Pharma Bashing

Ben Goldacre writes the Bad Science column for the Guardian newspaper in the U.K. and mostly he writes about pseudo-science because, as he puts it, “pulling apart bad science is the best teaching gimmick I know for explaining how good science works”. He has just put out a book called Bad Pharma, putting the foreword on his blog, an excerpt appeared in the Guardian and he put up a video of a TED talk he gave. So he is getting it out there.

The book, as a brief summary, takes the pharmaceutical industry to task for its clinical trial practices, wherein it skews the trials to favor their candidate, hides the results of unfavorable trials, covering up side effects and persuading doctors to prescribe their drug once it comes to market with misleading data published in industry sponsored journals. The game is rigged in favor of the big companies who then rake in the enormous profits.

Some people dispute this claim and John LaMattina put up his own take on the book and its contents.

So before my comments, my disclaimer. I suppose I am one involved in the pharmaceutical industry , though I have never worked for one directly, working for a industry contractor on research projects for several years, but these days I am more an interested observer, as I am at a non-profit research institute. I am also not by any means an expert on how clinical trials are run, exactly how things get approved for use or indeed very much at all about the ins and outs of the process. But I have a general idea.

Now the pharmaceutical industry have not done themselves any favors here. They have done all the things that Dr. Goldacre accuses them of, but the blanket statement that the whole industry is out to trick doctors and patients into taking their drugs is extreme to say the least. Pharmaceuticals in various forms have improved the lives of millions of people, saved them from death. Drug candidates are carefully vetted for efficacy and safety – more and more these days as there are so many treatments already available. Clinical trials are not just run against placebo but for approval, drugs need to show an improvement over a standard treatment. In short, that the system is occasionally circumvented does not mean the system does not fundamentally work.

If you look at it from the pharmaceutical company’s view, you can see why these sorts of things happen. Projects begin because there is a medical need for a treatment – essentially a gap in the market. So scientists work to come up with something that will meet that need. But the process of working that out is long and difficult and so many things can go wrong along the way. Worse still, the further along the path you get the more expensive the next step. A phase I failure is a disappointment for sure but it is a minor inconvenience compared with a late stage Phase III failure. Drug development is a high risk venture and there is no pay-off without a final marketable product. So at a certain point, the aim becomes the finish line of FDA approval. Anything that can lower the obstacles in the way would seem like an obvious route to take. Far from the drug companies preying upon the vulnerable and pushing through drugs that should not be, they suffer some dramatic failures – ask anyone in the Alzheimer’s field. Indeed if the system is set up to favor the drug companies, why is there so much talk of the barren drug pipelines and lack of new drug approvals? Pharmaceuticals have always been a high risk high pay-off investment but the risk seems to have risen and the prospect of a big pay-off seems to be receding.

Interestingly, as I was writing this (and re-writing it – curse that wordpress log-off), I came across Matt Herper’s post on Glaxo’s greater clinical trial transparency. This shows two things to me: firstly, that the pharmaceutical industry is aware of its image problem and are prepared to do something to counteract that perception. But also, that there are the problems talked about by Dr. Goldacre, with prominent doctors paid to talk up a new drug from GSK or pushing unapproved uses. That they are taking steps to reassure the general public can only be a good thing.

Quick addition: Ben Goldacre posted his response to GSK’s proposal and he voices some doubts about whether they will actually go through with it.

Local Guy Makes Good

Despite my stance as a Nobel curmudgeon, I will still stand up and salute a local scientist who did OK. Dr. Robert Lefkowitz of Duke Medical Center and Howard Hughes Medical Institute picked up the Nobel prize in chemistry today, along with Stanford’s Brian Kobilka for their work on G Protein-Coupled Receptors (GPCRs), an area of immense importance in the drug development area and also one that intersects with my own current work.

Congratulations to both men.

The Value of a Chemistry PhD

There has been a number of articles wondering if there are too many or not enough people studying science in general and chemistry in particular. Last week it was Daniel Lametti’s Slate piece, saying basically that unemployment among PhDs is much less than the general populace so we shouldn’t worry about them. ChemJobber did a very nice job rebutting that article but I wanted to add a little to what he said.

