AMR Awareness Week (Day 5): the lack of new antibiotics, and the dubious role of Big Pharma
Once again, we begin by quoting a section of the official blurb for AMR Awareness Week: “World Antimicrobial Awareness Week (WAAW) is a global campaign that is celebrated annually to improve awareness and understanding of AMR and encourage best practices among … all who play a critical role in reducing the further emergence and spread of AMR.”
And as we saw in yesterday’s blog, this critical role has to include the pharmaceutical industry. In particular this relates to the development of new antimicrobials to replace ones that are being made redundant by AMR.
By way of introduction to today’s blog, we start by quoting Dr. Unni Karunakara from 2012. He was then MSF’s International President and was making his keynote speech while accepting the William Fulbright Prize for International Understanding on behalf of the organisation. In the next paragraph he sums up this situation with the development of new drugs:
“The current system that we have to develop new drugs, diagnostics and vaccines, is driven by commercial rewards. A company develops a drug or diagnostic tool, receives a patent that allows the sale of the product at high prices, and the high prices in turn are expected to cover the costs of research and development, or R&D and generate substantial profit.”
As we will see, this system has a major flaw, at least in respect of antibiotic research because there has been a gap between the 'expectation' of profits covering ongoing R&D and reality. In every sense the system has been dominated only by expectation of higher and higher profits by the biggest drug companies.
Why new antibiotics are so important
(What follows is largely adapted from the book ‘Blowing in the Wind, Drug Resistant TB and the Poor’. It is not specific to TB nor to drug-resistant TB, and we will in fact discuss this particular pathogen in tomorrow’s blog. For now, we are focusing an antibiotic development and the lack of it).
Between 1945 and 1968, drug companies invented 13 new categories of antibiotics.
Between 1968 and today, just two new categories of antibiotics have appeared.
To be fair, this can partly be explained by the fact that fruits of antibiotic research that were easier to find (and safe) have already been found, and what’s left to find (and it’s a certainty that there still are antibiotics to be found) are much higher up the tree of research and development and so tougher to access. But this also reveals something else: that drug companies (in a period in which they commanded much lower profits than they do today) were much more actively researching new antibiotics, and in the more recent period when their profits have become enormous (Pfizer for instance have been forecast to double their annual revenue for next year compared to what it was in 2018).
As we’ve discussed previously in this series, antibiotic drug-resistance isn’t new: Alexander Fleming warned about it in 1945 so keeping up with antibiotic research has been vital for over 70 years. Brad Spellberg, head of a microbial resistance task force for the Infectious Diseases Society of America, explained this more recently: “What kept us out of trouble for the last 60 years is that every time drug resistance caught up to us, the pharmaceutical companies would go back to the drawing board and develop the next generation of drugs to keep us ahead of the game. That’s the part of the equation that’s changed. Drug companies are no longer trying to get one step ahead.”
So why hasn't research kept up?
Three reasons are trotted out as to why pharmaceutical companies have become so reticent on antibiotic research despite at least two decades of screaming alarms from the public health community.
The first is simply that there’s not much money in it (or at least not enough). The argument is given that, while a new antibiotic may bring in a billion dollars over its lifetime (isn't that enough?), a new drug for heart disease or cancer may net ten billion. For a business as profitable as Big Pharma, that has massive influence on policy-making regarding R&D strategy. Depression, anti-hypertensive and erectile dysfunction drugs — drugs typically taken daily for years, unlike antibiotics, which are used short-term — are typically seen to be much more profitable than antibiotics.
The second is that inventing and developing new antibiotics has become technically very challenging. This is unquestionably true, but it doesn’t excuse pharma companies from diverting some of their profits towards solving this problem.
The third is that those antibiotics that may be high up there in the tree hanging from those higher branches are quite possibly also much more dangerous with associated more side-effects which make both developers and regulators wary. This is also true. In fact, the FDA has been reluctant to approve new antibiotics at least since 2006 because of these safety concerns. “They’ve basically made it impossible for companies to develop and market antibiotics in the U.S.,” wrote David Schlaes on this topic (author of “Antibiotics: the Perfect Storm”).
