MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

Monthly Archives: January 2016

What a question, you might say. And you would be right, it’s a most awkward one, so much so that I cannot answer it for myself.

I NEED YOUR HELP.

Here is the story:

Ten years ago, with the help of S Lejeune and an EU grant, my team conducted a Cochrane review of Laertrile. To do the ‘ground work’, we hired an Italian research assistant, S Milazzo, who was supervised mainly by my research fellow Katja Schmidt. Consequently, the review was published under the names of all main contributors: Milazzo, Ernst, Lejeune, Schmidt.

In 2011, an update was due for which the help of Dr Markus Horneber, the head of a German research team investigating alt med in relation to cancer, was recruited. By then, Milazzo and Schmidt had left my unit and, with my consent, Horneber, Milazzo and Schmidt took charge of the review. I was then sent a draft of their update and did a revision of it which consisted mostly in checking the facts and making linguistic changes. The article was then published under the following authorship: Milazzo S, Ernst E, Lejeune S, Boehm K, Horneber M (Katja had married meanwhile, so Boehm and Schmidt are the same person).

A few days ago, I noticed that a further update had been published in 2015. Amazingly, I had not been told, asked to contribute, or informed that my name as co-author had been scrapped. The authors of the new update are simply Milazzo and Horneber (the latter being the senior author). Katja Boehm had apparently indicated that she did no longer want to be involved; I am not sure what happened to Lejeune.

I know Markus Horneber since donkey’s years and had co-authored several other papers with him in the past, so I (admittedly miffed about my discovery) sent him an email and asked him whether he did not consider this behaviour to amount to plagiarism. His reply was, in my view, unhelpful in explaining why I had not been asked to get involved and Horneber asked me to withdraw the allegation of plagiarism (which I had not even made) – or else he would take legal action (this was the moment when I got truly suspicious).

Next, I contacted the responsible editor at the Cochrane Collaboration, not least because Horneber had claimed that she had condoned the disputed change of authorship. Her reply confirmed that “excluding previous authors without giving them a chance to comment is not normal Cochrane policy” and that she did, in fact, not condone the omission of my name from the list of co-authors.

The question that I am asking myself (not for the first time, I am afraid – a similar, arguably worse case has been described in the comments section of this post) is the following: IS THIS A CASE OF PLAGIARISM OR NOT? In the name of honesty, transparency and science, it requires an answer, I think.

Even after contemplating it for several days, I seem to be unable to find a conclusive response. On the one hand, I did clearly not contribute to the latest (2015) update and should therefore not be a co-author. On the other hand, I feel that I should have been asked to contribute, in which case I would certainly have done so and remained a co-author.

For a fuller understanding of this case, I here copy the various sections of the abstracts of the 2011 update (marked OLD) and the 2015 update without my co-authorship (marked NEW):

 

OLD

Laetrile is the name for a semi-synthetic compound which is chemically related to amygdalin, a cyanogenic glycoside from the kernels of apricots and various other species of the genus Prunus. Laetrile and amygdalin are promoted under various names for the treatment of cancer although there is no evidence for its efficacy. Due to possible cyanide poisoning, laetrile can be dangerous.

NEW

Laetrile is the name for a semi-synthetic compound which is chemically related to amygdalin, a cyanogenic glycoside from the kernels of apricots and various other species of the genus Prunus. Laetrile and amygdalin are promoted under various names for the treatment of cancer although there is no evidence for its efficacy. Due to possible cyanide poisoning, laetrile can be dangerous.

OBJECTIVES:

OLD

To assess the alleged anti-cancer effect and possible adverse effects of laetrile and amygdalin.

NEW

To assess the alleged anti-cancer effect and possible adverse effects of laetrile and amygdalin.

SEARCH METHODS:

OLD

We searched the following databases: CENTRAL (2011, Issue 1); MEDLINE (1951-2011); EMBASE (1980-2011); AMED; Scirus; CancerLit; CINAHL (all from 1982-2011); CAMbase (from 1998-2011); the MetaRegister; the National Research Register; and our own files. We examined reference lists of included studies and review articles and we contacted experts in the field for knowledge of additional studies. We did not impose any restrictions of timer or language.

