Richard Lehman’s journal review—9 January 2017

richard_lehmanNEJM 5 Jan 2017 Vol 376
The trials of big pharma
As a fan of Ben Goldacre’s Bad Pharma and Peter Gøtzsche’s Deadly Medicines and Organised Crime, I was not expecting to think highly of a piece called “The Large Pharmaceutical Company Perspective” in the NEJM series called “The Changing Face of Clinical Trials.” It is written by Mike Rosenblatt, for many years the chief medical officer at Merck. It is a very compelling account of the difficulties and risks of developing two preventive drugs: a rotavirus vaccine and a bisphosphonate to treat osteoporosis. Large trials, he says, can now cost up to a billion dollars without any certainty of return. He identifies the chief enemy as complexity and lists a large number of factors.

He is certainly a very able Mephistopheles, but he hasn’t completely persuaded me to feel sorry for the fallen angels lurking in the shadows behind him. Why are they still wearing those tails and horns? For sure, I think pharmaceutical companies do have to invest a lot in the development and initial testing of their compounds. But what is the real level of financial risk for them in relation to their total profitability? In both the cited cases, there were precursor products from other manufacturers and the chances of huge sales were actually rather good. I don’t know what the eventual profits for these products were as compared with (a) the cost per child saved from rotavirus in relation to total health spend in low income countries or (b) the actual number of postmenopausal women who had an important symptomatic fracture prevented by alendronate. But I don’t think we need feel it has been an altogether altruistic exercise. As for complexity, I think that a lot of it is brought on by big pharma’s own habit of designing large trials with a mind to marketing as much as science.

JAMA  3 Jan 2017  Vol 317
How similar is biosimilar?
A few weeks ago I claimed that the easiest way to become a billionaire was to find a plausible cancer target, make an antibody to it, add the suffix uzumab, and then sell it to desperate cancer patients at $10 000 per notional added week of life. It is amazing how all these drugs end up costing about the same. The market solution to this should be competition from other people making similar antibodies. Myuzumab should bring down the cost of Youruzumab. In your dreamumabs, I hear you say. And yet it might be starting to happen for some antibodies that are running out of patent. One such is trastuzumab, used with chemotherapy for the treatment of HER2-positive breast cancer, which we now have to call ERBB2 positive. Somebody has now produced an as yet unnamed antibody to ERBB2 (anonymouzumab?) and compared it with trastuzumab in patients co-treated with taxane for their metastatic breast cancer. It looks like a good thing: it is certainly as effective as trastuzumab and may be better. Let’s hope it’s 10 times cheaper.

Not so often with zoledronic acid
In Mike Rosenblatt’s article, he refers to the long processes of dose finding that preceded the phase 3 placebo-controlled trials of alendronate for osteoporosis. Zoledronic acid is a far more powerful bisphosphonate. For the treatment of postmenopausal osteoporosis, 5mg given intravenously can put the osteoclasts out of action for a year. For metastatic cancer eating away at bone, however, the situation is less clear. Much higher doses are used, calculated according to body weight and renal function. Traditionally, the drug is given every four weeks, but here’s a trial that compared this with giving it every 12 weeks to patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma. Over two years, the less frequent dosing worked equally well.

Lancet  7 Jan 2017  Vol 389
Dementia and busy roads
Last week I referred to the village of Residual Confounding, and this week it’s the turn of the high road. Is living near a busy road associated with a higher risk of developing dementia? Yes. It says so here, in the Lancet. Do road traffic emissions cause dementia? Dunno. It’s plausible. On the other hand, it could be the dearth of town sparrows in high traffic environments and the absence of the protective effect of inhaling their aerosolised faeces. This is less plausible, I know, but I’d like to point out a highly suggestive study of sparrow droppings in relation to brain plaques in mice that I seem to remember reading in the Bulgarian Annals of Ornithology.

As I pointed out in relation to the “female doctors kill fewer patients” paper last week, when you go looking for associations and find one with a statistically significant effect size, that doesn’t mean that you should start hypothesising about causality. It is just as likely that you have failed to correct for some other factor that never occurred to you. The more you want to believe in causality, the more you should question yourself. I don’t want people to live in areas of high road traffic density; I don’t want motor vehicles to spew out carbon monoxide and dioxide, nitrogen oxides, or particulate matter; I don’t want to get dementia. This paper shows that in a large population based cohort in Ontario, living close to heavy traffic was associated with a 5% higher incidence of dementia, but not with Parkinson’s disease or multiple sclerosis. Avoid living near heavy traffic; feed your sparrows; don’t live in Ontario. Not sure which.

