The default standard would see US drug and biologic approvals require a single, robust pivotal study plus confirmatory evidence, instead of two trials.
The US Food and Drug Administration (FDA) is putting in place a new standard that is set to eliminate the long-standing two-study requirement to approve drugs and biologics in the US.
Details were announced in the NEMJ by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research (CBER) director Vinay Prasad, in place of issuing an official policy document.
In their letter, the agency officials affirmed that by default the FDA will require one adequate and well-controlled study, alongside confirmatory evidence.
“The FDA will carefully examine all aspects of study design with particular focus on controls, end points, effect size and statistical protocols.
“Without examination of the quality of a study, two trials may even provide a false assurance.”
Makary and Prasad anticipate the move will facilitate an increase in drug development, mainly through lowering costs, because “a single pivotal study can cost between $30-150 million”.
Additionally, “the number of clinical studies is no safeguard against valid inference if all other aspects of trial design are deficient” they argued.
“If the control arm is substandard, the end points dubious, the statistical plan generated post hoc, the power inadequate, or all of the above, erroneous conclusions may be reached even with two, three, or four studies.”
Makary and Prasad anticipate the move will facilitate an increase in drug development, mainly through lowering costs"
However, life sciences adviser and former Head of Global Quality Investigations, Surveillance and Regulatory Communications at Viatris Dr Deva Puranam argued that overall, the standard “creates space for outlier results to be mistaken for genuine breakthroughs”.
As such, it creates an environment where approvals rest “on fragile data, therapies that fail to deliver outside controlled settings, and harm that later regulators will have to address under pressure”.
Dr Puranam proposed several alternatives to modernise evidence evaluation. These include “a single trial that is truly robust, larger, more diverse and more rigorous… confirmatory post‑marketing studies that are mandatory, enforceable, and taken seriously [or] greater transparency around statistical assumptions, and better use of real‑world evidence to complement not replace strong pre‑approval data.”
Recent US regulatory developments
This latest news follows the CBER’s refusal this month to review Moderna’s BLA for its seasonal influenza vaccine mRNA-1010.
The FDA’s refusal-to-file letter stated the lack of an "adequate and well-controlled" study with a comparator arm that "does not reflect the best-available standard of care."
Stéphane Bancel, Chief Executive Officer of Moderna, said: "It should not be controversial to conduct a comprehensive review of a flu vaccine submission that uses an FDA-approved vaccine as a comparator in a study that was discussed and agreed on with CBER prior to starting.”
However, a week later the FDA overturned its initial position, agreeing to review the submission on the basis that Moderna does an additional study in older adults as a post-marketing requirement.
This development also follows the FDA’s plans announced last September to introduce new principles to streamline the regulatory approval process for ultra-rare diseases drug developers in the US.
The next month, the agency shared details of a new abbreviated new drug applications (ANDAs) scheme aimed at prioritising review of generic drugs manufactured in the US. It is intended to encourage the onshoring of pharma manufacturing to the US, as mandated in an executive order by Trump last August.
