Timeline

1986 — Employees of Lilly tamper with the fluoxetine (Prozac) data to remove the suicidal incidents, to provide better support for its application to the FDA. (See Oct 24, 1994)

December 29, 1987 — Prozac (fluoxetine hydrochloride) is approved by the FDA.

December 18, 1989 — Article: New York magazine publishes a cover article, “Bye Bye Blues” about Prozac, calling it a “wonder drug” for depression, weight loss, anxiety, PMS and nicotine withdrawal. The article is unremittingly positive: “Given the number of people taking Prozac and the absence of problems so far, most physicians are impressed.”

February, 1990 — Article: “Emergence of intense suicidal preoccupation during fluoxetine treatment” by Martin Teicher et al. The authors note that: “Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.”

1990 — Across the United States, Prozac Survivors Support Groups form to help people who have been harmed by Prozac, including a National Group headed by Bonnie Leistsch in Louisville, Kentucky. The Citizens Coalition on Human Rights sets up a hotline to put callers in touch with a support group in their area.

May 30, 1991 — (Allan Gelberg) Acting Chief, Surveillance and Data Processing Branch, Center for Drug Evaluation and Research (CDER) of the FDA notes that since it was marketed in 1988, Prozac (fluoxetine) has had the highest number of adverse event reports submitted to the FDA National Adverse Drug Reaction Reporting System Database.

June 19, 1991 — SKB submits A Review and Evaluation of Clinical Data, Original NDA 0-31, Paroxetine (Aropax). Martin Brecher, M.D., DM Sc. conducts the review. He finds that: “Together the safety and efficacy data allow for the conclusion that paroxetine is safe and efficacious and approvable for marketing.” The FDA response by Tom Laughren: “The safety and efficacy findings for paroxetine were presented to the PDAC on this date (10-5-92) and they unanimously agreed that Paroxetine has been demonstrated to be safe and effective.” The data reported in the review show a rate of suicidal acts that is 2.5 times higher in the paroxetine group than the placebo group, but the presentation hides this fact.

Sept 20, 1991 — FDA Pharmalogic Drugs Advisory Committee holds hearings on the resolution that: “there is credible evidence to support a conclusion that SSRI antidepressant drugs cause the emergence and/or intensification of suicidality and/or other violent behaviors.” Five of 9 Advisory Committee members, and 3 of the 6 consultants had clear conflicts of interest re: ownership of drug company shares, but at the hearing, the issue of conflict of interest is set aside as follows: “The following announcement addresses the issue of conflict of interest and is made part of the record to preclude even the appearance of such at this meeting. In accordance with the prepared agenda, there will be no specific issues dealing with a specific product or sponsor presented to the committee for review and evaluation during this meeting. Therefore, it has been determined that all committee members may fully participate in today’s meeting without the risk of any conflict of interest, as defined…” Despite a day of testimony from many people who have experienced Prozac-induced tragedies of violence and suicide, the Committee votes against the resolution, and no warnings are required for SSRIs. (See Hearings Transcript Page 10)

December, 1992 — FDA approves paroxetine (Paxil) for major depressive disorder (MDD) in adults in December, 1992 on the basis of the June 19, 1991 Review. When Study 329 becomes controversial, many critics acknowledge that while the adolescent studies appear to show that the drug does not work and might not be safe for this population, it has been proven safe and effective for adults when the actual data did not support this conclusion. A proposal for use of the drug for adolescents is initiated.

Aug 26, 1993 — SmithKlineBeecham approves the proposal to study use of paroxetine for MDD in adolescents. Dr Neal Ryan, Child Psychiatrist at Western Psychiatric Institute and Clinic Pittsburgh (UPMC), is named lead investigator. Shortly after, Martin Keller is designated as lead.

April, 1994 — Study 329 trials begin

Sept 28, 1994 — Trial: Joyce Fentress et al vs Eli Lilly commences in Louisville, Kentucky. Joseph Wesbecker was depressed, and his physician puts him on Prozac a second time in August, 1989, although he has a history of bad reaction to the drug. After two weeks in which his behaviour is increasingly bizarre and erratic, he goes to the print shop where he works, armed with an AK47, and wounds 12 people, kills 8 (including Kenneth Fentress), then turns the gun on himself. The evidence against the drug is solid so the defence uses a strategy of discrediting Wesbecker.

Oct 24, 1994 — Testimony: An expert witness on the proper conduct of randomized control trials (RCT) to test medication for approval, Dr Nancy Lord, testifies in Fentress about the trials conducted in the 1980’s to support Lilly’s FDA application to approve Prozac. She notes that “The data was flawed for a number of reasons”(See transcript pages 47 – 50):

• “They (Lilly) permitted the use of… psychotropic concomitant medications” “taking fluoxetine all by itself has never been studied”, (they allowed trial subjects to be given benzodiazepines, to reduce the side effects of Prozac by treating them);
• “They broke the blind.” (The investigators did things likely to reveal who was taking Prozac in the trials and cherry picked subjects for the next phase);
• “They did not code adverse experiences correctly.” (Adverse events were not reported to the FDA as required, or were reported as something less serious;
• “They never really did Phase 3; they did a large Phase 2. They did the same protocol over and over.” (Phase III trials are required for FDA approval; they test the drug on a population that matches real life as closely as possible);
• “They didn’t use adequate samples” (size not large enough to determine significance);
• “It looked like they did everything possible to kind of tone down the problems with the drug rather than give them a rigorous, systematic and comprehensive evaluation;”
• “At one point in 1984, Eli Lilly received word from the British authorities that they were not going to approve this drug because of their concern with suicidality and agitation …and Lilly then went over there and looked at the data again and pulled out cases that they didn’t think were suicide (but) how are they to know? The investigator thought it was a suicide attempt. They said, well, they don’t think it is.”. (In other words, the drug company overrode the investigator and tampered with the data).Back in 1984 Eli Lilly is manipulating data to prove efficacy and safety that is not real. Because they are first out of the gate, the Prozac data escapes the same scrutiny to which subsequently introduced SSRIs are subjected.

1994 — Italy’s Giovanna Fava, editor-in-chief of the journal Psychotherapy and Psychosomatics, writes that “long-term use of antidepressant drugs may increase, in some cases, the biochemical vulnerability to depression, and worsen its long-term outcomes and symptomatic expression. Since then, Fava has periodically revisited this issue, and he recently published an updated review of the literature in Progress in Neuro-Psychopharmacology and Biological Psychiatry.””Here is a sampling of what he found in the research literature:

Antidepressants increase the risk of a “switch” into mania, and thus into bipolar illness. Antidepressants also increase the risk that bipolar patients will become rapid cyclers, and that bipolar patients will develop a syndrome dubbed Chronic Irritable Dysphoria.”

