Meyboom, RHB., Egberts, ACG., Edwards, IR, Hekster, Y,A., Konig, FHP. & Gribnau, FWJ. 1997
Principles of Signal Detection in Pharmacovigilance. Drug Safety 16(6) 355-365.
Clinical trials are inherently limited in their ability to produce data regarding adverse effects,
especially when these are rare and unexpected. Therefore, at the time of marketing of a drug, the
knowledge of its tolerabiltiy is inevitably incomplete. Druing the years following the launch of a drug,
this knowledge of its tolerability is ineviably incomplete. During the years following the launch of a
drug, this knowledge usually increases, for example, with regard to pharmacology, clinical use and
adverse effects.1
Clinical trials (phase III and IV) are especially effective in providing information on type A adverse
effects. Characteristically, they combine qualitative with quantitative data, but their use is inhrently
restricted to effects with high frequency and a short induction time.2
Despite clinical trials prior to licensing, rare or delayed ADRs are often unknown at
the time a pharmaceutical product enters the market. This is because such trials are
limited in time and number of patients, usually have an efficacy rather than safety
focus, and are usually performed in selected patient groups. New Zealand (NZ)
implemented a national surveillance scheme in 1965 and was one
of the founding members of the World Health Organization (WHO) International
Drug Monitoring Programme when it was established in 1968. Today, the ‘New
Zealand Pharmacovigilance Centre’ (NZPhvC) is the national centre responsible for
monitoring adverse reactions to therapeutic products in NZ. The aims of the NZPhvC
are to identify any
side effects of a medicine as early as possible; to determine the frequency of such
adverse effects and which patient groups may be at highest risk of the adverse
event;
and to report these findings to Medsafe which in turn takes appropriate action
leading
to the safer use of medicines in NZ. The reports are prioritised, so that the more
serious adverse events receive early
Died—due to adverse reaction
Died—drug may be contributory
Died—unrelated to drug
Died
Unknown
1
Meyboom, RHB., Egberts, ACG., Edwards, IR, Hekster, Y,A., Konig, FHP. & Gribnau, FWJ. 1997 Principles of
Signal Detection in Pharmacovigilance. Drug Safety 16(6) 355-365
2
Meyboom, RHB., Egberts, ACG., Edwards, IR, Hekster, Y,A., Konig, FHP. & Gribnau, FWJ. 1997 Principles of
Signal Detection in Pharmacovigilance. Drug Safety 16(6) 355-365
Spontaneous reporting limitations Under-reporting—major weakness of all
spontaneous reporting systems
Selective reporting due to differing thresholds
for reporting amongst health professionals
(reporting bias)
Lack of denominator for events so not able to
provide incidence rates
Poor at detecting delayed ADRs
Rates of reporting influenced by publicity
With regard to your request for more information on suicides with antidepressants the data previously
provided for an OIA was as follows: How many people in New Zealand have committed suicide between
June
2001
and
June
2011
while
being
prescribed
Amitriptyline
One
report
Clomipramine
hydrochloride
No
reports
Doxepin
hydrochloride
One
report
Dothiepin
hydrochloride
No
reports
Imipramine
hydrochloride
No
reports
Maprotiline
hydrochloride
No
reports
Mianserin
hydrochloride
No
reports
Nortriptyline
hydrochloride
No
reports
Phenelzine
sulphate
No
reports
Tranylcypromine
sulphate
No
reports
Moclobemide
No
reports
Citalopram
hydrobromide
One
report
Fluoxetine
hydrochloride
Two
reports
Escitalopram
No
reports
Setraline
No
reports
Paroxetine
hydrochloride
Five
reports
Venlafaxine
One
report
Mirtazapine
No reports
Table : Source of spontaneous reports 2007-2011
Reporter Type % of 5 Years Total
GP 24.90
Hospital Doctor 11.64
Hospital Pharmacist 4.26
Community Pharmacist 8.23
Nurses 22.74
Other HCPs 2.82
Pharmaceutical Company 16.10
Public 1.61
Other 7.70
From the total number of spontaneous reports with suicidal behaviour or suicide
reaction terms 71.5% have been assessed as Causal.
