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# New Effectiveness Evidence Requirements Analyzed
- URL: https://www.fdaweb.com/new-effectiveness-evidence-requirements-analyzed/
- Published: 2026-07-29T12:00:00.000Z
- Updated: 2026-09-14T13:44:05.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5161540

As part of the HHS Operation TrialBlazer, FDA has revised a draft guidance on demonstrating substantial evidence of effectiveness in drug and biologic trials. Attorneys **William McConagha** and **Trevor Thompson** (Latham Watkins) say that while the revised guidance does not change the underlying statutory or regulatory paradigm for demonstrating substantial evidence of effectiveness, it introduces new concepts that sponsors should carefully examine.

Writing in an online [post](https://www.lw.com/en/insights/fda-revises-draft-guidance-on-demonstrating-substantial-evidence-of-effectiveness?ref=fdaweb.com), the attorneys list these key points:

· FDA notes that sponsors may opt to conduct more than one trial based on the needs of their specific development programs, but it frames one adequate and well-controlled trial plus supportive confirmatory evidence as the default requirement to meet the statutory “substantial evidence” standard;

· sponsors pursuing a single-trial development program will generally need to show either that the single trial is “highly persuasive” or that the confirmatory evidence is “strong”;

· FDA will consider the “persuasiveness and interpretation” of a single adequate and well-controlled trial’s results in the context of early-phase trials supporting the drug’s mechanism and selected dose, as well as any relevant external information relating to the overall drug development program, such as disease pathophysiology or natural history; and

· sponsors should align with FDA on an evidentiary strategy early in clinical development, particularly in settings where certain clinical considerations warrant “regulatory flexibility.”

“Overall,” the attorneys say, “the revised guidance meaningfully rewrites the 2019 guidance, but it largely expresses what has become FDA’s current practice and what FDA has described in other guidances and documents. The key takeaway is that it formally positions one adequate and well-controlled investigation plus confirmatory evidence as the default requirement for drug and biologic development programs.”

The attorneys say the guidance lists these factors affecting the strength of evidence: trial design, trial conduct, trial analysis plan, trial results, and aspects of the overall development program.

The post lists these practical implications for sponsors:

· **plan for a single-trial program as a viable possibility:** FDA suggests that one adequate and well-controlled trial plus confirmatory evidence is the new norm, shifting the focus away from the prior default of two adequate and well-controlled trials;

· **engage FDA early:** regardless of the approach taken, FDA stresses that sponsors should discuss their proposed development program with FDA early in development, and no later than at the end-of-phase 2 meeting;

· **build toward a highly persuasive trial:** sponsors considering a single-trial approach should read the revised guidance closely to ensure their trial matches the characteristics FDA associates with a highly persuasive trial, including a generalizable, representative design across multiple sites, a control arm, a clinically meaningful primary endpoint, and sufficient power to demonstrate an effect convincingly; and

· **ensure an adequately sized safety database:** FDA emphasizes that a finding of substantial evidence of effectiveness is necessary but not sufficient for approval, which also requires sufficient safety data and a favorable risk-benefit determination. In addition to ensuring a trial is highly persuasive, sponsors should plan to generate a safety database of adequate size and duration.