Oral contraceptives, venous thromboembolism, and the courts
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7363.504 (Published 07 September 2002) Cite this as: BMJ 2002;325:504All rapid responses
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What are clinicians to make of the judge’s ruling in the
third generation oral contraceptive trial that the ‘most
compelling evidence’ came from a novel and post-hoc
reanalysis of data first published three years earlier?
The judgement that there is no excess risk of venous
thromboembolism with third generation pills rests on
the acceptance of the validity of a single study
sponsored by the manufacturers (1). Using
epidemiological reverse engineering, data from a
case-control study, which had found an increase in
risk, were reanalysed using Cox regression technique
as if they came from a prospective cohort (2). Centre
stage was given to patients’, surely hazy, recollections
of their pill use up to 20 years previously. Justice
Mackay felt able to adjudicate on this very complex and
unorthodox application of the Cox model, which has
baffled epidemiologists, without the benefit of
independent statistical advice. Skegg in his editorial
called the judgement ‘bizarre’ (1).
Clinicians who may interpret the judge’s ruling as
allowing free prescription of third generation
contraceptives could reconsider Iain Chalmers
questions in bmj.com: What are the advantages to
women of third generation oral contraceptives? Which
outcomes, desired by women themselves, are more
likely to be achieved with third generation than with
second generation preparations? (3). These
questions, which are best addressed by randomised
controlled trials, have remained unanswered. When the
excess risk with third generation contraceptives
became known in 1995, doctors searched in vain for
evidence to support their use by over one million
women.
The discrepancy between company-funded and
independent epidemiology, which was commented on
by the judge, has important implications for oral
contraceptive research in general. Randomised trials
of oral contraceptives are funded almost exclusively by
the manufacturer for licensing purposes. As a number
of new contraceptives are coming onto the market,
complete transparency in reporting trials is essential. It
is reassuring that the leading contraceptive journal has
recently followed the example of top medical journals
and endorsed the CONSORT guidelines on reporting
of randomised trials (4). We await a similar
endorsement from other journals in the field.
Clinicians wishing to use third generation
contraceptives should continue to heed the advice from
the Medicines Control Agency. After reviewing all the
data, including the controversial study, the Agency
recommended that women should be informed of the
small excess risk of venous thrombosis with third
generation products (5). The excess risk is greatest for
women starting the pill.
1. Skegg DC. Oral contraceptives, venous
thromboembolism, and the courts. BMJ
2002;325(7363):504-5.
2. Lewis MA, MacRae KD, Kuhl-Habichl D, Bruppacher
R, Heinemann LA, Spitzer WO. The differential risk of
oral contraceptives: the impact of full exposure history.
Hum Reprod 1999;14(6):1493-9.
3. Chamers I. What are the advantages to women of
third generation oral contraceptives? http://bmj.com/
cgi/eletters/319/7213/795#4907
4 Grimes DA, Schulz KF. Randomized controlled trials
in "Contraception": the need for "CONSORT"
guidelines. Contraception 2001;64(3):139-42.
5. Medicines Commission. Combined oral
contraceptives containing desogestrel or gestodene
and the risk of venous thromboembolism. Current
Problems in Pharmacovigilance 1999;25:12.
Competing interests: I have consulted on prescribing
practice for the claimants in the third generation
contraceptive litigation.
Competing interests: No competing interests
The quotation from R.A. Fisher misrepresents him. His
words in context carry a rather different meaning:
"I do not relish the prospect of this science being
now discredited by a catastrophic and conspicuous
howler. For it will be as clear in retrospect, as it
is now in logic, that the data so far do not warrant
the conclusions based upon them."