NEW

We searched the following databases: CENTRAL (2014, Issue 9); MEDLINE (1951-2014); EMBASE (1980-2014); AMED; Scirus; CINAHL (all from 1982-2015); CAMbase (from 1998-2015); the MetaRegister; the National Research Register; and our own files. We examined reference lists of included studies and review articles and we contacted experts in the field for knowledge of additional studies. We did not impose any restrictions of timer or language.

SELECTION CRITERIA:

OLD

Randomized controlled trials (RCTs) and quasi-RCTs.

NEW

Randomized controlled trials (RCTs) and quasi-RCTs.

DATA COLLECTION AND ANALYSIS:

OLD

We searched eight databases and two registers for studies testing laetrile or amygdalin for the treatment of cancer. Two review authors screened and assessed articles for inclusion criteria.

NEW

We searched eight databases and two registers for studies testing laetrile or amygdalin for the treatment of cancer. Two review authors screened and assessed articles for inclusion criteria.

MAIN RESULTS:

OLD

We located over 200 references, 63 were evaluated in the original review and an additional 6 in this update. However, we did not identify any studies that met our inclusion criteria.

NEW

We located over 200 references, 63 were evaluated in the original review, 6 in the 2011 and none in this update. However, we did not identify any studies that met our inclusion criteria.

AUTHORS’ CONCLUSIONS:

OLD

The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk-benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.

NEW

The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk-benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.

END OF ABSTRACT

I HOPE THAT YOU, THE READER OF THIS POST, ARE NOW ABLE TO TELL ME:

HAVE I BEEN PLAGIARISED?

P S

After the response from the Cochrane editor, I asked Horneber whether he wanted to make a further comment because I was thinking to blog about this. So far, I have not received a reply.

Cancer-related fatigue (CRF) is one of the most common symptoms reported by cancer patients, and it is a symptom that is often difficult to treat. As always in such a situation, there are lots of alternative therapies on offer. Yet the evidence for most is flimsy, to put it mildly.

But perhaps there is hope? The very first RCT with a 2016 date to be reviewed on this blog investigated the efficacy of the amino acid jelly Inner Power(®) (IP), a semi-solid, orally administrable dietary supplement containing coenzyme Q10 and L-carnitine, in controlling CRF in breast cancer patients in Japan.

Breast cancer patients with CRF undergoing chemotherapy were randomly assigned to receive IP once daily or regular care for 21 days. The primary endpoint was the change in the worst level of fatigue during the past 24 h (Brief Fatigue Inventory [BFI] item 3 score) from day 1 (baseline) to day 22. Secondary endpoints were change in global fatigue score (GFS; the average of all BFI items), anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific QLQ (EORTC QLQ-BR23), and adverse events.

Fifty-nine patients were enrolled in the study, of whom 57 were included in the efficacy analysis. Changes in the worst level of fatigue, GFS, and current feeling of fatigue were significantly different between the intervention and control groups, whereas the change in the average feeling of fatigue was not significantly different between groups. HADS, EORTC QLQ-C30, and EORTC QLQ-BR23 scores were not significantly different between the two groups. No severe adverse events were observed.

The authors concluded that ‘IP may control moderate-severe CRF in breast cancer patients.’

The website of the manufacturer provides the following information on IP:

Inner Power is a functional food that provides various nutrients, such as zinc and copper. Zinc is a nutrient that your body needs to maintain your sense of taste. Zinc is also vital in keeping the skin and mucous membranes healthy and in regulating metabolism of proteins and nucleic acids. Copper helps the body form red blood cells and bones and regulates many enzymes that are found in the body. One pouch of Inner Power each day is the recommended daily serving.

  • Consuming a large amount of the product will not cure any underlying disease or improve your health condition.
  • Do not consume too much of the product because excessive zinc intake may inhibit the absorption of copper.
  • Observe the recommended daily serving of the product. This product should not be given to infants or children.