Chemistry unemployment is at a high level, with many jobs eliminated from the U.S. to go overseas or maybe just eliminated by the “synergy” created by the latest merger. But more than that, the type of jobs that are available has changed. A lot of chemistry folks have gotten out of chemistry, either out of need or disillusionment. I myself considered options beyond the laboratory when I was let go. After some soul-searching, I decided that I most wanted to stay in the lab and sought out a position, but the range of jobs of that type out there was very low indeed. The typical job in synthetic chemistry or medicinal chemistry is either a contract or, if you are lucky, with a small start-up or a more academic drug discovery effort (such as the Broad Institute in Boston or the Vanderbilt Center for Neuroscience). While good jobs, these are typically either short-term, lower paid or dependent on grant funding (in other words, could also be short term). Permanent medicinal chemistry jobs such as were the typical destination of a semi-decent Ph.D. synthetic chemist are now in very short supply and are savagely competitive, with many hundreds of applicants.

So to to get back to the title of this post, what is it worth to be a chemistry Ph.D.? If I wanted to be rich, I would have done something else; I did chemistry because of its challenges but also because I was interested and relatively good at it. I also followed it because it seemed like it was a degree that led to a career, rather than a qualification that would then need further training to start on the career path. So that latter consideration might cause me not to advise a young student of science to go into chemistry – the career path is much murkier now than it was when I started. And the advice I got around that time was lacking in many respects: what would set me on a true course toward a steady career? Getting a degree in a good school for a well-known professor was the basic advice (and the professor mattered more than the school). I think that remains true to this day, though it is more treacherous than it was then.

But still, things can change and today’s nadir could be tomorrow’s zenith. Labor differences between China and the US are narrowing, the US economy does at least appear to be recovering, albeit slowly. There will still be a need for new medicines. There is some kind of future for the pharmaceutical industry even if we don’t know exactly what that will look like. So if you were passionate about the subject, if it was something that you really wanted to do, then I would tell you to pursue that dream. I haven’t regretted it. But if you are looking at it as an easy way to a career, then it might bear some serious thought, because that easy path is no longer so straightforward. Pure research is a narrowing market, though if you are interested in chemical engineering, a talented engineer is still in demand (as seen by their consistently higher average salaries). Plus, further down the drug development track there is room, in drug formulation for example, but this rapidly becomes more clinical studies rather than medicinal chemistry. Something beyond benchwork is also a possibility – law or teaching or scientific writing for example. Some of those can be pursued without a PhD, though teaching, for example, can be easier to get into if you have a higher qualification, partly due to a lack of teachers in some subjects and science tends to be one of those.

I have had periods where I have questioned the value of doing a Ph.D., where we collectively wondered how easy it would be to erase that part of our life from our resume and take on the life of an associate. It is hard to separate all the things that have happened to you such that you could remove one facet and still remain the same person. But I have enjoyed the challenges of becoming a Ph.D., it gave me opportunities I never would have had otherwise. If I was to do it all over again, I might do it a little differently, apply myself a little more to some things, but as youth is wasted on the young, maturity can’t be granted retroactively. So I’d do it all over again, but if it were someone else, I would make sure they knew what they were getting into.

Professor Harran Arraigned

As reported by C&E News (with further commentary from the ever-present ChemJobber), Professor Patrick Harran was arraigned in LA court yesterday, on 3 felony charges of labor code violations. The next court date is October 9th, when a preliminary hearing will be held and the court will decide if there is enough evidence to go to a full trial. The court entered a plea of not guilty on behalf of the defendant, whose legal team had objected to the arraignment even occurring.

That it has got this far is amazing to me. I fully expected some sort of deal would be made, but it appears that all chances of that have ended, with offers from the DA office being rescinded. Perhaps they will work something out. Perhaps they are banking on the testimony of the investigator being thrown out. That seems likes a very risky strategy to me. I agree with CJ, I never thought this would actually go to trial, but as it stands, it is a judge’s decision away from doing exactly that.

