Too Much Safety?


Making drugs safer might cost you your job – or even your life! The ethical paradox at the heart of declining pharmaceutical R&D investment

On the 1st February 2011, one of the largest and most successful global pharmaceutical companies, Pfizer, announced the closure of its Sandwich (Kent, UK) site, with the loss of the 2,400 jobs.

Some, such as John Gapper at the Financial Times, see this as another step on the road to the complete out-sourcing of drug discovery by the major pharmaceutical companies.   And even the most bullish industry commentators don’t see this as the last downsizing of R&D in the sector.

The trend to reducing big pharma R&D spend on “conventional” drug discovery seems inevitable.  The return on this investment is likely to be punishingly low (if you calculate it properly, it is the return seen 10 years from now set against today’s R&D expenses that you need to project, not today’s returns, based on R&D done a decade or more ago, on today’s investment).  But the bigger question has to be “why is this?”  Its easy to assume its because big pharma are not very good at early stage discovery, and that out-sourcing will lead to an efficiency gain – better pipelines at lower costs.

To a degree, it probably will do (that is, after all, what you get for out-sourcing many non-core activities – and discovering blockbusters is not the core competency of big pharma: their competencies are in marketing and in late stage clinical development).  But there is a much bigger factor in play here…

Society’s attitude to the risk:benefit trade-off in medicines has changed beyond all recognition in 20 years.  In fact, society’s attitude to risk in all its forms has changed in this period, with wide ranging and almost entirely negative consequences.   Whereas risk was once seen as part of life in every sphere, today the focus is on removing risk – whatever the cost of doing so.

Investment in new rail infrastructure following the Hatfield rail crash in October 2000 was just one high profile example of this trend: while any accident is regrettable (and much worse than that if you or your family happen to be involved), a response that involves spending millions to try and prevent a similar event ever from happening again can only driven by political expediency.  By any rational measure, the same investment could have saved many more lives had it been directed at almost any other project.

Sometimes the cost of reducing risk is more indirect, and therefore less obvious.  Laudable attempts to eliminate discrimination (whether on the grounds of race, gender or sexual orientation) from the Police force are a good example: the positive effects of the policy are easy enough to measure, but the cost (in terms of paperwork to be filled in to monitor behavior) are largely hidden.  How many less criminals are we prepared to catch in order to be certain that undesirable discrimination is almost entirely eliminated?

Sometimes this apparently sensible elimination of risk harms the very people it is designed to protect.  Half a century ago, county agricultural shows in the UK were a highlight of the calendar for the  working classes – a chance for a day out without breaking the family budget.  Today they are very different affairs: modern toilet facilities are provided,  while the whole event is heavily policed to ensure public order.  In short, the quality and safety of the event has been improved in every area.  But as a result the price has gone up until it is all but out of reach for the people who valued it as part of their community fabric.  No-one did more than the last Labour government to take away opportunity for the poorest in society simply by legislating to drive up standards.

One of the biggest problems with eliminating risk is the non-linear relationship between cost and benefit.  No matter what area of life you examine, as you approach ‘completely safe’, each tiny improvement in safety comes at an increasingly high price.  Squeezing out the last drops of risk costs exponentially more.

This risk reduction mantra has dominated the regulatory agenda for pharmaceuticals as well.   Regulatory authorities are on a crusade to reduce risk as far as humanly possible on behalf of a grateful populace.  And that is the dominant factor that makes investing in new medicines such a poor long term investment.

Who could question the objective of making medicines safer and safer (or, for that matter making railways safer or reducing police discriminatory behavior)?  We all should.  The consequence is that developing new medicines is becoming economically unsustainable.

Who will suffer?  You and me.  The drug companies will morph into something else, using their current cash cows to achieve that transition (and we see the first phases of these changes happening already: GSK, for example, are increasingly focused on over-the-counter products and vaccines rather than traditional patent-protected medicines).  But if the big drug companies withdraw from the front line of drug discovery, we are left with fewer new medicines.

Like the unintended consequences of government policies to drive up standards that disenfranchise those too poor to afford the resulting level of quality, in the same way reduced registrations of new drugs is an unintended consequence of demanding ever greater levels of safety.

