PBAC Recommendations from the Review of Pharmaceutical Benefits Scheme Anti-dementia Drugs to Treat Alzheimer Disease
Page last updated: 3 April 2013
Word version of the Ratified PBAC Minutes of the December 2012 Meeting (67 KB)
Ratified Minutes of the December 2012 Special PBAC meeting. Item 4: Post-Market Review of PBS Anti-Dementia Medicines for Alzheimer Disease (AD)
The Review
This review includes the cholinesterase inhibitors (CEIs) donepezil, rivastigmine and galantamine; and the N-methyl-D-aspartate (NDMA) receptor antagonist memantine.
The PBAC recommended this review to ensure these medicines continue to be used appropriately and to ensure their ongoing cost effectiveness, as originally assessed by the PBAC. An initial review of CEIs carried out by the Drug Utilisation Sub-Committee (DUSC) of the PBAC showed that these medicines are being prescribed to a much larger population for longer periods of time than originally assessed as cost effective by the PBAC (Le Couteur et al. 2011). In March 2012, the PBAC approved the following terms of reference for the review.
Terms of Reference
a. Review recent Australian utilisation data on patient initiation and continuation rates to cholinesterase inhibitors and memantine.
b. Investigate if there is more recent evidence on the safety and efficacy of these medicines that would inform the PBAC about their cost-effectiveness.
c. Review whether the two point improvement in Mini-Mental State Examination continues to be an adequate surrogate for measuring improvement in patients with dementia treated with these medicines; and are there other more reliable measures of patient relevant outcomes?
d. Review the current PBS restriction continuation rule and the likely effect it has on cost-effective utilisation of these medicines.
Background
The Pharmaceutical Benefits Advisory Committee (PBAC) recommended the subsidy of cholinesterase inhibitors and memantine for AD in late 2000, following consultation with clinical experts and the pharmaceutical companies that make these medicines. At the time, PBAC recognised the clinical need for an effective treatment for people with AD but the evidence about the effect of these medicines on patients’ quality of life and on the benefits of treatment, beyond six months was very limited. For these reasons, PBAC recommended restricting the subsidy of these medicines beyond six months’ use to only those patients who demonstrated an improvement in their symptoms following treatment.
The current PBS restriction allows subsidised CEIs and memantine for patients who have a diagnosis of AD made by a specialist physician and a score of ≥10 in the Mini-Mental State Examination (MMSE). Continuing treatment beyond six months is restricted to patients who show an improvement of 2 or more points in the MMSE (or equivalent cognitive improvement in the AD Assessment Scale–Cognitive sub-scale [ADAS-Cog]). For those with MMSE scores lower than 10 points due to language or intellectual barriers, access may be sought based on the doctor’s assessment or clinician’s impression scale.
This restriction was recommended by PBAC when these medicines were first recommended for subsidy in 2000 to promote their cost effective use. However, many carers and clinicians consider there is benefit in continuing treatment with these medicines when there is stabilisation or a perceived slowing of symptom progression without the specified change in MMSE score being met, suggesting that the continuation rule may not always be adhered to in clinical practice.
An initial review of the CEIs, conducted by the DUSC of PBAC in 2009, indicated that these medicines were being prescribed to more people than originally expected for more than 6 months. Approximately 60% of those who initiate treatment in the Australian community continued treatment, substantially higher than the continuation rates expected from data from clinical trials, estimated to be between 15-35%. This additional use, while not necessarily inappropriate, may not be cost effective use as originally assessed by PBAC.
Main Findings of the Review
TOR a: Review recent Australian utilisation data on patient initiation and continuation rates to cholinesterase inhibitors and memantine.
The persistence results obtained from PBS data, were consistent with the results from the initial DUSC review and confirmed that approximately 60% of all those who initiate a CEI or memantine continued therapy beyond six months, as measured by filling a 7th prescription (see table ES1 below). There were small variations in the persistence results; however, this could be due to the application of different rules around breaks in therapy and switching. Persistence, according to drug initiated to, was highest for galantamine and lowest for memantine in both the 2009 and 2010 PBS cohorts (p.19, Part 2). There appears to be no compliance advantage associated with the use of rivastigmine patch compared to donepezil and galantamine.