As a result of these three factors, very few of the world’s 12 largest pharmaceutical companies are even researching new antibiotics currently - in fact most of the research that is being done appears to be being carried out by collaborative projects between two or more smaller companies and not by the big boys. In 2012, for example, Pfizer, the world’s biggest drug company (and currently probably the best known) closed its Connecticut antibiotics research center in the U.S. completely, laying off 1,200 workers in the process and announcing that it had moved its operation to Shanghai. But Pfizer struggled to open the Chinese facility and has apparently now abandoned antibiotic research in China completely, though it has established research centres in other fields of drug research in Shanghai, Wuhan and Beijing. (Pfizer’s official corporate policy position on AMR doesn’t include research into new antibiotics at all, incidentally, which is surely bizarre).
Here is a typical statement from the Infectious Diseases Society of America (IDSA) which sums up the problem:
“Resistance to the current library of antibacterial drugs is a serious problem in all parts of the world including the Asia-Pacific region, Latin America, Europe, and North America. Accordingly, the regulatory, financial, and scientific challenges/impediments to antibacterial drug development are a global problem.”
The complexities and paradoxes of these ‘Financial Impediments’ to antibiotic research
This financial challenge (or impediment, take your pick) was amplified in 2013 by Sally Davies, who was then the UK’s Chief Medical Officer. That year she made a premeditated media attempt to alert the G8 leaders to the problem, emotively describing the increasing resistance of gram-negative bacteria to existing drugs as a “ticking time bomb”, equivalent in scale of threat to that posed by global terrorism. She also promoted a solution - incentivisation. In separate press released to the BBC and to Reuters she was quoted:
“We haven't as a society globally incentivised making antibiotics," she said. "It's quite simple - if they make something to treat high blood pressure or diabetes and it works, we will use it on our patients everyday. Whereas antibiotics will only be used for a week or two when they're needed, and then they have a limited life span because of resistance developing anyway.” The key word here is ‘incentivise’, and it’s certainly an idea that has been picked up on successfully by the pharmaceutical industry itself. Three incentivising avenues have been regularly suggested: one is to increase public funding into one of the most profitable industries of our era; another is to lower the goal posts of approval; and the third (particularly if the second solution is adopted) is to share public liability with the pharmaceutical sector if things go wrong.
Given that the public should clearly be the beneficiaries of new antibiotics, the first solution certainly seems reasonable at face value – but only at face value.
Picking this story apart
The story has been spun that the long-relied upon blockbuster drugs like Lipitor have now come out of patent, and that it has been these drugs that have been keeping the sector financially healthy. With little new in the pipeline, with profitability apparently stagnating (!), and with a lack of new drugs, the sector (one of the three most profitable industries on the planet, no less) is thus jockeying for assistance.
Somehow not everything adds up. This is because, as a matter of tragic irony, in these same recent decades when the sector was most profitable it was simultaneously least focused on antibiotic research. In fact, given its focus on long-term drugs rather than these much-needed short-term ones for acute infections, the industry has come worryingly close to resembling the corner drug pusher who is intent on getting his punter on to addictive illegal class 'A' street drugs as fast as possible rather than supplying less addictive weekend highs.
What’s confusing is that the existing global antibiotic market is actually huge and what's more is currently forecast to grow annually by around 4.5%.
Furthermore, the argument that short term drugs are de facto unprofitable rings somewhat hollow given that the industry has the habit of dictating the prices of its new products as a result of patenting them anyway, and often doing so at exorbitant prices. What’s more, given that an AMR crisis is so regularly (according to all expert opinion) said to be impending, the ultimate demand for such new drugs is likely to actually be extensive if not massive. How, exactly, could a new antibiotic seriously not be profitable in such a scenario, given the probable demand for it?
But of course this industry does do exceptionally well off of a crisis, and may be prepared to wait for exactly because at that point its demands will suddenly carry much more weight with politicians and policy makers.
So with this in mind, here is a list of commercial dynamics that it is believed will incentivise interest by these huge multi-national companies (who exert so much control already over medical research because of their financial power) to better gear up their research into new antibiotics. Four categories of incentives have been proposed, termed respectively ‘push’, ‘pull’, ‘legoregulatory’ and ‘hybrid push-pull’.
‘Push’ intends to simply reduce the cost of R&D through public funding and tax incentives (which also, of course would have to be secondarily funded by the tax- payers to compensate for consequential lack of revenue). It’s worth identifying here that the UK tax system already grants 130% of qualifying expenditure as a legitimate tax deduction for R&D activities for large companies, the qualification criteria amounting to simply attempting "to advance science and technology" – in other words, tax breaks already exist, and they amount to a third more than the actual cost of the research).
‘Pull’ includes offering monetary prizes, advance market commitments etc. again funded by the public purse, although they could equally be funded by philanthopists or major NGOs. This is almost certainly the least attractive for the industry.