Table : Number of reports per year with reaction term “Suicide”
Year Report Received Number of Reports
1993 1
1994 1
1995 2
1998 1
1999 1
2000 1
2001 6
2002 2
2003 2
2004 3
2005 3
2006 1
2007 3
2008 3
2009 10
2010 3
2011 3
Thank you for contacting me. Answers to your questions below are as follows:
Reporting rate:
New Zealand, along with more than 100 other countries, is a member of the WHO National Centres
group. All of these countries send anonymised copies of adverse reaction reports to the WHO
International Collaborating Centre in Uppsala Sweden on a regular basis. The reporting rate is then
calculated on a six-monthly basis by the WHO Uppsala Collaborating Centre based on the number of
reports from the individual country and that country’s population. New Zealand was one of the
founding member countries of the WHO International collaboration and one of the first countries to
set up an adverse reactions reporting centre (1965) so reporting is well established here. Over time,
other countries have improved their reporting rates and in 2010 New Zealand was relegated to
second place by Singapore.
Reporters:
In the past, GPs have been the main group of reporters, however the numbers now show Nurses as
the largest group but this can be attributed to Practice Nurses completing the forms on-line for the
GPs and Immunisation Nurses sending in adverse reaction reports for vaccines. I have attached a
pdf showing the proportions over the years 2006 to 2011. Specialists operating in a Hospital setting
are included in the ‘Hospital Doctor’ group while private Consultants are included in the ‘Other
HCPs’ group. We are unable to identify the individual ‘Specialties’.
You will note there was a large number of reports from the ‘Public’ and ‘Other’ in 2008 and this was
due to the heightened public and media awareness of the Eltroxin product.
Enhanced Consumer Reporting:
CARM has always accepted reports from Consumers and in the past year we have included an online reporting form on our website which does not require a User and Password login (previously
required and only health professionals were accepted). We have not actively promoted this option
though as we do not have the resources to deal with a large increase in report numbers should it
occur.
Regards
Janelle
Janelle Ashton
Manager Information Systems
NZ Pharmacovigilance Centre
DDI:
+64-3-4799043
FAX: +64-3-4797150
Email: Janelle.ashton@otago.ac.nz
F15.1 = Mental and behavioural disorders due to use of other substances (alcohol)
Z91.5 = Suicide attempt
From:
To:
Subject:
RE:
Date: Mon, 26 Sep 2011 04:28:58 +0000
Toran
janelle.ashton@otago.ac.nz
taiwhenua1@hotmail.com
Henry
Dear Maria
We have been advised by the Ministry of Health that apparently there was an oversight in our
previous email correspondence to you in so far as we omitted to provide you with a copy of the entry
in the CARM database
The CARM database does hold reports of suicide and suicidal tendency with the SSRI’s and
by way of example over the history of use of Fluoxetine in New Zealand there are 9 reports
each of suicidal tendency and suicide attempt and 3 reports of suicide. Considering that
SSRI’s are prescribed for depression and as covered in the two extracts mentioned, it is not
possible in these reports to conclude that fluoxetine was a causal factor just as much as the
possibility that worsening depression in the early stages of treatment may be a factor.
Once again please accept my apologies for this late response.
With best wishes
Michael
Dr Michael Tatley
Director: New Zealand Pharmacovigilance Centre and
Centre for Adverse Reactions Monitoring
Dunedin School of Medicine
University of Otago
In the 1950s a brave American woman called Frances Kelsey did something I have come to learn is
rare in the world of drug regulation. She stood up against the pressure of a large pharmaceutical
company and refused to approve its drug because she had concerns that its clinical trials were not
sufficiently robust to provide a satisfactory level of evidence that the drug they wanted to market
was safe.
This company had conducted clinical trials that were poorly designed and ignored any results that
did not show the drug in a good light. The drug was launched on the British market for example, two
months after the researcher advised “it would seem unjustifiable to use the drug for long term
therapy, pending the results of more detailed study of its long term effects in a larger series of
patients.”
This company did not conduct tests on adverse reactions in pregnant women but marketed their
drug to prescribers as safe for both pregnant women and their babies and ignored reports that the
drug produced a wide range of adverse reactions which mirrored the results from its own trials. It
pushed its "completely nonpoisonous, completely safe" campaign in 50 advertisements in major
medical journals, 200,000 letters to doctors around the world, and 50,000 circulars to pharmacists.
By the end of the first year, sales had reached 90,000 packets per month. The drug found its way to
all comers of the globe including 11 European, 7 African, 17 Asian, and 11 North and South American
countries.
When a well known specialist, wrote asking whether the company had any knowledge of the drug’s
effects on the nervous system, despite reports to the company about such effects the drug company
replied "Happily, we can tell you that such disadvantageous effects have not been brought to our
notice."
Through connections with a friendly editor of a medical magazine, the company successfully delayed
publication of a paper which showed a strong link between the drugs use and a serious adverse
reaction. An internal company memo read "Sooner or later we will not be able to stop publication of
the side effects. We are therefore anxious to get as many positive pieces to work as possible."
