Drugs

Improve ‘Substantial Effectiveness’ Draft Guidance: Stakeholders

David McFarland

— 2 min read
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Four stakeholders are suggesting ways FDA could improve its draft guidance on substantial evidence of effectiveness for human drug and biological products. The Center for Science in the Public Interest (CSPI) says it “opposes any shift in the regulatory standard to a one-trial default….”

While the draft does not specifically state such a position, CSPI says, “the agency’s preferences are implicit and clear. The draft guidance thus needs significant revision to ensure that it aligns with the agency’s public health mission.”

CSPI asks FDA for its supporting evidence that justifies its position and also asks that it better define terms in the draft and consider the potential risks of extrapolation based on known effectiveness. “Two clinical trials not only serve to independently substantiate trial results (as the agency even acknowledged in the draft guidance) but also support the agency’s public health mission of ensuring the efficacy of human drug and biological products before they are released to the American public,” the comment letter says.

CPSI submits these specific comments:

  • FDA’s greater emphasis on relying on one trial plus confirmatory evidence is concerning;
  • the definitions of “confirmatory evidence” and “strong confirmatory evidence” are vague and subjective;
  • FDA should clarify expectations for a highly persuasive trial and define “early phase” confirmatory evidence;
  • the draft assumes knowledge not yet in evidence since no one can know before a trial is conducted how strong the evidence will be when it is completed;
  • FDA must place guardrails on extrapolation from one circumstance to another; and
  • FDA concedes the benefits of two trials.

In its comment, Pharmaceutical Research and Manufacturers of America (PhRMA) says it appreciates FDA’s efforts to articulate innovative, science-based approaches to demonstrate substantial evidence of effectiveness by revising an earlier draft guidance while upholding the agency’s gold standard of approval. PhRMA says it identified several areas in which the draft could benefit from revision and specificity:

  • relying on a single trial and confirmatory evidence;
  • clarifying the framework for relying on a single trial and confirmatory evidence;
  • definition of key concepts;
  • strength of evidence framework;
  • observational data;
  • externally controlled trials;
  • innovative trial designs;
  • regulatory flexibility;
  • safety databases and benefit-risk assessment; and
  • legal considerations.

The Duke-Margolis Institute for Health Policy says it is encouraged by FDA’s decision to revisit the legal standard for substantial evidence, given the institute’s focus on real-world evidence. It says there are three areas in the draft where further clarification by the agency would be most helpful going forward:

  • relationship to the 2023 draft guidance on demonstrating substantial evidence with one adequate and well-controlled clinical investigation and confirmatory evidence;
  • the role of real-world evidence and natural history data as confirmatory evidence; and
  • the term regulatory flexibility.

The Biotechnology Innovation Organization (BIO) says it welcomes FDA’s acknowledgement that substantial evidence may be established through an evidentiary framework tailored and adapted to indication and therapy, including one adequate and well-controlled study supported by confirmatory evidence when appropriate. “This approach,” BIO says, “appropriately recognizes that evidentiary considerations should be aligned with the specific characteristics of the disease, patient population, and therapy under evaluation and reflects a fit-for-purpose approach to evidence generation.” It asks that FDA consider these recommendations:

  • increase predictability and consistency of regulatory application;
  • clarify the one trial plus confirmatory evidence framework;
  • clarify confirmatory evidence and highly persuasive trial concepts;
  • expand practical guidance for rare disease drug development;
  • provide additional clarity about statistical considerations and evidence sources;
  • clarify interaction with existing FDA guidances; and
  • acknowledge global development and safety considerations.

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