On September 19, FDA released a highly anticipated new draft guidance for industry titled Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. The draft guidance expands on Section 115 of the Food and Drug Administration Modernization Act (FDAMA), as well as corresponding 1998 and 2019 guidance documents, which focused on demonstrating substantial evidence of effectiveness outside of the traditional two-study requirement.
The 2019 draft guidance provided several examples of situations when confirmatory evidence may be acceptable but did not provide much detail to be helpful to sponsors. This new draft guidance provides more examples and additional clarification on how the substantial evidence of effectiveness requirement can be met with one adequate and well-controlled clinical investigation and additional confirmatory evidence. The draft guidance does not address related topics such as demonstrating safety or demonstrating substantial evidence of effectiveness with a single, multicenter study.
FDA offers several general principles that sponsors should adhere to if they intend to demonstrate substantial evidence of effectiveness with a single adequate and well-controlled clinical investigation and confirmatory evidence. Like the earlier guidance, this draft guidance highlights that the quantity of confirmatory evidence required to demonstrate substantial evidence of effectiveness may vary depending on the clinical investigation. Adequate and well-controlled clinical investigations that are particularly strong may require less confirmatory evidence compared to a clinical investigation that is less compelling. Additionally, sponsors should have “scientific support” for their plan to demonstrate substantial evidence of effectiveness, including taking into account relevant “clinical context” factors. FDA also recommends that sponsors engage with the agency as soon as possible if they intend to use confirmatory evidence to demonstrate substantial evidence of effectiveness.
The draft guidance offers several examples of when certain types of confirmatory evidence could be appropriate for demonstrating substantial evidence of effectiveness:
- Related Indication. According to the draft guidance, clinical evidence from a drug’s use in a related indication can serve as confirmatory evidence in some instances. The two indications must be sufficiently similar for the evidence from a related indication to serve as confirmatory evidence. Additionally, the drug’s mechanism of action in each indication should be similar.
- Mechanistic or Pharmacodynamic Evidence. Another category of evidence that the draft guidance indicates could serve as confirmatory is mechanistic or pharmacodynamic evidence. Use of this type of evidence requires extensive understanding of both the underlying disease and the drug’s mechanism of action with respect to the disease. The draft guidance states that this type of evidence may be collected in vitro or by measuring a clinical endpoint.
- Animal Studies. The draft guidance also identifies certain instances in which animal studies may serve as confirmatory evidence. In order for animal data to qualify as confirmatory evidence, the disease state in the animal model must be well understood and sufficiently similar to the human disease state. Additionally, the drug’s mechanism of action between the animal model and humans should be similar. Given that animal studies are often conducted in the preclinical stage, FDA recommends consulting with the agency before those studies are conducted if the sponsor intends to use data from animal models as confirmatory evidence.
- Drugs in the Same Pharmacological Class. Clinical evidence from drugs that are in the same pharmacological class as the drug being developed can serve as confirmatory evidence, provided that the drugs have the same mechanism of action. The draft guidance states that using data from drugs in the same pharmacological class as confirmatory evidence is more appropriate when the pharmacological class is large and has an established, uniform effect.
- Natural History. The draft guidance also highlights instances in which natural history evidence may successfully act as confirmatory evidence. The primary instance in which natural history evidence may prove useful is demonstrating that the control group is an accurate representation of the typical disease course. To do so, there should be no overlap in the natural history data and the control data.
- Real World Evidence (RWE). Of particular interest to industry is the draft guidance on when real world data (RWD) and evidence can be used as confirmatory evidence. The draft guidance clarifies that RWD and RWE can be used as confirmatory evidence in two contexts: when seeking approval of a new indication for a previously approved drug and when completing post-study requirements. This has generated some concern that FDA may be limiting the instances in which RWD and RWE can serve as confirmatory evidence, including barring it from serving as confirmatory evidence for a first-time drug approval. Furthermore, the agency will look to factors such as the rigor of study design and statistical analysis to determine if the RWD meets the requisite standards for generating RWE.
- Expanded Use of an Investigational Drug. The final example of confirmatory evidence that the draft guidance provides is evidence from the expanded use of an investigational drug. The draft guidance points out that rarely will expand access protocols generate the requisite information for the data to be used for research. However, in the instances where expanded access data is reliable and complete, it can serve as confirmatory evidence for the results of an adequate and well-controlled clinical investigation.
The examples of confirmatory evidence listed in the new draft guidance on demonstrating substantial evidence of effectiveness are not exhaustive. However, these examples indicate the types of confirmatory evidence that may be accepted by FDA and highlight the factors that the agency looks to when determining whether data can serve as confirmatory evidence. This provides a roadmap for industry as to when sponsors may be able to demonstrate substantial evidence of effectiveness outside of the traditional two-clinical-investigation model.
Lauren Limbach, a law clerk in our Boston office, contributed to the drafting of this post.