Safety Concerns in Neurological Clinical Trials: A Challenge That the FDA Must Resolve.

Monoclonal antibodies approved by the FDA, lecanemab, donanemab, and aducanumab, are failing to meet the expected efficacy to treat early Alzheimer's disease, and aducanumab has been recalled. : Recently, it was reported that the clinical trials of these antibodies may have violated patient's rights and subjected them to high, likely lethal risk. The challenge with developing antibodies to treat neurological disorders is their poor blood-brain barrier (BBB) penetration if the antibody must enter the brain, resulting in almost negligible brain bioavailability, requiring high dosing that can be toxic. : The reported efficacy of these drugs should also be reviewed, considering the placebo effects, since all antibodies have shown severe side effects that are not prevented by the placebo responses. In this critical and urgent advice to the FDA, I am suggesting a guideline amendment to all clinical trials requiring proof of sufficient brain bioavailability at the site of action, where it is known. : For antibodies to cross the blood-brain barrier, there are proven options such as conjugating with transferrin protein, making clinical trials in its absence more questionable.