Unfortunately, the cost of improving safety still further are largely hidden – it’s the loss of an otherwise beneficial drug from the development pipeline because the implications (in terms of money and time) of demonstrating safety to the current threshold required by the regulatory authorities simply makes continuing to invest in that product too risky.   The attrition rate during clinical development ratchets higher: both because drug candidates genuinely fail to meet the new standards of safety, but almost as often because the cost of demonstrating the required level of safety is simply prohibitive.  Increasingly, there are vast areas of medicine where the economic model for a product is now so unattractive, no-one even contemplates initiating a discovery or development process in that field.

This attrition then manifests itself in the falling returns on capital from big pharma and in the low rates of new approvals for genuinely first-in-class medicines.  If you demand “completely zero risk”, perfectly good medicines, with perfectly sound risk:benefit trade-offs start to get rejected by regulatory authorities and, before long, get killed by their owners at an early stage before they consume too much of the massive R&D costs of late stage development.

Of course, its easier for policy makers and commentators on the industry to blame falling approvals and falling returns on capital on the structural inefficiencies of research in a large company environment.  For outsiders, its simpler to assume the problem is that big pharma just are not good enough at drug discovery and development.  Its just too obvious that improving safety is a desirable goal, while the costs of the relentless pursuit of that objective are just too well hidden.

But if you want to understand why Pfizer took the decision they did, and why John Gapper at the FT predicted the decline in R&D at big pharma, you need to look at society’s attitude to risk and how this is reflected in the actions of regulatory agencies that are, in the end, public servants.  Without a sea change in how we approach drug regulation (and indeed much else in life) in the future, the current trend will be the tip of the iceberg.  As investment in new medicines bleeds away, many of those currently employed in the industry will find themselves looking for a career outside of healthcare, and many of those with incurable illnesses will lament the lack of progress.  Bizarre as it seems, demanding ever safer drugs really could cost you not only your job but also your life!

 

This blog post is by Dr David Grainger. David runs a research lab in the Department of Medicine, Cambridge UK, where this blog first appeared on his lab website, GraingerLab. He is also biotech entrepreneur and a principal at ATPBio.

Advertisements

One thought on “Too Much Safety?

  1. David – this is a really interesting post. One of the things I found when researching my book, Get to Market Now! (http://www.get2marketnow.com), was that regulatory health agency personnel (FDA, EMA, NICE, etc.) themselves are very conflicted about risk mitigation and product safety. And I believe this conflict reflects the broader industry and societal conflicts you’ve suggested.
    It’s easy to sit in a guidance document writing group and discourse on the benefits of using risk-based decision-making; it’s much more difficult when sitting in an advisory committee meeting, seeing the data, listening to questions & answers, watching the executives and scientists, and formulating an opinion. And at the end of the day, that’s what it often comes down to: personal opinions, philosophies, and the comfort levels of an individual when dealing with risk. What is the precise risk:benefit ratio? And does it change for pediatric medicine versus geriatric medicines?
    The problem, of course, is that we as a civilization have long passed the point of coming up with solutions or fixes or cures that have no or minuscule risks. But as recent psychology writers (Dan Ariely, for one) have pointed out, we haven’t really accepted that at a gut level.
    The problem, then, for companies and organizations, is to figure out how to build in basic risk-based decisions all along the new product development path, starting way back in preclincal. An easy enough thing to say.
    More difficult, as you allude to, is the “how” to do this without breaking the bank, or making the odds of a successful molecule come out of preclinical even worse than they are today. I’ll admit that as I put in the case studies and examples into my book, there were times that I wondered if the lessons from this particular case study or that particular case study were completely, 100% transferable to every single company out there.
    The big companies like the Pfizer’s, the GSK’s, the J&J’s, are going to find adapting to be very disruptive to their R&D pipelines. It’s not that it can’t be done – many other big companies in other industries have done it quite successfully – it’s simply that it’s a challenge that involves far more than science, speaking to organizational dynamics, company culture, and risk-taking comfort levels amongst the leadership, from the CEO to the floor supervisor.
    Years ago, one big Fortune 50 firm I worked with had an unwritten mantra taught to everyone with budgetary authority: you can do anything you like except mess with the product. In other words, feel free to change the edges, but don’t ever change the core business processes.
    What’s happening in the pharma world of the 21st century, is that in order to survive and thrive, some of the core processes have to change. And for some firms, that’s a hurdle too high…and too risky.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s