An Egotistical Diatribe
One of the most impressive results of sharing thoughts on the internet the speed of insight – it doesn’t take long for two and two to bump together neatly. Last year, some bright sods noticed that I’d changed my by-line in my Chemistry World column. When once it said “Paul Docherty is a medicinal chemist based in London, UK”, it now reads “Paul Docherty is a science writer and blogger based in London, UK”. With my Facebook, Linked-In and Google+ accounts reflecting the change in more detail, it’s not surprising that most interested parties quickly realised that I’d ditched Pharma, and I think I should probably explain why
A bit of history…
At the beginning of 2007, a start-up (which was actually almost ten years old) called Arrow Therapeutics was purchased by AstraZeneca, the Anglo-Swedish BigPharma multinational. Arrow’s focus was on anti-infectives, primarily anti-virals, complementing AZ’s purchase of Cambridge AntiBody and US-based biologics giant, Medimmune. Arrow was definitely pocket-money in comparison to Medimmune, but still a significant purchase. Not long after the purchase, Arrow went-a-recruiting, and, amazingly, took on me along with another young chemist. I must say, it was a bit weird that many of the staff ‘knew’ me through these pages before I’d even interviewed, but the process was mercifully short in comparison to some of the multi-round affairs that many BigPharmas operate.
Less than three years later, things at AZ weren’t looking too hot [1, 2, 3 – I shan’t blame the messenger, Derek!]. The AZ Strategic Review was announced – but I have to say that I felt confident that they wouldn’t drop Arrow, as we’d bested all targets and delivered some tasty compounds. Also, buying a company and then selling them on three years later just looks dumb. But I was concerned about my career. Lay-offs were certain, adding to the pool of qualified and experienced medicinal chemists looking for work in the UK, especially after GSK had more-or-less closed their Harlow site. No-one else in pharma seemed to be recruiting, and certainly not at the team-leader level, which is where I wanted to be. Looking around, I really couldn’t see this happening for years – and frankly, that wasn’t what I signed up for. Having a job is great, but a career is what I wanted.
Come Christmas 2009…
… and my feeling of malaise about the Pharma industry reached breaking-point. Surfing the usual recruitment website – as one does just to see who’s hiring – had shown bugger-all in med-chem for months. So I decided to try again – career 2.0 – and applied to work alongside friends from my undergraduate days, in a different industry. And that’s where you’ll find me now – Project Leader with AkzoNobel in Global R&D. It’s not pharma, and I don’t wear a labcoat very often these days – I’ve got a team and a robot for that – but thinking like a chemist is still extremely important. The door to pharma isn’t closed for me, but I’m happy to sit the carnage out. Perhaps I’ll reconsider in a decade or so, but I’m enjoying my job and career with AkzoNobel too much to care for now.
So, Total Synthesis? Some might think that I’m now too far away to still be interested – but it’s no different to working in med chem. Sure, I did some pretty interesting reactions, but a lot of it was the Suzuki and amide bashing it’s thought to be. Total synthesis – for good and bad – is another world entirely. One that I still find fascinating and that keeps my brain (as an organic chemist) firmly in the fume-hood (HSE aside).
Well, we can still count on Big Pharma to make the wrong move. Yep, AZ decided to ‘divest Arrow Therapeutics as a Going Concern‘. In other words, they were shifting the company and hoping not to look too bad about it. I was still there for part of the ‘divestment efforts’ (whilst my move to AkzoNobel was going on in the background), and it was frankly torturous. AZ couldn’t decided which parts of Arrow’s IP were to move with Arrow, or remain with AZ. Months of shuffling paperwork ensued, and even though there were many interested parties, the doors closed on New Year’s eve for good. Bastards. Many of my former collegues have found employment; other are working their entrepreneurial arses-off, looking towards new horizons. And as these are some of the smartest people I’ve had the pleasure to meet, I’m sure it’ll work out well.
What did I learn?
I guess no-one reading this would disagree with me in my feeling that Pharma is on a serious down-turn just now. The reasons for this are multiple, but for me it all comes down to accountability.
In every R&D sector, projects & programmes move from early ‘I wonder what happens when…‘ science, through to identifying a commercial basis for a period of development to finally launching a product or service. What makes Pharma stand out to me is the length of that process – it’s quite routine these days for time-frame from idea to pill to be ten to fifteen years. So who is accountable for the NCE development over that timespan? Normally, there’ll be a Biological team, who try to develop some sort of assay that can be used for in vitro testing, giving the chemists those IC50s (or similar). Once there’s some sort of robust efficacy test, it’s time to do a bit of screening (perhaps a few million small molecules, or ten-thousand fragments) to give the Lead Identification team something to work with. After those chemists have played with the results for a bit, it’s off to the Lead Optimisation team, whose goal is to refine the structure into a Candidate Drug. If that looks good, and doesn’t kill too many things that go squeak, the Development and Formulation teams take what was a chemical sample into a drug, through the familiar Pre-Clinical and Clinical trials, FDA sign-off and $$$.