The recommended daily serving of the product (1 pouch/day) contains 43% of the reference daily intake of zinc and 50% of the reference daily intake of copper. Inner Power is neither categorized as a food for special dietary use nor approved individually by the Ministry of Health, Labour, and Welfare. You should eat well-balanced meals consisting of staple foods, including a main dish and side dishes.

I cannot say that this inspires me with confidence.

What about the trial itself?

To be honest, I am not impressed. The most obvious flaw is, I think, that there was not the slightest attempt to control for placebo effects. As I pointed out so many times before: with the ‘A+B versus B’ design, one can make any old placebo appear to be effective.

MORE than £150,000 was spent by NHS Grampian on homeopathic treatments last year. Referrals to homeopathic practitioners cost £37,000 and referrals to the Glasgow Homoeopathic Hospital cost £7,315 in 2014-15. In view of the fact that highly diluted homeopathic remedies are pure placebos, any amount of tax payers’ money spent on homeopathy is hard to justify. Yet an NHS Grampian spokeswoman defended its use of by the health board with the following words:

“We have a responsibility to consider all treatments available to NHS patients to ensure they offer safe, effective and person-centred care. We also have a responsibility to use NHS resources carefully and balance our priorities across the population as well as individuals. We also recognise that patient reported outcome and experience measures are valued even when objective evidence of effectiveness is limited. Homeopathy can be considered in this arena and we remain connected with the wider debate on its role within the NHS while regularly reviewing our local support for such services within NHS Grampian.”

Mr Spence, a professional homeopath, was also invited to defend the expenditure on homeopathy: “When a friend started talking to me about homeopathy I thought he had lost his marbles. But it seemed homeopathy could fill a gap left by orthodox medicine. Homeopathy is about treating the whole person, not just the symptoms of disease, and it could save the NHS an absolute fortune. If someone is in a dangerous situation or they need surgery then they need to go to hospital. It’s often those with chronic, long-term problems where conventional treatment has not worked that can be helped by homeopathy.”

What do these arguments amount to, I ask myself.

The answer is NOTHING.

The key sentence in the spokeswomen’s comment is : “patient reported outcome and experience measures are valued even when objective evidence of effectiveness is limited.” This seems to admit that the evidence fails to support homeopathy. Therefore, so the argument, we have to abandon evidence and consider experience, opinion etc. This seemingly innocent little trick is nothing else than the introduction of double standards into health care decision making which could be used to justify the use of just about any bogus therapy in the NHS at the tax payers’ expense. It is obvious that such a move would be a decisive step in the wrong direction and to the detriment of progress in health care.

The comments by the homeopath are perhaps even more pitiful. They replace arguments with fallacies and evidence with speculation or falsehoods.

There is, of course, a bright side to this:

IF HOMEOPATHY IS DEFENDED IN SUCH A LAUGHABLE MANNER, ITS DAYS MUST BE COUNTED.

The randomized, placebo-controlled, double-blind trial is usually the methodology to test the efficacy of a therapy that carries the least risk of bias. This fact is an obvious annoyance to some alt med enthusiasts, because such trials far too often fail to produce the results they were hoping for.

But there is no need to despair. Here I provide a few simple tips on how to mislead the public with seemingly rigorous trials.

1 FRAUD

The most brutal method for misleading people is simply to cheat. The Germans have a saying, ‘Papier ist geduldig’ (paper is patient), implying that anyone can put anything on paper. Fortunately we currently have plenty of alt med journals which publish any rubbish anyone might dream up. The process of ‘peer-review’ is one of several mechanisms supposed to minimise the risk of scientific fraud. Yet alt med journals are more clever than that! They tend to have a peer-review that rarely involves independent and critical scientists, more often than not you can even ask that you best friend is invited to do the peer-review, and the alt med journal will follow your wish. Consequently the door is wide open to cheating. Once your fraudulent paper has been published, it is almost impossible to tell that something is fundamentally wrong.

