CIOMS IV - Benefit–Risk Evaluation

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.

PROCESS

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.

RECOMMENDATIONS

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.

Benefit Evaluation

•   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’.

Risk Evaluation

•   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.

Benefit–Risk Evaluation

•   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.

Options Analysis

•   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).

INCORPORATION IN REGULATION

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.