“Surrogate Outcome Proves Something Beyond All Reasonable Human Doubt”

March 12th, 2007 by Ben Goldacre in bad science, fish oil | 59 Comments »

I’m very much looking forward to this important press release, of a study in 4 children, making massive international news. The experiment is part of the promotional activity for another omega-3 pill called VegEPA, and a Channel Five documentary on children and diet to be broadcast later this week: it is unpublished, and this time the study, amazingly, was funded by the TV production company Endemol. They love these stories so much, they’ve started paying for the research. This represents a really interesting new development in the interplay between commercial companies making seductive claims about pills solving complex social problems, and the media who love them. They’ll be giving out their own degrees next.

For more on the dangers of making great leaps of faith on the real world abilities of a treatment using a theoretical surrogate outcome, I’d always recommend reading the excellent Trisha Greenhalgh, here on “Evidence and Marketing”:

www.bmj.com/archive/7106/7106ed.htm

This is taken from her book “How to Read a Paper: The Basics of Evidence-Based Medicine”, a highly readable, industry standard, medical student text. As you are aware, the whole of badscience.net is really just a covert excuse to bring the joys of evidence based medicine and primary academic literature to the masses.

The fact that medical students are taught this kind of stuff – the critical appraisal of the evidence behind marketing claims – while nutritionists play actively into the hands of the people trying to sell them stuff with “science” is, to my mind, the key difference between “nutritionism” and real science. I honestly cannot recommend highly enough that you read the Greenhalgh chapter. Go on. Click the picture. Buy the book. Seriously. It’s got jokes about drug reps and everything. Much funnier than the dry online version. And evidence based medicine is the most significant development in the history of western thought for a generation [I’ve cheekily pasted the whole of the relevant chapter in the comments below now, sorry Prof..]

Diet pill ‘made children smart’

Press Association
Monday March 12, 2007 6:43 AM

Four children whose brains and mental abilities were suddenly transformed after they took a simple dietary supplement have astonished scientists.

Scans showed their brains underwent three years’ of development in just three months.

At the same time they displayed remarkable improvements in tests of reading, concentration, problem-solving and memory.

One boy who previously scorned books and was hooked on TV developed a love of reading and declared he was “bored” of television.

The three boys and one girl, aged between eight and 13, were taking part in a pilot study looking at the effects of diet on developing young brains.

Scientists believe the results are powerful evidence of the harm “junk food” is doing to Britain’s children.

The children were given a supplement called VegEPA, which contains a combination of omega-3 and omega-6 essential fatty acids, and encouraged to cut down on fatty snacks and fizzy drinks and be more active. At the end, they underwent brain scans at St Georges Hospital, London, in a machine that can detect a key biochemical indicator of brain development called NAA (N-Acetylaspartate).

Higher levels of NAA correspond to more nerve fibres growing in the brain..

Professor Basant Puri, from Imperial College London, who led the study, said: “The results were astonishing. In three months you might expect to see a small NAA increase. But we saw as much growth as you would normally see in three years.

“It was as if these were the brains of children three years older. It means you have more connections and greater density of nerve cells, in the same way that a tree grows more branches.”

© Copyright Press Association Ltd 2007, All Rights Reserved.

Sarah Lovell < ###@suzannemartin.biz> |
| Subject: Re: Children Improve by Three Years in Three month Study |
>——————————————————————————————————————-|

Professor Puri is available for Interview please call Suzanne Martin on
0207 ######## or 07950 #####

MIND THE FAT
A study reveals astonishing findings

We know that a bad diet can affect a child’s physical health, but could it
be bad for their minds as well? All is revealed in the FIRST EVER study of
its kind with dramatic findings on channel five, 15th March 2007 in a
documentary entitled ‘Mind The Fat: Does Fast Food = Slow Kids?

In this fascinating documentary, four clinically overweight children who
are struggling at school take part in a groundbreaking three-month study.

The four children taking part are eight-year old Zach, who weighs eight
stone; George and Rochel, who are both 11 and weigh 11 stone each; and
13-year old Gareth, who weighs 12 stone.

Leading neuroscientist Professor Basant Puri conducted the study whereby he
carried out a series of tests with the children, involving a number of
challenges including handwriting, concentration, problem-solving ability
and memory. One test in particular the Stroop test, where the child has to
say out loud the colour of each word printed (the words all describe the
names of colours, but they are not printed in the actual colour that they
describe) was also conducted.

Prof Puri also scanned the brains of each child using state-of-the-art MRI
techniques, at a major London teaching hospital to assess whether the size
and makeup of their brains will alter. The exact tests were carried out
again after the three-months.

Professor Puri is also prescribed the children a dietary supplement called
VegEPA – a unique patented formulation containing a natural source of
omega-3 and omega-6 essential fatty acids consisting of EPA from marine
fish oil and virgin cold-pressed evening primrose oil. Most distinctly,
VegEPA does not contain DHA- and each child had to take two capsules per
day during the three-month study as well as keeping to their healthy eating
and fitness regime.

While Puri’s existing research shows a strong link between mental
performance and EPA, he was hoping that combining these supplements with a
change in diet would produce even more remarkable results.

Puri explains “Junk food contains bad fats, and those bad fats insinuate
themselves into the brain. They replace the good fats and make brain cell
membranes dry up so that signals don’t pass well between one brain cell and
another.”

After a challenging three months during which all the participants
attempted to eat more healthily, exercise more and take daily the VegEPA
supplements, a weigh-in reveals that three out of four have lost weight.
Of course, this was not the primary purpose of the programme. More
significant is the fact that all the children now perform much better than
before in the four challenges. In fact, they all perform at least one and a
half years above the expected results for their age group.

Professor Puri comments, “The results of this study were astonishing. After
taking VegEPA daily for just three months, the children showed an increase
in reading age of well over a year. Also, during three months we would
expect their brains to have grown by three months’ worth. In fact, they
showed an increase in their brain growth by three years’ worth. This was
reflected in their improved arithmetical and constructional skills and in
their memory and concentration. Their teachers and parents noticed the
improvements, such as better concentration and attention in class, better,
neater and more accurate handwriting, and even, in the case of one of the
boys, developing a preference for reading over watching television (which
was in marked contrast to his view of reading just three months’ earlier).”

www.vegepa.com

Orderline 0845 ###

-ends-

For further information, to interview Professor puri or for samples of
VegEpa please contact Suzanne Martin or Tina Barratt on 0207 #### or
email at @suzannemartin.biz

There now follows a subliminal message.



This has now hit a phenomenal number of media outlets. The media love these stories so much, now they’re funding them for themselves!

Diet pill 'made children smart'
ic Wales, UK - 7 hours ago
Four children whose brains and mental abilities were suddenly transformed after they took a simple dietary supplement have astonished scientists.

Kids' brains boosted by pills
ITN, UK - 4 hours ago
Four children whose mental abilities were suddenly improved after they took a simple dietary supplement have astonished scientists.
Study points to omega benefits for children
Sydney Morning Herald, Australia - 1 hour ago
Scans on four British children who took an omega oil supplement for three months showed their brains developed dramatically – by the equivalent of three
Supplement 'boosts' brain power
BBC News, UK - 3 hours ago
Brain scans showed three years worth of development in just three months in the children, says Imperial College researcher Professor Basant Puri.
Pill that makes kids brainier
Manchester Evening News, UK - 5 hours ago
FOUR children are said to have seen their brains and mental abilities undergo three years of development in just three months after taking a simple dietary
Pill that can boost young brain by three years
This is London, UK - 6 hours ago
A daily dose of healthy fats can boost the brain development of children by three years in only three months, according to startling research.
'Startling' results in fish oil tests
The Northern Echo, UK - 8 hours ago
POWERFUL new evidence shows that children using a dietary supplement pioneered in the North-East are making huge advances, it was revealed last night.
FOUR children whose brain power was transformed by taking a simple
Glasgow Daily Record, UK - 11 hours ago
Scans showed their brains underwent three years of development in just three months of taking omega-3 and omega-6. In tests, they showed a reading age
Fish oil is kid brain booster
The Sun, UK - 12 hours ago
FOUR kids have stunned scientists after their mental abilities were transformed by a simple fish oil supplement. Scans showed their brains underwent three
brain boosting tablets for kids
Metro, UK - 14 hours ago
By ANNE CAMPBELL – Sunday, March 11, 2007. A food supplement helped the brains of four children achieve three years' worth of development in just three

And now, over to the Prof…

www.bmj.com/archive/7106/7106ed.htm

“Evidence” and marketing
If you prescribe drugs, the pharmaceutical industry is interested in you and is investing a staggering sum of money trying to influence you. The most effective way of changing the prescribing habits of a clinician is through personal representatives (known in Britain as “drug reps” and in North America as “detailers”), who travel round with a briefcase full of “evidence” in support of their wares.(1)