But cheating is not confined to original research. You can also apply the method to other types of research, of course. For instance, the authors of the infamous ‘Swiss report’ on homeopathy generated a false positive picture using published systematic reviews of mine by simply changing their conclusions from negative to positive. Simple!

2 PRETTIFICATION

Obviously, outright cheating is not always as simple as that. Even in alt med, you cannot easily claim to have conducted a clinical trial without a complex infrastructure which invariably involves other people. And they are likely to want to have some control over what is happening. This means that complete fabrication of an entire data set may not always be possible. What might still be feasible, however, is the ‘prettification’ of the results. By just ‘re-adjusting’ a few data points that failed to live up to your expectations, you might be able to turn a negative into a positive trial. Proper governance is aimed at preventing his type of ‘mini-fraud’ but fortunately you work in alt med where such mechanisms are rarely adequately implemented.

3 OMISSION

Another very handy method is the omission of aspects of your trial which regrettably turned out to be in disagreement with the desired overall result. In most studies, one has a myriad of endpoints. Once the statistics of your trial have been calculated, it is likely that some of them yield the wanted positive results, while others do not. By simply omitting any mention of the embarrassingly negative results, you can easily turn a largely negative study into a seemingly positive one. Normally, researchers have to rely on a pre-specified protocol which defines a primary outcome measure. Thankfully, in the absence of proper governance, it usually is possible to publish a report which obscures such detail and thus mislead the public (I even think there has been an example of such an omission on this very blog).

4 STATISTICS

Yes – lies, dam lies, and statistics! A gifted statistician can easily find ways to ‘torture the data until they confess’. One only has to run statistical test after statistical test, and BINGO one will eventually yield something that can be marketed as the longed-for positive result. Normally, researchers must have a protocol that pre-specifies all the methodologies used in a trial, including the statistical analyses. But, in alt med, we certainly do not want things to function normally, do we?

5 TRIAL DESIGNS THAT CANNOT GENERATE A NEGATIVE RESULT

All the above tricks are a bit fraudulent, of course. Unfortunately, fraud is not well-seen by everyone. Therefore, a more legitimate means of misleading the public would be highly desirable for those aspiring alt med researchers who do not want to tarnish their record to their disadvantage. No worries guys, help is on the way!

The fool-proof trial design is obviously the often-mentioned ‘A+B versus B’ design. In such a study, patients are randomized to receive an alt med treatment (A) together with usual care (B) or usual care (B) alone. This looks rigorous, can be sold as a ‘pragmatic’ trial addressing a real-fife problem, and has the enormous advantage of never failing to produce a positive result: A+B is always more than B alone, even if A is a pure placebo. Such trials are akin to going into a hamburger joint for measuring the calories of a Big Mac without chips and comparing them to the calories of a Big Mac with chips. We know the result before the research has started; in alt med, that’s how it should be!

I have been banging on about the ‘A+B versus B’ design often enough, but recently I came across a new study design used in alt med which is just as elegantly misleading. The trial in question has a promising title: Quality-of-life outcomes in patients with gynecologic cancer referred to integrative oncology treatment during chemotherapy. Here is the unabbreviated abstract:

OBJECTIVE:

Integrative oncology incorporates complementary medicine (CM) therapies in patients with cancer. We explored the impact of an integrative oncology therapeutic regimen on quality-of-life (QOL) outcomes in women with gynecological cancer undergoing chemotherapy.

PATIENTS AND METHODS:

A prospective preference study examined patients referred by oncology health care practitioners (HCPs) to an integrative physician (IP) consultation and CM treatments. QOL and chemotherapy-related toxicities were evaluated using the Edmonton Symptom Assessment Scale (ESAS) and Measure Yourself Concerns and Wellbeing (MYCAW) questionnaire, at baseline and at a 6-12-week follow-up assessment. Adherence to the integrative care (AIC) program was defined as ≥4 CM treatments, with ≤30 days between each session.

