FDA 483 - Jon B. Cole, MD - April 23, 2019

The FDA inspection revealed significant non-compliance in clinical investigations. The sponsor failed to submit Investigational New Drug (IND) applications for studies (b)(4) and (b)(4) prior to conducting them. Legally effective informed consent was not obtained for 747 subjects in study (b)(4) and at least 874 subjects in study (b)(4), with no applicable exceptions.

Numerous changes in research activity were not approved by the Institutional Review Board (IRB) prior to implementation. For study (b)(4), serious adverse events (SAEs) were not reported to the IRB, an additional treatment regimen (Haloperidol at 10 mg) was added without IRB approval, and 747 subjects were enrolled, exceeding the 500 approved and 737 reported to the IRB. An annual progress report was submitted past the approval expiration. For study (b)(4), SAEs were not reported, the study continued after a voluntary suspension and closure submission, subject enrollment notifications were discontinued, and over 874 subjects were enrolled, exceeding the 800 approved. An additional AMSS Data Validation sub-study was conducted without IRB approval.

Investigations were not conducted according to the investigational plan. Documentation was lacking for subject Notification of Enrollment forms and training of Research Volunteers. Case histories were inadequate, lacking identification of personnel for screening, EMR data collection, and data validation. There was no documentation of