CIOMS IV can be regarded as a logical progression from both CIOMS II and III.
CIOMS IV - BENEFIT–RISK
EVALUATION
RATIONALE
CIOMS
IV can be regarded as a logical progression from both CIOMS II and III. The
aim of the working group was to develop guidance for regu-lators and
manufacturers on assessing the balance between benefits and risks of marketed
products with a newly established or suspected major safety prob-lem. It would
also provide guidance for deciding what options for action should be considered
and on the decision-making process should such action be required. Pragmatic
approaches to reassessing the benefit–risk relationship, producing a standard
report and good decision-making practices are highly desir-able, but no
standard existed. Although most signals will not warrant formal benefit–risk
evaluation, it was recognised that any concepts proposed by the work-ing group
would be useful in any periodic or special evaluation of relative benefits and
risks.
In
formulating its proposals the working group devel-oped, reviewed and made use
of actual case histories taken from the experience of companies and regula-tors
in several countries. These examples were used to illustrate basic principles
and methodologies as well as to suggest ways of displaying data in connection
with benefit estimation, risk estimation and benefit– risk evaluation.
Guidance
on the decision-making process and the use of outside experts was supported by
informa-tion from a survey of regulators and companies in which details of
recent significant safety issues and the decision-making process were requested.
The
proposals are very different from the usual case-specific ADR evaluations
undertaken in pharmacovig-ilance departments. Conventionally, these reports
focus on the ADR of concern and provide relevant details of pre-clinical,
clinical trial and post-marketing experience. The benefit–risk assessment
proposed by CIOMS IV takes into account not only the new signal but also the
overall safety profile of the product rela-tive to that of an appropriate
comparator. It examines not only the benefits and risks to the individual being
treated but also the net benefits across individuals being treated or, as with
the case of vaccines, the net benefit to society.
The
outline for the recommended standard format and content of a benefit–risk
evaluation report is as follows.
Introduction
• Brief description of the drug and where
marketed.
• Indications for use, by country if there are
differ-ences.
• Alternative therapies, including surgery.
• Very brief description of the major safety
problem.
• Epidemiology and natural history of the
target disease(s).
• Purpose of treatment (e.g. cure,
prophylaxis).
• Summary of efficacy and general toleration
data compared with other treatments or no treatment.
Note
that benefit does not equate only with clin-ical trial efficacy data. It also
includes additional measures such as quality of life, compliance with ther-apy,
outcomes and experience in the ‘real world’.
• Introduction.
• Weight of evidence for the suspected risk.
• Detailed presentations and analyses of data
on the new suspected risk.
• Probable and possible explanations.
• Preventability, predictability and
reversibility of the new risk.
• The issue as it relates to alternative
therapies and no therapy.
• Review of the complete safety profile of the
drug, using diagrammatic representations when possible (‘risk profiles’); when
appropriate focus on, for example, the three most common and the three most
medically serious ADRs.
• Provide similar profiles for alternative
drugs.
• When possible, estimate the excess incidence
of any adverse reactions known to be common to the alternatives.
• When there are significant adverse reactions
that are not common to the drugs compared, highlight important differences
between the drugs.
• Summarise the benefits as related to the
serious-ness of the target disease and the purpose and effectiveness of
treatment.
• Summarise the dominant risks (seriousness/
severity, duration, incidence).
• Summarise the benefit–risk relationship,
quantita-tively and diagrammatically if possible, taking into account the
alternative therapies or no treatment.
• Provide a summary assessment and conclusion.
• List all appropriate options for action.
• Describe the pros and cons and likely
conse-quences (impact analysis) of each option under consideration, taking
alternative therapies into account.
• If relevant, outline plans or suggestions for
a study that could provide timely and important additional information.
• If feasible, indicate the quality and
quantity of any future evidence which would signal the need for a re-evaluation
of the benefit–risk relationship.
• Suggest how the consequences of the recommended action should be monitored and assessed.
It
will be noted that the emphasis of the benefit–risk evaluation is on
quantification wherever possible and an example of a report prepared to CIOMS
IV spec-ifications would have been useful. There are exam-ples of previous
benefit–risk evaluations that illustrate the various methodologies that have
been used but they are not necessarily directly applicable to a manu-facturer
faced with a request for an urgent assess-ment. In particular, it would have
been valuable to include some guidance on how to create summary metrics that
combine benefit and risk data to allow straightforward quantitative comparisons
of different treatment options. An example is given in terms of potential lives
saved as the result of treatment versus potential lives lost as a result of
adverse reactions. The CIOMS IV report calls for additional research and
development of appropriate methodologies and metrics to introduce more science
and less art to this important area.
While
the logic behind the inclusion of most of these points is self-evident, it is
recognised that obtain-ing the necessary information, especially on the risks
and benefits of other manufacturers’ new products as comparators, is either
very difficult, or impossible, in practice. For older, but not new, products
this infor-mation may be found in the literature (see dipyrone example).The CIOMS
IV report was published in 1998 (CIOMS, 1998).
While regulatory authorities occasionally request CIOMS IV style benefit–risk assessments for specific issues with marketed products, their current focus is on risk management. ICH E2E, Pharmacovigi-lance Planning, reached step 4 in November 2004 and provides guidance on the Safety Specification and Pharmacovigilance Plan that are submitted at the time of a licence application. These documents summarise the important identified risks of a drug, important potential risks, important missing informa-tion including the potentially at-risk populations, situ-ations where the product is likely to be used but have not been studied pre-approval and the manufac-turer’s plan for discharging these risks. In Europe, Safety Specifications and Pharmacovigilance Plans were required for all new drug applications from November 2005. It is of interest that, although repre-sented on ICH E2E, the FDA has introduced its own requirements for risk management planning that are not in line with those proposed by ICH.
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