During these last weeks of 2018, we have been digging deeply into the issue of market access for future market entrants in the field of Alzheimers’ Disease.   We always knew this to be a complex area, and indeed, we have not been disappointed on that front.  But we learned a lot and came to the following observations:

1. Failure is a massive driver for innovation

In the last decade, industry has had to live with significant development failures of promising compounds in AD.  While this is disappointing, these failures have advanced the scientific insights into the disease. 

They have also taught us a lot about the selection of target patient populations for research. The focus of research is shifting from symptomatic treatment in existing AD patients to modifying the disease progression in prodromal AD or even halting the onset in asymptomatic AD patients.  Biogen’s and Roche’s lead compounds, aducanumab and  gantenerumab have entered phase 3 clinical development and seem to confirm the anti-amyloid hypothesis as a way forward in early stages of the disease.

These developments don’t just take place at the therapeutic level, but go hand in hand with impressive developments in diagnostics: the identification and validation of biomarkers to measure the presence of AD in asymptomatic patients, and the development of crucial markers to measure (lack of) disease progression.   

2. ‘It will get worse before it gets better’

If the developments in early detection and treatment bear fruit, this could mean a major advance in the health of millions of persons who will either not get the disease, or can live better with fewer symptoms for a longer time.  This would be a spectacular result.  

But at the same time, the pool of existing patients with AD symptoms who need care will remain for many years to come.  The latter group, we know, represents a huge cost burden.  Not so much in terms of drug treatment, but in terms of health visits, (institutionalized) care, and indirect costs (e.g. caregiver).  As this group will continue to grow in the next decade, these costs will continue to rise.   

The costs associated with screening and treating early or asymptomatic AD patients – assuming products will reach the market – will add to the bill. Treatments and screening tools will not come cheaply.  It will take years before the economic pay-off in terms of longer functioning, lack of cognitive decline and less caregiver burden can be seen and the cost of treating existing AD patients will decline.  Therefore, the health budget expense for AD will get much worse before it gets better.  

3. ‘Don’t throw the baby with the bathwater’

Regulators and payers employ different standards to assess the worth of a new treatment for AD.  While EMA/FDA will look at clinical efficacy, HTA bodies will look at value under various guises: patient value, value for money, societal value, maybe also caregiver value, or a combination thereof. 

Assuming a product is able to jump the regulatory hurdle for patients with, say, prodromal AD, access to patients is by no means secured.  The HTA hurdle risks being even higher than the regulatory hurdle.   The uncertainties of long-term patient value are likely to remain immense, the selection of patients may be difficult to make, the long-term value will be difficult to model.    

With these hurdles, there is a genuine risk that products that have true promise will never reach the market and patients will remain deprived of a potential treatment that would help them.  The baby risks being thrown out with the bathwater.  

4. Outcomes and endpoints have to be created and jointly agreed

New outcomes measures will have to be developed and validated, especially in the asymptomatic and prodromal phases of AD.  Cognition is seen as the main outcome measure in asymptomatic or prodromal AD patients.  But how can we demonstrate that (no) change in cognition translates into better patient value, across a range of settings?  How can you demonstrate that a product works in a patient who tests positively for a AD marker but who has no symptoms?  How long do you have to study (lack of) progress to be able to measure effectiveness?  How can caregiver value be measured and how is it valued?

It becomes clear that HTA bodies, typically very wary of the use of surrogate endpoints in pivotal trials, will have to show some leniency on this front.  They will also need to live with the higher uncertainties in terms of the time horizon.   

The different actors in this process will have to find agreement on the selection of appropriate outcome measures, so that the developing companies can have security that their product can access the market if these endpoints are met.  

However, this process takes time.  There is a huge amount of background research being done in order to better understand the role and relevance of these outcomes.  Real world evidence has an important role to play here, to establish comparative effectiveness of new treatments, and to provide evidence of the effect of the disease on carers, resource use and disease progression.

The ROADMAP  collaborative initiative, representing academia, industry, patient and payer bodies has made an important step in this direction: its aims are to develop consensual key outcome measures for AD and enabling data integration tools for outcome classification, as well as guidelines on the handling and interpretation of RWE.  This distinguished group of experts recognizes it will be a long-term process.  

5. Time is not on our side

But products currently in late clinical development in AD will not be able to benefit yet from these research endeavors described in the ROADMAP initiative.  They will have to navigate without these tools.  The question will be: will HTA bodies accept their plans and live with more uncertainties?  Not sure.  

6. Affordability will be the next big thing 

Closely related to value is the very pressing issue of affordability.  Healthcare systems cannot afford to pay high prices for products that are used in large numbers of (asymptomatic) AD patients, especially as long as the long-term outcomes cannot be secured.   The objections they raise on outcome measures and the economic models could also be seen as a surrogate for their fear of a huge budget crisis coming up.

Industry will have to be aware of this and recognize these uncertainties. Innovative ways of pricing will have to be found and agreed.  Annuity payments, payment by results, adaptive pricing based on emerging evidence, all of these items, and more, should be considered and discussed.  Again, early discussions on this front will be crucial to dispel fears and manage expectations on all sides of the negotiating table.  

Conclusion: we’re all in it together

It is becoming clear that a solution to the worldwide epidemic that is Alzheimers’ Disease can only be found when all stakeholders work together and engage in constructive dialogue to get the right treatment to the right patient.  

In the short term, in the absence of solid evidence and guidelines on outcomes measures, this process can only work when every actor around the table genuinely understands and recognizes the position of the other: industry will have to carefully listen to regulators and payers’ fears and objections, but conversely, regulators and payers also have to fully recognize the difficulties facing industry in designing trials and gathering evidence.  

All sides will have to be prepared to relinquish some of their positions with regard to evidence requirements, outcomes, use of endpoints, pricing assumptions, the role of RWE, to come up with a workable solution.  Creativity, out-of-the box thinking will be key.  

But maybe most importantly, building mutual trust between industry and market access stakeholders will be the cornerstone of a successful industry and access policy in Alzheimers’ Disease.