Pharmaceutical “reps” do not tell nearly as many lies as they used to (drug marketing has become an altogether more sophisticated science), but they have been known to cultivate a shocking ignorance of basic epidemiology and clinical trial design when it suits them.(2) It often helps their case, for example, to present the results of uncontrolled trials and express them in terms of before and after differences in a particular outcome measure.(3) The recent correspondence in the Lancet and BMJ on placebo effects should remind you why uncontrolled before and after studies are the stuff of teenage magazines, not hard science.(4-12)

Summary points
Pharmaceutical “reps” are now much more informative than they used to be, but they may show ignorance of basic epidemiology and clinical trial design
The value of a drug should be expressed in terms of safety, tolerability, efficacy, and price
The efficacy of a drug should ideally be measured in terms of clinical end points that are relevant to patients; if surrogate end points are used they should be valid
Promotional literature of low scientific validity (such as uncontrolled before and after trials) should not be allowed to influence practice

Making decisions about treatment

Sackett and colleagues have argued that before giving a drug to a patient the doctor should:

identify, for this patient, the ultimate objective of treatment (cure, prevention of recurrence, limitation of functional disability, prevention of later complications, reassurance, palliation, relief of symptoms, etc);

select the most appropriate treatment, using all available evidence (this includes considering whether the patient needs to take any drug at all); and

specify the treatment target (to know when to stop treatment, change its intensity, or switch to some other treatment).(13)

For example, in treating high blood pressure, the doctor might decide that:

the ultimate objective of treatment is to prevent (further) target organ damage to brain, eye, heart, kidney, etc (and thereby prevent death);

the choice of specific treatment is between the various classes of antihypertensive drug selected on the basis of randomised, placebo controlled and comparative trials – as well as non-drug treatments such as salt restriction; and

the treatment target might be a phase V diastolic blood pressure (right arm, sitting) of less than 90 mm Hg, or as close to that as tolerable in the face of drug side effects.

If these three steps are not followed (as is often the case – for example in terminal care), therapeutic chaos can result.
Surrogate end points

A surrogate end point may be defined as a variable which is relatively easily measured and which predicts a rare or distant outcome of either a toxic stimulus (such as a pollutant) or a therapeutic intervention (a drug, surgical procedure, piece of advice, etc) but which is not itself a direct measure of either harm or clinical benefit. The growing interest in surrogate end points in medical research, and particularly by the pharmaceutical industry, reflects two important features of their use:

they can considerably reduce the sample size, duration, and, therefore, cost, of clinical trials; and

they can allow treatments to be assessed in situations where the use of primary outcomes would be excessively invasive or unethical.

In the evaluation of pharmaceutical products, commonly used surrogate end points include:

pharmacokinetic measurements (for example, concentration-time curves of a drug or its active metabolite in the bloodstream);

in vitro (laboratory) measures such as the mean inhibitory concentration of an antimicrobial against a bacterial culture on agar;

macroscopic appearance of tissues (for example, gastric erosion seen at endoscopy)

change in levels of (alleged) serum markers of disease (for example, prostate specific antigen(14) );

radiological appearance (for example, shadowing on a chest x ray film).

But surrogate end points have some drawbacks. Firstly, a change in the surrogate end point does not itself answer the essential preliminary questions: “what is the objective of treatment in this patient?” and “what, according to valid and reliable research studies, is the best available treatment for this condition?” Secondly, the surrogate end point may not closely reflect the treatment target – in other words, it may not be valid or reliable. Thirdly, overreliance on a single surrogate end point as a measure of therapeutic success usually reflects a narrow clinical perspective. Finally, surrogate end points are often developed in animal models of disease, since changes in a specific variable can be measured under controlled conditions in a well defined population. However, extrapolation of these findings to human disease is likely to be invalid.(15-17)

Features of the ideal surrogate end point

The surrogate end point should be reliable, reproducible, clinically available, easily quantifiable, affordable, and show a “dose-response” effect (the higher the level of the surrogate end point, the greater the probability of disease)

It should be a true predictor of disease (or risk of disease) and not merely express exposure to a covariable. The relation between the surrogate end point and the disease should have a biologically plausible explanation

It should be sensitive – a “positive” result in the surrogate end point should pick up all or most patients at increased risk of adverse outcome

It should be specific – a “negative” result should exclude all or most of those without increased risk of adverse outcome

There should be a precise cut off between normal and abnormal values

It should have an acceptable positive predictive value – a “positive” result should always or usually mean that the patient thus identified is at increased risk of adverse outcome

It should have an acceptable negative predictive value – a “negative” result should always or usually mean that the patient thus identified is not at increased risk of adverse outcome

It should be amenable to quality control monitoring

Changes in the surrogate end point should rapidly and accurately reflect the response to treatment. In particular, levels should normalise in states of remission or cure

The features of an ideal surrogate end point are shown in the box. If the “rep” who is trying to persuade you of the value of the drug cannot justify the end points used, you should challenge him or her to produce additional evidence.

One important example of the invalid use of a surrogate end point is the CD4 cell count in monitoring progression to AIDS in HIV positive subjects. The CONCORDE trial was a randomised controlled trial comparing early and late start of treatment with zidovudine in patients who were HIV positive but clinically asymptomatic.(18) Previous studies had shown that starting treatment early led to a slower decline in the CD4 cell count (a variable which had been shown to fall with the progression of AIDS), and it was assumed that a higher CD4 cell count would reflect improved chances of survival.

However, the CONCORDE trial showed that, although CD4 cell counts fell more slowly in the treatment group, the three year survival rates were identical in the two groups. This experience confirmed a warning that was issued earlier by authors suspicious of the validity of this end point.(19) Subsequent research in this field has attempted to identify a surrogate end point that correlates with real therapeutic benefit – that is, delayed progression of asymptomatic HIV infection to clinical AIDS, and longer survival time after the onset of AIDS.(20-21) Using multiple regression analysis, investigators in the USA found that a combination of markers (percentage of CD4:C29 cells, degree of fatigue, age, and haemoglobin concentration) was the best predictor of progression.(20)

Other examples of surrogate end points which have seriously misled researchers include ventricular premature beats as a predictor of death from serious cardiac arrhythmias,(22-23) blood concentrations of antibiotics as a predictor of clinical cure of infection,(24) and plaques seen on magnetic resonance imaging in monitoring the progression of multiple sclerosis.(25)

Before surrogate end points can be used in the marketing of pharmaceuticals, those in the industry must justify the utility of these measures by showing a plausible and consistent link between the end point and the development or progression of disease. It would be wrong to suggest that the pharmaceutical industry develops surrogate end points with the deliberate intention to mislead the licensing authorities and health professionals. However, the industry does, theoretically, have a vested interest in overstating its case on the significance of these end points. Given that much of the data relating to the validation of surrogate end points are not currently presented in published clinical papers, and that the development of such markers is often a lengthy and expensive process, one author has suggested setting up a data archive that would pool data across studies.(26)
How to get evidence out of a drug rep

Any doctor who has ever given an audience to a “rep” who is selling a non-steroidal anti-inflammatory drug will recognise the argument that “this NSAID reduces the incidence of gastric erosion in comparison to its competitors.” The question to ask the rep is not “what is the incidence of endoscopic signs of gastric erosion in volunteers who take this drug?” but “what is the incidence in clinical practice of potentially life threatening gastric bleeding in patients who take this drug?” Other questions, collated from recommendations in Drug and Therapeutics Bulletin(27) and other sources,(1)(3) are listed below.

See representatives only by appointment. Choose to see only those whose product interests you, and confine the interview to that product

Take charge of the interview. Do not hear out a rehearsed sales routine but ask directly for the information below

Request independent published evidence from reputable, peer reviewed journals

Do not look at promotional brochures, which may contain unpublished material, misleading graphs, and selective quotations

Ignore anecdotal “evidence,” such as the fact that a medical celebrity is prescribing the product

Using the STEP acronym, ask for evidence in four specific areas:
Safety – the likelihood of long term or serious side effects caused by the drug (remember that rare but serious adverse reactions to new drugs may be poorly documented)
Tolerability – best measured by comparing the pooled withdrawal rates between the drug and its most significant competitor
Efficacy – the most relevant dimension is how the product compares with your current favourite
Price – should take into account indirect as well as direct costs

Evaluate the evidence stringently, paying particular attention to the power (sample size) and methodological quality of clinical trials, and the use of surrogate end points. Do not accept theoretical arguments in the drug’s favour (|mKlonger half life,” for example) without direct evidence that this translates into clinical benefit

Do not accept the newness of a product as an argument for changing to it. Indeed, there are good scientific arguments for doing the opposite(28)

Decline to try the product via starter packs or by participating in small scale, uncontrolled “research” studies

Record in writing the content of the interview and return to these notes if the “rep” requests another audience

Checklist for evaluating information provided by a drug company

Does this material cover a subject which interests me and is clinically important in my practice?

