This was probably the most ambitious of the CIOMS initiatives to date.
CIOMS V GOOD CASE MANAGEMENT AND
REPORTING PRACTICES
This
was probably the most ambitious of the CIOMS initiatives to date. It addressed
many of the new chal-lenges faced in pharmacovigilance, such as the Inter-net
as a source of individual case reports, together with many of the older
unresolved issues from previ-ous CIOMS initiatives (e.g. reporting and
labelling of deaths). The completed report was intended as a handbook for
pharmacovigilance departments and still offers many pragmatic solutions to a
number of issues. The title Current
Challenges in Pharmacovig-ilance: Pragmatic Approaches (CIOMS, 2001) was, therefore, an apt one.
The report is divided into the following five main subject areas:
• Sources of individual case reports.
• Good case management practices.
• Good summary reporting practices – periodic
safety update reports (PSURs) reconsidered.
• Population exposure data.
• Worldwide clinical safety reporting
regulations.
It
is not the intention to review the details of all the topics in this chapter
but some of the recommenda-tions and guidelines are of particular interest and
will be highlighted for the reader.
The
value of consumer reports has always been a point of issue between Europe and
North America. The CIOMS V consensus was that it is the quality of the report
and not the quality of the reporter that is important. It was agreed that
medical confirmation should be sought for consumer reports and that it is
important to distinguish between verification (i.e. that the events as related
by the consumer occurred) and confirmation of a suspected ADR (i.e.
attribution). It may even be appropriate to submit a consumer report to the
regulatory authorities as an expedited report when medical confirmation is not
obtainable if the case might influence the benefit–risk relationship or has
implications for labelling changes.
Companies
should routinely search at least two inter-nationally recognised databases for
case reports not less frequently than monthly. The clock-start date for
reporting is the date the reference was identified. If the paper is not in
English it may be appropriate to translate the abstract or relevant sections
only. Auto-mated searches should be supplemented to include publications
relevant to the drug or circumstances. That is, it is not adequate to search
only for references specific to a particular drug (e.g. salbutamol) when class
review may be appropriate (e.g. beta2 agonists). It was not considered
necessary to monitor the lay media but if information is made available on a
case, then attempts should be made to ascertain details.
It
was not considered necessary to surf the Internet beyond the company’s own
site(s) but it is advis-able to screen the latter daily for ADR reports. There
was also a suggestion that it may be useful to visit known sites from which
patients may obtain infor-mation on specific drugs and diseases. There was some
concern over the validity of case reports posted here, since the reporter may
not always be identifiable. It was agreed that if the site is secure the
company could encourage ADR reporting via its ‘home page’. This could be used
to advantage in gathering good quality data by ensuring that some fields were
made mandatory for completion.
Patient
support programmes are frequently used by pharmaceutical companies to obtain
follow-up data on product use (e.g. smoking cessation help lines). During the
course of conversation the patient may mention the occurrence of an adverse
event. It was agreed that the source of this report is neither truly
spontaneous nor from a clinical trial. An additional case source, the solicited
report, was proposed. It was suggested that these cases be collected and
processed separately and that a company causality assessment is required before
expedited reporting of serious solicited reports.
As
there are a large number of external databases it is unreasonable to expect
companies to review them for ad hoc signals.
However, they should be proactively monitored
when there are known specific problems (i.e. when there is a hypothesis). As
databases are used to generate signals there is no need to report individual
cases on an expedited basis. However, if an increased frequency of a serious
ADR is determined in an epidemiology study it may be appropriate to notify the
regulatory authority. Since individual case report forms are not always
appropriate, CIOMS V introduced the concept of a ‘15-day letter of prompt
notification’.
This
is important for determining any further action required to characterise a
case, in particular to estab-lish the accuracy of the diagnosis and appropriate
coding. It also enables the case to be suitably priori-tised for follow-up
and/or expedited reporting. It was recognised that many companies are coding
every event of which they become aware, even if not causally related to the
drug. The concept of an ‘inci-dental event’ was introduced. This is an event
which, although it occurs in reasonable temporal association with the use of a
drug, is not the intended subject of a spontaneous report and there is no
implicit or explicit expression of possible drug causality by the reporter or
the company. Cases in which only the inci-dental events are serious should not
be submitted as expedited reports.
CIOMS
V recommended the universal adoption of the ICH E2A definition of seriousness,
including medically important events. For consistency it was suggested that all
companies maintain a list of terms which should always be considered serious.
However, it was recognised that this could never be fully comprehensive and
that it does not replace medical judgement.
Cases
with a fatal outcome are only serious when the ADR is a direct or indirect
cause of death.
