Substantial evidence, the evidentiary standard for effectiveness established in 1962 by the US Federal Food, Drug, and Cosmetic Act (FD&C Act), is the measure against which all drugs and biologics are approved in the United States. This standard is, in large part, what makes the FDA’s approval standard often considered the worldwide “gold standard” for drug approvals. Now, recent draft guidance issued by FDA looks to refine this standard even further.
Background
While FDA has long interpreted the substantial evidence standard to generally require two adequate and well-controlled clinical investigations, it has also long applied flexibility in applying the standard.
Amendments to the FD&C Act enacted by the US Congress in 1997 made clear that, among other things, FDA could consider evidence from one adequate and well-controlled clinical investigation coupled with “confirmatory evidence” to constitute substantial effectiveness of evidence in place of the standard requirement of two such studies.
To best understand FDA’s application of the substantial evidence standard, applicants and other stakeholders needed to understand how this standard has been applied across the scores of individual drug and biologic approval decisions, but could also consult the 1998 guidance for industry on Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.
In 2019, FDA published a second (complementary and updated) guidance titled Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.
While we understand that FDA may be working to finalize the 2019 guidance (and while both of these draft guidances touch on the concept of confirmatory evidence), the industry has not had, until recently, standalone or focused guidance on confirmatory evidence and has largely had to rely on understanding of individual approval decisions to triangulate FDA’s thinking on the topic.
New Draft Guidance
Given the frequency with which confirmatory evidence is employed in drug and biologic applications to establish—sometimes successfully and sometimes not—substantial evidence of effectiveness, guidance on this important topic was indeed welcome when in September 2023 guidance for industry titled Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence was published.
The draft guidance outlines considerations when planning to use confirmatory evidence in lieu of a second study, the types of data that may be appropriate in this circumstance, and how and when to engage with FDA on these matters.
When May One Study Combined with Confirmatory Evidence Be Sufficient?
In the draft guidance, FDA discusses the following factors when considering the use of confirmatory evidence and this paradigm:
- The clinical context matters, including with respect to any unmet clinical need that the development program is seeking to address as well as the size of the anticipated patient population;
- The quantity of confirmatory evidence required using this framework is expected to vary from application to application and is likely impacted by the “features of, and results from, the single adequate and well-controlled clinical investigation that the confirmatory evidence is intended to substantiate”;
- The value of confirmatory evidence can be called into question by conflicting evidence that otherwise must be submitted in a marketing application unless there is a sufficient justification to explain the conflict; and
- There may be instances in which the one study coupled with confirmatory evidence may not be appropriate, including when additional clinical data may be required for a determination that the product would be safe for its intended use.
Types of Data That May Be Considered Confirmatory Evidence
The draft guidance describes the types of data sources that may be used in employing the one study plus confirmatory evidence paradigm, noting that it anticipates that these assessments will be made on a case-by-case basis.
Specifically, FDA anticipates that confirmatory evidence data may arise from the following:
- Clinical evidence from a closely related indication, in particular where there are sufficient similarities between the two mechanisms of action and the efficacy endpoints used;
- Mechanistic or pharmacodynamic evidence, in particular where the physiology and mechanism of action are well understood and where the mechanism of action directly targets the driver(s) of the pathophysiology;
- Evidence from a relevant animal model, in particular where there are similarities in pathophysiology, manifestations of disease, and mechanisms of action sufficient to support that the animal data are translatable to human clinical benefits and outcomes;
- Evidence from other members of the same pharmacological class approved for the same indication, in particular where the class has a common mechanism of action, similar endpoints, and homogeneity of drug effects on clinical outcomes;
- Natural history evidence, in particular where there is uncertainty regarding the control group data in the clinical study and where the data is distinct from data otherwise employed in the clinical study;
- Real-world evidence derived from real-world data (RWD), in particular where there is high-quality and reliable RWD and, when applicable, with sufficient quality of study design; and
- Expanded access data, in particular if the relevant data is of sufficient quality and quantity.
Interactions with FDA Concerning Confirmatory Evidence
Applicants that are considering submitting marketing applications that seek to use the one clinical study coupled with confirmatory evidence paradigm are encouraged by FDA to discuss these plans early with FDA, including at a pre-IND meeting, but no later than when the applicant seeks feedback on its clinical investigations generally, such as at an end-of-phase 2 meeting.
Information provided to the agency in connection with such interactions should include (1) the scientific rationale for the approach generally, (2) the anticipated design of the single clinical study, and (3) the type/data source and quantity of anticipated confirmatory evidence.
Recommendations
Applicants seeking to use or plan clinical development programs using confirmatory evidence combined with data from a single trial should consider these recommendations early in development and engage with FDA on these matters early and often, in particular, as a development program may evolve. Interested stakeholders should also comment on this draft guidance, with the comment period currently scheduled to close on December 18, 2023.