Has this material been published in independent peer reviewed journals? Has any significant evidence been omitted from this presentation or withheld from publication?

Does the material include high-level evidence such as systematic reviews, meta-analyses, or double-blind randomised controlled trials against the drug’s closest competitor given at optimal dosage?

Have the trials or reviews addressed a clearly focused, important and answerable clinical question which reflects a problem of relevance to patients? Do they provide evidence on safety, tolerability, efficacy and price?

Has each trial or meta-analysis defined the condition to be treated, the patients to be included, the interventions to be compared and the outcomes to be examined?

Does the material provide direct evidence that the drug will help my patients live a longer, healthier, more productive, and symptom-free life?

If a surrogate outcome measure has been used, what is the evidence that it is reliable, reproducible, sensitive, specific, a true predictor of disease, and rapidly reflects the response to therapy?

Do trial results indicate whether (and how) the effectiveness of the treatments differed and whether there was a difference in the type or frequency of adverse reactions? Are the results expressed in terms of numbers needed to treat, and are they clinically as well as statistically significant?

If large amounts of material have been provided by the representative, which three papers provide the strongest evidence for the company’s claims?

In conclusion, it is often more difficult than you are being led to believe to weigh the potential benefits of a drug against its risks to the patient and cost to the taxpayer.(29) The difference between the science of critical appraisal and the pharmaceutical industry’s well rehearsed tactics of marketing and persuasion should be borne in mind when you are considering “evidence” presented by those with a commercial conflict of interest.

Incidentally, if anyone’s able to capture the TV footage on this that would be great. My favourite way of guerilla archiving TV stories at the moment is the video feature on cameraphone or digital camera. Hardly much worse than youtube. Can give you a way to email big files too. Bravo!


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If you like what I do, and you want me to do more, you can: buy my books Bad Science and Bad Pharma, give them to your friends, put them on your reading list, employ me to do a talk, or tweet this article to your friends. Thanks! ++++++++++++++++++++++++++++++++++++++++++

59 Responses



  1. Despard said,

    March 12, 2007 at 10:09 am

    I read about this in the Metro this morning, and it leaped out at me like a great big leaping-outy thing. Was going to submit it, but it seems like you’ve got there already!

  2. glutam9 said,

    March 12, 2007 at 10:28 am

    In the gruan today i think too

  3. standing_here said,

    March 12, 2007 at 10:48 am

    Is it possible that the Professor Basant Puri who conducted the study is the same Basant K Puri who wrote The Natural Way to Beat Depression: The Groundbreaking Discovery of EPA to Successfully Conquer Depression?

  4. standing_here said,

    March 12, 2007 at 10:49 am

    oh, and here’s the link:

    www.amazon.co.uk/Natural-Way-Beat-Depression-Groundbreaking/dp/0340824972/ref=sr_1_3/026-6429522-7505222?ie=UTF8&s=books&qid=1173696286&sr=1-3

    Apparently it suggests using VegEPA.

  5. simongates said,

    March 12, 2007 at 10:50 am

    So who is Prof Basant Puri? and should he know better?

  6. standing_here said,

    March 12, 2007 at 10:54 am

    …and it’s not just depression you can treat with VegEPA either. Behold:

    Chronic Fatigue Syndrome: A Natural Way to Treat M.E. , by Professor Basant K Puri

    www.amazon.co.uk/Chronic-Fatigue-Syndrome-Natural-Treat/dp/1905140002/ref=pd_sim_b_1/026-6429522-7505222?ie=UTF8&qid=1173696286&sr=1-3

    here’s a review from amazon:

    “This book is an extended advert for a product called VegEPA. The testimonials quoted are impressive as are the author’s credentials and I have no reason to doubt the accuracy of his claims for the product. However, VegEPA is mentioned in each chapter and is only commercially available from a single source. It is not available on prescription and there are no controlled medical trials quoted to back up anecdotal evidence. I suggest that this book be bought as one of a range of books about the possible causes of ME and CFS. Approach with caution.”

  7. Andrew Clegg said,

    March 12, 2007 at 11:12 am

    This VegEPA smells a bit fishy.

    Sorry.

    Andrew.

  8. Ben Goldacre said,

    March 12, 2007 at 12:11 pm

    www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=441604&in_page_id=1770

    Pill that can boost young brain by three years
    By LAURA CLARK – More by this author » Last updated at 07:40am on 12th March 2007

    Comments Comments (12)

    Study found that fish-oil capsules can boost young brainpower
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    A daily dose of healthy fats can boost the brain development of children by three years in only three months, according to startling research.

    More here…
    • ‘400,000 British children’ taking hyperactivity drugs
    • Anyone for a mackerel milkshake?

    Children given capsules of omega-3 and omega-6 fats grew additional “grey matter” which helps intelligence.

    Brain scans which showed the evidence of changes were re-inforced by results in tests of reading, concentration and short-term memory.

    Youngsters who took part in the study increased their reading age by an average of a year and a quarter during the three-month trial.

    Scientists behind the study say they were astonished by the changes in the four participating children, who were aged between eight and 13.

    Scans showed their brains developed three years in as many months as nerve fibres grew additional branches.

    It suggests pupils across the country are deficient in “smart fats” because the children in the study had typical youngsters’ diets – laden with refined sugar and junk food.

    Professor Basant Puri, who led the research, believes mass supplementation of schoolchildren is now needed.

    Because they are unlikely to consume optimum quantities of omega-3 and omega-6 – which are derived from oily fish and a pure form of evening primrose oil – through eating normal diets alone, they need to be given the fats in the form of supplements.

    His study adds to growing evidence that healthy fats can help improve children’s learning power, concentration and behaviour – even among those with no obvious problems.

    The professor even believes many adults would benefit from additional healthy fats because they help keep brain degeneration at bay.

    The scientist, who is professor of imaging and psychiatry at Imperial College London and consultant in neurological disorders at Hammersmith Hospital, has taken the supplements himself for three years.

    The study, funded by TV production company Endemol, will feature in a Channel Five documentary on Thursday.

    The children were given the supplement VegEPA, containing a combination of omega-3 and omega-6 fatty acids.

    The youngsters took two capsules a day for three months and were encouraged to cut down on fatty snacks, fizzy drinks and become more active.

    After three months, remarkable improvements were seen, according to Professor Puri.

    The average increase in the children’s reading age was a year and a quarter while their handwriting became more accurate and neater.

    In one measurement of concentration, three children scored perfect results even though they are not top of the class at school.

    They also dramatically improved their short-term memory.

    One boy who previously scorned books and was hooked on TV developed a love of reading and declared he was “bored” with television.

    However, the most striking finding emerged from the brain scans, which all suggested they had denser nerve fibres.

    Professor Puri said: “The results were astonishing. It was as if these were the brains of children three years older.”

    The Food Standards Agency reviewed the evidence but found the benefits were still a grey area.

    However, nutritionists are challenging the finding.

  9. Ben Goldacre said,

    March 12, 2007 at 12:14 pm

    The Prof Greenhalgh chapter is so valuable in interpreting this kind of thing that I’m worried some people might skip following the link, so I’m cheekily pasting it here. The fact that medical students are taught this kind of stuff, while nutritionists completely ignore it and play actively into the hands of the people trying to sell them stuff with “science” is, in many respects, the key difference between “nutritionism” and real science.

