These days, even the ordinary lay press writes a fair amount about what is, and is not, good science. You would have to have a worm in your brain to miss the debates over whether health effects of this or that substance is supported by good and credible scientific studies or junk science, whether it be vaccines or peptides or beef tallow or whatever.
And there is a lot of bad science out there. AI fabrications and predatory publishers mean that citations to “published” study papers in “peer reviewed” “journals” should be deemed suspect until vetted by someone with a wary nature and the scientific chops to ask probing questions.
Discerning good science from bad is, of course, part of our everyday Rule 702 practice on the product liability side of the life sciences house.
But solid clinical trials are even more important on the research and development side of the house. So our readers may be interested to know that the FDA has issued a revised draft guidance indicating that in some circumstances, just one well-done clinical trial may be sufficient for a manufacturer to demonstrate the “substantial evidence of effectiveness” necessary for approval of a new drug application (NDA), biologics license application (BLA), or supplement.
That’s a big change. The new draft guidance document is Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (June 2026), and it is intended to replace a 1998 guidance as well as a December 2019 version of this draft guidance.
The guiding light of this guidance is, of course, the statutory definition of “substantial evidence” of drug efficacy from FD&C Act § 505(d)/21 U.S.C. § 355(d): That is, evidence consisting of adequate and well‑controlled investigations by qualified experts, sufficient to support a fair and responsible conclusion that the drug will have the represented effect under labeled conditions of use.
Key Factors Affecting the Strength of Clinical Trial Evidence
The guidance addresses five factors for testing the strength of a clinical trial under the “substantial evidence” inquiry:
1. Trial design. The trial must be “adequate and well‑controlled” in the sense of 21 C.F.R. § 314.126—i.e., capable of isolating the drug effect from other influences (spontaneous disease fluctuation, placebo effect, biased observation). The guidance discusses methods for control and randomization, how non-inferiority (NI) trials can be acceptably designed, and numerous other design topics, from blinding to endpoints to clinical relevance.
2. Trial conduct. The clinical trial must not only be well designed, it must also be well run. FDA will be looking at Good Clinical Practice compliance, data quality, protocol compliance, management of missing data, participant attrition, protection of interim trial results while the trial is ongoing, and the like.
3. Trial analysis plan. The right statistical considerations must be evaluated and in place, and if the prior evidence of effectiveness is weak and the sponsor hopes to rely on just one study, then more stringent significance levels will be required. An adequate and well-controlled trial needs a pre-specified primary analysis aligned with a clinically meaningful estimand (the specific target quantity or treatment effect intended to be measured).
4. Trial results. The trial results must be clinically meaningful, not just statistically significant. The persuasiveness of the study results will depend on:
• The magnitude and clinical relevance of the observed effect;
• The associated uncertainty;
• The degree of consistency across multiple relevant endpoints; and
• Robustness to plausible violations of analytic assumptions.
5. The overall development program. A single efficacy study also will be evaluated in the broader context of the drug’s development, such as
• Early‑phase data on mechanism, dose selection, and related indications;
• External evidence on disease pathophysiology and natural history;
• Evidence from related diseases or drugs with similar mechanisms.
Three Pathways to Demonstrate Substantial Evidence of Efficacy
Having laid out expectations for evaluating efficacy trials, the guidance identifies three pathways for using quality clinical trials to meet the substantial evidence of efficacy (even as it acknowledges that these three pathways are not exclusive):
A. One adequate and well‑controlled clinical investigation plus confirmatory evidence
FDA devotes substantial attention to circumstances under which a single adequate and well‑controlled clinical investigation, combined with confirmatory evidence, may suffice.
The Agency indicates that it will consider:
• Trial design, conduct, analysis, and persuasiveness of the single trial;
• Source and strength of confirmatory evidence;
• Disease characteristics (seriousness, unmet need, prevalence); and
• Ethical and practical feasibility of multiple trials.
FDA suggests that, in this pathway, the single trial will typically need to be “highly persuasive” and/or supported by “strong confirmatory evidence” given the absence of a second adequate and well‑controlled trial.
Examples of the confirmatory evidence that the Agency expects would be adequate include:
• Prior adequate and well‑controlled trials of the same drug in closely related indications (e.g., different stages of a cancer; related infectious disease sites; diseases sharing a common precursor or pathophysiology).
• Adequate and well‑controlled trials of other drugs in the same pharmacologic class, with closely similar mechanisms of action, comparable endpoints, and similar effects. Presumably, these could even be a competitor’s studies.
Alternatively, even if strong external or related‑trial confirmatory evidence is not available, FDA indicates that a single trial may still provide substantial evidence if that single study is a “highly persuasive” adequate and well‑controlled trial and there is early‑phase evidence (e.g., mechanistic, pharmacodynamic, or other early‑phase data) that can serve as the confirmatory evidence.
The guidance also notes that where clinical trial results are really that good (e.g., pronounced mortality reductions), conducting a second trial would be unethical or impractical. That too may suffice as the confirmatory evidence.
B. More than one adequate and well‑controlled clinical investigation
The guidance also recognizes the traditional pathway of multiple adequate and well‑controlled trials as a robust means to demonstrate substantial evidence. More than one clinical trial may be necessary to demonstrate substantial evidence of efficacy where:
• A single trial is not representative of the intended treatment population;
• The safety or benefit‑risk assessment requires additional exposure; or
• Specific deficiencies in the single trial leave residual concerns.
C. Leveraging known effectiveness of an approved drug
Finally, the guidance also recognizes that, in some cases, sponsors can meet the substantial evidence standard without conducting any new adequate and well‑controlled effectiveness trials by extrapolating known effectiveness from an approved drug to:
• A new population (e.g., adult to pediatric); or
• A new dose, regimen, route of administration, or dosage form
provided such extrapolation is scientifically justified and legally permissible.
Regulatory Flexibility: When and How FDA May Tolerate Greater Uncertainty
The final section of the guidance discusses “regulatory flexibility.” While the statutory effectiveness standard is constant and unchanging, how that standard is met may vary with clinical context. Quite reasonably, drugs addressing particularly severe diseases, unmet needs, or rare conditions warrant more regulatory flexibility than others.
As with all draft guidances, this one is nonbinding and open for public comment.
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