Biobullshit

As the philosopher Harry Frankfurt notes, in his classic essay 'On Bullshit', "one of the most salient features of our culture is that there is so much bullshit. Everyone knows this. Each of us contributes his share".

Frankfurt's exploration of bullshit is, he points out, not concerned with "the rhetorical uses and misuses" of the stuff. He is more concerned with exploring "the structure of its concept". I can't recommend his essay [available as a single volume] highly enough.

But in the meantime, scroll down the page for a very brief sketch of some of the rhetorical applications of bullshit that you'll come across regularly in the biotechnology/drug development business. People like me wade through this stuff so you don't have to.

novel compounds

A euphemism for me-too drugs, apart from those very rare novel compounds that are genuinely first in class.

me-too drugs
An impolite way of referring to novel compounds, apart from those very rare novel compounds that are genuinely first in class.

genuinely first in class
A very rare type of drug that is a novel compound but not a me-too drug.

positive trend toward efficacy
We didn't hit the endpoint, but the trial wasn't a complete bust - at least not for the purposes of this press release.

high placebo response
No, the drug really isn't as bad as that - it worked great in the lab.

industry-leading pipeline
Everyone's got one, so why shouldn't we?

partner of choice
We are so desperate for a deal that we'll jump through any combination of hoops to get one.

potentially synergistic
Maybe a combination of these two drugs will be more than the sum of its parts; then again, maybe it won't.

financial terms of the agreement were not disclosed
Some of the details are a tad embarrassing, and we'd like to keep our dignity intact.

emerging therapeutic paradigm [this is a newly emerging cliche]
Our CEO, who's a business major and generally likes to steer clear of the science, loves saying this at corporate presentations. It makes him sound authoritative.

newly emerging threat
Be afraid, be very afraid - and give us a generous dollop of research funding so we can have a closer look.

clinically proven
Someone, somewhere did some sort of trial on this and established something or other, so it's all scientific and above board. [particularly useful for people flogging cosmeceuticals & nutraceuticals]

cosmeceutical
a failed drug that you can add to skin cream

nutraceutical
a failed drug that you can add to baby formula or dairy products

QUB's Misleading PR

Top marks to the publicity department at Queen's University Belfast for getting broad TV & print coverage for their role in the development of a new cystic fibrosis drug, called ivacaftor or VX-770. It's the first disease-modifying therapy in cystic fibrosis, so it's an important development,even if only a small percentage of CF patients (those with the G551D or 'Celtic' mutation) will benefit.

But on reading the press release, you'd be forgiven for thinking that most, if not all, of the work emanated from Queens, whereas American science and American dollars actually made it happen. Queens played a lead role in some of the clinical trials of the drug, but to state that "An international research team led by Queen’s University have [sic] developed a ground breaking treatment for Cystic Fibrosis sufferers" is hugely misleading - particularly when Vertex Pharmaceuticals, the company that actually developed the drug (with the longterm collaboration of the US Cystic Fibrosis Foundation), is not even mentioned in the press release. I'm amazed that the clinical researchers involved can stand over this.

More here on ivacaftor and on other disease-modifying CF drugs in development.

Unanswered questions on Cork trial

(This originally appeared in the Irish Examiner, 4 Sept. 2010, but it has not been available online up to now.)

The most urgent question to arise out of last week's ill-fated clinical trial at the Shandon Clinic is why the drug, rimcazole, was given to twelve healthy volunteers when it was previously linked with at least one seizure. The journal Psychopharmacology published a paper in 1984 on a Canadian trial of the drug in sixteen patients, during which one participant suffered a grand-mal seizure, while another experienced what the report described as "an episode of loss of consciousness of unknown origin".

Modern Biosciences, a London-based drug development firm, was responsible for designing the trial, which the Irish Medicines Board (IMB) approved on 11 June and which the Shandon Clinic subsequently conducted in Cork. Modern Biosciences now states that the seizures which three of the twelve volunteers suffered last week occurred "at doses predicted to be safe". Assuming that they actually received the correct doses - and an IMB investigation into the study will need to confirm this - it is clear that the data on which Modern Biosciences based its predictions were inadequate, to put it mildly. Another key question is whether the effects seen were due to the expected actions of the drug - it acts via a protein called the sigma receptor - or due to some unknown 'off-target' activity.