Table ES.1. Patients initiating to a CEI or memantine and followed for a minimum of 12 months
|
|
2004 |
2008 |
2009 |
2010 |
|---|---|---|---|---|
|
Proportion filling a 7th prescription |
62.85 |
59.8% |
Range 56-70% |
Range 55-69% |
|
Persistence at 12 months |
54.7% |
56.9% |
60% |
59% |
Source: Report to PBAC Review of PBS anti-dementia medicines for AD, 2012 p ES2
The utilisation review also reported on some patient characteristics of the population treated with CEI and memantine supplied through the PBS. Relevant findings included: approximately 30% of all patients dispensed a CEI were also dispensed medicines with anticholinergic effects, and 19% of veterans who started on a CEI or memantine did so in a residential aged care facility.
TOR b: Investigate if there is more recent evidence on the safety and efficacy of CEIs and memantine that would inform the PBAC about their cost-effectiveness.
There are only a small number of new trials assessing the efficacy and safety of CEIs and memantine published since the listing of these medicines on the PBS. Overall, the review concluded this more recent evidence on the efficacy and safety of CEIs and memantine to be consistent with the evidence previously considered by PBAC. The results of the trials for all four medicines show a small benefit relative to placebo. However, this average benefit more closely reflects stabilisation of symptoms, or relatively slower decline, as opposed to the level of improvement required to meet the continuation criteria in the PBS restriction. For example, the improvement from baseline MMSE score at 24 weeks after 10mg/day of donepezil ranged from -0.1 to 1.35 points with a weighted mean difference of 1.33 points (0.87 to 1.78 95% CI) in MMSE compared to the placebo group. Longer term evidence of efficacy is supported by lower quality evidence, but again, the benefit is small relative to placebo.
There is some evidence from observational studies that galantamine use is associated with higher MMSE scores and delaying death when patients are treated beyond six months; however, the quality of this data is considered to be low (as assessed using GRADE). There is also one small trial that has reported delayed admission to an aged care facility for some patients taking memantine compared to placebo.
There is no evidence that shows that one drug is significantly more effective than another, supporting the previous PBAC decisions to list all four medicines on the basis of equivalent effectiveness. The evidence to support any incremental benefit from taking two medicines together (donepezil and memantine) is also inconclusive and based on poor quality studies.
TOR C: Review whether the two point improvement in Mini-Mental State Examination continues to be an adequate surrogate for measuring improvement in patients with dementia treated with these medicines; and are there other more reliable measures of patient relevant outcomes?
The literature search found no gold standard for measuring cognitive function in AD other than the MMSE and ADAS-Cog assessment tools. The MMSE is a valid measure of cognition which also correlates with other global assessments of dementia/AD, but the relationship between change in MMSE and activities of daily living or quality of life assessments is highly variable. While the MMSE is reasonably reliable as a diagnostic tool, its use in clinical settings is subject to individual interpretation and variability. Overall, the review concludes that clinicians must exercise caution in interpreting small changes in MMSE, which could be due to measurement error, regression to the mean or the effect of repeated testing. Change in quality of life, overall survival, care-giver time (and quality of life) or time to nursing home placement would be preferable outcomes for evaluating cost effectiveness of these medicines. The validity of MMSE as a surrogate outcome for these final patient outcomes is unknown.
Stakeholder Views
Twenty-one submissions were received from a variety of stakeholders including families, carers, health professionals, non-government organisations and pharmaceutical companies. The general consensus was that these medicines should remain accessible to all Australians through the PBS.
The most commonly cited benefits for patients taking these medicines included slower disease progression, improvements in behaviour and social skills, greater independence, more time spent lucid with families and less reliance on residential care. Many submissions considered assessment based on the MMSE to be problematic, mainly because it does not assess all the functional and behavioural improvements that can occur such as improvements in activities of daily living and quality of life of patients. It also does not account for the effects of age, cultural background, social class, education status, poor vision or hearing, stroke and language.