Shaking off the Jet Lag

There was (if you didn’t notice) a little lapse in the usual sporadic pace of blogging, as I was away on summer vacation. We visited the city of San Francisco, California and did lots of very touristy things and had an excellent time.

The blog I probably would have written over my absence would have been about the Sheri Sangji case, but some sterling work by ChemBark, ChemJobber and, especially, Jyllian Kemsley (surely that should be Chemsley?) covered all bases and I have little to add to their words. Thanks, guys.

I mention my trip to California in particular as when we got back to home to North Carolina, there was the inevitable jet lag. I don’t know if it is just getting older, but the time changes seem to be harder to get over than there used to be. Even the one hour shift to daylight saving time from standard time knocks me off kilter for a few days. As it happened the transition to Pacific time was a breeze – effectively you sleep in and we tended to be heading to bed early anyway after a busy day wandering around and looking at stuff (as the fig allows, at least!). But back home, suddenly it is get up really early and go to bed really early. Even after the weekend, I was still wide awake at 1 in the morning, wondering how I was going to make it into work at a reasonable hour. Some dragging was involved.

It seemed to us that we were in a loop, we couldn’t get up as early as usual, so we would not feel sleepy enough at bed-time and stay up too late and have trouble getting up next day. So to break the cycle, my wife suggested a single dose of melatonin to get us back on schedule.

The over-the-counter medicine was a low dose (and pleasantly orange flavored too) but it really did do the trick of making me feel sleepy ahead of midnight. Which meant I could get up earlier, get back into the routine.

So what is this miracle? Well, it is a neurotransmitter made in the pineal gland which is involved in our normal sleep-wake cycle. Typically, levels rise through the evening and fall in the morning. It is affected by the light (and contributes to seasonal disorders when you live somewhere that gets dark early in the winter). That is a reason not to turn full lights on when you wake up in the night (or even at bed time) because you don’t want the melatonin levels to drop before you are back in bed and snoozing.

Interestingly, a study was done of the use of melatonin on sleep disorders and it concluded “There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.”

I definitely felt a sleepiness when I had my little pill. Was it the placebo effect? I’ll add that I went to bed early but read in bed for a while. That usually has a soporific effect unrelated to the quality of the reading material. So the idea of acting upon the problem got the circadian rhythm back on course? Just allowed us to break the cycle? That would seem to be the case.

Just as well, as school starts again next week – and that involves an even earlier start!

Perils of the Garden: the Common Fig

After my earlier post on the perils of poison ivy in the winter, here is a slightly less fraught tale of garden chemical hazards. Listing the most common complaints of the outdoors in summer in North Carolina, the fig would be low on most lists. Mosquitoes, snakes, spiders, the heat, the rampant weeds, all of these would rank ahead. But after doing some work in the garden last week, I came back inside and found my eye sore to the touch. I figured the culprit to be one of those all too common weeds, but my horticulturist wife saw it differently (and she knows her poison ivy!). Because among the work I had been doing out there was the arduous task of sampling the fruits of our splendid fig tree. When she pointed this out, I recalled taking the fruit and some white sap running down my fingers. All it took from there was for me to wipe at my eye, for fig sap is a known irritant.

Fortunately, it is relatively mild and some aloe and a day or two and all was well. No doctor visit for steroids required. But I was curious about the irritant in fig sap so I did a little digging.

One thing I found was about the photoactive ingredients of the sap, psoralen and bergapten, present in the sap but not the fruit.

These compounds increase your sensitivity to light and have been used as tanning activators, though that comes with a higher risk for skin cancer. Seems like a rough trade-off.

In addition to those furocoumarins, there are also some triterpenoids. A paper on PubMed talks about them. They note that “calotropenyl acetate, methyl maslinate and lupeol acetate showed potent and persistent irritant effects”. Just to show how complex this gets, lupeol is listed as an anti-inflammatory.

Though it just affected the membranes around my eyes, it can get much worse if you are allergic or sensitive to the sap or of course if you work with it. Such complaints are common among pickers and handlers. Fig latex (i.e. the milky sap) has been used in medicinal preparations for skin complaints and was also an ingredient in a household detergent in central America until too many complaints of reactions led to its withdrawal.