It would not be the first time that the scientific assumptions underlying a clinical trial have been proven to be false. The notorious trial of the TeGenero drug TGN1412 in London in 2006, in which six volunteers suffered life-threatening immune reactions and, potentially, longterm damage to their immune systems, is the most blatant example. One of the most immediate and obvious lessons learned from that case was the need to stagger the administration of new drugs being tested in man for the first time. It is not yet clear whether - or to what extent - this precaution was followed in the rimcazole trial. As the drug, unlike TGN1412, has a history of previous clinical research, it may not have been considered necessary.

Burroughs Wellcome (now part of GlaxoSmithKline) had originally tested rimcazole as a potential treatment for schizophrenia, but it wasn't effective enough to gain approval. It recently gained a second lease of life as a potential cancer drug on the strength of research conducted by Barbara Spruce of Ninewells Hospital University of Dundee, in Scotland. She showed that rimcazole has an unusual quality, which makes it particularly promising in cancer. It selectively triggers a biological process called apoptosis - or programmed cell death - in tumor cells, while not interfering with that process in normal, healthy cells. Apoptosis is switched off in many different types of cancer, which allows the tumor to grow uncontrollably. Switching it back on is one of the key overarching goals of cancer drug development.

Modern Biosciences licensed the University of Dundee's patents in 2007. The company is led by two prominent figures in the UK's biotechnology industry. Its CEO, Sam Williams, was previously a stock analyst at Lehman Brothers. Its chairman, Clive Dix, previously led a vaccines firm called PowderMed, which Pfizer acquired in 2006, and is also a former chairman of the UK BioIndustry Association. The extent to which it is responsible for the problems seen in the rimcazole trial should be established by the IMB investigation. It not uncommon for small firms with limited cash to move drugs into clinical trials prematurely. Promising clinical trial data are a form of currency in the pharmaceutical sector, allowing companies to drum up interest from investors and large pharmaceutical firms.

But there are additional reasons why the rimcazole trial is unlikely to be the last that leads to unexpected drug reactions. No less an authority than the U.S. Food & Drug Administration has highlighted the failure of the applied science of drug development to keep pace with the rapid advance of basic biomedical research: "Not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs." Industry-wide efforts to address these issues are underway in both Europe and the U.S., but it will take some time for these to produce any useful results.

Meanwhile, the three volunteers who suffered the most severe reactions to rimcazole appear, thankfully, to have made a full recovery, and their future health will hopefully not be adversely affected by their experiences. But their experience illustrates yet again the risks clinical trial participants undertake when they sign up for studies that, by their very nature, have unpredictable outcomes.

There is an economic dimension underlying all of this. Indeed, a Shandon Clinic executive recently commented in this newspaper that the current recession had made the task of recruiting volunteers much easier. It's one of the pharmaceutical industry's most uncomfortable truths. Most new drugs need to be tested in healthy volunteers, before they can be tested in patients. But how many senior industry executives would like to see their own sons or daughters sign up for these trials ?

Another Alzheimer's Setback

The late-stage clinical trial failure of Eli Lilly's Alzheimer's drug semagacestat does not necessarily mean the end of the line for the 'amyloid hypothesis', which holds that the best way of tackling Alzheimer's is by blocking the formation of the beta amyloid plaques that are pathological hallmarks of the disease. There remain far too many unanswered questions, both about the trial itself and about the wider drug mechanism, for any definitive conclusions to be drawn at this point.

But this latest setback - it follows several other late-stage recent failures, including Flurizan (flurbiprofen; Myriad Genetics) Alzhemed (tramiprosate; Bellus Health) and Dimebon (latrepirdine; Pfizer/Medivation) - further ups the ante on two antibody development programmes that also target beta amyloid, bapineuzumab (Elan, Johnson & Johnson, Pfizer) and solaneuzumab (Lilly). The list of failures is growing, while success remains frustratingly elusive.

Semagacestat works by inhibiting gamma secretase, which is responsible for processing amyloid precursor protein into beta amyloid, the abnormal deposition of which is thought by many to play a key role in the development of Alzheimer's. Bristol-Myers Squibb is also developing a gamma secretase inhibitor, BMS-708163, which is undergoing phase 2 trials.

Data from these studies could help to answer some questions about the Lilly trial. It is unclear whether a class effect is at work or whether semagacestat itself is the problem. Clinical evidence in support of the compound was thin on the ground before it entered phase 3 trials. Lilly relied on biomarker evidence rather than any real indication that it actually worked in patients.