‘Lego-regulatory’ incentives include extending patent periods, granting licences based on evidence from smaller-than-usual clinical trials, and sharing or even totally divesting public liabilities if things go wrong. Once again, the public purse is anticipated to cover the costs of these higher risk research activities by covering any litigatory costs if things go wrong.
Finally ‘hybrid push-pull’ which includes product development partnerships with public bodies.
Do these ideas sound familiar? They may well do, because in various ways they have been used during the COVID pandemic (certainly both 'push' and 'lego-regulatory have been), and used with enormous financial benefit to a few pharma companies. When good old Joe and Joanna Public are in a fix, the automatic expectation now is that the budget to solve their problem is almost limitless and comes almost immediately from the public purse.
Paul Stoffels (who until recently was Chief Scientific Officer for Johnson and Johnson) suggested a further idea some years ago – this one being ‘incentivising-with-trade-offs’, including both tax reductions and fast-track scrutiny of other drugs going through regulation as a ‘reward’. Win-win for the companies concerned.
Overall, the idea that research into new antibiotics could and should be at least partly publicly funded has become a pillar of the conversation around this problem, and may even seem a reasonable solution but, with the help of the larger picture, it does ring somewhat hollow. The story may be being spun that major blockbuster drugs are now coming out of patent pipeline, and that it is these drugs that have kept the pharma industry so healthy and supported their R&D, but this doesn’t tell the whole story.
What’s more, it doesn’t really all add up anyway because in these same decades when things have been so hunky-dory for the pharma industry they have chosen to be least focused on looking forward at solving the lack of new antibiotics in the drug pipeline and so have healthily rewarded their shareholders and chosen not to look to the future (and they could definitely have done both). In other words, these solutions, as practical as they may appear to be, ultimately promise rewarding this industry for its neglect and look to be massively favourable for the industry which already has such power and commands such profits.
Furthermore, these proposed solutions ignore the fact that the public purse picks up the bill on two counts if these incentives are implemented: firstly by subsidising the development of the product, and secondly by paying for it in the act of purchase.
Does this sound familiar in relation to the pandemic? It may well do too.
There is really only one main reason why companies do not want to manufacture new antibiotics when it is undeniable that there is an urgent need: such profits as might emerge, what is known in the trade as a ‘sufficient return’ (and there certainly would be return) are not anticipated to be enough either to satisfy their dividend-hungry investors or their corporate greed. But these profits can, of course, be increased with some careful maneouvering.
They can, for instance, just as profitably bide their time and await the opportunities that a public health crisis provides when they can most effectively work with desperate politicians.
So here's the kicker...
Given what we have witnessed in the recent pandemic, with drug companies making massive profits off pre-delivery orders of semi-tested vaccines and drugs ('warp-speed' public investments made in research, followed by orders made in states of panic by politicians many of whom were themselves compromised by conflicts of interest relating to their own investments and connections with these same companies, and all paid for by the public purse), then the sorry fact is that this recent story actually de facto dis-incentivises drug companies from developing more research to free up this vital pipeline, and incentivises them to wait and see.
Currently there's much more potential profit for them from simply sitting it out until the next pandemic crisis when the financial pipeline might start to gush dollars whether it be monkeypox or avian flu. And meanwhile, they still will have the threat of AMR up their sleeve anyway.
So here's a question...
In the course of the negotiations with the big companies which have made such huge profits from the pandemic (the likes of Gilead, Pfizer, AZ, J&J, Moderna) couldn't a clause have been included which made the purchase of their products contingent on ramping up their research into new antibiotics and took some of the control away from the drug companies and restored it with the people?
We think that it could have. In fact, as much as the pandemic presented an opportunity to maximise profits by these drug companies, it also offered an opportunity for politicians and health authorities to constrain the greed of these companies, direct them towards research into what is, by all accounts, an impending crisis caused by their own neglect, and so recalibrate the balance of power which so obviously currently is so much in favour of the conglomerates.
If we recognise what happened and then shame (and expose) the politicians and the global authorities for their reluctance to have been so subservient to the interests of these multi-nationals, maybe lessons will have been learnt before the next crisis hits. If the next one is a drug-resistant pandemic then, frankly we're already in big trouble, but if it's something else then possibly this problem of a stultified antibiotic pipeline can still be addressed by including terms and conditions to the blank cheques before it's too late.
In the next blog we will address what is an existing smouldering anti-microbial resistant pandemic that is drug-resistant tuiberculosis.