Some examples of studies that have been performed are discussed in this section.
SPECIFIC STUDIES USING INTENSIVE
MEDICINES MONITORING PROGRAMME DATA
In
addition to the routine data analysis performed for every monitored medicine,
the cohort and event databases of the IMMP are increasingly being used for
specific pharmacoepidemiology studies. Some examples of studies that have been
performed are discussed in this section.
The
IMMP has performed unique post-marketing safety studies on IUDs and has
effectively adapted PEM methodology for this purpose (Zhou, Harrison-Woolrych
and Coulter, 2003). Both the copper IUD Multiload Cu375 and the
levonorgestrel-releasing device Mirena have been monitored by the IMMP. Cohorts
were established with the use of registration forms supplied (by the
manufacturer) with each IUD. Doctors completed the registration form at the
time of IUD insertion and returned it to the IMMP. Follow-up questionnaires
were then sent annually for each woman, usually to her GP, but often to family
planning doctors or gynaecologists if this was more appropriate.
For
Multiload Cu375, in addition to the routine IMMP reporting (Coulter, 1997), two
specific studies were conducted using a cohort of over 16 000 women who used
this device in NZ during a 10-year period. The first study was an analysis of
insertion problems and reported an overall incidence of approximately 2% for
failed/difficult insertion and an incidence of about 1% for adverse reactions
to insertion (Harrison-Woolrych, Ashton and Coulter, 2002). This study, which
is thought to be the largest study of IUD inser-tion published to date, also
identified nulliparity and experience of the inserting doctor as risk factors
for inserting problems.
The
second Multiload Cu375 study investigated the incidence of uterine perforation
with this device (Harrison-Woolrych, Ashton and Coulter, 2003a). The rate of
1.6 per 1000 insertions was higher than previ-ously reported, and one reason
for this was thought to be the long period of intensive follow-up (10 years) in
the IMMP study compared with other studies. Most uterine perforations (86%)
were not diagnosed at the time of insertion with some remaining undiagnosed for
several years.
The IMMP also performed a comparative study of the Multiload
Cu 375 device and the levonorgestrel IUD Mirena (Harrison-Woolrych, Ashton and
Coulter, 2003b). This reported a significantly higher incidence of insertion
problems with the Mirena device than with the copper IUD, although difficult
insertions were reported in fewer than 4% of Mirena insertions. The
levonorgestrel IUD is now widely used in NZ and many other countries for contraception
(and menorrhagia) and comparative studies of this kind are of great value in
assisting women and their doctors to make appropriate choices
(Harrison-Woolrych, 2003).
Using
similar methodology to the UK PEM scheme, the IMMP routinely collects
information on pregnan-cies in women taking the monitored medicines. All
pregnancies are followed up to determine outcome for the mother and baby. In
the IUD studies, infor-mation was collected on both inadvertent pregnancies and
planned pregnancies after device removal.
Paediatric
use of atypical antipsychotic medicines has been a recent focus of interest for
the IMMP. A population of children (defined as age 15 years or under) has been
identified from the IMMP cohorts, and specific follow-up questionnaires have
been sent to child/adolescent psychiatrists and/or the children’s GPs. This
study is seeking information primarily on adverse events in children but also
on indication for use, the duration of treatment and reasons for stop-ping the
medication. Data on the safety of medicines in children are often very limited,
and frequently pre-licensing trials do not include a paediatric popula-tion, so
post-marketing studies of this type are very important.
Earlier
in this chapter, we explained how the NHI number of every patient in the IMMP
cohorts can be linked to national morbidity and mortality databases to perform
record linkage studies. Generally, this type of pharmacoepidemiology study is
most useful for study-ing deaths and more serious events, which result in
hospital admission (GP consultations are not recorded in the NZHIS databases),
and NZ is an ideal country in which to perform such studies.
The
IMMP is currently developing a data-linkage approach to perform studies on the
four atypical antipsychotic medicines
clozapine, olanzapine, quetiapine and risperidone. Having these four
cohorts established for the same time gives the potential to perform
comparative studies. Routine IMMP follow-up of patients on these medicines (via
their doctor) has proved very difficult, and response rates have been
significantly lower than for other medicines. Using record-linkage methodology
allows a higher propor-tion of patients to be followed up, often in a more
time-efficient manner. Information obtained on clin-ical events from national
databases can subsequently be checked or supplemented with further detail from
patients’ doctors.
There
are limitations to data-linkage studies
e.g. usually less detailed information will be obtained than from IMMP
follow-up questionnaires, information on risk factors for events is frequently
not available and only events resulting in hospital admission or death are
recorded. However, for the investigation of specific events, e.g. ectopic pregnancy
in Mirena users or sudden cardiac death in patients taking sibu-tramine,
data-linkage methodology may be extremely useful.
The
ability to identify individuals who are suscepti-ble to ADRs has the potential
to reduce the personal and population costs of drug-related morbidity. Data
from the IMMP cohorts and events databases have been used to initiate
pharmacogenetic studies, and it is hoped that this will be another area of
future development.
A
pilot study has been conducted to investi-gate the methodology of linking PEM
studies with pharmacogenetics in the IMMP (Clark et al., 2004). This study used a nested case–control design to
investigate whether patients with genetic variants in P-glycoprotein and CYP2C9
are more susceptible to psychiatric or visual disturbances following COX II
inhibitor use than matched controls taking the same medicine without
experiencing an adverse event. This paper by Clark et al. also discusses some future direc-tions for linking
pharmacoepidemiology studies with pharmacogenetic investigations.
A
high priority for the IMMP is provision and feed-back of information to
prescribers and patients. Every spontaneous report submitted to the IMMP
receives a detailed individual reply that includes (anonymized) information
from the IMMP databases. Similarly, information is provided in response to
telephone or other enquiries on a daily basis. In addition, summaries of IMMP
work on particular medicines are regularly provided to individual doctors or
those working in a specialist area – e.g. a summary of work on the Mirena IUD
was e-mailed to all family plan-ning clinics in NZ via the Family Planning
Associa-tion network.
Reports
of IMMP data and studies are regularly provided to the Ministry of Health
(Medsafe) and the MARC, with summaries of these reports published in the MARC
minutes. IMMP reports may raise new signals or other issues for consideration
or might provide reassuring data on emerging issues. The IMMP also provides
reports for information to the NZ licensing committee (MAAC) and – with the
agree-ment of the NZ Ministry – will provide information to other national
committees or other international regu-latory authorities on request. As NZ is
a small country, collaboration in pharmacovigilance with other coun-tries is
valuable, and data may be pooled and expertise shared.
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