RESULTS:

Of 128 patients referred by their HCP, 102 underwent IP consultation and subsequent CM treatments. The main concerns expressed by patients were fatigue (79.8 %), gastrointestinal symptoms (64.6 %), pain and neuropathy (54.5 %), and emotional distress (45.5 %). Patients in both AIC (n = 68) and non-AIC (n = 28) groups shared similar demographic, treatment, and cancer-related characteristics. ESAS fatigue scores improved by a mean of 1.97 points in the AIC group on a scale of 0-10 and worsened by a mean of 0.27 points in the non-AIC group (p = 0.033). In the AIC group, MYCAW scores improved significantly (p < 0.0001) for each of the leading concerns as well as for well-being, a finding which was not apparent in the non-AIC group.

CONCLUSIONS:

An IP-guided CM treatment regimen provided to patients with gynecological cancer during chemotherapy may reduce cancer-related fatigue and improve other QOL outcomes.

A ‘prospective preference study’ – this is the design the world of alt med has been yearning for! Its principle is beautiful in its simplicity. One merely administers a treatment or treatment package to a group of patients; inevitably some patients take it, while others don’t. The reasons for not taking it could range from lack of perceived effectiveness to experience of side-effects. But never mind, the fact that some do not want your treatment provides you with two groups of patients: those who comply and those who do not comply. With a bit of skill, you can now make the non-compliers appear like a proper control group. Now you only need to compare the outcomes and BOB IS YOUR UNCLE!

Brilliant! Absolutely brilliant!

I cannot think of a more deceptive trial-design than this one; it will make any treatment look good, even one that is a mere placebo. Alright, it is not randomized, and it does not even have a proper control group. But it sure looks rigorous and meaningful, this ‘prospective preference study’!

The following short passage originates from the abstract of an article that I published in 1998; it is entitled TOWARDS A RISK BENEFIT EVALUATION OF PLACEBOS: the benefits of placebos are often not clearly defined. Generally speaking, the potential for benefit is considerable. The risks are similarly ill defined. Both direct and indirect risks are conceivable. On balance, the risk-benefit relation for placebo could be favourable. Under certain conditions, the clinical use of placebos might therefore be a realistic option. In the final analysis, however, our knowledge for a conclusive risk-benefit evaluation of placebo is incomplete.

Today, I would phrase my conclusion differently: the benefits of placebo therapy are uncertain, while its risks can be considerable. Therefore the use of placebos in clinical routine is rarely justified.

What brought about this change in my attitude?

Lots of things, is the answer; 18 years are a long time in research, and today we know much more about placebo. In my field of inquiry, alternative medicine, we know for instance that, because the mechanisms by which placebos operate are now better understood, some alt med enthusiasts are claiming that placebo effects are real and therefore justify the use of all sorts of placebo treatments, from homeopathy to faith healing. They say that these ineffective (i.e. no better than placebo) therapies are not really ineffective because they help many patients via the well-documented placebo response.

If you are of this opinion, please read the excellent article David Gorski recently published on this issue. Here I want to re-visit my question from above: WHAT DO WE KNOW ABOUT THE RISKS BENEFIT BALANCE OF PLACEBO?

The benefits of placebo can seem impressive on first glance: after receiving placebos, patients can feel better, have less symptoms, need less medication and improve their quality of life. Who would be against any of these outcomes, particularly considering that placebos are usually inexpensive and readily available everywhere?

However, before we get too enthusiastic about the benefits of placebos, we need to consider that they are unreliable. Nobody can predict who will respond to placebo and who won’t. Despite intensive research, it has not been possible to identify placebo-responders as a distinct group of individuals from non-responders. The usefulness of placebos in clinical routine is therefore quite limited. Furthermore, placebo effects are normally only of short duration. Therefore they are not suited for any long-term therapy.

Crucially, placebos almost never effect a cure. They may improve subjective symptoms, but they do not normally cure the disease or remove its causes. A placebo therapy will reduce pain, for instance, and thus it can ease the suffering. If a back pain is caused by a tumour, however, a placebo will not diminish its size or improve the prognosis.

