Originating from the EMA Benefit-Risk Methodology Project, the effects table has become one of the most commonly discussed tools in the area of benefit-risk assessment (PrOACT-URL (Oct16)). In fact, its prominence has grown significantly since February 2015 when it became a CHMP requirement for EMA clinical assessors to include an effects table in European Public Assessment Reports (EPARs).
So, what is it? Well, an effects table is a useful qualitative tool for displaying a concise summary of the key benefits and risks of a new product (single or multiple doses) compared to either placebo or an existing product, and it may take both clinical and non-clinical endpoints into account. On initial inspection it may look simple to create but actually in reality this is not always the case. Some non-trivial decisions are needed regarding endpoints selection and study vs. meta-analysis results to include, handling different populations or data sources, or even whether to present subgroup effects. The answers may depend on the intended audience and their specific areas of focus.
With no standard format for these tables, our advice is to keep it simple, focussed and concise. Usually, columns of the table represent the treatment options and rows represent the endpoints. For real-life examples used to date in the regulatory environment we would point you to the EMA website for access to recent published EPARs.
OK, so that’s what they are but why should you create one?……Read on and find out….
- It drives alignment on key benefits and risks
Clinical trials traditionally include many endpoints and one of the challenges of constructing an effects table is to choose the most relevant and important ones to focus on for a balanced benefit-risk assessment. Nearly everybody involved on a drug development team will have an opinion on what the most important endpoints should be, these opinions however may not be consistent! You will need to decide as a multidisciplinary team (preferably in advance of new data) the list of key favorable and unfavorable endpoints, taking care to avoid inclusion of similar endpoints to ensure a fair assessment.
- It clarifies the way to measure and/or present key benefits and risks
For some endpoints, particularly in established disease settings, there is a well-accepted standardized approach for measurement. However, in other settings it may not be so straightforward. For continuous endpoints, data may be presented as a mean or % mean improvement, or dichotomized to understand how many patients reach a certain threshold, like 30% or 50% improvement. One measure needs to be selected for inclusion in the effects table. You also need to decide on the comparison to present i.e. absolute change within treatment arms, difference between arms and whether this is expressed as an absolute or relative difference. There may be even more fuzzy concepts like speed to onset of action. This will need to be conceptualized clearly but, for example, this may be measured using a time to event type of approach, a response at a specified time point or a mean change at a time point.
- It permits an opportunity to rank key benefits and risks
Arguably not all benefits and risks have the same importance and it may depend on the intended audience. For example, convenience will play a big role for some audiences but not for others. Ordering the rows of the effects table provides an easy way to reflect this importance. If more complex methods for weighting are used, these can be incorporated as well in the effects table with a column describing the weights.
- It can be used to look for consistency of the benefit-risk ratio across subgroups
An integral part of clinical trial analysis is to investigate whether the estimated overall treatment effect is broadly consistent across various subgroups of the intended population. You could most effectively achieve this by scanning down an effects table and/or forest plot that displays all subgroup analysis results for key benefits and risks together in one place.
- It’s an efficient tool to aid communication
Having a draft effects table in place before data read-out will enable discussions after database lock to focus on the results and what they actually mean. With all the key benefits and risks summarized together in one place, a simultaneous assessment of both favorable and unfavorable effects is made easier and facilitates communication of the key facts to internal and external stakeholders. Often the effects table is a precursor to further analysis steps, including visualization graphs. It’s fairly common now to see sponsors complimenting an effects table with a Forest Plot.
- The regulators will be creating one
Given that it’s now a CHMP requirement for EMA clinical assessors to include an effects table in their assessment reports it would seem prudent for sponsors to be proactive in preparing an effects table in advance. Better still, if it can be shared with regulators prior to submission then this may speed up decision making. Instructions for EMA clinical assessors to construct an effects table are given in section 5.6: EMA guidance on the content of the Rapporteur day 80 critical assessment report.
- It will facilitate internal governance reviews
“What was known before, what is new now and how does it change our view?” This is a typical question an internal governance committee might ask a team about the benefit-risk balance of the new product at a key milestone review or other decision point during product development. With an effects table in place, you could easily facilitate such discussions and show changes to the benefit-risk profile that have been driven by new data.
- It may help in payer discussions
EMA are ascertaining whether effects tables, as currently included in EPARs, are helpful for Health Technology Assessment bodies when carrying out relative effectiveness assessments of drugs. In preparing for payer interactions you may find it necessary to fine-tune the contents of your effects table. For example, a payer may be more open to inclusion of a patient preference based endpoint in the benefits section.
What’s your experience with effects tables? Please take a moment to share benefits and challenges that you have faced when creating and utilizing an effects table…..and stay tuned, our next blog will be coming soon to provide further guidance on how to select the right endpoints…..
By Delyth Jones, Veronique Robert, Alberto Garcia-Hernandez, and Alexander Schacht