He had good reason to be concerned, as he says
elsewhere:
"It disproves at about the 1 per cent. level the
hypothesis that inhalers and non-inhalers have the
same cancer incidence. Even equality would be a fair
knock-out for the theory that smoke in the lung causes
cancer. The fact, however, and it is a fact that
should have interested Hill and Doll in 1950, is that
inhalers get fewer cancers, and that the difference
is statistically significant." (p47)
"And what makes it far more exasperating, when they
put into effect an exceedingly important research, based
on the habits of the medical profession, by asking
about 60,000 doctors in Great Britain to register
their smoking habits, and about 40,000 of them did
so co-operatively, I am sorry to say that the question
about inhaling was not in that questionnaire. I
suppose the subject of inhaling had become distasteful
to the research workers, and they just wanted to hear
as little about inhaling as possible." (p20)
Today Fisher might be yet more concerned. I think he
might want to know why, in calculating deaths due to
smoking, the results of biased rather than randomized
sampling are used. And why the results of the only
controlled trial of the efects of giving up smoking, the
Whitehall study, have been consigned to oblivion and are
never quoted.
I think that today Fisher would despair at the misuse
and debasement of the science he so loved.
Competing interests: No competing interests
Editor – Professor David Skegg’s editorial(1) comment that “Consumers
might receive fairer treatment from a system of no fault compensation”
seems likely to secure considerable support. We must remember that the OC
litigation before Mr Justice Mackay has not been the first vastly
expensive and totally unhelpful action of this type in the High Courts
this year.
An earlier example(2) was the action in which Amanda Claire Smith
unsuccessfully sued the Secretary of State for Health for terrible damage
attributed to Reye’s syndrome. It seems likely that the legal teams on
both sides received fees but the gravely and sadly damaged patient got
nothing. Many of us professionally involved had our activities disrupted
to no good cause whatever.
The disruption caused by the OC litigation was far worse and the basis of
the trial far more nonsensical. The legal principals for both sides
agreed(3) that unless it could be shown that the true risk of venous
thromboembolism with the third generation oral contraceptives was at least
twice as great as with the third generation OCs compared with the second
generation OCs then the action at law could not proceed beyond this point.
This agreement ignored the facts that the value of delta in the
Transnational study (the biggest relevant field study) was set at two or
greater and that any difference of this order of magnitude would relate to
the relevant categories of patients and not to individuals. Again,
despite the number of weeks many of us spent on this trial, the legal
teams were the only ones to have benefited. Certainly the injured
patients didn’t.
In 1989(4), in a joint conference with the Royal Society of Medicine, we
published a paper on “No fault compensation – the BMA proposals” It is
saddening that vast sums should be spent on actions of this type at law
whilst the injured patients themselves gain nothing. It is time to revisit
this issue and evolve a scheme (perhaps modelled on Swedish experience)
which would aid patients and not fritter vast sums from which few but the
lawyers gain.
Ronald D Mann MD, FRCP, FRCGP, FFPM, Professor Emeritus, University
of Southampton.
email:DrMann@manorcottage, fsbusiness.co.uk
References:-
1. Skegg, DCG. Editorial, BMJ 325, 504-505.
2. Mann, RD. A New medico-Legal Hazard to Pharmacoepidemiology.
Pharmacoepidemiology and Drug Safety 2002; 11, Page S89
3. Mackay, The Honourable Mr Justice. Case Number 0002638, Approved
Judgment; para 20, (1)
4. Bolt, D. No Fault Compensation – the BMA Proposals. In No Fault
Compensation In Medicine (Editors Mann, RD & Havard, J.) London, Royal
Society Of Medicine. 1989; 93-97
Competing interests: No competing interests
To talk about economic and legal methods for making whole the loss of
a life partner is to trivialize the issues of this debate. To have this
"justice" hinge on whether or not third generation contraceptives kill 1.7
or 2.5 times as many women from pulmonary emboli than older and less
profitable ones trivializes it to absurdity.
Pharmaceutical companies, their officers and their minions within our
own profession all act appropriately to maximize their profit. It is good
business. If the courts are to help these corporations regulate their own
behavior, then they must use a system of damages proportionate to the
product of the monetized injury and the probability that the injury was
caused by the drug, rather than the "reasonable degree of medical
certainty" standard used.
