What are the difficulties of implementing innovative pharmacy practice models in the care of patients with dementia?

KEYWORDS:

• Analytic Hierarchy process (AHP)
• cancer
• Multi-Criteria Decision Analysis (MCDA)
• preference
• reimbursement

Although Alzheimer´s Disease (AD) and other dementias cause devastating conditions for those affected and their families, and although more than 50 million people globally are suffering of AD and other dementias [1], and although the societal costs are enormous – more than one trillion US$/year globally [1], and although there are now hopes that disease modifying treatments (DMT) for AD may enter the market, there are nevertheless concerns whether such treatments will be available for the majority of the AD-patients [2]. Why is it so?

1. Treatment failures

Yet no innovative pharmaceutical treatments such as DMT are approved. So far, most DMT-AD trials have failed [3,4]. Still, there are many compounds in pipeline [5]. For the moment (September 2020). Biogen´s drug aducanumab is under consideration by FDA for approval in the US [6], and BAN2401 [7] is another compound in a phase 3 trial. The mode of action theory for these two compounds is based on the amyloid hypothesis as the cause for AD [8,9]. There are also compounds in pipeline that target tau for treatment of AD [10]. However, even if these DMTs will show enough statistic significant efficacy for approval, there have been concerns by analysts about their effect size and clinical meaningfulness [11,12].

2. Infrastructure for an early diagnosis

If a DMT will be approved and available, it will be of great importance that treatment start early, that is in a predementia state since the underlying pathological process in the brain has been ongoing for many years when symptoms appear [8]. However, to diagnose early AD, that is in the state of mild cognitive impairment due to AD (or even earlier?), is complicated. Since the potential target population for DMT will be large, there will be a great stress on the diagnostic infrastructure (primary care and specialists) to handle the expected demand for an early AD diagnosis. Studies from RAND Corporation [13,14] have shown that the capacity for early AD diagnostic work-up is insufficient in the US and in Europe. There are now hopes that blood markers can be of use as first level filters [15,16], that is to select people at risk for AD, but how this will work on a large scale is unclear.

Even with blood markers, or other first level filters such as cognitive tests adapted for early symptoms, the well-known interaction between prevalence and predictive values must be considered. Even with a sensitivity of 95% and specificity of 90% (which is very optimistic on a large scale) and with a prevalence of about 8% (a reasonable figure in a general elderly population) the positive predictive value will be only about 44% [17], indicating a great risk of false positive cases. After this first step diagnostic process (a screening phase), the burden on the specialist clinics will be great to confirm or reject a suspected early AD. It is also important that the label of ‘positive’ cases is ‘at risk’ and not ‘early AD’ or similar, to avoid stigmatizing a person as having early AD. Even later on in the diagnostic process (with better but more expensive and sometimes invasive biomarker diagnostic tools such as CSF, PET scan, etc.), there will be uncertainties (also great capacity problems and still, but less, problems with the predictive values) that will make the whole diagnostic process problematic if a DMT would be available.

3. Infrastructure for treatment

The most promising compounds that for the moment may enter the market will not be available as pills. There will be a need for resource demanding infusions or injections with associated needs for staff and safety monitoring, which be added to the burden on the specialist clinics for diagnostics and clinical follow-ups.

4. Expected costs of DMT

Although there is no price set for a DMT, since no such drug is yet on the market, a DMT will not be a cheap treatment, particularly in comparison with the available, but symptomatic drugs, with expired patents. Who will pay for it? There will be high costs in the beginning (for diagnostics and the DMT) during a period (years) where the costs even without treatment of early AD are rather low. Potential benefits will occur later (many years) in terms of reduced need of long-term care and less need of informal care [18]. Another great challenge, and a consequence of the increased number of people with AD and other dementias, are the rising costs of long-term care. Even if it can be assumed that a DMT for AD in the future (years-decades) will result in a decrease in long-term care costs, the aggregated and immediate budget effects of costs of long-term care and new and costly DMTs will be great.