    Over to Prof.

    www.bmj.com/archive/7106/7106ed.htm

    “Evidence” and marketing
    If you prescribe drugs, the pharmaceutical industry is interested in you and is investing a staggering sum of money trying to influence you. The most effective way of changing the prescribing habits of a clinician is through personal representatives (known in Britain as “drug reps” and in North America as “detailers”), who travel round with a briefcase full of “evidence” in support of their wares.(1)

    Pharmaceutical “reps” do not tell nearly as many lies as they used to (drug marketing has become an altogether more sophisticated science), but they have been known to cultivate a shocking ignorance of basic epidemiology and clinical trial design when it suits them.(2) It often helps their case, for example, to present the results of uncontrolled trials and express them in terms of before and after differences in a particular outcome measure.(3) The recent correspondence in the Lancet and BMJ on placebo effects should remind you why uncontrolled before and after studies are the stuff of teenage magazines, not hard science.(4-12)

    Summary points
    Pharmaceutical “reps” are now much more informative than they used to be, but they may show ignorance of basic epidemiology and clinical trial design
    The value of a drug should be expressed in terms of safety, tolerability, efficacy, and price
    The efficacy of a drug should ideally be measured in terms of clinical end points that are relevant to patients; if surrogate end points are used they should be valid
    Promotional literature of low scientific validity (such as uncontrolled before and after trials) should not be allowed to influence practice

    Making decisions about treatment

    Sackett and colleagues have argued that before giving a drug to a patient the doctor should:

    identify, for this patient, the ultimate objective of treatment (cure, prevention of recurrence, limitation of functional disability, prevention of later complications, reassurance, palliation, relief of symptoms, etc);

    select the most appropriate treatment, using all available evidence (this includes considering whether the patient needs to take any drug at all); and

    specify the treatment target (to know when to stop treatment, change its intensity, or switch to some other treatment).(13)

    For example, in treating high blood pressure, the doctor might decide that:

    the ultimate objective of treatment is to prevent (further) target organ damage to brain, eye, heart, kidney, etc (and thereby prevent death);

    the choice of specific treatment is between the various classes of antihypertensive drug selected on the basis of randomised, placebo controlled and comparative trials – as well as non-drug treatments such as salt restriction; and

    the treatment target might be a phase V diastolic blood pressure (right arm, sitting) of less than 90 mm Hg, or as close to that as tolerable in the face of drug side effects.

    If these three steps are not followed (as is often the case – for example in terminal care), therapeutic chaos can result.
    Surrogate end points

    A surrogate end point may be defined as a variable which is relatively easily measured and which predicts a rare or distant outcome of either a toxic stimulus (such as a pollutant) or a therapeutic intervention (a drug, surgical procedure, piece of advice, etc) but which is not itself a direct measure of either harm or clinical benefit. The growing interest in surrogate end points in medical research, and particularly by the pharmaceutical industry, reflects two important features of their use:

    they can considerably reduce the sample size, duration, and, therefore, cost, of clinical trials; and

    they can allow treatments to be assessed in situations where the use of primary outcomes would be excessively invasive or unethical.

    In the evaluation of pharmaceutical products, commonly used surrogate end points include:

    pharmacokinetic measurements (for example, concentration-time curves of a drug or its active metabolite in the bloodstream);

    in vitro (laboratory) measures such as the mean inhibitory concentration of an antimicrobial against a bacterial culture on agar;

    macroscopic appearance of tissues (for example, gastric erosion seen at endoscopy)

    change in levels of (alleged) serum markers of disease (for example, prostate specific antigen(14) );

    radiological appearance (for example, shadowing on a chest x ray film).

    But surrogate end points have some drawbacks. Firstly, a change in the surrogate end point does not itself answer the essential preliminary questions: “what is the objective of treatment in this patient?” and “what, according to valid and reliable research studies, is the best available treatment for this condition?” Secondly, the surrogate end point may not closely reflect the treatment target – in other words, it may not be valid or reliable. Thirdly, overreliance on a single surrogate end point as a measure of therapeutic success usually reflects a narrow clinical perspective. Finally, surrogate end points are often developed in animal models of disease, since changes in a specific variable can be measured under controlled conditions in a well defined population. However, extrapolation of these findings to human disease is likely to be invalid.(15-17)

    Features of the ideal surrogate end point

    The surrogate end point should be reliable, reproducible, clinically available, easily quantifiable, affordable, and show a “dose-response” effect (the higher the level of the surrogate end point, the greater the probability of disease)

    It should be a true predictor of disease (or risk of disease) and not merely express exposure to a covariable. The relation between the surrogate end point and the disease should have a biologically plausible explanation

    It should be sensitive – a “positive” result in the surrogate end point should pick up all or most patients at increased risk of adverse outcome

    It should be specific – a “negative” result should exclude all or most of those without increased risk of adverse outcome

    There should be a precise cut off between normal and abnormal values

    It should have an acceptable positive predictive value – a “positive” result should always or usually mean that the patient thus identified is at increased risk of adverse outcome

    It should have an acceptable negative predictive value – a “negative” result should always or usually mean that the patient thus identified is not at increased risk of adverse outcome

    It should be amenable to quality control monitoring

    Changes in the surrogate end point should rapidly and accurately reflect the response to treatment. In particular, levels should normalise in states of remission or cure

    The features of an ideal surrogate end point are shown in the box. If the “rep” who is trying to persuade you of the value of the drug cannot justify the end points used, you should challenge him or her to produce additional evidence.

    One important example of the invalid use of a surrogate end point is the CD4 cell count in monitoring progression to AIDS in HIV positive subjects. The CONCORDE trial was a randomised controlled trial comparing early and late start of treatment with zidovudine in patients who were HIV positive but clinically asymptomatic.(18) Previous studies had shown that starting treatment early led to a slower decline in the CD4 cell count (a variable which had been shown to fall with the progression of AIDS), and it was assumed that a higher CD4 cell count would reflect improved chances of survival.

    However, the CONCORDE trial showed that, although CD4 cell counts fell more slowly in the treatment group, the three year survival rates were identical in the two groups. This experience confirmed a warning that was issued earlier by authors suspicious of the validity of this end point.(19) Subsequent research in this field has attempted to identify a surrogate end point that correlates with real therapeutic benefit – that is, delayed progression of asymptomatic HIV infection to clinical AIDS, and longer survival time after the onset of AIDS.(20-21) Using multiple regression analysis, investigators in the USA found that a combination of markers (percentage of CD4:C29 cells, degree of fatigue, age, and haemoglobin concentration) was the best predictor of progression.(20)

    Other examples of surrogate end points which have seriously misled researchers include ventricular premature beats as a predictor of death from serious cardiac arrhythmias,(22-23) blood concentrations of antibiotics as a predictor of clinical cure of infection,(24) and plaques seen on magnetic resonance imaging in monitoring the progression of multiple sclerosis.(25)

    Before surrogate end points can be used in the marketing of pharmaceuticals, those in the industry must justify the utility of these measures by showing a plausible and consistent link between the end point and the development or progression of disease. It would be wrong to suggest that the pharmaceutical industry develops surrogate end points with the deliberate intention to mislead the licensing authorities and health professionals. However, the industry does, theoretically, have a vested interest in overstating its case on the significance of these end points. Given that much of the data relating to the validation of surrogate end points are not currently presented in published clinical papers, and that the development of such markers is often a lengthy and expensive process, one author has suggested setting up a data archive that would pool data across studies.(26)
    How to get evidence out of a drug rep

    Any doctor who has ever given an audience to a “rep” who is selling a non-steroidal anti-inflammatory drug will recognise the argument that “this NSAID reduces the incidence of gastric erosion in comparison to its competitors.” The question to ask the rep is not “what is the incidence of endoscopic signs of gastric erosion in volunteers who take this drug?” but “what is the incidence in clinical practice of potentially life threatening gastric bleeding in patients who take this drug?” Other questions, collated from recommendations in Drug and Therapeutics Bulletin(27) and other sources,(1)(3) are listed below.

    See representatives only by appointment. Choose to see only those whose product interests you, and confine the interview to that product

    Take charge of the interview. Do not hear out a rehearsed sales routine but ask directly for the information below

    Request independent published evidence from reputable, peer reviewed journals

    Do not look at promotional brochures, which may contain unpublished material, misleading graphs, and selective quotations

    Ignore anecdotal “evidence,” such as the fact that a medical celebrity is prescribing the product

    Using the STEP acronym, ask for evidence in four specific areas:
    Safety – the likelihood of long term or serious side effects caused by the drug (remember that rare but serious adverse reactions to new drugs may be poorly documented)
    Tolerability – best measured by comparing the pooled withdrawal rates between the drug and its most significant competitor
    Efficacy – the most relevant dimension is how the product compares with your current favourite
    Price – should take into account indirect as well as direct costs

    Evaluate the evidence stringently, paying particular attention to the power (sample size) and methodological quality of clinical trials, and the use of surrogate end points. Do not accept theoretical arguments in the drug’s favour (|mKlonger half life,” for example) without direct evidence that this translates into clinical benefit

    Do not accept the newness of a product as an argument for changing to it. Indeed, there are good scientific arguments for doing the opposite(28)

    Decline to try the product via starter packs or by participating in small scale, uncontrolled “research” studies

    Record in writing the content of the interview and return to these notes if the “rep” requests another audience

    Checklist for evaluating information provided by a drug company

    Does this material cover a subject which interests me and is clinically important in my practice?