“Incompatible” kidneys and survival
When I was a medical student 45 years ago, immunology was still a very young science and renal transplantation was a very new procedure. But even then we knew about human leucocyte antigen (HLA) and the need to find a compatible kidney donor. Or did we? Does this need actually exist in the current era of better immunosuppression? From an outcomes study in the UK comparing HLA compatible and incompatible donor kidney transplants, it seems that matching may no longer be important. But this is a complex analysis in a complex subject that’s way beyond my competence: if you need to know the detail, look up the study. And this whole sentence applies to pretty well everything I write about.

The BMJ  7 Jan 2017  Vol 356
Colon cancer & NSAIDs or aspirin
Objective: To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis.” Full marks for ambition and effort. Since most of us understand English better than Greek, it’s worth pointing out that “metachronous neoplasia” really means “getting another significant tumour later on.” So you could call this a systematic review of drugs for the secondary prevention of bowel cancer.

When you are using potentially risky drugs for any kind of prevention, harms can be as important as benefits. Calcium, vitamin D, and folic acid were broadly harmless and useless. We know that the potential harms of NSAIDs vary drug by drug. So I eagerly searched this lengthy paper for a drug by drug analysis of effects, but all I could find initially was a comparison between aspirin and the sum total of other NSAIDs. Reading the text more carefully, it seems that the only two NSAIDs in these trials were sulindac and celecoxib, and that these agents had the highest protective effect. It’s an entirely open question therefore whether all NSAIDs are better than aspirin for the secondary prevention of bowel cancer, though the abstract concludes “Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile.” More trials with commoner agents such as naproxen and ibuprofen, please, before offering such generalisations.

Prediabetes and screening
Saving the best until last, here is the systematic review of screening for diabetes and pre-diabetes that we’ve all been waiting for. It’s a far ranging, penetrating, and superbly intelligent analysis under the title of “Efficacy and effectiveness of screen and treat policies in prevention of type 2 diabetes: systematic review and meta-analysis of screening tests and interventions.” In a way, we shouldn’t need this review, because Simon Griffin and colleagues so impressively demonstrated the failure of a screen and treat policy in a single definitive 10 year trial (ADDITION-Cambridge) published in 2012.

But this has made little difference to a policy that chimes so well with the pharma dominated diabetes industry. Even The BMJ recently published a review that looked quite favourably at the concept of “pre-diabetes.” This latest review all but explodes the concept, and throws serious doubt on how we currently define the threshold of type 2 diabetes itself, in a series of excellent illustrations comparing HbA1c, fasting glucose, and glucose challenge tests. This won’t come as news to those who have enjoyed John Yudkin’s presentations on the subject, but for these pictures alone everyone who treats or writes about T2DM needs to keep this article handy on their favourites list.

Plant of the Week: Helleborus lividus “Silver Rose”
As a whole, the Northern Hemisphere keeps cooling down until 19 January, and this is a time of misery for north Europeans. Not everywhere or always, however. Just now, England is enjoying a few days of mild weather with occasional pale sunshine. The birds are singing wildly in the mornings, and even in the evenings when it is nearly dark. Yesterday I watched a young thrush bashing a small, living snail on a lump of stone. It won’t last, but at least one can feel that spring will come some day. Not soon, but eventually. By May, possibly.

The early spring flowers to be looked forward to with greatest anticipation are the hellebores. Helleborus orientalis varieties grow very freely in our alkaline clay, and they are all lovely in their promiscuous profusion. None are out yet. Various choice hybrids are also taking their time, and should be out with the snowdrops in about two or three weeks. Hellebores have been much improved over the 30 years I’ve been looking for them. Doubles, blacks, and yellows used to be rare and expensive, and so did the varieties with beautiful mottled grey foliage and red stems. Now anybody can hunt them down and get them for a reasonable sum.

Our latest is a variety of Helleborus lividus called Silver Rose. So far we’ve seen the silver but not the rose. This silver takes the form of beautiful fringed grey leaves. Their lack of chlorophyll hasn’t stopped them doubling in size since we bought a couple of plants at £1.99 each in the autumn. The flower buds are just beginning to form, but we expect them to be pale pink with tassels of pale yellow stamens. What more could you ask of a hardy, early flowering perennial?