It just goes to show it is hard to know where you might be safe out in the garden. Best to run back inside, wash your hands and enjoys the figs.

Orexin Antagonist Helps Merck Get Some Sleep

Blogging time has been sparse and I am only now catching up on a post I started last week. But it is about an area I am interested in, so I will continue regardless of the point that it is not quite so timely as it was when I started typing.

I think it is fair to say that Merck have had a rough time of late what with Vioxx and other assorted adventures. I’d wager that some of their management are having a little trouble getting their 8 hours a night. So it was probably comforting to hear the news about their insomnia drug currently in clinical trials (piece here on Bloomberg).

Suvorexant is the drug, which works a little differently to the already established Ambien, which is a GABA agonist. GABA agonists work by putting you to sleep, whereas suvorexant is an orexin receptor antagonist, which works by counteracting wakefulness. In principle, this should lead to less side effects and a better mental state (less drowsiness) next day. Ambien also has problems of drug tolerance, dependence and other adverse CNS side effects. And indeed, suvorexant has met the Phase III study goals and should be in the final phase of getting approved. Though the field of sleep aids is rather crowded, this one might just have an edge in overall tolerance and less side effects.

It is not all plain sailing. The other player in the Orexin field is GSK. They co-developed a compound called almorexant from Swiss company Actelion and that failed in its clinical trial. They have another compound in phase II, SB-649,868, so they have not given up on it yet. More worrying is that almorexant was abandoned because of its side effect profile, which seems counter-intuitive to what everyone is saying about suvorexant.

It Shipped Today!

I ordered a chemical a couple of weeks ago. It was fairly obscure and I was happy to get it for a reasonable price and from a company I trust too. Order placed, I got back on with other things.

A week or so later, I started wondering where it had gotten to. I don’t recall any back-order notifications. Other chemicals our group had ordered at the same time had arrived. Plus it was not the highest priority, so I merely shrugged and assumed that it was on its way. Any day now.

With a full 3 weeks elapsed since time of order, I finally get on the phone to our purchasing department. The lady there looks into it and I get the call back. It just shipped! I got it the very next day.

Now call me cynical if you will, but I never believe the line that “we just the minute got your order ready and we’re just putting it on the truck”. I mean, it could happen, but it just seems so unlikely that exactly on the day 21 days (not 20 days and not 22 days) after we placed our order, on the very day we call and ask, that they just this minute got it in the box for shipping. How uncanny that as you were pouring in the packing peanuts, the phone rang. That is quite the coincidence. It is like you were reading my thoughts that I must have broadcast telepathically. Astounding. Are you sure you didn’t just forget to send it?

Well, at least they did send it eventually.

Defining Cannabimimetic

Following up my previous post, I went into the proposed legislation and found the relevant section, which I reproduce here:

SEC. 1152. ADDITION OF SYNTHETIC DRUGS TO SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT.

(a) Cannabimimetic Agents- Schedule I, as set forth in section 202(c) of the Controlled Substances Act (21 U.S.C. 812(c)) is amended by adding at the end the following:

‘(d)(1) Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents, or which contains their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation.

‘(2) In paragraph (1):

‘(A) The term ‘cannabimimetic agents’ means any substance that is a cannabinoid receptor type 1 (CB1 receptor) agonist as demonstrated by binding studies and functional assays within any of the following structural classes:

‘(i) 2-(3-hydroxycyclohexyl)phenol with substitution at the 5-position of the phenolic ring by alkyl or alkenyl, whether or not substituted on the cyclohexyl ring to any extent.

‘(ii) 3-(1-naphthoyl)indole or 3-(1-naphthylmethane)indole by substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent, whether or not substituted on the naphthoyl or naphthyl ring to any extent.

‘(iii) 3-(1-naphthoyl)pyrrole by substitution at the nitrogen atom of the pyrrole ring, whether or not further substituted in the pyrrole ring to any extent, whether or not substituted on the naphthoyl ring to any extent.

‘(iv) 1-(1-naphthylmethylene)indene by substitution of the 3-position of the indene ring, whether or not further substituted in the indene ring to any extent, whether or not substituted on the naphthyl ring to any extent.

