Maintaining the integrity of the scientific record
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7313.588 (Published 15 September 2001) Cite this as: BMJ 2001;323:588
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The initiative undertaken by the International Committee of Medical
Journal Editors in order to assist in maintaining the integrity of the
scientific record should be welcomed by all those engaged in attempting to
speedily produce and accurately report unbiased, good quality research.
The symbiotic relationship between researcher and funder is a
delicate one needing awareness, mediation and action by a third party such
as those who publish. Editors of biomedical journals are best placed to
ensure the integrity of publications submitted to them. However, as with
all new regulations and initiatives , they take some time to become
effective, particularly when projects drawn up some while ago are still
extant and not yet at the publication stage. New attitudes to
accountability and responsibility of all parties in a research enterprise
take some while to take hold: it is a fine line of equipoise.
The revision and strengthening of the document: Uniform Requirementws
for Manuscripts Submitted to Biomedical Journals: Writing and Editing for
Biomedical Publication, in particular the section of the document relating
to publication ethics, will assist researchers by enabling them to
maintain their independence and integrity (whilst still acknowledging
their interdependence) and to retain their objectivity in the face of
commercial, political or other types of pressures from sponsors.
It would therefore be helpful if those journals supporting this new
initiative could also lead the way by also calling for an elimination of
`permission to publish` rulings on work in progress. Some programmes are
still putting these requirements on researchers, although others have
softened their approach already.
Competing interests: No competing interests
Sir - The average scientific standard of what pharmaceutical sponsors
present to regulators is far superior to that observed by medical
journals. Despite laudable efforts recently by various editors in
employing statistical reviewers, much still finds its way into print that
is, not to put too fine a point on it, nonsense. If the MCA did its gate-
keeping job as badly I would be alarmed.
Nor are ethical standards superior outside the industry. In my time
working for the pharmaceutical industry I came across the following
behaviour from the sort of external investigator you wish the industry
would prefer to contract research organisations. 1. Faking data. 2.
Changing procedures in the interests of personal research without seeking
approval either from the company or the ethical committee. 3. Refusing to
agree to abide by the pre-specified (and mutually agreed) analysis because
this would jeopardise the possibility of publication.
An example of the latter was particularly illustrative of the
arrogance one may encounter towards the industry if one works in it. I was
informed that my source of employment meant that my opinion regarding
statistical analysis carried no weight. (This was a cross-over trial, a
topic on which I had published a monograph.1) A third and academic opinion
was insisted upon and when this person, although chosen by the
investigator, agreed with me, the investigator then disagreed with us
both. To my then employer's credit, they refused to be party to the
publication that resulted, even though the results would have been more
positive to them than the pre-specified analysis.
I am of the cynical opinion that a much greater improvement in our
evidence-base would be obtained by the MCA influencing the standards
observed by medical journals than by having their editors influence the
regulatory process. My hope for the future is that sponsors and regulators
will move towards publication of regulatory dossiers on the web thus
bypassing the need to read a very unreliable literature. This development,
when it occurs, should not, it goes without saying, be seen as an attack
on journal editors.
Reference
1. Cross-over Trials in Clinical Research, Wiley, Chichester, 1993
Declaration of interest. The author is a consultant to the
pharmaceutical industry. This letter represents his personal opinion and
should neither be ascribed to his employer, nor to any clients.
Competing interests: No competing interests
Who has control over the publication of research results is clearly
an important issue. However, I have two concerns about the issues raised
in this editorial. One is whether the newly announced policies will
achieve their desired objective, and the other is that the editorial
implies that wresting contol over publication from Pharmaceutical
Companies and placing it in the hands of investigators will automatically
result in an improvement in the quality of published papers.
On the first of these, I don't see how the new measures will have any
impact on Companies withholding publication of results which are
unfavourable to them. As the editor points out, it is very hard to know
how often this happens (although publication bias is not a new
phenomenon). However, I've worked in Contract Research Organisations
(CROs) for the past 20 years, and during this time I can recall only one
instance where the CRO was put under pressure by a Pharmaceutical Company
to engage in unethical practices. In this instance, the Company wanted
the CRO to repeat a study, which was to be used for a regulatory
submission, because they thought they might then get a 'better' result. I
am pleased to say that, although it meant loss of business, the CRO
involved refused to do this.
