FDA Drafts Guidance on Demonstrating Substantial Evidence of Effectiveness

The US Food and Drug Administration (FDA) on Thursday issued draft guidance on demonstrating “substantial evidence” of effectiveness for drugs and biologics, expanding on decades old guidance issued to address statutory changes brought on by the Food and Drug Administration Modernization Act of 1997 (FDAMA).
 
Specifically, the 18-page draft guidance builds on FDA’s 1998 guidance Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, which detailed FDA’s expectations for evidence to support the approval of new drugs and biologics or applications for supplemental indications in light of FDAMA’s clarification that a single adequate and well-controlled clinical trial and confirmatory evidence can be used to support approval.
 
While FDA says its “standard for demonstrating effectiveness has not changed” since the 1998 guidance, the agency says that new guidance is necessary to keep up with scientific advancements and changes in drug development over the last two decades.
 
"As our scientific knowledge advances, and drugs and biologics with novel mechanisms are being developed to treat conditions that were previously without treatments, there is a need for additional guidance on the flexibility in the amount and type of evidence needed to establish their effectiveness,” said FDA Principal Deputy Commissioner Amy Abernethy.
 
Within the guidance, FDA discusses the level of quality and the quantity of clinical evidence needed to demonstrate effectiveness and provides examples of “circumstances where additional flexibility may be warranted,” such as for treatments for rare diseases or life-threatening or severely debilitating conditions where there is an unmet medical need.
 
"There are circumstances where evidence generated using a variety of clinical trial designs, endpoints and statistical methodology can support effectiveness, such as in certain drug development programs for rare diseases,” Abernethy said.
 
In addition to the “gold standard” randomized, double-blinded, controlled superiority trials, which FDA says are “regarded as the most rigorous design,” the guidance also discusses other types of designs, including placebo concurrent control, dose-comparison concurrent control, no treatment concurrent control, active treatment concurrent control and historical control designs.
 
The guidance also discusses when different amounts of evidence are appropriate to support approval, including two adequate and well-controlled clinical investigations or a single adequate a well-controlled large multicenter trial.
 
Additionally, the guidance provides examples of approaches based around a single adequate and well-controlled study:
 

• One adequate and well-controlled clinical investigation on a new indication for an approved drug, supported by existing adequate and well-controlled clinical investigation(s) that demonstrated the effectiveness of the drug for its other, closely related approved indication(s);
• One adequate and well-controlled clinical investigation supported by data that provide strong mechanistic support;
• One adequate and well-controlled clinical investigation with compelling results, supported by additional data from the natural history of the disease; and
• One adequate and well-controlled clinical investigation of the new drug, supported by scientific knowledge about the effectiveness of other drugs in the same pharmacological class.

 
FDA