Nick Karachalias PhD of Osprey Health Consulting says that the FDA’s lowering of the regulatory bar in granting conditional approval to Alzheimer’s drug aducanumab comes with many and far-reaching  dangers – but also creates opportunity for the best prepared pharma companies

The approval last month by the FDA of Biogen’s Alzheimer’s drug aducanumab has resulted in feverish coverage in the world’s media, from the enthusiastic and uncritical hailing of a new ‘miracle’ treatment by the more populist end of the press, to distinctly sceptical noises from commentators in trade and scientific journals.

With an estimated 30 million people living with this degenerative and currently uncurable condition around the world, news of a breakthrough medicine being approved for use must have seemed like the answer to their prayers.

Of course, no-one wants to dash their hopes by being a sceptic, but the level of evidence put forward to gain FDA approval was certainly not enough to convince the body’s advisory committee, which voted almost unanimously not to approve the treatment – a vote which was ultimately ignored when the final decision was made.

With other pharma companies now encouraged to bring forward their own products for approval – even where the level of evidence is equally incomplete – does this mean that the bar has been forever lowered when it comes to gaining market approval?  And what are the implications for those who are also developing similar therapies – have they already lost the race, or is there everything still to play for?

Policy evolution

This particular FDA decision may have raised eyebrows, but it is indicative of a shift in policy which has been occurring for some time.  Perhaps it is because of societal pressure to green-light new therapies in diseases where there is huge pent-up demand – as in Alzheimer’s – but this is not the first drug which has been approved with less than absolutely conclusive evidence.

In oncology in particular we have seen this kind of decision made over the past few years, as well as in other, more niche, disease areas such as muscular dystrophy (although a review of accelerated approvals in cancer in the last five years reveals that the use of a molecular response as a surrogate endpoint is far from common, having only been used in chronic myelogenous leukaemia).  There would appear to have been an explicit desire on the part of the FDA to take the same approach in neurology, with the body reportedly even bringing in its own oncology expert to help guide the decision-making process.

However, neurology is not oncology, and this is where the situation becomes significantly more sticky.  Cancer is a rapidly-developing disease where a drug’s ultimate efficacy becomes obvious very quickly: it either works or it doesn’t.

Alzheimer’s is a completely different proposition altogether.  This is a long-term, chronic condition with an enormous patient population.  It is also a condition which is best treated as early as possible, before even the degenerative symptoms start to show themselves.  It is for this reason that commentators have likened aducanumab to a vaccine – which is fine if you have concrete evidence that it works.  But we don’t.

And without that evidence, the approval of the drug implies putting a huge population on the therapy for a long-time – at an estimated cost per patient of more than $50,000 a year.  Without even being conclusively sure that it will eventually prevent or indeed cure the disease.

Blockbuster potential

There is no doubt that an effective drug for Alzheimer’s has the potential to be the biggest blockbuster drug in the history of pharma.  You don’t need to delve into the numbers in any detail to see that: if a third of the US’s 2.1 million sufferers were prescribed the drug, that would be worth around $40 billion dollars to Biogen.  Every year.

This, in the way of health economics, is money which would otherwise be spent elsewhere in the healthcare system, in all likelihood on treatments with proven efficacy – it’s not a precise zero sum game, but it’s not far off.

It will also prove an irresistible attraction for other players in the sector; if you do this for one drug, how do you turn down others with similar levels of inconclusive evidence?  The process has already started; Eli Lilly has already announced plans to file for accelerated approval for its own Alzheimer’s prospect donanemab later this year, despite downplaying the prospects of doing so as recently as May.

They certainly won’t be alone.  If you have a drug in development for Alzheimer’s, and you have data on amyloid, you will definitely be going back and looking at that data and asking yourself whether you can get approval on the back of the aducanumab decision.

Potentially the bar has been lowered to the extent that you don’t need conclusive data, just a notion that your product might work.  And as well as opening the regulatory flood gates, this decision has the potential for promoting bad science, either pursuing vague, inconclusive data, or continuing to invest in biochemical pathways with uncertain effectiveness to the detriment of other approaches.