On the second point, during my time in CROs I have been involved in
many trials, many of them designed by Pharmaceutical Companies or CROs,
but also some which are termed 'investigator sponsored'. This does not
necessarily mean that the investigator provides the funding, but that he
or she is given full control over the study and its analysis,
interpretation and reporting, and the Company simply provides (some of)
the funding and some technical assistance - as a sort of thank you to the
investigator for their help with other trials. I would have no hesitation
in saying that the trials which are controlled by the Companies are
conducted to a far higher scientific standard than those left in the
control of the investigators.
It would be astonishing if it were otherwise. Most investigators who
take part in these trials are not professional researchers: they are
primarily clinicians. All their training is aimed at treating patients -
if they have any training at all in research methods it's a single 20-
lecture (or so) course in statistics in the first or second year of their
degree, i.e. before they really appreciate how important rigorous research
methods are in order to do good science. Pharmaceutical companies and
CROs, on the other hand, contain staff whose primary professional
expertise lies in knowing how to run a clinical trial in such a way that
it gives meaningful and unbiased results. The analysis and interpretation
of data from a major multi-center clinical trial takes a team of people
many weeks to achieve: it would not be possible for individual
investigators to do this work to anything like the same standard, even if
they had the appropriate skills, whilst at the same time juggling with
their primary duties as a physician.
There might be one beneficial outcome of the new policy. Currently,
when the industry does publish its trials, it usually does so under the
name of the principal investigator in the belief that the paper will then
have greater influence on medical opinion. Perhaps now we'll see this
happening less often, with more trials being published under the names of
the professionals who actually designed and analysed the trials.
The views expressed in this letter are my own personal views and
should not be taken as representing those of my employer.
Dr Dennis O Chanter
Quintiles
Competing interests: No competing interests
Carol is exactly right ..........Pharmecutical companies are corrupt
in the way they test , publish and market their products hoodwinking
doctors into believing a load of rubbish .
Thyroxine being the most notable case in point
There is not one study anywhere in the world which proves that
Synthetic T4 actually replaces the T4 /T3/T2 /T1 which a normal thyroid
produces
Instead Thyroxine was introduced as a grandfathered drug on the wild
assumption that somehow patients bodies converted T4 to the other active
forms the cells need to use .
When Thyroid patients complain they feel anything but well on
Thyroxine they are ridiculed by their GPS, Consultants etc as if they are
too darned stupid too know how rotten they feel .
The entire medical community should hang its head in shame for its
treatment of Thyroid patients with a useless synthetic drug when a
perfectly good natural form of Thyroid was available and giving good
results
But of course Natural products cant be patented and dont make
fortunes >>>>>so we cant have that can we !!!!!!!!!
Far far better to keep people sick and dependant on Incapacity
benefit that bother to do some proper research and make them well enough
to be back at work and contributing to society
Who benefits ?????only the egos of the companies who grandfathered in
a copy drug which they know is inadequate but refuse to admit
Competing interests: No competing interests
The editorial rightly notes that governments, too, have a vested
interest in the nature of research and may seek to influence outcomes --
surprise!. But so too do academics, whose careers to a great extent are
based on volume of published work, and less of whether that work 'made a
difference' in some respect. Of course, much scientific research often
has no immediate impact, and often must wait in the fullness of time to be
appreciated, peer review or not.
We should, however, not be kidded into thinking that the peer review
process is pure and unsullied, and automatically leads to truth. In these
days of evidence-based medicine, one is remined of the futile efforts of
the logical positivists who tried to establish an empirical basis for
truth. And there are too many examples where peer pressure within
scientific communities has conspired to suppress novel perspectives --
this has always been Kuhn's point.
Is there a science of science? Do we actually know that peer review
is better than, say, chance? Do we know that peer review processes are
not really a sophisticated game amongst players who depend on one another
for their public reputations?
