Synthesising licensing data to assess drug safety
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7438.518 (Published 26 February 2004) Cite this as: BMJ 2004;328:518
All rapid responses
The Alice in Wonderland world of hormones gets curiouser and
curiouser. Nothing is as peculiar as double-blind fascism and medicine-by
-sound-byte reigning, like the Queen of Hearts.
The comments on periodontal disease (seen elsewhere in rapid
responses) can go further: periodontal disease may be a heart disease
predictor and is clearly improved with estrogen.
Recently, since the (unwarranted) influence of WHI (Women's Health
Initiative) and HERS (Heart and Estrogen Replacement Study), and until
Hodis’, et al.’s insightful discussion in the New England Journal of
Medicine it was “off with her head” for intrepids advocating
individualized use of estrogen at onset of menopause for -- among other
benefits -- preventing atherosclerosis. (The HERS study itself, later
showing 35% less new-onset diabetes supports this; diabetes is a coronary
artery disease equivalent).
Editorialist Bailar opines, “Curiously, Hodis, et al. seem reluctant
to accept their own results at face value.” He misreads Hodis’ credible
perspective. Herrington & Howard cite flaws in large studies,
favoring tailored, eventually molecular, individualization. They accede
that “… in physiology averages give nothing real." From the Rabbit Hole
crawl muddied but perspicacious physician-clinicians weighing disparate
evidence.
With tongue in cheek and teeth preserved (unless estrogen-deprived
periodontal disease, another CAD equivalent ) we seek the toothless grin
of the Cheshire cat with Alice as she ages, through the looking glass,
until pivotal pieces of the puzzle prove Hodis et al.’s point.
References:
1 Lewis Carroll. Alice's Adventures in Wonderland and Through the
Looking-Glass, by Lewis Carroll, John Tenniel (Illustrator) (Mass Market
Paperback), Dec. 2002.
2 Hodis HN, Mack WJ, Azen SP et al. Hormone therapy and the progression of
coronary-artery Atherosclerosis in Postmenopausal Women N Engl J Med
2003;349:535-545.
3 Bailar J.Hormone-replacement therapy and cardiovascular disease N Engl J
Med 2003;349:521-522
4 Herrington DM, Howard TD. From presumed benefit to potential harm —
Hormone therapy and heart disease N Engl J Med 2003;349:519-521
5 Krall EA, Dawson-Hughes B. et al. Postmenopausal estrogen replacement
and tooth retention. Am J Med 1997;102:536–42.
6 Madianos PN, Bobetsis GA et al.. Is periodontitis associated with an
increased risk of coronary heart disease and preterm and/or low birth
weight births? J Clin Periodontol. 2002;29 Suppl 3:22-36.
Pepi Granat, MD
Private Family Practice
Clinical Professor of Family Medicine, voluntary
University of Miami School of Medicine, Dept. Family Medicine and
Community Health
e-mail: pgranat@pol.net
Competing interests:
I have written the chapter on Menopause in Robert Taylor's Textbook of Family Medicine; I was formerly on Speaker's Bureau for Wyeth AFTER having given independent talks on estrogen and lipid and cardiovascular effects
Competing interests: No competing interests
"Many excellent notions or experiments, by sober and honest men, are
suppressed." Robert Boyle. 1661
Little has changed, it seems.[1] This report of hidden, unpublished
drug company data about HRT is depressingly similar to the SEROXAT anti-
depressant drug scandal, where GlaxoSmithKline "managed" (i.e. held back)
data from clinical trials internally within the company "in order to
minimise any potential negative commercial impact." [2]
Public exposure of this scandal on the BBCC "Panorama" programme was
made possible by researchers working closely together with patients and
public. The researchers` report [3] also compared adverse drug reaction
reports from professionals with those of users. Analysis of professional
reports was made possible through negotiated access to `Yellow Card`
reports from the Medicine and Healthcare Products Agency and Committee on
Safety of Medicines: probably the first such analysis of the scheme. The
users` analysis was from 1374 e-mails sent in response to the "Panorama"
programme. The programme also received 67,000 calls.
This successful exposure demonstrated the important active role that
public and patients can play in partnership with professional researchers
in producing evidence about a treatment`s harms and benefits. Evidence is
incomplete unless effects on quality of life are included. It is time
clinician-researchers became equally alert to the motivations of drug
companies and the pernicious effects of conflicting interests.
Over a decade ago we were told that under-reporting of research is
unethical and constitutes scientific misconduct. [4] For too long,
obtaining evidence in randomised controlled trials about side-effects was
deemed an optional extra. Even when included in a trial protocol, data are
not always comprehensively gathered or reported. [5] This raises questions
about the degree of open-ness in clinician/pharmaceutical research
partnerships.