The fact that all of the corporate-funded studies come in below this
standard, and most publicly funded studies meet the standard does raise to
a high likelihood that the former studies are either deluded or
fraudulent, or both.
It is our mission to act with our prescribing pen in the best
personal and fiducial interests of our patients and the health system.
The fact that we continue to have our patients pay more for medicine that
is more likely to kill them means that we are really not doing our job.
Perhaps we are more appropriate targets for scorn.
Competing interests: No competing interests
Dr Hall's proposal would not work at all. To follow his logic, where
the probability that a person's damage was caused by a drug or medical
treatment was 10%, he would get 10% damages. Or 1% for a 1% risk. Such a
system could lead to a monstrous explosion of claims for compensation.
What Dr Hall, and Dr Jennifer A Smith, both ignore is that a patient
who is informed that a treatment carries a certain risk, and elects to
have it, also elects to run that risk in return for the benefits of
treatment. The solution is for that person if he/ she wished, to insure
against the possibility of ill health. The NHS can only spend each pound
once.
I am sure that Dr Hall would not feel liable to pay damages if he
prescribed (for example) hormone replacement therapy, having informed the
recipient that the risk of breast cancer would be increased by 25% after
10 years, to the (approximately) one in 100 if his patients that would be
so affected.
Competing interests: No competing interests
Part of the trouble is the curious cut off point of culpability- the
mystical "balance of probability." This appears to mean that the adverse
event is not "more likely than not" to have been due to the putative
agent.
Suppose 25 out of 100 have trouble with the old drug and 50 out of a 100
have trouble with the new drug. The relative risk is 2:1. The proportion
of adverse events in those receiving the new drug and caused by it is 50%.
So it's a toss up for each particular case whether the damage is due to
the new drug or not. But this is obviously not the right answer or the
right question. Half of those on the new drug having side effects have
these because of the new drug. Fairness demands that any compensation due
should be distributed equally as no one is sure who is suffering from the
new drug. Therefore each person on the new drug with side effects should
receive a half of the damages payable if it were known that they had
suffered because of the new drug. Or is this too simple for both the
statisticians and the judiciary?
Competing interests: No competing interests
I t is intuitive to feel that a patient should receive some
compensation when suffering an adverse outcome after medical care. A
parent faced with the psychological and financial Everest of raising a
disabled child after unexplained damage during labour and delivery
deserves all the help they can get. But what about the self-employed
builder with wound infection after an inguinal hernia repair? Apart from
the arguments regarding the appropriateness of the current legal structure
to settle medical claims, serious questions arise in determining
compensation in a “no fault” setting. Most adverse outcomes result in some
loss of earnings or quality of life, temporary or permanent. Who will
decide whether more minor adverse events like surgical wound complications
deserve pecuniary compensation? Is the NHS capable of funding the process
and payments? In the fully informed and appropriately consented patient
who suffers an adverse outcome, who should pay?
Competing interests: No competing interests
The suggestion that "consumers might receive fairer treatment from a
system of no fault compensation" for injuries allegedly caused by by drugs
is misconceived. The oral contraceptive pill litigation was advanced as a
strict liability claim under the Consumer Protection At 1987; it concerned
allegedly defective products rather than allegedly negligent conduct.
Moreover, the court considered only the issue of causation. Consideration
of fault was not relevant to the determination of this case. The pill
case failed on causation.
Systems of compensation for alleged drug induced injury include fault
based (negligence) tort, strict liability under the Consumer Protection
Act 1987, and limited no fault schemes (for example, the Vaccine Damage
Payments Act 1979). All such schemes require proof of causation as a
condition of compensation.
The court has to make a decision that is just, certain and final. By
contrast science is uncertain and often controversial; a "scientific
consensus is unlikely to emerge", whether from the courts or the journals.
Any judicial determination of causation based on probabilistic
epidemiological evidence is at best approximate. However, it is
preferable to the presumption 'post hoc ergo propter hoc' relied on by so
many claimants and their lawyers.