5. Budget silo effects

There will also be budget silo effects. The payers for this early DMT will in most countries in some way be linked to the medical-health sector (more or less reimbursed), while the cost savings many years later to a great extent will occur in the social care sector (less nursing home care etc.). In high income countries, there are systems for reimbursement, but how this situation will be handled due to the complexity mentioned above (time, budget silo effects) is unclear. Most people with AD worldwide also live in low-and-middle income countries [1], where resources for early diagnostics and reimbursement for any drug treatment are limited (or non-existing).

6. Time

Linked to the discussion of the disease modifying effect is the issue of time. Randomized controlled trials (RCTs) last for a period of months – some years, while the period with untreated AD (from predementia AD, such as MCI due to AD) to the end stage in severe dementia is many years-decades. How do we know these expensive drugs have meaningful effects in the long run? How do we know they are cost-effective in the long run? We cannot, for practical, economic, and ethical reasons, conduct RCTs lasting for decades. One method is to focus on surrogate outcomes, indicating that a reduction in, for example, beta amyloid in the brain, will result in a reduction in long-term effects. Another way is to use registry data in phase 4 trials to see what happens in terms of, for example, institutionalization or survival. Such studies are always more or less biased by selection effects. A third method is to make economic simulations. Pharmacoeconomic modeling has been frequently used for the current symptomatic drugs for AD and for hypothetical effects by hypothetical DMTs [19]. Any economic model is dependent on its inputs and assumptions, and models are often questioned for being biased by commercial interests. However, to catch the potential long-term and life-time effects, economic models are necessary and even unavoidable [20]. The key issue in models is transparency. In several conferences and workshops under the umbrella of International Pharmaco-Economic Collaboration on Alzheimer’s Disease (IPECAD) [21], the methodological aspects of modeling have been one of the main issues.

7. Cheaper alternatives

How to convince payers and regulators that these drugs are better than the much cheaper and currently available symptomatic drugs (acetylcholineesterase inhibitors (AChEIs) and memantine)? The magic bullet here is the label ‘disease modifying,’ indicating the treatment really has an impact on the underlying pathologic process in AD (neuronal damage and neuronal death). Notable is that ‘disease modifying’ does not assume a ‘curing’ effect (a complete stop or reverse of the pathologic process), it ‘modifies’ (or halts) it to some extent, in contrast to the current symptomatic drugs, which have effects mainly on transmitters in the brain, but not on neuronal damage/death. However, it has been suggested that also AChEIs may have some disease modifying effects in AD [22], and there may be gray areas between the concepts of ‘symptomatic’ and ‘disease modifying.’ If DMTs and symptomatic drugs are rather similar in short-term efficacy, how do we (patients, clinicians, decision-makers, payers) value the added values of the much more expensive DMTs?

8. Prevention?

Why not focus on prevention instead of DMTs? Experiences from many observational studies [23], and from randomized prevention projects [24], and particularly the FINGER project [25] indicate that there are modifiable risk factors for dementia including AD. The actions that can modify the risk for dementia (such as treating hypertension, more physical activity, stop smoking) are already embedded in the health system and thus not cost driving. The observed trend of a decrease in dementia prevalence in high income countries [26] may in fact be a result of already ongoing prevention actions.

9. Ways forward

Although there are great expected challenges if DMTs will enter the market for the treatment of AD [27], there are ways forward. There is, for example, no contradiction between new treatments such as DMT, and current drugs and prevention. On the contrary, and based on the experiences from treatment of tuberculosis, HIV, diabetes, cancer and many other conditions [28], a cocktail of treatments such as current drugs (AChEIs and memantine), and amyloid DMTs (if approved), and tau DMTs (if approved) and prevention can be the way forward.

Furthermore, alternative ways of valuing and pricing expensive treatments and regulatory actions after approval, such as conditional approval, can also enhance the probability for new innovative drug treatments to enter the market [29,30] but still, the societal willingness to pay is the crucial issue.

Declaration of interest

Outside this article, the author has received grants from MSD, consultant fees from Biogen, European Union: grants for several projects, WHO: honoraria for WHO´s GDO project. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.