After six months of antidepressant treatment, the drugs “generally fail to protect” against a return of depressive symptoms. (In other words, maintenance treatment is ineffective, compared to placebo.)

Two-thirds of patients maintained on antidepressants suffer from “residual symptoms”, with “anxiety, insomnia, fatigue, cognitive impairment, and irritability the most commonly reported.”

As patients are switched from one antidepressant to another or to a polypharmacy regimen, their illness may be propelled “into a refractory phase, characterized by low remission, high relapse and high intolerance.”

January, 1995 — Verdict: The jury in Fentress et al vs Eli Lilly finds 9:3 for Lilly. Lilly takes the opportunity to publicize the verdict as a vindication of Prozac. Judge John Potter is suspicious that the case was actually settled behind the scenes, and launches a series of actions to determine the truth. He files a motion to change his own post-trial order from “dismissed after verdict” to “dismissed as settled”. This places the Justice in a position where he is now a defendant, but it forces Lilly into a defensive position and ends their public declarations of exoneration.

May 23, 1996 — The Supreme Court of Kentucky decides the case of the Hon John W Potter vs Eli Lilly unanimously in Judge Potter’s favor, citing the lawyers’ serious lack of candor, evidence of bad faith, abuse of process, and fraud, because it had been shown that Lilly had agreed to settle the trial after its first phase, in exchange for plaintiff lawyers refraining from introducing evidence of problems with another Lilly product, Oraflex.

This is an important milestone in the U.S. legal system’s challenge to the gap between the marketing message on SSRIs, and reality.

August 12, 1997 — The FDA issues its first draft of Guidance for Industry: Consumer-Directed Broadcast Advertisements.

Previously, advertising of drugs had been restricted by the FDA requirement that all prescription drug ads disclose a brief summary including all the warnings, precautions, contraindications, and adverse events known for the drug. This had effectively limited advertising to print media.

The new guidance eliminated the requirement for the summary, and substituted an “adequate provision” clause: instead of having to tell consumers about all the risks, pharmaceutical companies had to make adequate provision for them to find out for themselves, for example by providing a phone line.

1997 — Congress passes the FDA Modernization Act (FDAMA), and the Best Pharmaceuticals for Children Act (BPCA). This amendment gives 6-month patent extensions to drug makers who conduct pediatric clinical trials of existing drugs and get them approved for use in children, through 2007.

November, 1997 — Article: A Double-blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Children and Adolescents With Depression. In a study of 96 youth ages 7 to 17 with major depressive disorder, Graham Emslie et al find that 27 out of 48 (56%) of those receiving fluoxetine and 16 out of 48 (33%) receiving placebo are rated “much”or “very much” improved. He concludes that “Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients.”

Data from this NIMH-funded trial was used by Eli Lilly to gain an additional 6-month patent exclusivity for Prozac (FDA, 2001). See FDA Medical Review Sept 14, 2000.

December, 1997 — Acute phase of Study 329 is completed.

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: “Conclusions from these studies:

• 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. This paper, viewed with the hindsight knowledge of subsequent events, is a chilling illustration of what happens when safety issues are weighed alongside competitive / commercial ones.

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”.

July 19, 1999 — Jim McCafferty, SKB Executive, sends Sally Laden a memo with suggestions for edits. The two “minor” ones are (1) the article should not imply that most of the trial subjects have a family history and a diagnosis of major depression when they do not, and (2) the statement that there are unlikely to be any more tricyclic antidepressant trials because of expired patents, while true, is too direct and sounds too commercial. The third, “major” issue he raises is safety. He writes:

“It seems incongruous that we state that paroxetine is safe and yet report so many SAEs*. I know the investigators have not raised an issue, but I fear the Editors will. I am still not sure how to describe these events…” *serious adverse events

August, 1999 — Martin Keller submits the article (see deposition transcript page 370) “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial” to the Journal of the American Medical Association (JAMA) as the preferred publication vehicle because this journal reaches primary care doctors and paediatricians as well as psychiatrists.

August, 1999 — The FDA releases its final Guidance for Industry: Consumer-Directed Broadcast Advertisements.

Direct-to-Consumer (DTC) advertising has given a major boost to drug sales. In a 2002 article, “Paxil is Forever”, Minneapolis City Pages quoted:

“DTC is a great way to create demand,” the trade journal Drug Topics quoted one marketing VP as saying. “Advertisers are trying to help consumers recognize a specific symptom and then recognize that something can be done to alleviate the symptom.” The same article noted that: “During the first half of (2002), (Paxil’s) sales were up 18 percent in the United States. Every day an estimated 3,000 to 5,000 Americans begin taking Paxil.”

October 22, 1999 — Three peer reviewers at JAMA flag concerns about whether the study really shows that paroxetine is effective and JAMA declines to publish the study. The peer reviewers “pointed to the low HAM-D cut-off, the [confounding] effect of supportive care, the high Placebo response, the small or absent differences in rating scales, the significant incidence of Serious Side Effects with Paroxetine, and the inappropriately [escalating and high] dosing with Imipramine”.

The rejection letter states that “this rejection is no reflection on the scientific quality of your manuscript…”, and “The 11 journals published by the AMA constitute an editorial consortium to give each submitted manuscript more than one option for publication. This consortium includes The Archives of General Psychiatry, to which we would be happy to forward your paper, should you so wish.

Obviously, your paper will not be guaranteed publication mainly on the strength of being referred by us. However, we would be glad to forward all copies of your manuscript to the editor for evaluation, along with the reviews (copies enclosed for your information). Further disposition would then be decided by the specialty journal editor.”

December 7, 1999 — Letter: Sally Laden writes to Jim McCafferty of SKB:

“Dr Keller submitted the manuscript to JAMA in early August, 1999. The journal elected not to publish the paper and notified Dr Keller in November. In a conference call in November involving Drs Keller, Ryan, and Strober and Jim McCafferty, the action plan itemized below was agreed upon:

1. Sally Laden and Jim McCafferty will summarize the reviewers’ extensive comments and draft a memo outlining the changes to be made.
2. This memo will be circulated to all authors for their review and approval.
3. The current draft will be revised and circulated to all authors for review and approval.
4. The revised manuscript will be submitted to American Journal of Psychiatry.

Resubmitting this manuscript is our top priority, and we will be asking for rapid review when we send materials to the authors…”

Note that, at this point, the plan is to submit the revised manuscript to the American Journal of Psychiatry.

