Research Article: What is the impact of regulatory guidance and expiry of drug patents on dementia drug prescriptions in England? A trend analysis in the Clinical Practice Research Datalink

Date Published: May 29, 2018

Publisher: BioMed Central

Author(s): Venexia M. Walker, Neil M. Davies, Patrick G. Kehoe, Richard M. Martin.


Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016.

We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer’s disease, receiving their first prescription for each drug class—namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-d-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest.

The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, − 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, − 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister’s Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials.

Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively.

The online version of this article (10.1186/s13195-018-0379-6) contains supplementary material, which is available to authorized users.

Partial Text

There are currently four licensed treatments that provide symptomatic relief for patients with Alzheimer’s disease in England—three acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and one N-methyl-d-aspartate (NMDA) receptor antagonist (memantine). These drugs are collectively referred to as drugs for dementia in the British National Formulary, despite their licensing for Alzheimer’s disease only [1]. Since the first of these drugs became available in 1997, there have been several changes in national guidelines for the treatment of Alzheimer’s disease, as well as several initiatives to encourage better diagnosis and treatment of the disease. Despite this, there has been little research into whether such changes to guidelines and initiatives have directly influenced clinical practice [2, 3]. We examined how prescription rates in England have changed since the launch of these drugs up to 1st January 2016, using data from the U.K. Clinical Practice Research Datalink (CPRD). We investigated how prescribing was affected by changes in National Institute for Health and Care Excellence (NICE) guidance (including the 2006 guidance that was subject to legal challenges), the addition of dementia to the Quality and Outcomes Framework (QOF), the introduction of ambitious government dementia strategies, and the expiry of drug patents. The timing of each of these changes, which may have influenced aspects of drug prescribing and clinical practice, is discussed further below and summarized in Table 1.Table 1Events prior to 1st January 2016 that potentially affected prescription ratesEvent dateEventMay 1997Donepezil first recorded in CPRDSeptember 1998Rivastigmine first recorded in CPRDJanuary 2001Galantamine first recorded in CPRD and first NICE guidance releasedDecember 2002Memantine first recorded in CPRDNovember 2006NICE recommended restricting drug accessSeptember 2007QOF revised to include dementiaFebruary 2009First National Dementia Strategy launchedMarch 2011NICE removed recommendation restricting drug accessJanuary 2012Galantamine patent expiredFebruary 2012Donepezil patent expiredMay 2012Prime Minister’s Dementia Challenge launchedJuly 2012Rivastigmine patent expiredApril 2014Memantine patent expiredFebruary 2015Prime Minister’s Challenge on Dementia 2020 launchedCPRD Clinical Practice Research Datalink, NICE National Institute for Health and Care Excellence, QOF Quality and Outcomes Framework

The first trend change for the proportion of patients with probable Alzheimer’s disease receiving their first prescription for an AChE inhibitor occurred in October 2012 (95% CI, September 2011 to April 2013, p = 0.816). At this time, a long-term steadily increasing trend became a very strong increasing trend. This surge could be related to two factors. Firstly, the patents expired on the three drugs in this class in 2012—galantamine in January 2012, donepezil in February 2012 and rivastigmine in July 2012. Secondly, the Prime Minister’s Dementia Challenge launched in May 2012. It is likely that the reduction in cost of these drugs, which resulted from their patents expiring, in combination with increased awareness of dementia due to the Prime Minister’s Dementia Challenge, led to this substantial change in prescription rates we observed. In addition to these factors, a large amount of literature concerning AChE inhibitors had been published ahead of the revisions to the NICE guidance in 2011. Although this is unlikely to have caused the sharp surge that we observed, it could have contributed to the long-term steadily increasing trend observed prior to this change. A systematic review which covers the literature through November 2014 (i.e., after all join points identified in our analysis but 13 months before the end of our study) summarizes the literature available at that time [33]. It shows that several studies published between 2003 and 2008 suggested that patients with mild to moderate Alzheimer’s disease could benefit from AChE inhibitors with estimated ‘improvements on the order of 1.5 MMSE (30-point scale)’. We therefore cannot rule out a potential effect of the literature on prescribing, even though the authors of the review questioned whether such an improvement was clinically meaningful when all the evidence was presented together. Further to the support from the literature, the Google Trends data for news searches in England also suggested increased awareness around the time of this trend change. The interest for the search term ‘Alzheimer’s disease’ was at its maximum in September 2012 (based on the data available from January 2008 to December 2015, inclusive), which could indicate interest among the public.

Analysis of both drug classes indicates that inclusion of dementia in QOF had no effect on prescribing trends and the other factors had mixed effects. NICE guidance on the prescribing of drugs for dementia aligned with trend changes for NMDA receptor antagonists but not AChE inhibitors. The guidance that had the noticeable effect was released in March 2011 and allowed the NMDA receptor antagonist memantine to be used outside of clinical trials. All other guidance for both this drug and AChE inhibitors, including that which recommended restricting access, did not align with trend changes. Government dementia strategies also appear to have had mixed results, with the Prime Minister’s Dementia Challenge (launched May 2012) being the only strategy to align with a trend change. Although this strategy is likely to have increased awareness of dementia around the time of the October 2012 trend change for AChE inhibitors, we believe that the more likely cause of this change is the patent expiry of the drugs in this class. This will have reduced the cost of these drugs and potentially led to a surge in prescribing, such as that observed in our trend analysis. The events considered here highlight the many factors that may have influenced prescribing rates and the challenges in assessing the impact of a given event. Overall it would seem that the proportion of patients receiving prescriptions increased over the period studied, regardless of changing guidelines and other initiatives. Furthermore, given the increase in diagnoses of dementia and, more specifically, Alzheimer’s disease reported in the CPRD (Fig. 1), the absolute number of prescriptions has increased considerably over the period studied.




Leave a Reply

Your email address will not be published.