfs KE. Cognition, function, and caregiving time patterns in patients with mild-to-moderate Alzheimer disease: a 12-month analysis. Alzheimer Dis Assoc Disord. 2005;19:29-36.
Figure 2: Galantamine and placebo response by severity group 70 60 % of patients responding (NICE definition) 50 40 30 20 61.6 24 mg 16mg placebo 42.9 42.9 43.3 43.7 32.9 36.50 23 16.20 10 0 N = 200 N = 45 N = 118 N = 320 N = 78 N = 136 N = 94 N = 19 N = 29 Mild Moderate Advanced Moderate Severity