March, 2000 — Article: “Emergence of antidepressant induced suicidality” by Dr David Healy finds that out of 20 healthy volunteers with no history of depression or suicidal ideation, two became suicidal on sertraline (Zoloft), an SSRI. This is important refutation to the contention that suicidal acts of people on SSRI medications could always be attributed to underlying depression.

April, 2000 — Study 701 on the effectiveness of paroxetine (Seroxat, Paxil) in treating children and adolescents with major depressive disorder (MDD) is completed. Study 701 involves 206 pediatric patients, 149 who complete the study. Nine Paxil patients (8.9 percent) withdraw from the study due to adverse events vs two (two percent) on the placebo, mostly due to depression, “emotional lability” (suicidality), agitation, hostility, and nervousness. In addition, three Paxil patients withdraw from the study due to “emotional lability” soon after the last dose of study medication. One Paxil patient overdoses and cuts herself, another experiences suicidal ideation, and three others experience exacerbation of their depressive symptoms. All these events are considered unrelated to Paxil by the study’s investigators. Another overdose is regarded as related to the Paxil. Overall, the patients on Paxil fare worse than those on placebo on the primary measures. The study is never published.

April 26, 2000 — Letter: In a missive entitled “Revision of Paroxetine Adolescent Depression Manuscript”, Sally Laden writes to Jim McCafferty noting the revisions she is making to the Study 329 manuscript, and outlining the plan for resubmission of the article to the Journal of American Psychiatry. All the revisions are “cosmetic” they relate to wording and presentation: “Dear Jim,

…I attempted to make as many of the JAMA reviewer comments (sic) as practical. A summary of the more substantive points is listed below:

1. A more thorough discussion of the high placebo response rate in the Conclusions section.
2. A “study limitations” paragraph has been added to the Conclusion that addresses the fact that the study was not designed to directly compare paroxetine and imipramine; that the HAM-D score at baseline was low relative to adult studies; and that patients with externalizing disorders were eligible for enrollment. (italics added)
3. The mean imipramine plasma concentrations at weeks 4 and 8 will be stated (SB: please provide this data), and it is stated that a more thorough discussion of this data will appear in a separate publication.
4. A new figure (Fig. 3) showing the HAM-D total score response vs time.
5. As noted by several reviewers, the definitions of remission and response overlap. Boris Mirmaher suggested that the definitions be revised to delete mention of remission and simply describe response. This suggestion is reflected in the enclosed manuscript.
6. As suggested by Reviewer #2, the title is revised to delete the phrase: but not imipramine.”

This letter is interesting because it clearly illustrates who is making the decisions about the content of the final manuscript, a document that will impact the lives of thousands of young people. Sally laden decided that it was not “practical” to deal with the safety issues. The significant incidence of adverse events (11 out of 93) in paroxetine group, 7 of whom had to be hospitalized, is not addressed. Subjects experiencing adverse events on paroxetine continue to be omitted from the considered data.

May, 2000 — According to the April 26, 2000 letter from Sally Laden to Jim McCafferty, the intention is to submit the “revised” Study 329 manuscript to the Journal of American Psychiatry. Apparently the decision changed at some point in May, 2000 to submit it to the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) instead. The reason for this change is not stated. At the time, Graham Emslie, one of the Study 329 authors, is on the Board of JAACAP.

July 27, 2000 — Letter: Mina Dulcan, M.D., Editor of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) writes to Dr Martin Keller acknowledging submission of Study 329:

“Dear Marty, Your manuscript has come back from review, and I enclose copies of the reviewers’ comments and suggestions. If you will revise your manuscript to meet their concerns, we will be happy to consider it further for publication.” The reviewers’ comments included the following: “Were they really persistently depressed over that entire year? In clinical settings most “depressed” youth have moods that are more labile and reactive. Is this well reflected in methods using standardized interviews? Is there possible informant bias…? There are other issues that need addressing, including:

1. The rate of serious adverse events in the paroxetine arm is somewhat high (11 subjects, presumably out of 93). This is included in the results but not discussed at all.
2. Similarly, each group had a fairly high rate of not completing the 8-week trial that is somewhat glossed over.
3. Given the high placebo response rate, what algorithm should clinicians follow when treating a depressed teenager? Are SSRIs an acceptable first-line treatment if approximately one half of youth get better with only supportive interventions.
4. Although it is implied, a stronger statement could be made regarding the lack of indications for tricyclic antidepressants given the lack of efficacy and side effect profile.
5. In the discussion section, there is a statement suggesting that a traditional three arm comparative trial was not done due to the risk of exposing additional subjects to clinical research. This seems rather self-serving, since I suspect the power issues and sample size limitations prevented this from being done, not human subjects concerns.
6. In the discussion section, there is a statement that the entry HAM-D score required was lowered to greater than or equal to 12 “to reflect the severity of their disorder”in a pediatric population. What does this mean? Is the scale not valid for youth? Are their scores somehow different than adults’?”

September 14, 2000 — Medical Review: Lilly submits application to FDA to gain an additional 6-month patent exclusivity for Prozac. The application later updated to include Lilly’s integrated safety data summaries (ISS) from 3 pooled Prozac pediatric trials: the NIMH-funded trial (Emslie, 1997)*, a Lilly-funded trial with depressed children (Emslie, 2002), and a trial with children diagnosed with obsessive-compulsive disorder (Geller, 2001).

In 2002, Dr Andrew Mosholder does the medical review on the efficacy of fluoxetine (Prozac), compared to placebo, for children and adolescents with major depression. He finds:

• “7.2.7 Conclusions: This study…failed to show statistically significant effect of fluoxetine according to the protocol specified primary outcome measure”
• “8.2 Deaths: There were no deaths in these pediatric studies.”
• “The supplement is approvable, in my opinion.”

The FDA granted Lilly the requested 6-month patent extension.

*see November, 1997 and June 22, 2004

2000 — Marketing Facts: Between 1995 and 2000 the number of marketing staff working for US pharmaceutical companies increases by 60% while research staff declines by 29% (see page 15). GlaxoSmithKline spends $91.8 million US advertising the SSRI Paxil in the US, almost $15 million more than Nike spends advertising its top brands of running shoes. (See Page 17) This level of spending is associated with a $355.6 million increase in sales between 1999 and 2000.

February, 2001 — The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) accepts Keller et al article “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial” for publication (see Aug, 1999 and July, 2001)

Despite the fact that Dr Keller has been made aware of the concerns of the 3 JAMA reviewers, and the JAACAP reviewers (see July 27, 2000), the safety concerns are not addressed (see transcript page 371–383) in the version accepted for publication, including those by the JAACAP reviewers.