Four years after the drug hit the market, nearly 64 million tablets had been prescribed and the
company was sending pamphlets to doctors claiming that it could “be given with complete safety to
pregnant women and nursing mothers without adverse effect on mother or child."
The drug Frances Kelsey refused to approve was Thalidomide.
Following the Thalidomide disaster, adverse reaction monitoring programmes were established by
the World Health Organisation in recognition of the fact that clinical trials are a very poor vehicle for
identifying potentially disastrous adverse reactions and that the real testing for adverse effects
commences once the drug is unleashed on an unsuspecting public.
The Journal of Drug Safety explains
Clinical trials are inherently limited in their ability to produce data regarding adverse effects,
especially when these are rare and unexpected. Therefore, at the time of marketing of a drug, the
knowledge of its tolerabiltiy is inevitably incomplete. Druing the years following the launch of a drug,
this knowledge of its tolerability is ineviably incomplete.
Pharmacovigilance, according to the WHO is “the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other drug-related problem.”
Both the World Health Organisation and the New Zealand Government promote the view that New
Zealand has one of the best pharmacovigilance programmes in the world. The combination of
spontaneous reporting, intensive medicines and vaccine monitoring, the performance of causality
assessments for all reports received and feedback to reporters are amongst the features of our
system that are credited with our apparently having the highest adverse reporting rate in the world.
So, with an international pharmacovigilance programme in place the events that led to the
Thalidomide disaster couldn’t happen again could they? And New Zealanders, having such a superior
pharmacovigilance programme should be safer than most when it comes to adverse drug reactions,
right?
How would we measure that? Well according to the WHO the aims of PV are “to enhance patient
care and patient safety in relation to the use of medicines; and to support public health programmes
by providing reliable, balanced information for the effective assessment of the risk-benefit profile of
medicines.”
So does New Zealand have a superior record in patient care and safety in relation to medicine use?
Does it inform its public health programmes with reliable, balanced information based on effective
risk-benefit assessment of medicines?
In a word…No . In several words, the evidence is that we actually do worse on these measures than
other countries.
According to Medsafe, New Zealand reports approximately 5% of all adverse reactions. Their
evidence of this? That our adverse reaction reports are higher than other countries per head of
population. In fact, it is entirely possible that in fact we have a higher rate of adverse reactions to
medication than other countries. Perhaps because we have high prescribing rates, significant
populations of people from ethnic groups with higher prevalence of genetic variations which
influence the metabolism (and therefore the adverse reaction rates) and a host of other factors.
In response to an information request to the Chief Coroner, a TV journalist was advised that while
Coroner’s do not systematically gather or record data on medication use of suicide victims, there is
evidence that "Of the 497 deaths ruled as suicide in the 2008 calendar year, 162 had been
prescribed some sort of anti-depressant, anti-psychotic or anti-anxiety medication at the time of
their death." That’s a third of all suicide victims and does not include those where no information
was gathered by the coroner, where the victim was withdrawing from the drug or where other drugs
such as anti-acne and smoking cessation drugs strongly linked with suicide, were being prescribed.
So in what proportion of those cases did a medical professional report a suspected adverse reaction
to our pharmacovigilance agency CARM? Data provided by Dr Michael Tatley, director of CARM
shows that in 2008 CARM received 3 reports of Adverse reactions containing the reaction term
‘suicide.’ That is, 1.85% of the most conservative estimate of suicides that year, who had current
prescriptions for psychiatric drugs with known links to suicide, were reported to CARM.
My son hanged himself that year, 15 days after being prescribed fluoxetine. The trainee psychiatrist
who prescribed the drug did not report a suspected adverse reaction to CARM. Neither did that the
consultant psychiatrist who was his superviser, another consultant psychiatrist who was assigned to
oversee his care, any of the six other psychiatrists who reviewed his file prior to his inquest, the
psychiatrist who was the clinical director of the clinic he attended, his GP or any other medical
professional involved in his care. His mother reported but her report fell through the cracks and as a
result of an oversight, she was not provided with an acknowledgement of its receipt, a causality
assessment or data on other suicides on the drug until 3 and a half years after his death –
conveniently after the inquest into his death had been completed and the causality assessment
could not be used as evidence to support recommendations the Coroner might make to prevent
future suicide deaths.
SSRI antidepressants and severe agitation, severe restlessness/akathisia, and/or increased
suicidality “The removal of these reactions has been recommended by the MARC due to a good level
of prescriber awareness having been achieved.”
5