Some submissions considered the MMSE to be useful as an objective measure of change that could be valuable in justifying stopping treatment to family members when a patient’s symptoms continue to deteriorate. Others considered assessment based on observations by carers and clinicians would be the best way to determine a patient’s response to these medicines and subsequent changes in functional ability. Another submission considered that patients should have a trial of stopping these medicines following admission to a high-level aged care facility.
Some pharmaceutical companies who supply these medicines proposed that they are now more cost effective than when first listed on the PBS. The price of two medicines, galantamine and memantine, has decreased due to their patent expiry and the subsequent listing of generic products on the PBS.
TOR D: Review the current PBS restriction continuation rule and the likely effect it has on cost-effective utilisation of these medicines.
The current restriction and continuation rule for these medicines was originally developed by PBAC to target the most likely cost-effective population, that is, those patients who demonstrated an improvement in cognitive symptoms (demonstrated by a 2 point or greater increase in MMSE score) after a trial of six months treatment. At that time, PBAC predicted that approximately 34% of patients would respond to treatment, based on the results in the clinical trials. The current review found that based on the available clinical trials, between 8.6% and 40% (mean, 28%) of patients demonstrate a response or improvement in symptoms equivalent to a 2 point increase in MMSE. Current PBS utilisation data shows that approximately 60% of PBS patients are continued on treatment with CEIs or memantine beyond 6 months, approximately double the rate expected from the trials.
A higher rate of response or improvement in the PBS population relative to the trial populations is considered to be unlikely given the PBS population is older, have more co-morbidities and nearly one-third use concomitant medicines with sedative and anticholinergic effects. A more likely explanation for the higher continuation rate in the PBS population is that prescribers are continuing treatment in some patients in the absence of a 2 point improvement in MMSE. While this may not be clinically inappropriate use, it is highly unlikely to be cost effective use at the current price, given the case presented for cost effectiveness in the original submission.
In addition, the cost-effectiveness of subsidising these medicines at their current price for the 33% of people who continue treatment for more than three years and the 15-19% who initiate these medicines after admission to residential aged care, is also questionable. This is because previous models demonstrating the cost effectiveness of these medicines rely on the assumptions that continuation rates will be similar to those seen in clinical trials (less than 33% at 3 years), change in MMSE predicts change in quality of life, and that there are economic benefits due to delay to admission to residential aged care.
PBAC Consideration and Advice to the Minister for Health
PBAC was asked to consider the following five questions in its advice to the Minister:
1) Whether the current PBS restriction, in particular the continuation rule, should be revised to include an alternate assessment tool or be removed completely?
PBAC agreed with the advice of the Economic Sub-Committee (ESC) that the requirement to demonstrate clinical improvement based on MMSE in the restriction was ineffective in targeting the population in which use is most likely to be cost-effective, as originally intended by PBAC.
The PBAC recognised that the MMSE is useful as a screening tool in patients suffering dementia/AD; however, its reliability in measuring change in a patient’s condition over short time frames is poor. In addition, there is insufficient evidence that the MMSE tool is a valid surrogate for activities of daily living, quality of life, care giver time, admission to nursing home, or overall survival.
The PBAC therefore requested the Restrictions Working Group to review the restrictions and provide new options for the PBAC to consider. These should include potentially a simpler restriction for these medicines, without the requirement for patients to demonstrate an improvement in MMSE. An alternative continuation rule requiring a clinical assessment six months after commencing treatment is needed to ensure that patients who continue treatment beyond 6 months have a clinically meaningful response. The PBAC considered that there needs to be some reassessment at six months to promote continued use only in those patients who are experiencing benefit from taking these medicines. The PBAC also noted that such changes to the continuation rule could potentially increase the number of patients accessing these medicines. Therefore, there would need to be concurrent consideration of a price reduction for CEIs and memantine to ensure that the risk of use that is not cost effective is minimised.