March, 2001 — In an email to PR company Cohn and Wolfe, SKB writes: “Originally we planned to do extensive media relations surrounding this study [329] until we viewed the results. Essentially the study did not really show Paxil was effective in treating adolescent depression, which is not something we want to publicize.”

April 25, 2001 — An e-mail from Sally Laden to GSK makes the following request: (see page 355) “Marty Keller is a corresponding author and will need a supply of reprints. I anticipate that he will need a sizable quantity because of the importance of this paper. Probably in the vicinity of 500 reprints. Dr. Keller is wondering if GSK will fund the purchase of these reprints.”

Subsequent testimony confirmed that GSK paid for the reprints, they were delivered to Dr. Keller, and presumably used to send to practitioners inquiring about the use of paroxetine in treating their patients.

June 6, 2001 — Tobin vs SmithKline Beecham Pharmaceuticals Verdict. A U.S. District Court jury in Wyoming awards $6.4 million to the relatives of Don Schell, a Gillette man. With a prior history of a poor response to an SSRI, Don was put on Paxil. Forty-eight hours later he put three bullets from two different guns through the heads of his wife, Rita, his daughter, Deborah, and his granddaughter, Alyssa. Then he shot and killed himself. The jury rules that the global pharmaceutical company is 80 percent responsible for the deaths for failure to provide doctors with pertinent information and warnings. (From Let Them Eat Prozac, by David Healy, 2004)

June 11, 2001 — Dr David Healy concludes, based on reading records of trials carried out by the manufacturers which showed healthy volunteers were suffering withdrawal symptoms after taking the drug for just a couple of weeks, that thousands of people in the UK could be hooked on the anti-depressant drug Seroxat (paroxetine/Paxil), without knowing it.

Dr Healy had been given access to GSK’s archives because he was an expert witness in the Tobin case. He says more than half of people on Seroxat/Paxil (paroxetine) may have “significant” withdrawal problems: (see page 14) “It was clear from early on that the company had recognised that people who had been on this drug even for relatively brief periods of time could go through withdrawal when they halted, and they ran healthy volunteer trials to look at this further and found that in some instances up to 85% of the volunteers who had been on this drug for only two or three weeks had withdrawal problems when they halted.”

June 14, 2001 — Ian Hudson, who had just changed jobs from worldwide safety director for GSK to Director of Licensing at the U.K. Medicines Control Agency, repeats his position from the Tobin trial that an individual case cannot tell you one way or the other if a drug is responsible for a violent or suicidal act – only randomised controlled trials can do that. This is reported in several news outlets as is Dr Healy’s response that: “randomised control trials are the wrong tool to establish whether serious side effects are occurring. The way to investigate what is happening is to carry out a challenge-rechallenge trial, where people are given the drug, taken off it and then put back on.”

Dr. Healy notes that GSK has never done such trials.

Ian Hudson is now head of MHRA, which watches over the safety of the British public. “If he takes the position with the MHRA that he took at the trial, then none of us is safe with any drug in the UK at the moment,” says Dr Healy. “How would Mr. Hudson even be able to blame alcohol for making someone drunk?”

During his Tobin deposition, when Dr Hudson is asked if, as Director of Safety for SmithKline Beecham, he believes Paxil causes akathisia in some patients, he responds: I”I’ve seen no evidence to suggest a cause and effect relationship between Paroxetine and akathisia. I’ve seen some case reports, but I’ve seen nothing that suggests a cause and effect relationship.”

June 25, 2001 — GSK complies with a request from the British Regulator to issue a warning to doctors and to patients about Seroxat (paroxetine). GSK insists the timing of the warning has nothing to do with the Tobin decision.

The warning reads: “The possibility of suicide is inherent in depression and may persist until significant therapeutic effect is achieved, and it is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.” Dr Healy objects to this wording, noting that: “The person taking the drug is left thinking he or she has a problem, rather than that the pill caused them the problem.”

July 2001 — STUDY 329 IS PUBLISHED

Article “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial” by Keller MB, et al, is published in The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP). The study concludes that: “Paroxetine is generally well tolerated and effective for major depression in adolescents.” The article is published without having addressed the concerns of the reviewers (see July 27, 2000). That is:

• Whether or not the claim of persistent depression in the patients over the whole year was justified was never clarified.
• The high rate of serious adverse events in the paroxetine group remained unaddressed.
• The high drop-out (non-completion) was never properly explained.
• Whether SSRIs are an acceptable first-line treatment was not considered; and
• The suitability of use of HAM-D for children vs. adults is not discussed.

August 16, 2001 — In a memo to all GSK sales representatives selling Paxil, copied to Dr. Martin Keller, Sales management for the product make this statement about Study 329: “This cutting edge, landmark study is the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE efficacy and safety in the treatment of adolescent depression.”

December, 2001 — In the U.K, the Drug Safety Committee of the MHRA, the CSM: “reviewed the suicidal behaviour, aggression and akathisia issue, December 2001, concluding the possibility of this affecting “a small high-risk population could not be ruled out “, and advised the risk of akathisia occurring be added to all SSRI Summaries of Product Characteristics (SPC). The UK assessment report was discussed at the PhVWP which agreed, but considered further discussion was required to clarify definition of the term akathisia.”

July, 2002 — The Guardian reveals that Seroxat tops the league table for complaints of side-effects made by doctors to the U.K. government’s committee on the safety of medicines under the yellow card scheme. A total of 1,281 complaints have been filed; more than the combined total for the rest of the top 20 most cited drugs.

August 3, 2002 — News item: “United States Professional football sensation Ricky Williams last week sparked a blaze of publicity when he revealed that he had social anxiety disorder and was benefiting from therapy and Paxil (Seroxat/paroxetine), the drug that earned GlaxoSmithKline global sales last year of US $2.7 billion (£1.7 billion, €2.7 billion)… Celebrity selling is just one more way in which pharmaceutical companies are indirectly shaping public perception…”(BMJ Celebrity Selling Article Part 1)

Two years later, this Heisman trophy winner whose dream had been to join the NFL, quit football after becoming involved with illegal drugs and apparently losing interest in playing.

Sept 16, 2002 — The last of 9 clinical trials conducted by GSK and its predecessor SKB, attempting to find evidence of efficacy of paroxetine in the treatment of MDD in paediatric populations, concludes. None of the trials was ever able to demonstrate a positive outcome. Many of the trials avoided noting safety concerns by attributing suicidality and other adverse events experienced by subjects to factors other than being in the active drug group.

October, 2002 — Article: Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial.