    Has this material been published in independent peer reviewed journals? Has any significant evidence been omitted from this presentation or withheld from publication?

    Does the material include high-level evidence such as systematic reviews, meta-analyses, or double-blind randomised controlled trials against the drug’s closest competitor given at optimal dosage?

    Have the trials or reviews addressed a clearly focused, important and answerable clinical question which reflects a problem of relevance to patients? Do they provide evidence on safety, tolerability, efficacy and price?

    Has each trial or meta-analysis defined the condition to be treated, the patients to be included, the interventions to be compared and the outcomes to be examined?

    Does the material provide direct evidence that the drug will help my patients live a longer, healthier, more productive, and symptom-free life?

    If a surrogate outcome measure has been used, what is the evidence that it is reliable, reproducible, sensitive, specific, a true predictor of disease, and rapidly reflects the response to therapy?

    Do trial results indicate whether (and how) the effectiveness of the treatments differed and whether there was a difference in the type or frequency of adverse reactions? Are the results expressed in terms of numbers needed to treat, and are they clinically as well as statistically significant?

    If large amounts of material have been provided by the representative, which three papers provide the strongest evidence for the company’s claims?

    In conclusion, it is often more difficult than you are being led to believe to weigh the potential benefits of a drug against its risks to the patient and cost to the taxpayer.(29) The difference between the science of critical appraisal and the pharmaceutical industry’s well rehearsed tactics of marketing and persuasion should be borne in mind when you are considering “evidence” presented by those with a commercial conflict of interest.

  10. manigen said,

    March 12, 2007 at 12:37 pm

    Oh dear Ben, over 2,000 words. If it wasn’t such a fascinating quote, I’d call you a looser.

  11. simongates said,

    March 12, 2007 at 12:53 pm

    I suppose it’s too much to hope that any of the papers have said anything about where this incredible research has been published. Thought not.

  12. Andrew Taylor said,

    March 12, 2007 at 12:53 pm

    Endemol made me “bored of television” as well. Can I be in the news?

  13. ceec said,

    March 12, 2007 at 1:51 pm

    It is very hard to imagine how someone with Prof Puri’s publication record could consent to be represented in this way after a four-person intervention:

    “Professor Basant Puri, who led the research, believes mass supplementation of schoolchildren is now needed.”

    Mass supplementation of school children? From a non-blinded, non-controlled, etc. etc. study? This sort of thing brings Imperial’s reputation for scientific excellence into disrepute.

    By the way, if you google Basant Puri Imperial his Imperial page comes up, and on the right, top of the “sponsored links” is this:

    Feeling Blue? Try VegEPA
    Patented formulation recommended by
    world-leading expert Professor Puri
    www.igennus.com

  14. BrickWall said,

    March 12, 2007 at 1:56 pm

    Ben! How can we defend this site against the over enthusiastic bloggers when you go and do that…twice!

    Does this new evidence mean older people should take less Omega fats as I’m not keen on accelerating my brain development to match my grandmother’s!

  15. steck said,

    March 12, 2007 at 2:12 pm

    I see that the BBC are now running with:- news.bbc.co.uk/1/hi/health/6440979.stm

    “Supplement ‘boosts’ brain power ”

    I thought that an “n” of 4 in any research is invalid??

  16. simongates said,

    March 12, 2007 at 2:43 pm

    #16. n of 4 doesn’t make research invalid; it’s possible to perform a high quality randomised controlled trial with 4 participants. A study this small is just very very unlikely to show anything. Especially if isn’t a high quality RCT, for example if it doesn’t have a control group or it only measures a surrogate outcome of highly dubious clinical relevance.

  17. TimD said,

    March 12, 2007 at 2:44 pm

    #14: “It is very hard to imagine how someone with Prof Puri’s publication record could consent to be represented in this way after a four-person intervention”

    He’s already appeared on C4 lunchtime news supporting this ‘trial’ and claim. Krishnan went in with a couple probing questions but I don’t think he really knew where to begin…*sigh*

  18. Despard said,

    March 12, 2007 at 2:48 pm

    Not any research. Visual neuroscience researchers often use 3 or 4, and in motor control we tend to use less than 10. But then the vision scientists and ourselves are investigating very stereotyped behaviours which do not vary very much from person to person.

    But for a study on the benefits of the effects of a couple of chemicals plus a change in diet and greater physical activity on such a range of behaviours, you need a lot more than that…

  19. Despard said,

    March 12, 2007 at 2:49 pm

    Whoops. That was addressed to #16, so… what #17 said. :-)

  20. dredge said,

    March 12, 2007 at 3:57 pm

    Would this be the same Basant K Puri the inventor who works with Igennus, the producers of VegEPA

    www.patent.gov.uk/patent/p-journal/p-pdj/2005-6083.pdf

    GB2409644 (GB0428508.6) 31 Dec 2004
    IGENNUS LIMITED
    (INCORPORATED IN THE UNITED
    KINGDOM)
    Inventors:
    PURI, BASANT K
    Formulation comprising
    eicosapentaenoic acid or an ester thereof
    and a triterpene or an ester thereof

  21. crana said,

    March 12, 2007 at 5:52 pm

    Found this talk on @ Cambridge University tonight if anyone’s interested:

    Beanbags, fish oil and rose-tinted spectacles; navigating the path through dyslexia ‘cures’
    Professor Dorothy Bishop, Department of Experimental Psychology, University of Oxford
    Monday 12 March 2007, 20:30-21:30
    Cockcroft Lecture Theatre, New Museums Site, U of Cambridge
    talks.cam.ac.uk/talk/index/5860

  22. steck said,

    March 12, 2007 at 6:35 pm

    Thanks for the comments about the issue of “n” numbers. With reflection the particular study that I was referring to (neuroscience) required an “n” of 20, but because the research team only managed to recruit and “n” of 4, the study was deemed invalid and the DoH pulled funding.

  23. evidencebasedeating said,

    March 12, 2007 at 8:11 pm

    I predict a few canards on the quackometer being generated from the ‘publications’ so far. But lets deconstruct what we know already – thanks to the media interest in this story – and sorry for the ultra-long posting. getting to be a habit on this blog item! .

    Lets see just how many of the following are addressed properly in the programme. Any less than all indicates some bad science going on…and indicate that even the most eminent neurologist shouldn’t dabble in areas outside their domain of clinical expertise…….

    1. FOUR OBESE CHILDREN:

    as many as takes to make a ‘Trail by Television’, but far short of the number needed to make this more than anecdotal report – as Prof Puri should know, being a bona fide researcher in a past life……

    WILL PROF PURI DISCUSS: WHY such a small number were evaluated?

    2. THESE ARE ALL BIG KIDS

    all 4 kids above the 99.4 weight centile for their age, as reported in the media, and compared to conventional weight/height growth charts used in the UK.
    www.childgrowthfoundation.org/

    that is, their weight puts them in the absolute highest category for their age group. So high is their reported body weight in the media reports so far issued, that they represent the heaviest 1 in 200 of kiddie population for their age. This means it is likely that their diets had a high level of total, and presumed saturated fat. This has two issues of metabolic interest:

    a) saturated fat will be desaturated to arachidonic acid in the body, a fatty acid that can be used to generate pro-inflammatory mediators that up-regulate inflammation in the body, producing inflammatory prostaglandins (2 series) and leukotrienes (4 series). This pathway ‘competes’ with the the healthier omega-3 pathway (that generate the much-less-inflammatory 3-series prostaglandins, and 5-series leukotrienes). A lot of saturated fat will severely reduce the conversion of omega-3 fats to their healthy end-products..dietary fats are really competitive…

    b) excess body fat also produces adipokines, which are ‘supporters’ of inflammation, and in simple terms, make inflammation worse.

    c) inflammation can impede some of the desaturation mechanisms, thus making the ‘parent’ fat – linoleic acid (omega-6) or linolenic acid (omega-3) less likely to convert to the ‘active’ componants of or DHGLA, or EPA. Thats the reason for the ingredients in ths ‘VEGEPA’ supplement being those ‘further down the desaturase chain’.

    d) so being obese – if the premise is true – impedes normal desaturation of omega-3 fats, reducing the ‘active’ end-products. And the high level of saturated fat iin a typical overweight childs’ diet successfully competes with and over-rides the same ability to generate EPA from normal dietary sources.

    so,

    WILL PROF PURI DISCUSS: why body weight , and type and amount of dietary fat -wasn’t addressed in these children, not only from a blunting of beneficial metabolic pathways for fat metabolism, but also in the context of reducing the risk of damage to blood vessels caused by background inflammation associated with obesity.?..