While the commercialisation of research may upset the academic
fraternity, who profess to enjoy independence, they are as trapped as
anyone if they are human. To suggest that they are immune from infuence
is at least naive as we are subject to normal psychological processes
which affect how and what we do, which includes seeking social approval,
and self-esteem.
We work toward answers to questions in many ways; it is this
pragmatic pluralism, rather than adherence to a specific orthodoxy, that
has characterised human intellectual progress.
In time, perhaps a more informed position on the quality of
scientific literature will emerge in time, to help us determine whether a
peer review process actually filters out unpublishable (i.e. bad) as
apposed to unpopular science.
I would also be interested to know whether ALL those people who
profess to be authors of papers really did the work. And how much
exploitation of graduate students if buried in the CV's of the
professoriat?
Competing interests: No competing interests
Until legislation is passed enforcing pharmaceutical companies to
pool a percentage of their profits into a research fund, managed by
individuals distanced from the medical world, the NHS will always be a
free-for-all for pharmaceutical companies.
Boot's study of levothyroxine was quite significant for thyroid
patients, not just because it showed that their product was no better than
other makes, but because it has helped us to look at other myths
surrounding synthetic thyroxin. For example; the consensus that synthetic
T4 is the same compound as a measure of T4/T3/T2 and other residues mixed
together. It also helped to highlight the disempowering treatment,
especially for British patients compared to the rest of the world.
All British doctors should know that synthetic thyroxin was 'not'
introduced with scientific studies to support it, hence the FDA's change
of heart on its status as a grandfathered drug now.
In contrast, our Medicines Control Agency (MCA) has continued its use
without a review of any kind, simply on the basis that it is medicine used
for chronic conditions. Under their review system someone who needs a one
off painkiller for a headache has 100% more protection from the MCA than
someone whose life, and quality of life, is dependant on daily drugs, as
bazaar as this may seem.
No one has proved that synthetic thyroxin is better for the patient
than naturally derived products, nor do they have to call a product by the
same name. Yet British doctors do not give patients a choice of medicines,
supporting the perception that patients are partners in their care, why?
Given the findings of the Boots study it may prove too much of a challenge
for the makers of synthetic thyroxin's to carry out comparative studies,
but until then should it be assumed by GP's that one medicine is better
than the other?
Therefore there can be no scientific reason for the prescribing
habits of British GPs and their disempowerment of their thyroid patients,
other than an over baring influence of the pharmaceutical industry. There
is no reason to believe that similar situations are not echoed with the
treatment of other chronic conditions.
Another point is that the drug is unlikely to be anymore stable in
Britain than it is in America, despite an obvious assumption from British
doctors that it is. The MCA's reviewing procedure for drugs used for
chronic conditions supports a market without the safety measures all
people expect daily from the food industry. So it is unlikely that British
patients will ever know how stable their drug is, until they have
experienced the nasty effects of a new batch, as I did one time.
As a patient and lay person I puzzle at such articles which discuss
ethics and integrity as if it could exist alongside commercialism. There
is not, and never will be either concept, as long as there is money to be
made in medicines. I have absolutely no doubt that any patient who has
ever laid in a NHS hospital bed next to one which is being used for drugs
trials would agree with me. In fact, like me, they might find much of the
pharmaceutical and medical world antics obscene and inexcusable.
Competing interests: No competing interests
I have worked for 5 years as a Medical Writer for the Pharmaceutical Industry based in Spain. In this period of time I have written many articles; these have been further published in scientific journals of prestige. In any case, the authors were obliged to publish the data in other way different as the data were obtained. Moreover, authors always had the final decision on revision of data published, content and discussion of data, journal selected, etc. Many protocols of clinical trials include a statement on publication policy, based in that recommended by the ICH guidelines on Good Clinical Practice. This statement usually contains the phrase "the data obtained during this clinical trial cannot be published without prior permission of the pharmaceutical company X". I do not know any case where a company had published data without commenting it to the investigators, although this reverse condition is not usually stated. The publication of data obtained from clinical trials is a milestone in the history of drug research. Data can be revised by others than the staff of the researching company or the regulatory agency. Moreover, this revision can de done at a world-wide level. We need to strengthening this concept of open communication through a close collaboration between academical authorities, including editorial boards, and industry. The final beneficiary will be the research but also the populations expecting new therapeutic alternatives.