122 children and 97 adolescents with MDD are randomly assigned to placebo or fluoxetine. The authors report that significantly more fluoxetine-treated patients (41%) meet the prospectively defined criteria for remission than placebo-treated patients (20%). They also note that there are no significant differences between treatment groups in discontinuations due to adverse events ( =.408).

Emslie et al conclude that Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients.

October 10, 2002 — Russell Katz, Director of Neuropharmacological Drug Products at the FDA, sends an approvable letter to GSK for Paxil in children requesting additional information about Paxil.

Dr David Healy describes this letter as follows: “the letter notes that GSK had already told the FDA that Study 329 showed that Paxil doesn’t work for depressed children. FDA were happy to go along with GSK’s suggestion that this should not be mentioned in the labeling of the drug. Given that the Study 329 publication majored on how effective Paxil was, it would have been inconvenient if the label said otherwise.”

There are many notable things in this approvable letter. Perhaps the most interesting is FDA asking GSK to clarify just what emotional lability meant.

FDA have later spun this into a story that their reviewers detected there was an increase of emotional lability events in Study 329 that needed looking at. In fact this idea came on their radar after plaintiff’s lawyers visited the FDA on August 28th and suggested that the FDA explore the issue of emotional lability.

FDA at the time had a few weeks to respond to GSK’s request to market Paxil for children. Neither Jofre nor the lawyers knew at the time that GSK were seeking pediatric approval for Paxil.”

October 13, 2002 — BBC Panorama broadcast “Secrets of Seroxat” —Scottish journalist Shelley Jofre, after learning of the Schell/Tobin lawsuit, does a show on Seroxat (Paxil) revealing that the drug can cause suicidal and violent thoughts, and serious withdrawal problems. In response to this broadcast, the BBC receives 67,000 phone calls and nearly 1,400 e-mails.

November 2002 — Review: Treatment of mood disorders, by Nemeroff CB and Owens MJ is published in Nature Neuroscience. It notes that “available antidepressant drugs are safe and effective” and “highlights” specific mechanisms that will lead to better treatment. They conclude that both mifepristone and a transdermal lithium patch are promising treatments for mood disorders, without disclosing that Dr Nemeroff has a significant financial interest in both.

November 14, 2002 — In response to public concerns about Seroxat following the Panorama broadcast, the Committee on Safety of Medicines (CSM) in the U.K. decides to convene a panel of experts. On Nov 14, in preparation for the first meeting of this ad hoc committee, CSM officials meet with GSK. At the meeting, GSK does not raise any concern about lack of efficacy or adverse reactions in the clinical trials in the paediatric population.

November 21, 2002 — The U.K. CSM ad hoc group meet with MHRA representatives and independent experts to discuss issues relating to SSRIs. The meeting is focused mainly on withdrawal reactions although suicidality is also discussed.

At this meeting Dr David Healy presents research relating to suicidal behaviour, including reanalysis of studies on fluoxetine, to a group of CSM and external experts who conclude that no change in regulatory position in relation to suicide is necessary, but advise changes to UK Seroxat PIL to clarify withdrawal reactions.

December 20, 2002 — Letter: Child Psychiatrist Jon Jueidini, M.D. and Prof Anne Tonkin, from the University of Adelaide, alarmed by what they see as potentially serious issues with Study 329, write a letter to the Editor of JAACAP suggesting that it might be a good idea to sort out their differences immediately, and “off-line”:

“We write to request that you reconsider your decision not to give us access to Keller et al’s reply to our letter prior to its publication in the middle of 2003. Our letter raises significant concerns and impact on the standing of the journal and profession that we believe cannot wait 6 months for our further attention.

We would not wish to pursue these concerns if Keller et al have sucessfully refuted our criticisms. We think it is important and urgent to know whether we are correct in raising concerns about journal standards. We therefore request that you forward us a copy of Keller et al’s response as soon as possible.”

December 26, 2002 — Reply: Editor Mina Dulcan sends a response with a very negative tone to the Dec 20 Jureidini and Tonkin request:

“Dear Dr. Jureidini,

It is not the policy of the Journal to share responses to letters before publication. We do not have a backlog, and your letter and the Keller response will be published as soon as our production process allows. This is not a debate. We are under no obligation to publish whatever rejoinders you wish to make (or your original letter, either, which was quite rude and accusatory). Your approach to this process leads me to believe that whatever Dr. Keller says, you will disagree. Our readers will see both letters and make their own judgments. Frankly, your haste seems odd, since the article was originally published in July of 2001. I find your adversarial tone and urgency tedious.

You have not been appointed as the guardian of the Journal, or of the profession of child and adolescent psychiatry. Many highly expert child and adolescent psychiatrists were participants in that study, and others that were similar, and others equally contributed to the review process. In addition, the prescription of SSRIs for youth, not only in this country but around the world, far predated any research data on their effects with youth, so this article could hardly be blamed or praised for that trend.

I noticed that you are members of Healthy Skepticism. Is this organization backed by anyone we should know about, for potential conflict of interest?”

Interesting context to Dr Dulcan’s remark about Jureidini and Tonkin’s “tedious sense of urgency” is provided by Graham Aldred’s data chart (see April 27, 2004). He calculates that in 2002, Paxil was causing up to 52* suicides per day in the USA alone (all ages).

*19,271/365

February, 2003 — Article: Physicians Raise Concerns About Undisclosed Financial Ties Between Researcher, Pharmaceutical Companies.

Bernard J Carroll, Scientific Director, Pacific Behavioral Research Foundation, and Robert T Rubin, Professor of Neurosciences and Psychiatry at Drexel note Charles Nemeroff’s conflict of interest. “Rubin and Carroll said that they sent a letter to the editors of the Nature journals in February to ask them to publish a letter that outlined Nemeroff’s conflicts of interest. They said that they have not received a response. Jennings said that the editors have considered the request and also may revise their disclosure policy.”

The details of their concerns are published in an editorial letter in Nature Neuroscience in Oct, 2003.

See: Nov, 2002, Sept 26, 2003, Aug 25, 2006

February 28, 2003 — GSK pre-emptively sends the MHRA additional data on paroxetine as it related to suicidal behaviour to support a planned June request for approval of expanded use of the drug for young people. The letter accompanying the submission of the data, dated Oct 25, 2002, indicates that “there was no signal identified as regards suicidality revealed by these analyses.” Only later does the MHRA discover that this submission contains adverse event data but fails to identify or differentiate between adult and paediatric trials. Paediatric studies have been merged together with the adult data, thus “hiding” the higher rate of paediatric adverse events. (Source: Bad Pharma, by Ben Goldacre, Page 60)

March, 2003 — Article: “Lines of Evidence on SSRIs and Risk of Suicide” by David Healy. This meta-analysis reveals clear indications of “a possible doubling of the relative risks of both suicides and suicide attempts on SSRIs compared to older antidepressants or non-treatments” and recommends further studies.

