FDA issued a draft guidance, Demonstrating Substantial Evidence of Effectiveness for Human Drugs and Biological Products (Draft Guidance), on December 19, 2019, as an expansion of its 1998 guidance, Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998 Guidance). The 1998 Guidance provided examples of evidence that FDA could consider to be confirmatory evidence to potentially support FDA approval of a marketing application based on one adequate and well-controlled clinical trial. The new Draft Guidance provides further detail on clinical trial design considerations, as well as forms of confirmatory evidence that sponsors may consider when proposing to rely on a single adequate and well-controlled clinical trial.

FDA was careful to state that its evidentiary standard for effectiveness has not changed since 1998. However, because there are more programs studying serious diseases that lack effective treatments, more programs in rare diseases, and more programs for therapies that are targeted at disease subsets, there is a need for more guidance on FDA’s exercise of flexibility in the amount and type of evidence needed to meet the substantial evidence standard.

Per the Draft Guidance, FDA may rely on one large multicenter trial without confirmatory evidence when the trial demonstrates “a clinically meaningful and statistically very persuasive effect on mortality, severe or irreversible morbidity, or prevention of a disease with potentially serious outcome,” and where confirmation of the result in a second trial would be impracticable or unethical. Notably, while FDA provided specific examples of situations in which a second study would be unethical, the agency did not provide further guidance on when a second trial would be impractical. However, assumedly, one situation in which a study could be impracticable may be when there is a small available patient population. FDA also cautioned that, when relying on a single large trial, there must be close scrutiny of trial conduct and any inconsistent findings from other studies.

FDA may also rely on a single adequate and well-controlled trial plus confirmatory evidence. Whether FDA will do so, however, depends on a number of factors, including the following:

  • The persuasiveness of the trial
  • The robustness of the confirmatory evidence
  • The seriousness of the disease and if there is an unmet medical need
  • The size of the patient population
  • Whether it is ethical and practicable to conduct more than one adequate and well-controlled study

Confirmatory evidence could include any of the following:

  • Adequate and well-controlled studies in a related disease area
  • Certain types of real-world evidence
  • Compelling mechanistic evidence
  • A well-documented natural history of the disease
  • Scientific knowledge about the effectiveness of other drugs in the same pharmacological class

When an approved drug is under development for a new population, dose, regimen, or dosage form, FDA states that, when scientifically justified and legally permissible, it may rely on previous findings of effectiveness, thus not requiring additional adequate and well-controlled studies. This ordinarily would be appropriate when other types of evidence demonstrate effectiveness for the new population, dose, regimen, or dosage form. The Draft Guidance does not, however, provide further information regarding when reliance on previous findings of effectiveness may be legally permissible. The 1998 Guidance, though, specifically discusses the extrapolation of adult study data to pediatric use, which is addressed in the Federal Food, Drug, and Cosmetic Act. Assumedly, legal permissibility may also depend on whether other products have blocking FDA exclusivities and whether reference-listed drugs, to the extent applicable, have Orange Book-listed patents.

Overall, FDA is more apt to exercise flexibility on the number of required studies and study designs when a product is for a life-threatening and severely debilitating disease with an unmet medical need, for certain rare diseases, or potentially for more common diseases where the availability of existing treatments makes trial design choices infeasible or unethical. The Draft Guidance specifically outlines trial design, endpoint, and statistical considerations for each of the above circumstances, as well as the number of trials that FDA may require.

As a final point, one portion of the Draft Guidance that may be of interest even to those sponsors who are planning to conduct two adequate and well-controlled studies is FDA’s discussion that two trials with design differences may be more persuasive in supporting a product candidate’s efficacy than two identical trials. FDA states, “Although two positive identically designed and conducted trials can provide substantial evidence of effectiveness, precise replication of a trial is only one of a number of possible means of obtaining substantiation of a clinical finding and, at times, can provide less persuasive evidence of a benefit, as it could leave the conclusions of both trials vulnerable to any systematic biases inherent to the particular study design.” Instead, “[t]wo positive trials with differences in design and conduct may be more persuasive, as unrecognized design flaws or biases in study conduct will be less likely to impact the outcome of both trials.” For example, sponsors may use two studies using the same endpoint but with distinct study populations within the same proposed indication. Sponsors may also use two trials in the same disease state with different but related clinical endpoints.

The Draft Guidance is further evidence that FDA is addressing patient advocacy group and industry concerns regarding the need to find more workable approaches to reduce the time and cost of clinical trials, especially for drugs for unmet medical needs. Sponsors considering a one-study development program should use the guidelines in the Draft Guidance to construct the development rationale presented to FDA. Additionally, FDA is accepting comments until February 18, 2020, providing industry with an opportunity to further shape this policy.