The U.S. Food and Drug Administration (FDA) has warned drugmakers seeking to enter the U.S. market based on overseas clinical trials. The message is to "think again" if they are building approval strategies around data obtained from sites the FDA has not been able to inspect directly or from environments where research ethics are in question.
The FDA will increase direct inspections of overseas clinical trial sites and strengthen oversight especially of phase 1 trials and early-stage research. It also plans to verify the sources of clinical trial data and research environments with drugmakers from the early stages of development, not just right before filing for approval.
On the 2nd (local time), four heads of key FDA departments published a joint editorial on the FDA's official channel, "FDA Voice," containing these points. The title is "Good clinical practice (GCP) is not optional: The FDA's commitment to protecting human subjects and the highest quality science in the era of global clinical research."
In the editorial, the FDA stressed that to decide whether to approve investigational drugs, it must be able to verify that the clinical data submitted by drugmakers are reliable.
It will also check whether subjects' rights and safety were protected, whether the trial underwent independent ethical review, and whether voluntary consent was obtained after sufficient explanation. It added that, when necessary, it must be able to directly review trial sites and related records such as source data and consent forms.
The FDA said the same standards must apply "whether in Boston or Beijing," and said it would block any perception that, simply because a site is overseas, there is a lower chance of inspection or that the same level of data can be accepted even if the FDA's access is limited.
Going forward, if the FDA cannot access trial sites and therefore cannot verify data, it may decline to recognize some or all of the materials submitted in an approval application as evidence.
If manipulated or invalid data, or duplicate data, are found, they may be excluded, and if the remaining materials do not meet approval requirements, the FDA can refuse, hold, or revoke approval.
The FDA said this is not about creating new regulations but about applying existing laws and principles to the global clinical trial environment.
It will also step up on-the-ground oversight. The FDA will expand overseas bioresearch monitoring (BIMO) inspection staff and increase foreign site inspections. Oversight will be strengthened in particular for phase 1 and early-stage research, investigator-initiated trials, and first-in-human clinical trials conducted outside the United States.
Verification will also be strengthened for research conducted overseas outside the investigational new drug (IND) or investigational device exemption (IDE) processes. Until now, such research could be used in U.S. approval applications if certain conditions were met.
The FDA noted that in early feasibility studies or phase 1 trials, geopolitical situations or human rights issues may make it difficult to confirm whether subjects' consent was truly free and voluntary. It also said past audits uncovered cases where sham trial participants were created, health status and test results were manipulated, and adverse events were concealed.
It will also move up the timing of communications with drugmakers. Rather than stopping at confirming data sources or whether IND or IDE applies just before filing, it will discuss related issues from the early stages of clinical development. The FDA plans to engage proactively with companies using pre-investigational new drug (pre-IND) meetings and formal inquiry procedures.
The FDA also decided to expand disclosures about future inspection findings. It is considering ways to inform companies and the public when it could not access overseas sites, investigators, or relevant documents, or when inspection conditions were limited.
At the end of the editorial, the FDA urged drugmakers to meet GCP and human subject protection principles from the start of clinical development and to design trials in environments where the FDA's access is not blocked.
It added that if a company is building its U.S. approval strategy around data from sites the FDA cannot inspect or from environments where serious questions have been raised about research ethics, it should "think again."
This FDA move draws attention as it coincides with a rapid increase in global clinical trials in China. According to the National Bureau of Economic Research (NBER), fewer than 8% of global clinical trials were conducted in China as of 2010, but by 2020, China had surpassed the United States in the number of clinical trials registered annually.
In August, Republican Reps. John Moolenaar and Ben Cline sent a letter to Acting FDA Director General Kyle Diamantas, noting that "accepting Chinese clinical data could pose a real risk to patients."