May 11, 2003 — BBC Panorama broadcast “Emails from the Edge” – Shelley Jofre follows up the many e-mails and calls the BBC has received after its first broadcast. In this segment, Alastair Benbow of GSK admits that the company knows that their study shows that more people are suicidal on Seroxat/Paxil than on placebo, and that he does not consider this important. David Healy’s research, showing that it is the drug, and not depression that causes suicidality, is quoted.

May, 2003 — Letter: The Jon Jureidini and Anne Tonkin letter to the Editor of JAACAP, (see Dec 26, 2002), pointing out flaws in Study 329, is finally published:

PAROXETINE IN MAJOR DEPRESSION

To the Editor:

The article by Keller et al. (2001) is one of only two to date to show a positive response to selective serotonin reuptake inhibitors (SSRIs) in child or adolescent depression. We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process. The study authors designated two primary outcome measures: change from baseline in the Hamilton Rating Scale for Depression (HAM-D) and response (set as fall in HAM-D below 8 or by 50%). On neither of these measures did paroxetine differ significantly from placebo. Table 2 of the Keller article demonstrates that all three groups had similar changes in HAM-D total score and that the clinical significance of any differences between them would be questionable. Nowhere is this acknowledged. Instead:The definition of response is changed…In reporting efficacy results, only “response” is indicated as a primary outcome measure, and it could be misunderstood that response was the primary outcome measure…Given that the research was paid for by GlaxoSmithKlein, the makers of paroxetine, it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light.

Given the frequency with which it is cited,… this article may have contributed to the increased prescribing of SSRI medication to children and adolescents. We believe it is a matter of importance to public health that you acknowledge the failings of this article, so that its findings can be more realistically appraised in decision-making about the use of SSRIs in children.

May 23, 2003 — A first meeting of the CMA Expert Working Group is called to discuss proposed communication by GSK with the prescribing community following the May 11 Panorama programme. At this meeting, GSK hands out a briefing document relating to an application to extend indications for Seroxat to include use in children. GSK draws the Agency’s attention to an increased rate of events relating to suicidal behaviour among paediatric patients with major depressive disorder (MDD) treated with Seroxat.

June 10, 2003 — Based on the information provided by GSK May 23, a “Dear Doctor” letter is issued by the MHRA warning against prescribing Seroxat to paediatric populations. At this time, 7,000 – 8,000 people under 18 are being treated with the drug in the U.K.

Late June, 2003 — U.K. CSM Expert Working Group on SSRIs produces its first finding, on Prescribing SSRIs to people under the age of 18. They conclude:

“The balance of risks and benefits for the treatment of depressive illness in under-18s is judged to be unfavourable for paroxetine (Seroxat), venlafaxine (Efexor), sertraline (Lustral), citalopram (Cipramil), escitalopram (Cipralex) and mirtazapine (Zispin). It is not possible to assess the balance of risks and benefits for fluvoxamine (Faverin) due to the absence of paediatric clinical trial data.Only fluoxetine (Prozac) has been shown in clinical trials to be effective in treating depressive illness in children and adolescents, although it is possible that, in common with the other SSRIs, it is associated with a small increased risk of self-harm and suicidal thoughts. Overall, the balance of risks and benefits for fluoxetine in the treatment of depressive illness in under-18s is judged to be favourable.”

Sept 26, 2003 — The Editors of the Nature group of publications, which includes Nature Neuroscience, announce a change in editorial policy requiring that conflicts of interest be disclosed in all published material. They note that Dr Nemeroff did not violate the policy in place in 2002, thereby acknowledging that until the revised policy, reviews which look like scientific analysis can be biased product promotions without readers being aware of this fact.

Oct 1, 2003 — The Pharmacovigilance Group of the MHRA refers the matter of GSK failing to advise the regulator on a timely basis about issues relating to safety and lack of efficacy of Paroxetine. However, GSK’s failure to advise the MHRA about the known lack of efficacy and dangers of paroxetine did not result in a prosecution. The MHRA report gives a number of reasons for its decision not to prosecute:

• Relevant EU legislation requires the reporting of adverse reactions occurring in the normal conditions of use. A clinical trial in relation to an unlicensed indication did not fall within “normal conditions of use”.
• Although EU legislation also required adverse events to be reported in “post authorisation studies”, such studies did not include studies on a product outside of its licensed indications.
• UK legislation did require the reporting of adverse events during clinical trials, but it applied only to clinical trials in the UK and a failure to do so was not a criminal offence.
• Although 2002 UK legislation required a marketing authorisation holder’s Qualified Person to report any information relevant to the risk/benefit evaluation of a product, the MRHA received legal advice that the legislation was not sufficiently clear that this obligation applied to clinical trials outside a product’s licensed indications.

December, 2003 — In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) issues an advisory warning against prescribing SSRI antidepressants, with the exception of Prozac (fluoxetine), to under 18s.

January 21, 2004 — American College of Neuropsychopharmacology (ANCP) report declares that SSRIs do not increase suicide risk in people under 19. The report notes that:

“The evidence linking SSRIs to suicide is weak,” said J. John Mann, M.D., Co-Chair of the ACNP Task Force. “There are strong lines of evidence in youth – from clinical trials, epidemiology and autopsy studies – that led the ACNP Task Force to conclude that SSRIs do not cause suicide in youth with depression.”

ACNP established the Task Force after regulatory agencies in the US and the UK voiced concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk for suicide. The FDA is convening an advisory committee hearing to review the issue on Feb. 2, 2004. “The most likely explanation for the episodes of attempted suicide while taking SSRIs is the underlying depression, not the SSRIs,” said Graham Emslie, M.D., Co-Chair of the ACNP Task Force…”The potential benefits of SSRIs outweigh the risks.”

Of the 10 members of the Task Force (J John Mann, Graham Emslie, Ross J Baldessarini, William Beardslee, Jan A Fawcett, Frederick K Goodwin, Andrew C Leon, Herbert Y Meltzer, Neal D Ryan, David Shaffer and Karen D Wagner), 9 are paid consultants to drug companies that sell SSRIs. Seven (names underlined) are fated to become targets of Iowa Senator Chuck Grassley for failing to disclose to their universities all the payments they receive from pharma, in violation of conflict of interest policies. (See April, 2008)

February 1, 2004 — Andrew Mosholder, an epidemiologist with the FDA, is told he cannot testify at the planned FDA hearings (see Feb 2, 2004). Dr. Mosholder has reviewed all the published and unpublished data on SSRIs, and concluded that the risk of suicidal events and serious self-harm is about twice as high for young people taking these medications. His review of paroxetine 4-11-02 finds “The three randomized, controlled trials in MDD, listed above, all failed to show a separation of paroxetine treatment from placebo on their primary efficacy measures.”