Professor Skegg rightly deplores the "futility" of the pill
litigation; the case was, of course, brought by the claimants and funded
largely at public expense. It represents yet another failed legally aided
group action and accords with the near zero success rate of legally aided
pharmaceutical claims against the industry. In the context of a
collapsing health service, is this an appropriate use of public monies?
Anthony Barton
The author is employed as a legal consultant by CMS Cameron McKenna (solicitors), who acted
for two of the defendants in the oral contraceptive pill litigation.
Competing interests: No competing interests
Regarding the increased risk of venous thromboembolism secondary to
the use of desogestrel, gestodene and more recently cyproterone containing
COCP's;
The answer is not judges and courts. How can an issue that has yet to
be satisfactorily resolved by both impartial resesarchers and drug
companies be hammered out over a few days by an individual who like myself
has very limited understanding of Cox regression etc. Furthermore, it is
hardly surprising that medical experts appear out of the woodwork for the
benefit of mankind or indeed monetary gain, although more so that some
evidence is ever accepted by the courts.
The issue is fairly clear to me. Patients who were not appropriately
counselled, (after prescribers were informed of the risks by their
regulatory bodies)who then suffered injuries should be compensated. It is
precisely because the clever doctors, statistician's and lawyers cannot
decide upon the real truth that no fault compensation is crucial in the
UK.
regards,
Anil Sharma
Competing interests: No competing interests
Re: Clinical implications of ruling on third generation contraceptives
In questioning whether there has ever been supportive evidence
for the introduction of desogestrel, gestodene, and norgestimate
as oral contraceptive (OC) progestogens, Paul O’Brien [1] ignores
the issue of arterial disease.
One rationale for the development of these steroids was a
widespread belief during the 1970’s that further safety
improvements could be made to OC beyond simply reducing the
doses of steroids. Although the majority of OC users appeared to
be content with existing formulations, there was a concern that
progestogens such as levonorgestrel were too closely related to
testosterone, the male hormone. An ideal progestogen was
envisaged as one that displayed progestogenic but not
androgenic activity. When combined with an estrogen, OC
containing these new steroids were predicted not only to reduce
the incidence of nuisance side-effects such as acne and hirsutism,
but also to reduce the risk of OC-induced arterial diseases such as
acute myocardial infarction (AMI) and stroke, both considered at
that time to be linked to ‘maleness’.
Whereas there was no consensus as to the mechanisms by which
OC increased the risk of venous disease, their influence on classic
determinants of arterial disease such as plasma lipoproteins, as
well as emerging markers such as glucose and insulin
metabolism, offered up a clear route to the development of ‘safer’
OC [2]. Against a background in the USA and elsewhere that
arterial diseases in both sexes were eminently preventable, the
metabolic profile of OC containing steroids such as desogestrel [3]
was of obvious interest.
The use of disease surrogates can and should be challenged: new
markers are constantly emerging while at the same time the
predictive value of established risk factors is under challenge. In
this instance the role of arterial disease surrogates in directing OC
reformulation is now supported by epidemiological evidence [4]
that, as predicted, ‘third generation’ OC do not cause AMI.
Competing interests: I have been consulted on the issue of arterial
disease risk by the defendants in the third generation OC litigation.
I was paid for that work.
[1] O’Brien PA. Clinical implications of ruling on third generation
contraceptives. eBMJ 1 October 2002
[2] Stadel BV. Oral contraceptives and cardiovascular disease. N
Engl J Med 1981;305:612-18
[3] Godsland IF, Crook D, Simpson R et al. The effects of different
formulations of oral contraceptive agents on lipid and
carbohydrate metabolism. N Engl J Med 1990;323:1375-81
[4] Spitzer WO, Faith JM, MacRae KD. Myocardial infarction and
third generation oral contraceptives: aggregation of recent studies.
Hum Reprod 2002;17:2307-14
Competing interests: No competing interests