    3. HOW DID THEY KNOW THE KIDS TOOK THE SUPPLEMENTS??

    Look out for erythrocyte membrane fat analysis – measuring the type of fat in the membranes of red blood cells, which give a fairly good indication of the profile of the types of fat in your diet over the last 120 days

    WILL PROF PURI DISCUSS: this method confirming fatty acid intake from diet and supplements?

    4. THE BRAIN ACTIVITY ON MRI SCANNING SHOWS ‘MORE ACTIVITY OF N-ACETYL-ASPARTATE (NAA), A PROXY-MARKER OF NEURONE/ BRAIN DEVELOPMENT – ‘GROWING 3 YEARS WORTH IN 3 MONTHS!!!!!’

    Couple of problems here. First, even Prof Puri in a previous paper suggests that NAA appears to be related to neuron activity, but not yet proven in terms of interpretation….and there seems to be some rather biologically implausible evidence (by Prof Puri) suggesting EPA ‘generates’ NAA.

    kids were told to avoid junk foods, probably including sugary drinks. Imagine obese kids substituting their ‘fat’ cokes and other sugary beverages for diet versions. The most popular sweetener in the UK for drinks is Nutrasweet/ Canderel. Its an intensely sweet protein made from a molecule of aspartic acid, and a molecule of phenyl-alanine. Both of these are amino acids, ie building blocks of protein.
    Aspartic acid can be metabolised into several substances, including (ahem) NAA. Previous quack nutritionists have taken issue with this sweetener ‘cos of its potential effects in brain tissue’. Its perfectly safe, but how do we know these obese kids just didn’t take a few cans of thinny cola, generated their own NAA, which made their brain seem ‘brainier’ on MRI activity???

    WILL PROF PURI DISCUSS: the potential confounding variable of dietary sweeteners in MR NAA activity?
    And whether age-and- sex matched controls were used, to compare the brain ‘growth’ of those not on the supplements, to the 4 kids studied. This is the VERY LEAST to be expected in a titchy ‘trial’ such as this..

    lets wait and see………….

  24. simongates said,

    March 12, 2007 at 9:40 pm

    #24 I think we can all make a good guess at the answers… something along the lines of; we couldn’t be bothered with all that tedious sciencey stuff, we just wanted to go straight for a catchy headline to shift more bucketfuls of pills.

  25. ncullum said,

    March 12, 2007 at 9:44 pm

    I have just submitted a “General Comment” to the BCC Website concerning the balance of their report and associated links. I did not feel it warranted a “Complaint” though I may be wrong.
    Sadly, as a long term and frequent critic of those illiterate plonkers I suspect that my attempt to connect their illiteracy with their treatment of a story such as this will end up in the bin. They rarely respond anyway. I honestly feel they don’t care.
    So, if anyone else wants to join in, maybe we can convince them that an even bigger story lies in debunking Prof Puri’s claims, particularly since it would involve the BBC in “taking the moral high ground” (that fits with their self-image) and – just by the way – attacking a competitor…

  26. Dr Aust said,

    March 12, 2007 at 9:54 pm

    Prof Puri does seem to have rather gone media-happy, by the looks of it.

    His publications on Medline: www.ncbi.nlm.nih.gov/entrez/

    – search for “Puri BK”

    show a startlingly prolific chap, with a long-ish history of work on essential fatty acids since the late 90s – he has published a lot of stuff with the late David “father of omega-3s” (and father of Cathra Kelliher, one half of the couple who run Equazen) Horrobin and also with Dr Alex Richardson at Oxford. Prof Puri is a proper doctor, MBBCh PhD MRCPsych no less, and is a consultant, though not quite clear what in (psychiatry?). He has published lots of stuff on brain imaging.

    Prof P does seem to have some form for “small sample case reports”, though of course these are not uncommon in the medical lit – note:

    Richardson AJ, Easton T, Puri BK. “Red cell and plasma fatty acid changes accompanying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid.” Eur Neuropsychopharmacol. 2000 May;10(3):189-93.

    Puri BK, Richardson AJ, Horrobin DF, Easton T, Saeed N, Oatridge A, Hajnal JV, Bydder GM. “Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes. Int J Clin Pract. 2000 Jan-Feb;54(1):57-63.

    – both of which appear to be one-patient case reports, and possibly of the same patient.

    …but nothing to overtly suggest someone who would be all over the news making overheated claims for a 4-patient trial funded by the a TV company.

    Having said that, the plethora of books he has written recommending EPAs as a cure for practically everything – there are a bunch of them, check the list at

    www.amazon.co.uk/exec/obidos/search-handle-url/202-6959889-0707828?%5Fencoding=UTF8&search-type=ss&index=books-uk&field-author=Basant%20K.%20Puri

    – and a clear interest (which sounds like it could well be financial) in a company marketing the stuff…. hmmm.

    BTW, On Amazon I see that due out later this year are two MORE books by Prof Puri, “Natural Energy” and its companion “The Natural Energy Cookbook” (I kid you not). Doubtless the publicity surrounding the present story will have a salutary effect on sales.

  27. Dr Aust said,

    March 12, 2007 at 10:11 pm

    PS Did anyone read the Northern Echo story Ben linked to above?

    Worth checking out as an old friend of Bad Science appears, a bit like Banquo’s Ghost in Macbeth – this is Dr Madeline Portwood of Durham CC (columns passim ad nauseam). She is quoted saying that Puri’s new results totally vindicate her and Durham (how predictable) and show the kids in Durham will be making major advances. I’ll post the story below in case you can’t bothered following the link.

    Note, incidentally, the comment in the story that “Professor Basant Puri, from Imperial College London,…worked with Dr Madeleine Portwood when similar trials began in the North-East.”. I can’t find an actual paper with Puri’s and Portwood’s names on it. At a guess it might refer to:

    Richardson AJ, Puri BK. “A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties.” Prog Neuropsychopharmacol Biol Psychiatry. 2002 Feb;26(2):233-9.

    – if the kids in this study were from Durham. Alex Richardson used to visit this blog occasionally when we were first discussing the Durham Fish Trials so if she’s still about maybe she can clarify this.

    ————————————————————————————————–
    ‘Startling’ results in fish oil tests
    The Northern Echo

    www.thisisthenortheast.co.uk/display.var.1251482.0.startling_results_in_fish_oil_tests.php

    POWERFUL new evidence shows that children using a dietary supplement pioneered in the North-East are making huge advances, it was revealed last night.

    Scans on youngsters in London, aged between eight and 13, showed their brains underwent three years’ worth of development in only three months.

    The results support Durham County Council’s decision to give thousands of children fish oil. The new study says the supplements have a dramatic effect on pupils, improving reading, concentration, problem-solving and memory.
    advertisement

    The latest evidence came after brain scans were carried out at St George’s Hospital, in London. They showed a biochemical indicator of brain development called N-acetylaspartate (NAA), higher levels of which correspond to more nerve fibres growing in the brain.

    The research was done by Professor Basant Puri, from Imperial College London, who worked with Dr Madeleine Portwood when similar trials began in the North-East.

    There have been criticisms of the North-East study, suggesting it is not as effective as supporters claim. But Dr Portwood, a senior educational psychologist with Durham County Council, said the London results reinforced its findings.

    She said: “In 2001, we conducted the biggest-ever clinical trial in the world by giving primary-age children fatty acid supplements.

    “Professor Puri’s recent study is showing that you can measure changes in brain cells. This is adding further evidence to the idea that fish oil can enhance performance.

    The recent study gives much better weight to our findings that the structure of the brain can be affected by fish oils.”

    Dr Portwood said the programme in the region was ongoing. More than 3,000 year 11 pupils take capsules to help them concentrate on GCSE revision.

    She is also carrying out research on primary school pupils in Middlesbrough and 69 primary-age autistic youngsters from Durham and Sunderland.

    In December, she published a report into trials with three-year-olds in County Durham, whose language skills had developed by nine months during the five-month programme.

    Children in the London study were given a supplement called VegEPA, which contains omega-3 and omega-6 essential fatty acids, for three months and encouraged to cut down on fatty snacks and fizzy drinks and be more active.

    Tests showed an increase in reading age of well over a year, handwriting became neater and more accurate, and they paid more attention in class.

    In one measurement of concentration, three children scored perfect results.

    Prof Puri said: “The results were astonishing. In three months, you might expect to see a small NAA increase, but we saw as much growth as you would normally see in three years.

    “For all the children, there was a marked change, but in the three boys, there was a massive increase in NAA.”

    The growth appeared to be spread throughout the cerebral cortex, the part of the brain that deals with thinking.