The notion that placebos might cause harm seems paradoxical at first glance. A placebo pill contains no active ingredient – how can it then be harmful? As I have stressed so often before, ANY INEFFECTIVE TREATMENT BECOMES LIFE-THREATENING, IF IT IS USED AS A REPLACEMENT FOR AN EFFECTIVE THERAPY OF A SERIOUS DISEASE. And this warning also applies to placebos, of course.

Seen from this perspective, the much-praised symptomatic relief brought about by a placebo therapy can become a very mixed blessing indeed.

Let’s take the above example of the patient who has back pain. He receives a placebo and subsequently his agony becomes more bearable. Because this approach seems to work, he sticks with it for several month. Eventually the analgesic effect of the placebo wears off and the pain gets too strong to bear. Our patient finally consults a responsible doctor who diagnoses a bone cancer as the cause of his pain. The oncologist who is subsequently consulted regrets that the patient’s prolonged placebo therapy has seriously diminished his chances to cure the cancer.

This may look like an extreme example, but I don’t think it is. Exchange the term ‘placebo’ with almost any alternative treatment, or replace ‘back pain’ and ‘cancer’ with virtually any other conditions, and you will see that such events cannot be rare.

In most instances, placebos may seem helpful but, in fact, they offer little more than the illusion of a cure. They very rarely alter the natural history of a disease and usually achieve little more than a slight, short-term improvement of symptoms. In any case, they are an almost inevitable companion to any well-administered effective treatment. Prescribing pure placebos in clinical routine is therefore not responsible; in most instances, it amounts to fraud.

The nice thing about New Year is that one sometimes tries to get some order into the chaos of one’s files and thus finds things that were long forgotten. Such a thing, for instance, is the 1996 book ‘DURCH AEHNLICHES HEILEN‘ edited by the Austrian homeopath, Perter Koenig. It contains lots of uncritical, pro-homeopathy articles by homeopaths, but also an article I wrote upon invitation.

When I composed it, I had just started my research in Exeter after leaving my post in Vienna. The subject I had been asked to address was ‘THE PLACE OF HOMEOPATHY WITHIN MEDICAL SCHOOLS’. My short article arrives at the following conclusions (as it is in German, I did a quick translation):

What place does homeopathy have in medical schools? An extremely low one! Even homeopathic optimists cannot reasonably doubt this answer. And how can its position be improved? Only through systematic research! This research should best be conducted in cooperation between experienced homeopaths and university-based methodologists. It must fill the existing gaps in our current knowledge, particularly in respect to the proof of homeopathy’s clinical effectiveness, and the research methods must comply with the currently accepted quality standards. History demonstrates fairly clearly that conventional medicine has changed according to new knowledge. In homeopathy, such a demonstration is so far missing.

Would I change this conclusion now that 20 years worth of research is available?

Yes!

The cooperative evaluation of homeopathy that I had in mind has happened.

And what are its conclusion?

The Australian National Health and Medical Research Council (NH&MRC) has made the most thorough and independent assessment of homeopathy in its history. On 11/3/2015, the NH&MRC has released its final report on homeopathy. In essence, it concluded that there is no scientific basis for homeopathy and no quality evidence of its efficacy: Homeopathy should not be used to treat health conditions that are chronic, serious, or could become serious. People who choose homeopathy may put their health at risk if they reject or delay treatments for which there is good evidence for safety and effectiveness. People who are considering whether to use homeopathy should first get advice from a registered health practitioner. Those who use homeopathy should tell their health practitioner and should keep taking any prescribed treatments.

In view of this, I would today revise my conclusions as follows:

What place does homeopathy have in medical schools? Its place is in the history books of medicine! Even homeopathic optimists cannot reasonably doubt this answer. Systematic research in cooperation between experienced homeopaths and university-based methodologists complying with the currently accepted quality standards has filled the gaps in our knowledge, particularly in respect to the proof of homeopathy’s clinical effectiveness. Now it is up to homeopaths to demonstrate that they are sufficiently responsible to adapt to this new knowledge in the best interest of their patients. If they don’t, they cannot be considered to be members of the community of ethical health care professionals. 

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