Erosion of trust

Biogen has committed to undertaking confirmatory trials to measure the efficacy of aducanumab in the coming years.  In theory they have a full nine years to do this, that’s nine years of income against the drug, even if approval is eventually revoked should they prove inconclusive.

But worse than that, conducting those post-marketing studies is in itself problematic.  Given the acres of newsprint already devoted to this ‘new wonder drug’ how many patients are going to agree to take part in a randomised trial where they may receive a placebo?

Some have suggested conducting those confirmatory trials in regions not covered by the FDA’s approval, such as Europe, or else recruiting amongst Americans who do not have the insurance to access the drug.  Both routes lead to an ethical minefield; using people in other markets, or those who cannot afford access to the drug, for our experiments.

All of this risks eroding trust in pharmaceutical science, just as scientific scepticism is riding at an all-time high both in the shadow of Covid and on a mood of populism.  It’s notable that coverage in the consumer media has been full of hope and happiness about this ‘miracle cure’ for Alzheimer’s, while commentary in trade and scientific press has been considerably more cynical.

If that scepticism starts leaking into the consumer arena – at a time when pretty much all we have been talking about for 18 months is public health – then that erosion of trust could be very damaging.  Right now, it is in all our interests to be able to look at the FDA and the EMA as bastions of critical scientific rigour and transparency – and certainly not sacrificing that rigour and transparency in order to deliver what might be false hope.

But this is not what we see.  Instead, everyone is knocking at the regulator’s door with ‘breakthrough therapies’, and it’s difficult to see how they can say no.  As well as the trust issue, there are some fundamental practical problems with this.

The first, and most obvious, question is: how do we pay for this?  The potential cost is enormous; will insurers be willing to pay out for a treatment where the efficacy is uncertain at best?

And what of the healthcare systems?  Is there the capacity to do the diagnostic testing required to identify a suitable patient population for this new treatment? Is there enough space in infusion centres to accommodate all the new patients?

A crowded market

And in all of this, what does it mean for pharma more widely?  Just a short time ago this was a market which had nothing; now it has something; soon it will have lots of somethings.  For those one step behind, perhaps months away from even being able to bring forward a prospect for conditional approval, understanding this new regulatory environment will be critical.

And in a potentially crowded market, achieving differentiation is going to be very difficult, especially as no-one will have any conclusive endpoints.

For pharma marketers, then, there is a big issue on findings the right messages to be putting out there about your product.  Clarity about surrogate endpoints, a compelling reasons to believe, linking these endpoints to outcomes as closely as possible, and some thoughts about how to react to the financial conversation which this approval has ignited, will all be important.

Because with the regulatory bar lowered, this is going to be a competitive market, and one in which the key question – given the lack of conclusive evidence of efficacy – is how do you help the healthcare system to get people onto your drugs?  You need to be sure not only that you are coming in with a dataset that proves what you set out to prove, but also help healthcare systems create additional capacity and provide services that go beyond the drug itself.

The answer is likely to lie not in the conditional approval, but in those post-marketing confirmatory trials.  To gain competitive advantage will require fast, effective data gathering (which should be the case anyway if pharma is to fulfil its social and moral contract, but that’s an issue for another article!).

From a commercial point of view, it will not be the first to conditional approval which will be the ultimate winner.  Once someone has confirmatory data which shows that their product actually stops Alzheimer’s  – or at least its progression – then at that point it’s game over for everybody else who doesn’t have that evidence.

We need to accept that the bar has been lowered, and follow Biogen over it.  The real prize is the confirmatory data, so that is where pharma’s eyes need to be.

The wider question of whether regulation has been diluted by the aducanumab decision is however a real one, the implications of which are likely to rumble on.  Even if it at first glance reduces the burden of evidence gathering for pharma, if it causes an erosion in trust in medical science amongst the public, then no-one wins: not patients, not healthcare systems, and not pharma.  And that is the real worry.