Competing interests: No competing interests
Maintaining the integrity of the scientific record and setting it straight about razoxane ‘Razoxin’
The recognition by Editors of medical journals that suppressing
publication of research results unpalatable to the sponsors of that
research is a distortion of the scientific record and is tantamount to
research misconduct is long overdue[1]. It is said that research which is
not published does not exist which is precisely why research funders hope
that results which they believe conflicts with their interests and which
fails to be published will remain in limbo.
Rarely however can the results of a clinical trial that has exceeded
all expectations, that has been written up, that has had the approval of
the participating clinicians to be published, failed to appear even after
20 years though it is still of current interest. Following the discovery
of the normalization of tumour neovasculature by razoxane[2] and the
application of this discovery to psoriasis because of certain similarities
in the characteristics of their respective blood vessels[3] several large
pilot studies were followed by a formal clinical trial organised and
controlled by ICI Pharmaceuticals to validate the promising findings of
the pilot studies.
The multi-centre trial involved some 30 dermatologists and accrued
only patients with severe psoriasis requiring systemic treatment on which
most of them had already failed. The trial seems to have begun in 1980 and
lasted some 2 years. It appears to have recruited its required number of
patients who were for the most part evaluable for toxicity which was low
and for response which was high (75%).
Despite the fact that razoxane was known to be useful in treating
acute leukemia, there were reports[4] that years of chronic neutropenic
overdosing with razoxane could lead to the appearance of AML in some 1% of
those patients who had already been exposed to other cytotoxics. These
reports did not however deter the dermatologists, who not only wanted the
results of the trial published, but who also suggested the removal of a
misleading statement in the package insert that ‘razoxane is
contraindicated in psoriasis’. The statement was misleading because it was
unqualified. In the event the results were not published and the
misleading statement was not corrected. If the scientific record had been
set straight by publication of the results of the clinical trial, it is
doubtful if it would have been possible to maintain that razoxane was
contraindicated in psoriasis. Failure to publish was not only an
impediment to medical progress, but was also poor thanks to all the
patients, clinicians and originators who had participated in the trial. It
certainly did nothing for the integrity of the scientific record.
The importance even now 20 years later of publishing the results of
this clinical trial is due to the fact that it might give some indication
as to the long term toxicity of the dextro optical isomer (dexrazoxane)
which is now used to prevent the cardiotoxicity of the anthracyclines[5].
Despite the anthracyclines’ well known carcinogenicity and leukemogenic
activity and that more than 1000 patients have been exposed to the
combination of dexrazoxane and an anthracycline (mostly doxorubicin) not a
single case of acute leukemia has been reported [6].
That razoxane is highly effective in psoriasis is not in doubt, but
the reality of the leukemia issue should now be re-examined in the light
of new knowledge and in relation to therapeutically effective dosages,
previous treatment, effect on presumed aetiological factors in the
causation of psoriasis and most importantly patient views in the
assessment of the risk/benefit ratio. Only when this has been done can an
attempt be made to restore the integrity of the scientific record for
razoxane.
1. Smith R. Maintaining the integrity of the scientific record. BMJ
2001;323:588
2. Le Serve AW, Hellmann K. Metastases and the normalization of tumour
blood vessels by ICRF 159: A new type of drug action. BMJ 1972;1:597.
3. Atherton DJ, Wells RS, Hellmann K. Razoxane (ICRF 159) in psoriasis.
Lancet 1976;ii:1296.
4. Horton JJ, Caffrey EA, Clark KCA et al. Leukaemia in psoriatic patients
treated with razoxane. Br J Dermatol 1984;110:633.
5. Swain SM, Whalley FS, Gerber MC. Cardioprotection with dexrazoxane for
doxorubici-containing therapy in advanced breast cancer. J Clin Oncol
1997;15:1318.
6. Swain SM. (Private communication).
Competing interests: No competing interests