    Imaging expert Professor Kishore Bhakoo, from the Medical Research Council’s Clinical Science Centre, said the results had implications for the debate on junk food.

    Prof Puri, who wants to repeat the experiment with a larger number of children, said: “It does make you think about education and whether we should be giving all children these supplements.”

    North-East mother Kelly Parkin backed the findings. Until a year ago, her six-year-old daughter, Catherine, was taking fish oil supplements, having started the treatment as a four-year-old, but it became too expensive at £10 a bottle.

    Mrs Parkin, of Birch Avenue, Shildon, County Durham, said: “I would have liked to have kept her on them. We noticed a difference in her concentration as soon as we took her off them.

    “She cannot seem to sit for five minutes, which is what it was like before.” Prof Puri’s work is to feature in a Channel 5 documentary on Thursday, Mind the Fat: Does Fast Food Slow Kids?

  28. bstirling said,

    March 12, 2007 at 11:29 pm

    Puri explains “Junk food contains bad fats, and those bad fats insinuate
    themselves into the brain. They replace the good fats and make brain cell
    membranes dry up so that signals don’t pass well between one brain cell and
    another.”

    I’m sorry, does this really say that if you don’t take these pills, your brain will dry up? I’m not a scientist, but this immediately makes me raise an eyebrow. The media can’t seriously be swallowing this one whole (pardon the pun)!

  29. standing_here said,

    March 13, 2007 at 12:33 am

    “Professor Basant Puri, from Imperial College London, who led the study, said: “The results were astonishing. In three months you might expect to see a small NAA increase. But we saw as much growth as you would normally see in three years.”

    Now it seems unfair to do anything other than take prof Puri at his word here, and I don’t have any medical qualifications, but as a layman I’d have guessed that anywhere that you’re showing the kind of growth you’d expect over three years in the space of three months would be worrying re:cancer. can anyone better qualified than i am comment?

  30. Robert Carnegie said,

    March 13, 2007 at 1:22 am

    Dr. Death’s Death Drug Ages Children’s Brains 3 Years

    “A Rush Towards The Grave,” Says Commentator

  31. jackpt said,

    March 13, 2007 at 1:35 am

    Just Professor Greenhalgh’s bit, and at first I had a problem with the idea of endpoints, because it’s a phrase that has multiple contexts (then I looked it up in the right context). The naughty usage of surrogate endpoints as a promotion tool strikes me as a pattern that is repeated everywhere, in that they can constitute misdirection by implying relationships when their may be none. Sort of like journalists buying into post-hoc, when there may not even be a reason to get past the hoc because of the dodgy nature of the trial. Or like buying a car for the fuel efficiency but being influenced by by the salesman saying that the car is very efficient (for a 5.9 litre V12). Etc. Indirection/misdirection at its best.

  32. McCruiskeen said,

    March 13, 2007 at 1:44 am

    Dr Portwood refers to her 2001 “Clinical trial” but is careful to refer to, “programme in the region,” when referring to the farce involving over 3,000 year 11 pupils taking fish oil capsules to help them concentrate on GCSE revision, or whatever the farce comprises.

    This “trial” that suddenly became an “initiative” and is now apparently a “Programme” was set up in its meaningless form by David Ford, Head of Achievement Services, for reasons explained by Councillor Claire Vasey in reply to a Public Question asked by Paul Thompson at a meeting of Durham County Council on 7th February 2007 as follows:

    Question:

    “Why has Durham County Council, in conjunction with Equazen, not undertaken what appears to many to be an obvious and unique opportunity to carry out a scientifically controlled trial, with appropriate controls, of the possible efects of fish oil supplements on the academic performance in mainstream children in the county’s schools?”

    Answer:

    “This initiative is an opportunity for young people and their families to choose to try, at no cost to themselves or the local authority, a supplement which may assist them in their learning. Our approach meant that the opportunity was open to all. A controlled experiment by definition denies some students that opportunity.”

    So Durham County Council (and one presumes Dr Portwood) didn’t want to deny any of their Year Eleven students benefits that they had not yet demonstrated to exist, but only believed might be the case.

    It reminds one of certain Faith Schools and “Creationism” where “belief” seems to override rational thought.

    David Ford, DCC’s Head of Achievement Services, enthusiastically stated in the Durham Advertiser on13th January 2007, “We are absolutely delighted with the level of take-up. Clearly parents and pupils share our belief that the initiative, although not a scientifically controlled one, is worth doing.”

    So that’s all right then!, (So long as enough people believe in it.) Faith, after all, can allegedly move mountains, so a few improved GCSE grades should be no trouble at all.

  33. simongates said,

    March 13, 2007 at 9:27 am

    #28 Alex Richardson was first author on the Oxford-Durham study, the one Durham fish oil trial that has made it into print (in Pediatrics 2005) (on kids with Developmental Coordination Disorder). Puri’s affiliation on the paper mentioned above is given as Oxford Dept of Physiology so clearly he worked there at about the time the Oxford-Durham trial was going on.

    I could go on to criticise the design of the Oxford-Durham study but I’ll resist…

  34. Teek said,

    March 13, 2007 at 9:40 am

    surrogate end points appear to be de rigeur in industrial pharmacuetical research too. FDA rules in the US were changed in the 90s, so that where companies had to prove that a drug aimed at CHD (for example) raised life expectancy or lowered morbidity (real end points), they could show that their drug lowered a proximate (or surrogate) marker such as cholesterol. this meant that even if a compund has no overall treatment benefit to a patient, a drug could be approved.

    this is a bit like what happens in “goodscience” publications too. e.g. from the field i work in, a group will take embronic stem cells, culture them in the presence of certain growth factors, and then probe for the expression of (for instance) genes found in mature muscle cells or retinal cells or liver cells. if they find greater expression of these tissue-specific markers (as we nerdy types calle them), they conculde that ‘we managed to take a stem cell and coax it down the specific pathway that lead to its differentiation into a muscle/liver/retinal cell,’ whereas it is known that expressing one particular gene that belongs to a specific tissue doesnt make that cell a true hepatocyte/myocyte/photoreceptor etc.

    anyway (apologies for nerdy science-rant), the point is that surrogate end points are useful in a way (i.e. they’re readily assayed-for, they require shorter study periods than ultimate end points and they point towards a mechanism of action for a compound), you shouldn’t extrapolate from “X causes Y to rise, Y is associated with increased brain function” to “therefore X increases brain function”

  35. Dr Aust said,

    March 13, 2007 at 11:18 am

    Nicely put, Teek.

    Agree with you 100%, probably no great surprise as I work in research too (just read a PhD thesis on stem cells full of said surrogate end-points..!). Surrogate end-points are great for research, but cannot be used as reasons to give people drugs / treatments which don’t alter morbidity / mortality – the real end points

    As Ben has stated repeatedly, this surrogate outcome sleight-of-hand is most pronounced in Alt /Nutri-health (see Patrick Holford, Matthias Rath and the Vit C-kills HIV-virus-in-a-dish saga) but is also found in the pharmaceutical mainstream (as I understand it this is the basis for the spat between NICHE and the campaigners / pharma companies about anti-Alzheimer’s drugs). And most journalists seem to wilfully ignore it, because (one is forced to conclude) overblown hype and ludicrous extrapolation make for a splashier news story.

  36. MJ Simpson said,

    March 13, 2007 at 4:31 pm

    So let me get this straight. You take an extremely obese child who is addicted to junk food. You put them onto a healthy diet and an exercise regime and you make them the focus of attention by assorted adults, both of which naturally boost their self-confidence.

    And astoundingly, they start performing better at school! Who’d have thunk?

    Of course, it was the fish oil what done it.

  37. Bob O'H said,

    March 13, 2007 at 7:38 pm

    Here’s a study someone could carry out. Get, say, 4 children who are mal-nourished and underweight. Give them a good diet and exercise for, say, 3 months, as well as fish oils. Weigh them before and afterwards, and watch their weights go up. Then claim that fish oils are bad for children’s health, because they promote obesity.

    Bob

  38. evidencebasedeating said,

    March 13, 2007 at 9:20 pm

    nah, not just the fish oil.
    A tv camera and allocated media slot have a large confounding effect.
    plus the on-the-sofa interviews.
    does wonders for the ego of all concerned…

  39. Nickynockynoonoo said,

    March 14, 2007 at 3:37 am

    Does anyone fancy coming to an event where Professor Puri will be speaking?

    I’ll buy your ticket, a whole £3 but it’s the gesture that counts.

    When I heard that he will be a guest speaker, I started to Google, as you do. At first he appeared to be reputable. Being a “nutrition cures all” sceptic, I dug further and found this excellent site.