Events
are only expected when they are included in the ADR section of the reference
safety information (RSI). If they differ in nature, severity, specificity or
outcome, then they are unexpected. Class labelling and statements such as
‘relationship not established’ or ‘observed with similar frequency to placebo’
do not imply expectedness.
This
was perhaps the most contentious of all the discussions. Some regulators
considered that they needed to know about all reports of deaths, while
manufacturers generally maintained that they would be swamped with reports,
especially for drugs used in serious medical conditions. It was upheld that
cases with a fatal outcome were only serious when the drug caused or
contributed to death but there was general disagreement about whether this
could always be determined from individual case details, or implied if the case
was a spontaneous report. Further discussion centred on whether death was
considered expected or unexpected if it was not specifically mentioned in the
label (e.g. ‘anaphylaxis’ versus ‘anaphylaxis, some-times fatal’). It was
agreed that physicians should be aware of medical conditions frequently
associated with a fatal outcome and therefore the working group decided
actively to discourage indiscriminate labelling of deaths. The final outcome of
this discussion was to recommend that fatal reports should be expedited until
labelled and that all reports with a fatal outcome should undergo special
medical review.
Guidance
is given on prioritising cases for follow-up, the highest priority being given
to all serious cases; unexpected cases; special interest cases and those which
are uninterpretable in order to seek clari-fication. As always, the topic of
whether cases should be followed to resolution was raised as there was concern
that a non-serious rash, for example, may become Stevens–Johnson Syndrome. It
was suggested that when a letter of acknowledgement was sent, as is good
practice, the reporter should be asked to notify the company if any further
information becomes avail-able on the case.
Whilst
agreeing that the full ICH E2C format PSUR should be produced every 6 months
for most drugs, the working group recognised that this presents a number of
practical difficulties in terms of format and content. At one extreme, there
are high volume reports that may contain thousands of ADR case reports or an
unmanageable volume of publications. At the other extreme, there are older
drugs with a well-established profile for which there is little or no new
information to report. Modifications to PSUR content are proposed for the
former high volume reports and recommen-dations for simplifying reports, with
an example, are given for the latter. It is emphasised that the working group
is not suggesting new format reports but simply offering pragmatic suggestions
for adapting the ICH E2C content and format in certain circumstances.
One
of the greatest dilemmas in producing PSURs is fulfilling the different
frequency and periodicity requirements for different regulatory authorities in
different countries. For example, in Europe, the sched-ule for submission
changes to annual after 2 years and then 5-yearly after the first renewal.
Under ICH E2C provisions, regulators who do not wish to receive 6-monthly
reports are expected to accept two 6-monthly reports as an annual report or the
appropriate series of reports as a 5-year report. The working group therefore
proposed the use of the summary bridging
report to facilitate the review of a
series of reports. The summary
bridging report is a concise document integrating the information presented in
two or more PSURs that is submitted to a regulatory authority to cover a
specified period over which a single report is required. An example is
presented in the final report.
The
concept and use of the IBD for PSURs have not been fully accepted by all
regulators. Some require that PSURs are scheduled according to the local
approval date and, in addition, not all companies will have synchronised their
renewal dates by bringing them forward to the IBD in those countries where this
is permissible. To avoid producing additional reports for those countries
perceiving that any report with a DLP more than 60 days before submission is
out of date, the working group recommended the use of an addendum report. This is an update to the most recently completed
scheduled PSUR when a regulatory authority (or the company) requires a safety
update outside the usual reporting cycle, and more than a brief amount of time
has elapsed since the most recent PSUR. The working group proposed the minimum
information for inclusion in the addendum report.
Finally,
other issues of practical importance in managing the preparation of PSURs that
are not directly related to format and frequency are discussed. Many of these
topics were issues raised in a survey undertaken by the working group to
identify the current PSUR burden to industry.
This
chapter summarises the diversity of current regulatory reporting requirements,
pre- and post-marketing, for expedited and periodic safety update reporting,
many of which purport to be based on exist-ing harmonisation initiatives. It is
hoped that the plea for improved harmonisation will be heeded.
The
CIOMS V report was published in 2001 (CIOMS, 2001).
The CIOMS V Working Group addressed a range of the challenges that frequently arise in routine pharma-covigilance and therefore it is not surprising that their recommendations have been incorporated into more than one ICH guideline. As mentioned previously in this chapter, the practical guidance on the prepara-tion of periodic safety update reports was used in the addendum to the ICH E2C guideline and the defi-nitions and standards, including the new sources of individual case safety reports (e.g. Internet, solicited sources) and good case management practices, were used as a basis for the ICH E2D guideline on post-approval safety data management. Finally, CIOMS V is referenced under the design and conduct of obser-vational studies in the ICH E2E guideline on pharma-covigilance planning.
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