The Food and Drug Administration (FDA) recently updated an important guidance document that is commonly referred to as the ‘substantial evidence guidance.’ This post explores the background of the substantial evidence standard, why it matters for rare disease therapy development, and what the RARE Foundation suggested in our comments to the FDA on the draft updates.
What is the Substantial Evidence Standard?
Since 1962, the law, or statute, governing how the FDA evaluates new treatments has required ‘substantial evidence of effectiveness based on adequate and well-controlled studies.’ As with most new laws, after Congress passes it, a federal agency is tasked with issuing rules or guidance to help implement it. After the FDA was first tasked by Congress to evaluate the effectiveness of a new treatment — rather than just safety, as was the case prior to 1962 — the Agency had to decide what Congress meant by “adequate and well controlled” studies. In 1970, the FDA published a final regulation, or rule, that required at least two clinical trials be completed that meet one of a list of acceptable trial designs, including placebo, active, or historical controls. Over the next decades, the “two-trial” standard became the default because the FDA wanted to ensure that results were reproducible to eliminate uncertainty.
While requiring two trials can and should work in many instances, most notably in larger disease populations with easy-to-measure outcomes, in rare diseases it is often not feasible or ethical to conduct two clinical trials, especially placebo-controlled trials. And while the FDA didn’t demand only placebo-controlled trials, over the years it has been treated as the default requirement with other types of controls largely considered as inferior.
Thankfully, in 1997, Congress clarified that the FDA can accept one adequate and well-controlled study plus “confirmatory evidence” to determine that there is sufficient evidence of effectiveness. In 1998, the FDA made it official by publishing guidance detailing examples of what it considers “confirmatory evidence,” including when repeating a trial may not be necessary or feasible. As science and regulatory tools have evolved, the guidance has been updated to provide more detailed examples of trial designs, analysis methods, and types of evidence that can be used.
The bottom line is that, through all the changes in law and guidance, one thing has remained consistent: the FDA must find substantial evidence from adequate and well-controlled studies to approve a new treatment. What has changed is the pathway that can provide that proof.
Where are we now?
In June, the FDA released an updated version of the substantial evidence guidance, primarily to clarify when they would consider one well-controlled trial and confirmatory evidence the “default” option rather than the exception. The update also provided more details on the type and strength of confirmatory evidence required.
Because of the unique challenges involved in developing and evaluating treatments for rare diseases, the FDA has largely considered one adequate and well-controlled trial plus confirmatory evidence as an acceptable way to meet the law’s requirement to demonstrate substantial evidence of effectiveness.
This begs the question: do the updates to the substantial evidence guidance matter for our rare disease community and if so, why?
Clear, up-to-date guidance is particularly important for rare disease therapy development, which often requires more adaptive, fit-for-purpose regulatory approaches, often referred to as regulatory flexibility. While we need flexibility, we also need predictability and consistency, two concepts that may seem to conflict with each other. Regulatory guidance is one way to provide greater predictability and consistency in decision-making without making requirements overly rigid, enabling a “fit-for-purpose” or “flexible” approach. When done well, guidance provides insight into HOW the FDA will approach decisions, giving companies and patient organizations working on rare disease therapy development the confidence they need to design studies, choose outcome measures, and plan statistical analysis.
Our Comments for the FDA
After reviewing the updated substantial evidence guidance with members of our Community Congress Regulatory Working Group, the RARE Foundation identified several areas that we felt needed clarification before the guidance is finalized to best strike that balance between clarity and preserving flexibility.
What did we ask FDA to address?
- Clarify the “highly persuasive” standard. The updated guidance introduced the concept of “highly persuasive” confirmatory evidence. In rare diseases, where a single well-controlled trial plus confirmatory evidence is already used in most cases, it is important for the FDA to ensure the bar they have set for “highly persuasive” is feasible in rare disease populations.
- Recognize patient experience and real-world evidence. The guidance recognized that in some rare disease treatments, it is reasonable to expect additional uncertainty in the evidence used to show a treatment has met the substantial effectiveness standard. We want to know more about how the FDA will use tools such as patient experience data, patient preference information, natural history studies, registries, and real-world evidence to inform decisions.
- Clarify that surrogate endpoints are not an “alternative approach” for many rare diseases. For many rare diseases, waiting for traditional clinical endpoints may take too long or may not be feasible, so measuring effectiveness using surrogate endpoints is the only path to a treatment. The updated guidance suggested that surrogate endpoints should be considered only as an “alternative approach” when using clinical endpoints isn’t feasible, but it did not specify what they consider when determining feasibility. FDA should clarify that surrogate endpoints are an accepted evaluation tool, not merely an “alternative approach,” and should work with sponsors and patient communities to qualify more surrogate endpoints so the accelerated approval pathway is more accessible to rare diseases.
- Use the Rare Disease Innovation Hub to improve consistency. There are A LOT of regulatory guidances, some narrowly focused on topics (like how to use patient input to develop an outcome measure), and some that are broader in scope (such as one providing advice on the approach to rare disease products overall). Recently, the FDA consolidated guidances relevant to rare diseases here, but we need to know more about how the advice in these guidances interacts and how they are applied in decision-making. The Rare Disease Innovation Hub is the perfect partner to ensure sponsors, reviewers, and patient advocates understand how related guidances, programs, and pathways fit together and how key terms should be applied in rare disease contexts.
What happens now?
The FDA will review all the comments they received, (you can too here). We are hopeful that the FDA will use these comments to adjust the draft guidance and then issue a final guidance soon. There is no deadline for this to occur, so for now, companies will use the insights from the updated draft guidance and continue to focus on engaging directly with the Agency early and often to try and obtain clear information about the type and amount of evidence needed to determine a treatment has met the substantial effectiveness standard.