A year ago, one analyst told this writer that the trial wasn't expected to demonstrate efficacy, as the dose was too low. Safety was the main concern. That the drug actually proved toxic for patients bears out this suspicion.

Inhibiting gamma secretase can interfere with notch signalling, which is centrally involved in many cellular communication processes. The increased risk of skin cancer, which Lilly observed in patients receiving the drug, may be linked to disruptions in the notch pathway. One recent review of the topic (Panelos J. & Massi D., Cancer Biol. Ther., 8, 1986-1993, 2009) is baldly titled Emerging role of Notch signaling in epidermal differentiation and skin cancer.

The over-riding problem with nearly every late-stage Alzheimer's drug trial underway at present - certainly those that target beta amyloid formation and deposition - is that blocking beta amyloid formation and/or deposition may be too late for the mild-to-moderate patients who are usually recruited onto drug trials. The damage may already be done by the time they have been diagnosed.

Earlier recruitment - assisted by better biomarkers - could help. But the failure of semagacestat and other drugs shows that our biological understanding of the condition remains hugely incomplete.

Ireland Not Included In Merck Restructuring

No one's talking about it on the Irish media (from what I've heard at least) but I'm sure anyone in the vicinity of Wilton Place this afternoon must have heard some very audible sighs of relief coming from IDA Ireland executives - to say nothing of Merck/Schering-Plough employees in Clonmel, Carlow and in Brinny, County Cork.

Merck has detailed the R&D and manufacturing facilities it will close, following the Schering-Plough acquisition - and its Irish facilities appear to emerged unscathed from the shake-up. That's a major achievement for the local management(s) here. Research facilities in the US, Canada, Denmark, Germany and Scotland are affected; so too are manufacturing sites in Italy, Portugal, Mexico, Brazil, Singapore and the US.

300 ≠ 87

The pharmaceutical industry's great giveaway to the people of Ireland is not quite as generous as it has successfully managed to spin.

Although the Irish Pharmaceutical Healthcare Association (IPHA) claims to have cut the cost of 300 drugs by 40 per cent, the lobby group has displayed all the cunning of a sheep farmer on the Cooley peninsula applying for EU headage grants. There's a lot of double- and even triple-counting going on.

The IPHA's list of products included in the initiative contains multiple entries, denoting different dosages. It also contains different versions of the same drug made by different manufacturers.

In reality, there are, according to my tally, only 87 unique drugs on the list. And as they're all off-patent anyway, they should have been available at rock-bottom prices before now in any case.

The real test of the industry's 'generosity' will be the level of discount it will apply to some of its biggest moneyspinners, which are coming off patent in the next couple of years.

Extraordinary Measures, Extraordinary Story

Biotech gets the Hollywood treatment in Extraordinary Measures, a forthcoming film about a father who doesn't take on the pharmaceutical/medical establishment in order to find a cure for his kids - he becomes part of it. The man in question is John Crowley, CEO of Amicus Therapeutics , whom I met last February while on a study tour of the greater Philadelphia area. More on Crowley's and his family's extraordinary story in Technology Ireland's March/April 2009 issue -it's a rather large, clunky file but go to page 17 for the story.

Plenty of 'smarts' in programme for government

Fianna Fail's and the Green Party's recently revised programme for government is liberally sprinkled with references to the smart economy.

It will, the document confidently asserts, take us to a smart new world, in which we will be smart and work smart - at sustainable jobs supported by smart capital. We will travel to these jobs by a process called smart commuting. This may involve cycling. We will live in smart homes, whose [low] energy consumption will be measured by smart metres (sic). Some people may even be lucky enough (or smart enough) to live in a 'smart town'.

In all, the words 'smart' or 'smarter' appear in the 43-page document 27 times.

Our world will be just so smart, we won't really need stupid old science any more, apart from a couple of settings:-

"We will support Teagasc in enhancing its scientific capacity to enable it to foster science-based innovation on farms and in firms."

"Through sustainable management based on scientific advice, we will work to rebuild fish stocks and maintain the quota fished annually by the Irish Fleet."

That's all folks - those are the sole references to science in the entire document. To be fair, it contains numerous references to research and technology. By why are they so afraid of one 's-word'? And so addicted to another?

Stepping away from a civic science

It's hard to know whether pity, derision or even mild annoyance is the most appropriate response to Tanaiste Mary Coughlan's recent gaffe, when she confused Albert Einstein with Charles Darwin.

