May, 1998 —Completion of Study 377, companion study to 329 outside US, on 286 pediatric patients, to determine if paroxetine (Seroxat, Paxil) is effective in treating major depressive disorder (MDD) in this population. 196 subjects finish the entire 12 weeks. 60.5 percent of the Paxil patients respond, but so do 58.2 percent of those on placebo, forcing GSK to concede that "no statistically significant differences were observed at any time point." The study also fails on secondary measures. Twenty Paxil patients (11 percent) withdrew from the study due to adverse events vs seven (7.5 percent) in the placebo group, most from nervous system effects, including agitation, anxiety, and "emotional lability". There are four reported suicide attempts or drug overdoses in the Paxil group, all considered by investigators to be unrelated to the drug. Two experience "emotional lability" with suicidality and another was para-suicidal one day. All these events are recorded as unrelated to the drug. The results are never published.

April 3, 1998 —Consultant Sally Laden of Scientific Therapeutics Information (STI), responding to GSK invitation, submits a proposal to ghostwrite the results of Study 329. It is accepted.

October 14, 1998 —A memo from SKB employee Jackie Westaway to a number of people explains that the RCT did not show what the company had hoped:

"Please find attached to this memo a position piece, prepared by Julie Wilson of CMAT, summarizing the results of the clinical studies in adolescent depression.

As you well know the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of adolescent depression. The possibility of obtaining a safety statement from this data was considered but rejected. The best which could have been achieved was a statement that although safety data was reassuring, efficacy had not been demonstrated. Consultation of the marketing teams via Regulatory confirmed that this would be unacceptable commercially…"

October 14, 1998 —Attached to the Westaway memo (see item above) was the CMAT document,the Seroxat/Paxil position piece on the Phase III clinical studies, 329 and 377. It is marked FOR INTERNAL USE ONLY.

The position paper includes the following statements:

• There were no differences in the safety profile of Seroxat/ Paxil in adolescents when compared to that already established in the adult population.
• The efficacy data from the above clinical trials are insufficiently robust to support a regulatory submission and label change for this patient population."
• Based on the current data, and following consultation with SB country regulatory and marketing groups, no regulatory submission will be made for either efficacy of safety statements relating to adolescent depression… (because):
  1. regulatory agencies would not approve a statement indicating that there are no safety issues in adolescents, as this could be seen as promoting off-label use.
  2. It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine. This memo is interesting in light of the fact that SKB/GSK went on to protect the profile of paroxetine at the expense of young patients by promoting off label use.

Significant space is dedicated to analyzing "competitor activities". The paper makes reference to Lilly having almost completed

their phase III trials, while Pfizer (sertraline/Zoloft) are licensed in the US for treatment of adolescent OCD.

December, 1998 —Six-month extension phase of 329 trials completed.(See CMAT document, above)

December, 1998 —Sally Laden submits her first draft of the manuscript for the Study 329 article. The conclusion (see transcript page 139) on the first draft is: "Paroxetine is a safe and effective treatment of depression in the adolescent patient. Further studies are warranted to determine the optimal dose and duration of therapy".