PBAC Advice:
The PBAC agreed to consider possible changes to the restriction in 2013 for all four medicines with the view to: making the restrictions consistent; replacing the current requirement to use the MMSE or ADAS-Cog tools with a more appropriate clinical assessment of response to the medicines at six months; and consider the effect of any such restriction change on the cost effectiveness of these medicines following any agreed price reductions.
2) Whether the PBS restriction includes a stopping rule that includes a trial withdrawal from treatment within 6 months of entering a high level aged care facility?
The PBAC agreed that initiating a CEI or memantine in patients in residential aged care is unlikely to represent cost-effective use as originally assessed by PBAC, as previous economic modelling assumed cost offsets from delayed admission to an aged care facility. However, the PBAC did not agree that requiring a trial withdrawal of treatment for patients following admission to a high-needs aged care facility was workable or necessarily appropriate. Withdrawal from these medicines in some cases may be clinically inappropriate and place undue stress on patients, relatives and staff. However, cessation of treatment with these medicines should be encouraged whenever the patient’s condition is clearly deteriorating and this needs to be incorporated in the educational strategy proposed for question 5.
PBAC Advice:
PBAC does not recommend that the PBS restriction include a trial withdrawal from these medicines six months following admission to a high-needs aged care facility.
3) Whether a price reduction across all the drugs (donepezil, rivastigmine, galantamine and memantine) is required to compensate for the non-cost-effective proportion of PBS prescriptions supplied to patients continuing beyond six months; based on the differential between trial responder rates and the continuation rate in the PBS population?
PBAC agreed with the ESC and the DUSC advice that there is use of these medicines in a broader population than originally intended by the PBAC. The PBAC reaffirmed the view that the population-based, average benefits associated with these medicines were small and poorly supported by comparative trial evidence. The PBAC also considered that there was little to be gained by updated cost effectiveness models of these medicines in the absence of more conclusive clinical data on health outcomes. The previous economic models rely on the assumption that change in MMSE predicts change in quality of life or time to institutionalisation, but there is still insufficient evidence to link small changes in MMSE to patient relevant clinical outcomes. In addition, the economic models previously presented to PBAC were difficult to assess as many assumptions were implicit in the model, and implausible results occurred when the models were tested with revised assumptions.
The PBAC agreed with the ESC advice that the current use in those patients continuing treatment beyond six months is approximately double that considered likely to be cost-effective by PBAC in 2000. Therefore, the price of these medicines should be reduced to reflect this broader use. On the basis of current PBS utilisation and the ESC advice, PBAC agreed that a price reduction of approximately 40% on the current prices would be required to re-establish cost-effective use of these medicines.
PBAC Advice:
The PBAC recommends the Department seek a reduction of approximately 40% on the current price of these medicines when listed on the PBS.
4) Whether any of the four medicines in the review should be delisted from the PBS, and if so on what grounds?
The PBAC considered that the evidence on the clinical effectiveness and safety of these medicines is similar, and any differences are not sufficient to justify delisting or changing previous PBAC decisions, i.e. that these medicines should all be listed on a cost minimisation basis with each other.
PBAC Advice:
PBAC does not recommend delisting any of the CEIs or memantine.
5) Whether an educational strategy to improve clinician and consumer awareness of optimal and cost-effective prescribing of these medicine be developed with the NPS and organisations representing specialist prescribers, consumers and the pharmaceutical industry?
The PBAC agreed that an educational strategy should be developed to target prescribers in both general practice and specialist practice, along with consumers and staff involved with the care of people suffering from dementia. The education strategy should be delivered by the NPS and promote the findings of this review and any subsequent changes to the PBS restriction. The NPS should also work to engage the participation of professional organisations representing prescribers and allied health professionals involved in the care of patients with AD in this educational program.
PBAC Advice:
PBAC recommends the development of a professional educational program by the NPS aimed at prescribers and carers of patients with AD.