He also notes that: “The most prominent adverse reactions not seen in corresponding adult trials appear to involve behavioral effects; these events were coded with terms such as hostility and emotional lability. As previously noted, the sponsor’s method of coding these events was potentially confusing, and thus additional information will be helpful for the purpose of definitively assessing the potential behavioral toxicity of paroxetine treatment in pediatric patients.”

February 2, 2004 — The FDA Psychopharmacologic Drugs Advisory Committee convenes special hearings with the Pediatric Subcommittee to determine if there is any basis for †recent concerns about reports of suicidal ideas and behavior developing in some children and adolescents during treatment of depression with an SSRI or similar newer antidepressants.†

The committees hears from 51 witnesses who are granted leave to present. Committee members express uncertainty regarding the implications of different classifications for adverse events, including events relating to suicidality.

Among the criticisms of methodology presented at the hearing is the following by Dr. Irving Kirsch and Dr. David Antonuccio:

“The effect of SSRIs is statistically significant, but it is not clinically significant…(and) These results were drawn from studies with design flaws that typically favor the study drug. For example, they frequently exclude placebo responders before random assignment, rely on ratings by clinicians who have a vested interest in the outcome, and are likely to be unblinded by medication side effects. Furthermore, …adding unpublished studies, most of which have negative results, will surely shrink the difference between antidepressants and placebo even further …Clinically meaningful benefits (of SSRI use) have not been adequately demonstrated in depressed children. Therefore, no extra risk is warranted.”

February 7, 2004 — Traci Johnson, a 19-year-old college student and a subject taking part in trials for Cymbalta (Lilly’s “next generation” version of Prozac), is found hanging by a scarf from a shower rod in a drug company laboratory. After this event, the fact that 4 other young people had committed suicide on Prozac in earlier trials is revealed. None of these deaths were attributed to the medication. As the Independent (U.K.) notes on June 5, 2005:

“Now, medical researchers attempting to establish the truth about Cymbalta are asking why her (Traci’s) disturbing and very public suicide is completely absent from the official record, at least as it is released to academics and the public. According to an investigation by The Independent on Sunday, this and at least four other suicides by volunteers have been hidden by the US regulators, the Food and Drug Administration (FDA).

As the FDA admits, even a young woman’s death counts as a commercial secret in the world of pharmaceuticals.”

February 13, 2004 — Report: GSK: Paxil Sales Depressed By Generics explains the impact on GSK of losing its patent protection on Paxil in the 3rd fiscal quarter of 2003. ” “GlaxoSmithKline has announced that sales of its antidepressant Paxil (paroxetine) fell 40% in Q4 2003. The company must now look to minimizing the impact of generic competition by focusing attention on its newer controlled release version, Paxil CR.

At the annual results meeting, GlaxoSmithKline announced that its leading antidepressant Paxil had suffered a 40% decline in sales from $597 million in Q3 2003 to $325 million in Q4 2003. The company says that performance in the US had been severely impacted by generic competition, which began in September 2003, resulting in a decline in global sales from $3,084 million in 2002 to $3,078 million in 2003.” (bolding added)

February 16, 2004 — “Because of concerns about whether the varied events identified by sponsors under the broad category of “possibly suicide-related” could all reasonably be considered to represent suicidality, the FDA asked Columbia University (See Page 5) to assemble an international panel of pediatric suicidality experts to undertake a blinded review of the reported behaviors using a rigorous classification system*. The Columbia group submitted its completed review to FDA in June 2004.”

Columbia was invited because they had already developed a suitable classification system.

March 2, 2004 — Article: Drug Company Experts Advised Staff To Withhold Data About SSRI Use In Children appears in the Canadian Medical Association Journal (CMAJ). It begins:

“An internal document advised staff at the international drug giant GlaxoSmithKline (GSK) to withhold clinical trial findings in 1998 that indicated the antidepressant paroxetine (Paxil in North America and Seroxat in the UK) had no beneficial effect in treating adolescents.”

The internal document referenced is the Oct 14, 1998 Jackie Westaway memo. The publication of this information is noted by the Office of the Attorney General in the State of New York and provides important ammunition for a fraud lawsuit against GSK. See Oct 14, 1998, June 3, 2004)

April 27, 2004 — In a Letter to Congressmen Joe Barton and James Greenwood, the AHRP notes that: “A new and accurate method for calculating the number of patients that have died as a result of taking SSRIs was developed by our colleague in the UK, Graham Aldred, a systems engineer whose wife, Rhona died just 11 days after being prescribed Paxil /Seroxat.” This methodology is used by the IMR (Institute of Medical Research).

Noting that the most dangerous time is within a couple of months of starting the drug, and taking the number of people who started on Paxil in the USA every year from 1993 to 2002, Mr. Aldred calculated that at a bare minimum there were 6,004 suicides in America that were solely attributable to Paxil during this time, with a still-conservative and more likely estimate of 19,271 suicides. About these rates, Mr Aldred asked: “Assuming the lowest rate (32/100K) would the FAA support an airworthiness certificate for a certain aircraft type, that for 10 years consistently crashed and killed 300 to 1,000 passengers per year and injured many others? How would the FAA react if the aircraft manufacturer consistently blamed the crashes on the passengers but not the aircraft?”

May 1, 2004 — EU Directive, Directive 2001/20EC, regarding legal requirements for the disclosure of adverse events in clinical trials, comes into force, fixing gaps and inconsistencies in the previously existing legal framework. Failure to report such events from trials within the EU became a criminal offence.

June 3, 2004 — New York State Attorney General Elliot Spitzer files a lawsuit in New York State Supreme Court accusing British drug giant GlaxoSmithKline PLC of “repeated and persistent fraud” for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents.

The suit contends that Glaxo hid the fact that in some of its trials Paxil failed to show better efficacy in adolescents and children than a placebo and in some cases could be more likely to cause suicidal thinking.

This lawsuit is different that the civil suits of individual plaintiffs harmed by Paxil. A charge of consumer fraud for medication is unprecedented, although arguably warranted given that Study 329 probably represents the greatest divide in all of medicine between what the academic literature says about the drugs and what the data actually show.

