FDA did not issue any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, let's look at the clinical inspection summaries for Addyi (Flibanserin) submitted by Sprout Pharmaceuticals (subsequently purchased by Valeant Pharmaceuticals. This compound has had a long history; more information on that may be found here, here and here.
The first set of inspections were conducted in 2010, when Addyi was known as Girosa and Boehringer Ingleheim sponsored two studies of this new molecular entity (NME) for HSDD in women. Three clinical sites were selected for inspection based on enrollment and contribution to the primary efficacy endpoints. FDA also notes that a Dr. Muckerman's site was closed by the sponsor due to a lack of involvement and oversight by the Principal Investigator (PI), failure to adhere to the protocol and suspected misconduct on another trial. The sponsor was inspected as well. Site inspections ranged from three to twenty four days, and the sponsor inspection lasted a week.
Dr. Conter was inspected and received a 483 for:
- Failure to report an adverse event and the associated concomitant medication used to treat the adverse event. Benadryl was used to treat a rash in one subject.
Dr. Comer was inspected and received a 483 for:
- A study progress report was delayed by two months for the required submission to the IRB.
Dr. Muckerman was inspected and received an inspection rating of "Official Action Indicated" (OAI) based on an extensive 483. (NOTE: There is no warning letter that is currently available on the FDA website for Dr. Muckerman.) According to FDA, the 483 included, but was not limited to:
- For study 75, 16 out of 51 subjects had one or more out of window visits. Fourteen of 28 subjects on study 84 had one or out of window study visits.
- For study 75, 2 of 28 subjects were randomized outside the protocol-defined screening window. Nine of 28 subjects were randomized outside the window for study 84.
- "Multiple" subjects were randomized to both studies despite meeting exclusion criteria or an incomplete review of inclusion criteria.
- The study coordinator for study 75 conducted assessments, despite lacking the qualifications to do so.
- Multiple subject visits for study 75 were not conducted per protocol; instead they were conducted via phone with study medication mailed to subjects.
- Drug accountability for both studies was inadequate.
- FDA notes that the PI was minimally involved, the designated study coordinator was not qualified and the data collected by the site were unacceptable. The sponsor was required to conduct a sensitivity analysis on the exclusion of the data, and chose to exclude the data for study 84 from the application.
Sprout Pharmaceuticals submitted the marketing application for Addyi in 2013 and three sites were selected for inspection, based on treatment effect, enrollment and a lack of a recent FDA inspection. Pages 200 through 208 here contain detail on how FDA applies statistical methodology to selection of sites for audit, as well as specific questions that the FDA inspectors were instructed to evaluate.
Dr. Lee was inspected and received a 483 for:
- Enrolling a subject who met exclusion criteria
- Missing subject questionnaires for four subjects
- Transcription errors in adverse event data for three subjects
- Six errors between source documents and a CRF page for one subject's data for one visit.