This article was originally published on Westlaw.

Background

A drug’s effectiveness must be established by “substantial evidence,” which is defined as:

“…adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

In 1997, Congress authorized FDA to accept, “based on relevant science,” data from one adequate and well-controlled clinical investigation and confirmatory evidence as sufficient to establish substantial evidence. Previously, the statute was interpreted by FDA generally to require two adequate and well controlled clinical investigations.

FDA’s Confirmatory Evidence draft guidance provides additional details on the sources of confirmatory evidence, supplementing FDA’s December 2019 draft guidance “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” and May 1998 final guidance “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.”

Importantly, the draft guidance shows how the use of a single study plus confirmatory evidence exists on a sliding scale in which the quantity of evidence needed to confirm the findings from a single adequate and well-controlled clinical investigation may vary based on “the features of, results from” the single study. As the agency states: “It may be possible for a highly persuasive adequate and well-controlled clinical investigation to be supported by a lesser quantity of confirmatory evidence, whereas a less-persuasive adequate and well-controlled clinical investigation may require a greater quantity of compelling confirmatory evidence to allow for a conclusion of substantial evidence of effectiveness.” Note that the single study need not always be “highly persuasive.” Under the draft guidance, a single study that does not reach the level of being “highly persuasive” may still be sufficient depending on the quality and quantity of the confirmatory evidence.

Last, while generally outside the scope of the new guidance, FDA notes that when relying on prior findings of safety and effectiveness for another drug product as confirmatory evidence, based on studies for which the sponsor lacks a right of reference or does not own, additional considerations beyond those applicable to standalone applications may apply.

Examples of confirmatory evidence to establish substantial evidence of effectiveness

Clinical evidence from a related indication. Data from a clinical investigation for a “different but closely related indication” may provide confirmatory evidence, particularly when the product is approved for one indication and an adequate and well controlled investigation is conducted to support a new indication. Among the factors critical for demonstrating substantial evidence with this type of confirmatory evidence are: (1) the degree of similarity between the indications, (2) the degree of similarity in the drug’s mechanism of action in the diseases, and (3) the degree of similarity between the efficacy endpoints in the two diseases.

Mechanistic or pharmacodynamic (PD) evidence. Mechanistic evidence of the drug’s effect in a particular disease may be appropriate to use as confirmatory evidence. In such cases, (1) the pathophysiology of the disease should be well understood and (2) the drug’s mechanism of action should be both clearly understood and shown to directly target the major driver or drivers of the disease pathophysiology. Mechanistic evidence may be obtained from a variety of sources, including clinical testing of a relevant and well-understood pharmacodynamic endpoint not accepted in itself as an endpoint to establish effectiveness or in vitro testing.

Evidence from a relevant animal model. The draft guidance provides that “[i]nfrequently… sponsors can use data from an established animal model of disease as confirmatory evidence of effectiveness,” and in such cases, “sponsors should discuss in advance these planned nonclinical studies with the appropriate FDA review division.” Whether data from an established animal model of disease would be suitable as confirmatory evidence depends on such factors as the:

• similarity of pathophysiology and manifestations of the disease in the animal model and in humans,
• elucidation of the drug’s mechanism of action with evidence of similar pharmacology and pharmacodynamics in the animal model and humans with disease, and
• evidence that the results of efficacy studies conducted in the animal model reasonably support clinical benefits and outcomes in humans with disease.

Evidence from other drugs in the same pharmacological class. FDA advises in the draft guidance that evidence of effectiveness from adequate and well-controlled trials of other drugs in the same pharmacological class may provide confirmatory evidence, depending on the following factors:

• The mechanism of action of the new drug, which should be the same as that of approved members of the class.
• The extent to which similar endpoints were measured across the class, and the homogeneity of each drug’s effect on clinical outcomes.
• The consistency and predictability of the measured effect among drug class members.
• The number of drugs approved in the class.

Natural history evidence. FDA notes in the new guidance that natural history evidence is useful “when there is uncertainty about whether the outcomes observed in the control group accurately reflect those that would have been expected in the absence of the intervention.” These data should be distinct from data used as a control within the single adequate and well-controlled clinical investigation.

Real-world data/evidence. As we have previously analyzed online here, FDA recently developed its program to evaluate the potential use of real-world evidence (RWE) to help support the approval of a new indication for an already-approved drug or to help support or satisfy post-approval study requirements. Whether a real-world data (RWD) source may be appropriate to develop RWE that serves as confirmatory evidence depends on several factors, including but not limited to the reliability and relevance of the RWD source and, when relevant, the quality of the study design and the use of appropriate prespecified statistical methods and analyses.

Evidence from expanded access use of an investigational drug. The new draft guidance also briefly addresses how patient outcome information collected under expanded access use of the drug may be considered by FDA for use as confirmatory evidence, so long it “is of sufficient quantity and quality to be highly persuasive.”

The agency cautions, however, that “typically…only limited and inconsistent information is available from expanded access” because “source documents are often lacking, diagnostic criteria and stage of disease may vary, [and] monitoring and outcome assessments vary across patients.” As a result, “such information provides an incomplete picture of the course of events, which may make the information unfit for use as confirmatory evidence,” the draft guidance warns. Even so, with some advanced planning, we believe there are steps sponsors can take to enhance the quality of data from expanded access use in an effort to persuade FDA to accept that data as confirmatory evidence. We previously discussed FDA’s latest expanded access guidance online here.

Next steps

Whether a single adequate and well-controlled clinical investigation supported by confirmatory evidence provides substantial evidence of effectiveness is determined on a case-by-case basis. Moreover, it is important to remember that successfully leveraging confirmatory evidence to establish effectiveness does not mean that the same evidence will necessarily be sufficient to support drug safety; these are separate requirements for drug approval and the scope of the guidance is limited to effectiveness. As always, FDA recommends that sponsors discuss early with the agency plans for use of clinical investigations and confirmatory evidence to establish substantial evidence of effectiveness.

FDA is accepting comments on the draft guidance through December 18. If you wish to submit a comment, or have any questions on using clinical investigations and confirmatory evidence to demonstrate “substantial equivalence,” please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

Authored by Lynn Mehler, Dave Fox, Robert Church, Blake Wilson, Komal Karnik Nigam, and Bryan Walsh

This article was originally published on Westlaw.