‘(v) 3-phenylacetylindole or 3-benzoylindole by substitution at the nitrogen atom of the indole ring, whether or not further substituted in the indole ring to any extent, whether or not substituted on the phenyl ring to any extent.

‘(B) Such term includes–

‘(i) 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (CP-47,497);

‘(ii) 5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (cannabicyclohexanol or CP-47,497 C8-homolog);

‘(iii) 1-pentyl-3-(1-naphthoyl)indole (JWH-018 and AM678);

‘(iv) 1-butyl-3-(1-naphthoyl)indole (JWH-073);

‘(v) 1-hexyl-3-(1-naphthoyl)indole (JWH-019);

‘(vi) 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200);

‘(vii) 1-pentyl-3-(2-methoxyphenylacetyl)indole (JWH-250);

‘(viii) 1-pentyl-3-[1-(4-methoxynaphthoyl)]indole (JWH-081);

‘(ix) 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122);

‘(x) 1-pentyl-3-(4-chloro-1-naphthoyl)indole (JWH-398);

‘(xi) 1-(5-fluoropentyl)-3-(1-naphthoyl)indole (AM2201);

‘(xii) 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole (AM694);

‘(xiii) 1-pentyl-3-[(4-methoxy)-benzoyl]indole (SR-19 and RCS-4);

‘(xiv) 1-cyclohexylethyl-3-(2-methoxyphenylacetyl)indole (SR-18 and RCS-8); and

‘(xv) 1-pentyl-3-(2-chlorophenylacetyl)indole (JWH-203).’.

(b) Other Drugs- Schedule I of section 202(c) of the Controlled Substances Act (21 U.S.C. 812(c)) is amended in subsection (c) by adding at the end the following:

‘(18) 4-methylmethcathinone (Mephedrone).

‘(19) 3,4-methylenedioxypyrovalerone (MDPV).

‘(20) 2-(2,5-Dimethoxy-4-ethylphenyl)ethanamine (2C-E).

‘(21) 2-(2,5-Dimethoxy-4-methylphenyl)ethanamine (2C-D).

‘(22) 2-(4-Chloro-2,5-dimethoxyphenyl)ethanamine (2C-C).

‘(23) 2-(4-Iodo-2,5-dimethoxyphenyl)ethanamine (2C-I).

‘(24) 2-[4-(Ethylthio)-2,5-dimethoxyphenyl]ethanamine (2C-T-2).

‘(25) 2-[4-(Isopropylthio)-2,5-dimethoxyphenyl]ethanamine (2C-T-4).

‘(26) 2-(2,5-Dimethoxyphenyl)ethanamine (2C-H).

‘(27) 2-(2,5-Dimethoxy-4-nitro-phenyl)ethanamine (2C-N).

‘(28) 2-(2,5-Dimethoxy-4-(n)-propylphenyl)ethanamine (2C-P).’.

SEC. 1153. TEMPORARY SCHEDULING TO AVOID IMMINENT HAZARDS TO PUBLIC SAFETY EXPANSION.

Section 201(h)(2) of the Controlled Substances Act (21 U.S.C. 811(h)(2)) is amended–

(1) by striking ‘one year’ and inserting ‘2 years’; and

(2) by striking ‘six months’ and inserting ‘1 year’.

My first impression is that it reads like a patent. That is likely the best angle to take on this, something broad enough to cover what might be made but narrow enough to avoid over-reaching and impinging upon unrelated research work.


It looks like they covered the basic structural motifs seen in CP-47,497 (along with some related compounds like HU-243) and JWH-018, along with some related JWH indoles. I was glad to see that they were quite careful with the wording on the indoles, so that clear derivatives of the CB agonists would be covered but not necessarily all indole chemistry. They included the pyrroles and indenes but no specific examples of those, which I thought a weakness of the statement. The broad number of examples in the indoles leads me to think they are basing it on examples found in incense and bath salt products. I will also applaud the inclusion of a specific phrase that includes the measured biological activity (in binding and functional assays), which is to me at least the most defining feature of a CB agonist.