Clarifying differences between proposed RWE guidelines and observational studies guidance

Jennifer Carroll

Could you clarify how the proposed RWE guidelines differ from the existing PAAB Guidance on Observational Studies? Most RWE data comes from observational retrospective and prospective cohort studies. Are these proposed guidelines going to supersede/replace the existing guidelines? The box, icon, and disclosures are not featured as requirements in the existing Observational Studies guidance.

In comparison to the current approach, the proposed future approach represents a substantial broadening of the sorts of RWE presentations that can be included in an APS. We’ve contrasted between the current approach and the proposed future approach below.

Current approach

In short, the guidelines in current use limit observational study presentations to those that replicate the findings from an acceptable RCT. Additionally, the observational study presentation in the APS must be preceded by the corresponding RCT presentation for the same claim.

We currently determine that the observational study supports the same claim (as opposed to a new claim) by ensuring that the following are aligned with the RCT:

ENDPOINT:
The endpoint in the observational study presentation must be identical to that in the corresponding RCT.
COMPARATOR(S):
The observational study presentation in the APS may be comparative or non-comparative. If the observational study presentation is comparative, the comparators are limited to those in the corresponding RCT or TMA presentation.
DURATION:
The duration of the observational study can be no longer than the duration of the corresponding RCT. A longer observational study is not accepted as this would convey a new claim relating to extended duration of effectiveness.
MAGNITUDE OF EFFECT OR SAFETY:
The magnitude of effectiveness or safety in the observational study is NOT expected to be identical to that in the RCT. However, they must be similar enough to avoid the suggestion of a different degree of effectiveness or safety. The magnitude of effect must not differ from that demonstrated in the corresponding RCT presentation in a way that would be medically relevant to HCPs who are knowledgeable in the medical condition.
STUDY POPULATION:
The population in the observational study is NOT expected to be identical to the that in the RCT. However, they must be similar enough to avoid the suggestion of effectiveness or safety in a different population.

Ultimately, under the current approach, the observational study is not the evidentiary basis for an APS presentation. It merely conveys an additional context in which the results from an RCT were replicated. The PAAB assessment is therefore predominantly focused on ensuring that there is adequate alignment in the endpoint, comparator, duration, magnitude of effect, and study population when the observational study is employed to corroborate findings in the TMA or an acceptable RCT.

There is currently no requirement for a box, icon, or statement of limitations as the observational presentation does not act as the evidentiary basis for an APS presentation. Rather, the preceding RCT is the evidentiary basis. That was a first step in acceptance of RWE in advertising.

The proposed future approach

The proposed draft guideline outlines the next step forward. Per these proposed guidelines, there is no need for the RWE to have the same comparators, duration, magnitude of effect, and/or study population as an acceptable RCT.

There is no requirement to precede the RWE with an RCT evaluating the same subpopulation, endpoint, and/or comparator. In fact, such an RCT need not even exist.

As the RWE would now act as the basis of evidence for the presentation, prominent differentiation from other presentations (as achieved by the icon & box) and a clear disclosure of limitations becomes critical.

Will the proposed future guidelines replace the existing ones?

No, it will be added to the existing guidance. RWE presentations limited to findings that have replicated those from an acceptable RCT (and which follow the corresponding findings from that RCT in the APS) will continue to be permissible. They will continue not to require the icon, box, and key study limitations. This is intended to minimize impact on previous ad approvals.
Presentations which are not limited to findings that replicated those from an acceptable RCT (or which do not follow the corresponding findings from that RCT in the APS) will become permissible if the standards in the proposed guidance are met (as opposed to requiring deletion).