[1] Klim McPherson, Elina Hemminki. Synthesising licensing data to
assess drug safety. BMJ 2004; 328:518-20
[2] bmj.com UK Health News. Company `held back` data on Seroxat for
children. 3rd February 2004. Source: The Guardian.
[3] Charles Medawar, Andrew Herxheimer. A comparison of adverse drug
reaction reports from professionals and users, relating to risk of
dependence and suicidal behaviour. International Journal of Risk and
Safety of Medicine. 2003/4; 16:5-19
[4] Chalmers I. Under-reporting research is scientific misconduct.
JAMA 1990; 263:1405-1408
[5] Hazel Thornton. Questions about anastrozole for early breast
cancer. Lancet 2002;360:1890
Competing interests:
None declared
Competing interests: No competing interests
In 1985 the claim of the nurses’ study authors, that postmenopausal
oestrogen use reduced the risk coronary artery disease, conflicted with
the results of the Framingham study.1,2 In the latter study women aged 50
to 83 using oestrogens had 50% more risk of heart disease and twice as
much cerebrovascular disease than non-users.
The nurses were aged 30 to 55 when enrolled and those taking
oestrogen were five times more likely to have had hysterectomies and twice
as likely to have used oestrogen/progesterone contraceptives than non-
oestrogen users. At each two year survey women who had already got
coronary artery disease were excluded from further follow-up because they
might alter their pattern of hormone use. There was no reduction in total
mortality when women with cancer at the base-line were eliminated.1 By1993
only 9% of the nurses were current HRT takers but 43% were taking
vitamins. Nine out of ten women did not believe that HRT was beneficial.3
The epidemiology of hormone use is particularly unreliable because
few women have never been given hormones at some time or other. Even
randomised trials do not have clean never user groups and can
underestimate risks and therefore claim non-existent benefits.
1 Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of
postmenopausal estrogen therapy and coronary heart disease. N Eng J Med
1985: 313:1044-49.
2 Wilson PWF, Garrison RG, Castelli WP. Postmenopausal estrogen use,
cigarette smoking and cardiovascular morbidity in women over 50. The
Framingham Study. NEngJMed 1985 ;313:1038-43.
3 Stampher MJ, Colditz GA. Estrogen replacement therapy and coronary
heart disease: a quantitative assessment of the epidemiologic evidence.
Prev Med 1991 ;20:47-63.
Competing interests:
None declared
Competing interests: No competing interests
On-line ABPI Register Lists HRT Trials
Dear Sir
McPherson and Hemminki make a number of interesting points in their
article “Synthesising licensing data to assess drug safety” , some
important but some erroneous. The Association of the British
Pharmaceutical Industry (ABPI) supports the retrospective registration of
phase III trials involving UK patients when used in an application for a
marketing authorisation. Indeed the ABPI launched its clinical trial
register on 6 May 2003 (http://www.cmrinteract.com/clintrial) and a search
on 11 March 2004 produced nine HRT trials. In registering trials,
companies commit to considering reasonable requests for further
information on the trial and so we would suggest that in future McPherson
and Hemminki and other researchers check the website when seeking
pharmaceutical industry sponsored trials.
In the summary points section of the paper, there are two statements
relating to adverse events. Under ICH GCP which was published and adapted
by industry in January 1997, the requirement for reporting of adverse
events is clear. This is now to be strengthened from 1st May 2004 through
the implementation of the Clinical Trials Directive (2001/20/ec) in UK
law. The reporting of serious adverse reactions in clinical trials will
be a legal requirement for all investigators and they will be entered into
a central European database.
McPherson and Hemminki imply that there was promotion of an
unlicensed indication with HRT ie the prevention of coronary heart
disease. Such promotion by pharmaceutical companies in the UK is illegal
and would be investigated either by the MHRA or the Prescription Medicines
Code of Practice Authority. It is possible that discussions might have
promoted such use but not at the instigation of companies.
McPherson and Hemminki introduce the issue of compliance bias and
indeed this might have been a factor but it is also well known that
patients are not good compliers with medication and often take their
medicines haphazardly. I suggest that compliance bias may not be as
important as stated.
Finally I return to the register of clinical trials. Clearly further
information would have been available by approaching registering companies
directly but an approach to the MHRA would have led to the relevant
companies being contacted for permission to release information and these
matters would have been considered on a case by case basis. Therefore it
might have been more appropriate for McPherson, a member of the CSM,
directly to approach the MHRA rather than rely on a personal communication
from Michael Rawlins who retired as chairman of the CSM a few years ago.
Yours sincerely
Dr Richard Tiner
Medical Director
The Association of the British Pharmaceutical Industry
Competing interests:
Medical Director of The Association of the British Pharmaceutical Industry (ABPI), 12 Whitehall, London SW1A 2DY
Competing interests: No competing interests