Anyone can make a slip of the tongue - presuming that that is indeed what occurred. One strongly suspects, however, that the minister responsible for our science-powered drive to economic utopia, otherwise known as the smart economy, isn't overly acquainted with the work of either scientist. At an individual level that hardly matters. At a societal level, it matters greatly - as Chris Mooney & Sheril Kirshenbaum argue in the snappily titled 'Unscientific America'.

Their work represents a plea to include science in America's common culture. Back in 2003, Mary Harney delivered a similar message, when she occupied the post that Coughlan does now. It is arguably the most interesting speech on science & technology ever made by an Irish politician. (Which isn't saying an awful lot - they're usually pretty dreary.)

In 'Towards a Civic Science: A Mission for the 21st Century', an address to the Royal Irish Academy, Harney called for the creation of a 'civic science', that is, "a science engaged with and invited into the national dialogue"; one that is "responsive to the public and worthy of the public trust"; and one that is "embraced and valued by students, educators, industry and communities and, yes, the government".

It's early days yet, of course. But it's safe to say that that particular mission has yet to be accomplished.

No Irish at iGEM

Now that Ireland finally has a large-scale effort in systems biology underway, maybe it's time to establish a small-scale effort in building genetically engineered machines.

The MIT-hosted International Genetically Engineered Machine competition (iGEM) for students is now in its seventh year - the final jamboree kicks off at Cambridge, Mass., on 30 Oct. However, an Irish team has yet to pull on the green jersey and splice some DNA for the nation - or, ahem, fiddle about with biobrick components for the nation.

Synthetic biology - is it lego for genetic engineers or biology's final frontier? Who knows? But the competition is one good way to get undergraduate students thinking along interdisciplinary lines, as their professors would have it; or thinking along biological hacker lines, as they would have it. Which is, of course, a whole other can of worms.

Science in Europe: siloed and silenced

Europe's efforts to build a knowledge-based society are doomed because of its inability to embrace innovation. Instead, according to Brussels-based scientific public affairs consultant David Zaruk, we are building an "influence-based society", in which policy is determined not by scientific considerations but by "eco-religious fundamentalists".

Zaruk sets out his stall in an extensive and stimulating interview with EuroActiv. He sees the European Commission's silo-based approach to policy as part of the problem - while DG Research is actively promoting scientific research, DG Sanco is actively hampering it through an overly zealous embrace of the precautionary principle.

Speaking at the World Conference of Science Journalists in London back in July, the UK's chief scientific adviser John Beddington was also critical of the absence of a scientific input into the European Union's policy-making process. The European Commission has scientific committees that speak when they are spoken to, he says. But neither the president of the Commission nor any individual commissioners has an independent scientific adviser. "We see real problems there," says Beddington.

But the problem extends beyond Brussels. Ireland and the UK are, he says, the only EU member states with a chief scientific adviser. The contrast between the EU and the USA couldn't be stronger. Barack Obama's administration is packed with heavy hitters, such as Steven Chu, Steve Koonin, Harold Varmus and John Holdren. Where - or, heaven help us, who - are their European counterparts?

What's another year - of declining interest in science?

Science and technology are only guaranteed prominence on the news agenda during two weeks of the year. One is in January, when the BT Young Scientist Exhibition helps to fill the news vacuum created by the post-Christmas lull.

The other is in August, when the leaving certificate exam results become available, and employers' lobby groups like IBEC , ICT Ireland and The American Chamber of Commerce in Ireland line up to complain - or, in lobbyist speak, 'express serious concern' - about Irish students' declining interest in science and maths. It's a wholly predictable annual ritual.

The proposed solutions to this perceived problem include overhauling teaching, establishing incentives - for both science teachers and science students - and improving the 'image' of science-based careers. Interestingly, none of the concerned employers seems to feel the need to work on improving the actual substance of the careers they offer [economic circs permitting].

Better teaching - of any subject - is always a good thing, so if genuine improvements in science education can be made, let's have them. Giving students accurate and useful careers information can only be a good thing too. But pandering to disinterested second-level students and then shoehorning them into unsuitable university courses will not work. Arguably, we're already doing this to an extent.

Of course, the phenomenon is by no means unique to Ireland. It's on the OECD radar as well. But one voice seems to be entirely absent from this debate - that of the students themselves. Why are they opting out of science? Are they wilfully turning their backs on lucrative, rewarding careers? Or do they simply see more attractive options elsewhere?