The point is, the project is passed from team-to-team over many years, each of which accepts the project from the previous team in a different state. Of course, there’s also an Exec-team (perhaps a Review Board) who are following the progress, and analysing results to determine which projects get to pass through the stage-gates and onto the next step in development. Sounds great, but there are some pretty large elephants in the room at this point. Firstly, none of these Execs is hanging around for fifteen years – five sounds a lot more reasonable. So it’s not too surprising that when a new project comes in from biologists and LI team, it looks all shiny and amazing. Perhaps three years later, it gets passed to the LO team, and by now some of that shine has worn-off, “…but it’s still viable, right? Sure, there are probably some other players in the field by now, but we’re going to be better and faster, right?” So the LI team does it’s job, and gets us 100g or so of something pretty decent. Fluorine atoms hanging-off it in random places, morpholine groups, benzimidazoles and quinolines have been tacked-on, “…but it’s got a great IC90. Who cares if the mice died? The dog didn’t…” So it’s off to the pre-clinical team, and it now looks like Rival A and Rival B have options that are both better and further ahead. But “We’ll push this through, after-all, we don’t have anything else to take it’s place…” And maybe it makes it to the end, and gets launched, but only in a few markets, and it’s neither first nor best in class. More donkey-derby runner-up than prize-winning thorough bred. But who can be held accountable? There won’t be anyone left on the Review Board who remembers the project in Lead Identification. Ten-fifteen years is simply too long for any person or group to be responsible.
And it’s not like these Review Boards are effective anyway. Helping lame-duck projects through the stage-gates is all too common – “after all, we need to keep the number of CDs, Phase I and Phase II candidates up, right“? Most of the review meetings are exercises in Group Think, as no-one wants to be the person to kill a project that might have legs. And they don’t care if it all goes wrong, because they’ll be in a new job, at another company, long before the chickens come home.
It’s a number game
That actually touches on one of the more ridiculous aspects of Big Pharma – setting Targets for R&D teams. It’s fairly common for Med-Chem teams to have a quota of CD’s that they should produce every 1/2 years. But it’s nonsense, as there’s no way to quantify the quality of those results – so any old shit can get shiny’d-up so that it’ll pass the Stage Gate, even though most of the people involved know that’s not quite there. And this attitude gets all the way through to candidates entering Phase III trials that aren’t anywhere near ready. Remember Torcetrapib? Surely someone knew that this wasn’t a winner – at least before Pfizer spent all of that $1B + on it’s development. And this is why I think attrition rates keep increasing.
Of course, the Execs running the show aren’t idiots – there are a lot of very smart and sharp people in those boardrooms. But the problem is again numbers. How do you quantify quality? After all, if the quality can be kept high, and the quantity can be worked on, then Board’s on to a winner. This is more-or-less the idea behind the (Lean)6-Sigma, and AstraZeneca tried to apply it to varying degrees of success. The problem is, how does one define or quantify the quality of a candidate? Guidelines, such as Lipinski’s
rules, can be used to judge the ‘crazyness’ of an idea, but can also limit the creativity of the medicinal chemist. But do they really help, or do they mean that most LO sets are average compounds, with average properties? I know a fair bit about 6Sigma – I’m hopefully going to get my Green Belt this week, and train for a Black Belt next month. But it applies really well to our R&D processes, unlike those of Pharma.
However, if there’s one thing worse that spending a billion on developing on a few tonnes of solid organic waste, it’s being sold a lemon. In particular, paying way too much in M&A (mergers and acquisitions) – reading an article about M&A failure is a history of big Pharma over the last few decades. Just look at Pfizer’s stock over the last ten years – it’s halved in that time from over $40 to $18.15 today. Buying-a-Biological-company was a trend that I think all small-molecule chemists watched with some concern, as some of those pipelines looked a little light for the price. Looking back, it’s now clear that there was a degree of desperation to fill product pipelines with something potentially generic resistant, and perhaps to keep-up with the Jones’…
Everyone in Pharma is well aware of the fact that there’s no such thing as a ‘Silver Bullet’ – a drug or therapy that has no side-effects and targets the source of disease infallibly. But for some reason, the management teams seem to think that the process of drug discover can have it’s own silver bullets – new ideas or approaches that will magically solve the pipeline problems and save them from the patent cliff. There was combinatorial chemistry in the 1980’s, diversity-oriented synthesis in the 2000’s along with fragment-based drug-discovery, in-silico and virtual screening…
All are fantastic ideas, and have their relative merits, but for some reason Big Pharma leaps upon these ideas and chucks the baby out with with bathwater. Surely the appropriate way to introduce a new technology or ideology is to adopt it portion-wise, rather than jumping in with both feet?
So, Pharma Quo Vadis?
I’m a long way from being the first person to voice these opinions, but seeing some of these issues first-hand was both enlightening and traumatising. So how does Pharma fix itself? I’ve no idea – but from my point of view, these can’t hurt:
ContentQuality is king – but relying on a spreadsheet to tell you where the good stuff lies will always result in an average compound. And an average compound is never going to be best or first in class.
- You can’t buy a pipeline – the overheads in M&A and the loss of productivity will always sabotage the ‘synergies’ that were desired.
- Separating the compound design chemists from the synthetic chemists isn’t a great idea – you need time for ideas to evolve, and running another column is good time to do that. Plus, it really doesn’t inspire high morale in the split =-team.
- Make sure the project Review Board are actually reviewing something. Endless pre-meetings and pre-pre-meetings will only reduce the opportunity for a worthwhile decision making process. And make sure the board are packing collective balls.
That’s it. It certainly made me feel better. But my opinion is neither broad nor particularly deep – so let me know what you think!