    Whilst I have a basic knowledge of food and supplements and am not a complete dork, I do not have the scientific knowledge to throw any awkward questions at him. More to the point, the answers would probably be over my head!

    He will be addressing a group of fibromyalgia sufferers. It’s similar to ME. There’s no cure as yet. BUT WAIT, maybe the Vegepa for ME scheme will work??????????

    www.thevegepaformescheme.com

    The meeting is 11th May at 11am -1:30 in Horsham.

    Who fancies a bun fight?

  40. thaumaturge said,

    March 14, 2007 at 7:07 am

    Funny, and today I just read a review paper in a recent issue of Journal of Affective Disorders: A. F. Thachil et al., “The evidence base of complementary and alternative therapies in depression.” When the authors looked at DHA, an omega-3 fatty acid, they found randomized controlled trials that showed “unequivocally negative results.” I wonder why this isn’t in the news?

    It happens to be in a free online sample issue so anyone can read it: www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2X-4KPN9PM-1&_user=10&_coverDate=01%2F31%2F2007&_rdoc=5&_fmt=full&_orig=browse&_srch=doc-info(%23toc%234930%232007%23999029998%23639799%23FLA%23display%23Volume)&_cdi=4930&_sort=d&_docanchor=&_ct=37&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2dcc04c593fee8e8575aa8d61485b0dc

  41. wewillfixit said,

    March 14, 2007 at 10:01 am

    Nickynockynoonoo – have you posted this in the forum (activism section might be most appropriate)? You might get some takers there.

  42. Wonko said,

    March 14, 2007 at 3:13 pm

    # 41

    Couldn’t access the paper you are citing.

    There was a Japanese study on the link between fish oils and depression in which the trial group became more depressed while the placebo group improved – was this the one? The trouble is, to be fair, that the research design was as poor as some of the nutri-science stuff.

    The broader point, that there is no evidence that omega-3 can be used to treat depression is spot on. It is also worth noting that people affected by depression are particularly vulnerable to the claims in favour of quick-fixes such as VegEPA. If there isn’t a trade descriptions issue here, there bloody well should be!

  43. wewillfixit said,

    March 14, 2007 at 5:02 pm

    If you cut and paste the whole link rather than clicking on it, it should get you there.

  44. standing_here said,

    March 15, 2007 at 10:51 am

    # 46

    there’s also a link straight from Portwood to Holford’s Food for the Brain organisation. Apparently Portwood’s part of Food for the Brain’s team.

    www.foodforthebrain.org/content.asp?id_Content=1658

    the whole nutritional woo business is beginning to look more inbred than the hapsburgs.

  45. gadgeezer said,

    March 15, 2007 at 12:04 pm

    #47 and then some when one looks at the “Who Are We?”

    www.foodforthebrain.org/content.asp?id_Content=1604

    All the usual suspects on the Advisory Board. The list of people/organisations who have donated time/money/resources is interesting (Equazen, Yorktest, Dr. Portwood).

  46. j said,

    March 15, 2007 at 3:03 pm

    Worryingly, some sensible organisations (e.g. MIND) have affiliated themselves to food for the brain, too.

  47. Robert Carnegie said,

    March 16, 2007 at 2:36 am

    If I was told right, the kids were only advised to take a healthy diet, and are believed not to have done??

    If this stuff is just sold as a weight cure then it serves everyone right, I think.

  48. Idolator said,

    March 16, 2007 at 3:00 am

    Don’t know if anyone else has said so yet, but…

    [i]“It was as if these were the brains of children three years older. It means you have more connections and greater density of nerve cells, in the same way that a tree grows more branches.”[/i]

    [b]WRONG!!![/b] You’re born with as many synapses (“connections”) as you’ll ever have. The total number [b]decreases[/b] with age. (Of course, there’s no reason to think a professor of neuroscience should know that…)

  49. simongates said,

    March 16, 2007 at 10:29 am

    And on the same line as #51;

    “Leading neuroscientist Basant Puri…” He’s a psychiatrist isn’t he? That’s not the same as a neuroscientist is it?

    And as for “more connections and greater density of nerve cells”, I’m not sure you can see individual cells and synapses on an MRI. All they’re really saying here (with the absence of a control group) is that the brain scans didn’t look quite how they expected. Which may have been something to do with their expectation.

  50. Camp Freddie said,

    March 16, 2007 at 3:50 pm

    So the real non-story is:
    “A healthy diet, regular excercise and extra adult supervision increases the ‘cleverness’ of lazy fat kids.”

    Perhaps if they said the lords prayer at bedtime, we’d get headlines saying that christainity makes people brainier…
    On second thoughts, it probably best not to give those nutters any ideas!

  51. dynamo said,

    March 16, 2007 at 4:34 pm

    More information for simongates #52:

    You can’t see individual cells and synapses. NAA is normally used as a surrogate for ‘functioning neurons and synapses’, certainly not for growing neurons. Levels start out low at birth and have probably pretty much reached adult levels by about 18 y.o. A back-of-the-envelope calculation based on Pouwels et al. (Pediatric Research volume 46 p474 1999) shows that for these kids, brains ‘3 years older’ would have about 3% more NAA. Unfortunately that’s about the same sort of difference as you’d typically expect to see if you scanned someone two days in a row (i.e. noise). In other words if there really was that kind of difference, you’d struggle to see it with just four patients.

    If the research showed an ‘astonishing’ difference, then the kids brains were either abnormal before the treatment, or afterwards. Either way such a study could not possibly justify the claim that ‘Scientists believe the results are powerful evidence of the harm “junk food” is doing to Britain’s children.’

  52. Robert Carnegie said,

    March 16, 2007 at 10:21 pm

    The recent view is that brain tissue does grow, surely?

  53. dynamo said,

    March 17, 2007 at 11:04 am

    Re #55. Yes, it seems that neurons can change their shape and connectivity. (www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16366735)
    However, what NAA is measuring is roughly-speaking (because I’m not an expert and no-one is sure anyway) the density of normally-functioning neurons. So that gives a high figure in adults, and a considerably lower one in babies: but infant brains are doing a lot more ‘growing’ than those of adults.
    In summary, changes in NAA concentrations could be used as a marker for neuronal development but with fairly low sensitivity, and with quite a few doubts as to interpretation. As Ben pointed out, it’s extremely unlikely that a study of four people could come to a meaningful conclusion.

  54. kim said,

    March 19, 2007 at 1:03 pm

    There’s a big feature in the Telegraph today about hyperactivity that contains a fairly uncritical account of Robin Pauc’s use of diet etc. to treat hyperactivity and other conditions.

  55. evidencebasedeating said,

    March 19, 2007 at 10:15 pm

    #27 Dr Aust says:

    “On Amazon I see that due out later this year are two MORE books by Prof Puri, “Natural Energy” and its companion “The Natural Energy Cookbook”

    thats OK then. So its ‘natural’ energy being touted – so guess its a cookbook with oodles of fat, sugar, alcohol and protein – ie those ‘natural energy’ products in our diet.
    Phew. glad its ‘natural’ energy
    wouldn’t want a book on ‘unnatural’ energy – or even ‘supernatural’ energy….

  56. Jo said,

    March 21, 2007 at 4:01 pm

    Wasn’t there a very robust study showing that women wearing bikinis couldn’t
    concentrate because they were too busy holding their tummies in? That’s my
    theory as to why this ‘works’. The kids lost a bit of weight and their school
    uniforms fitted them better leaving them free to get on with their education
    without worrying about buttons bursting and whatnot.

  57. Robert Carnegie said,

    April 1, 2007 at 5:46 pm

    Oh, here’s the discussion on “our” forum. Still murky – dark hints of naughtiness that may or may not be proved.
    badscience.net/forum/viewtopic.php?t=2067

  58. ak said,

    November 24, 2007 at 6:36 pm

    Well said. As part of the Consultation on prostate cancer for the WHO, it was my task to examine PSA as a surrogate for mortality in prostate cancer. We used a very simple definition for surrogates: 1) correlates with true outcome and 2) varies as outcome varies. We found specific evidence that PSA does not fulfill the criteria for a surrogate endpoint in prostate cacner, which was ultimately our published position.

  59. sicknotstupid said,

    June 24, 2008 at 8:53 pm

    I suspended usual cynicism and tried Vegepa. For 6 months. No difference in my condition. Apparently dr Puri thinks we should take 8 a day to kick over the “active energy barrier” – so that’s quite expensive then. Then i read his book, expecting some decent science,and MRI scans, it’s just a shameless advert that says Vegepa can cure everything. Gone back to my cod liver oil (i still hate fish after all)Sick people are desperate and tired to trawl through the literature. What’s he doing at Imperial College?