June 21, 2004 — Launch of class action lawsuit , Beverly Smith vs Smithkline Beecham, for false and deceptive business practices and false and misleading advertising of Paxil, in California.

June 22, 2004 — Letter: The Alliance for Human Research Protection (AHRP) writes to Thomas Insel of the National Institute of Mental Health complaining that:

“clinical trial data about the potential hazards of Prozac (fluoxetine) for children and adolescents may have been concealed from physicians, other health care professionals, and the public.” “According to FDA documents posted on the FDA website on September 25, 2003, at least 2 of 48 children treated with Prozac in the NIMH-sponsored trial attempted suicide. In the published report, there is no mention of any children attempting suicide. Instead, the published report states: Side effects, as a reason for discontinuation, were minimal, affecting only 4 patients who were receiving fluoxetine. (Emslie et al., 1997, p. 1033)”

Referring to the FDA medical review of the application, AHRP notes that: “According to the FDA medical review, the ISS summaries indicate that 22 children dropped out because of ADRs in the Prozac-treated group compared to 5 in the placebo groups. The FDA review also states that there were 3 suicide attempts among the Prozac-treated group versus one such attempt among the placebo group. The FDA’s review refers to additional children being hospitalized for suicidal events: “In addition, one fluoxetine patient was hospitalized because of suicidality” (p. 26)”.

August 26, 2004 — GSK announces that it will pay US $2.5 million as part of a settlement of the lawsuit filed by New York Attorney General Eliot Spitzer. GSK also agreed to publicly disclose all of its clinical drug trials about the safety of paroxetine for children in a “Clinical Trials Registry”

“We are pleased that the Attorney General believes the Clinical Trial Register we have been developing will provide useful information to the medical and scientific community,” said Mark Werner, Senior Vice President for US Legal Operations at GlaxoSmithKline. “We believe that GlaxoSmithKline’s initiative to launch this register is a responsible step in ensuring transparency of our clinical trial data.”

September 23, 2004 — Statement of Robert Temple, M.D., Director, Office of Medical Policy, FDA. In his statement to the Committee, Dr Temple explains why Andrew Mosholder was not allowed to testify at the Feb 2 hearings:

“While CDER was moving ahead with plans for the February 2, 2004, Advisory Committee meeting, Dr. Mosholder was nearing completion of his review of the data from the clinical trials provided in response to our July 22, 2003, request. Based on his review, he believed that the available data were sufficient to reach a conclusion about an association between the use of anti-depressants and suicidality in children and to recommend additional regulatory action, without the need for the more in-depth case classification or analyses that had already been initiated by DNDP. Dr. Mosholder had shared his conclusions with his supervisors and with the DNDP/ODE I review team involved in reviewing this issue. The review team and Dr. Mosholder’s direct supervisors did not agree that the available data were sufficient to reach a conclusion and believed that definitive action should await the re-analysis by Center staff using the Columbia data. There was a discussion within the DNDP/ODE I review team, as well as higher CDER management including Drs. Katz, Laughren, and Temple, as to whether Dr. Mosholder’s scientific and regulatory conclusions on the data should be presented in some form at the February meeting, given that they did not represent the Agency’s (but rather an individual staff member’s) determination; it was concluded that they should not be.”He concluded 20 pages of testimony, which appears to have been accepted by the committee, despite the clear “red flags” in Dr Mosholder’s review being known inside the FDA. He made this comment:

“The results of pediatric depression studies to date raise very important problems. First, the poor effectiveness results, except for Prozac, make it very difficult for practitioners to know what to do to treat a very serious, life-threatening illness. While we believe that these drugs may be effective in children, studies have not shown this to be true.” (italics added)

Sept 13-14, 2004 — Committees from Feb FDA special hearings reconvene (Sept 13, Sept 14) and conclude that there is a causal link between the newer antidepressants and pediatric suicidality. They vote 15 to 8 that a Black Box warning label be placed on all antidepressant medications for which data had been presented (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa, Wellbutrin, Luvox and Serzone), indicating the special risks for young people.

October 3, 2004 — BBC Panorama broadcast “Taken on Trust”. In the third of four episodes about Seroxat (paroxetine, Paxil) Shelley Jofre interviews a number of people who confirm that the drug made them suicidal, paranoid, and violent. One man described his father committing suicide after being on the drug 4 days.

Dr. David Healy notes that: “I think in due course we may look at all of this and think this was one of the biggest medical scandals ever.”

Oct 14, 2004 — Dr David Healy statement to the U.K. House of Commons Health Committee includes the following: “In the case of fluoxetine an early series of clinical trials failed to establish efficacy for this drug in treating childhood nervous problems. This work led to a study that started in 1990, which involved extensive pre-screening of patients so that less than one-fifth of those screened entered the study, and those who did were put through a placebo washout phase in an effort to reduce the high rate of placebo responsiveness found in SSRI trials in children. Using these procedures, [the Nov. 1997 Emslie article] claimed that Prozac could produce beneficial effects for children and adolescents. However, in fact on the primary end-point measure, Prozac was no better than placebo and on secondary measures benefits were apparent on physician-based ratings but not on patient or carer ratings. In addition, there was a 29% drop-out rate on Prozac and the rate of behavioral side effects was greater on Prozac than on placebo.”

October 15, 2004 — The Food and Drug Administration (FDA) issues a Public Health Advisory directing manufacturers of all antidepressant drugs to revise the labeling for their products to include a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these medications, and to include additional information about the results of pediatric studies.

Dec 6, 2004 — Report Of The CSM Expert Working Group On The Safety Of Selective Serotonin Reuptake Inhibitor Antidepressants is published. The findings for children and adolescents have already been issued in June, 2003. Findings for the safety of SSRIs for other age groups are as follows:

Young Adults (18-24)

“The clinical trial data for each product was reviewed in relation to a possible effect in young adults, and the GPRD study looked specifically at this age group. From these analyses, the Group concluded that there is no clear evidence of an increased risk of self-harm and suicidal thoughts in young adults of 18 years or over. However, given that individuals mature at different rates and that young adults are at a higher background risk of suicidal behaviour than older adults, as a precautionary measure young adults treated with SSRIs should be closely monitored.”

Adults

“There is no clear evidence that there is an increased risk of self-harm or suicidal thoughts when SSRIs are discontinued. Evidence of a relationship between suicidal behaviour and increasing/decreasing dose is not robust; however, patients should be monitored around the time of dose changes for any new symptoms or worsening of disease.”

Dec, 2004 —The MHRA issues a warning about Seroxat for adults.

February 3, 2005 — The FDA regulation, introduced Oct, 2004, requiring a black box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and adolescents and a warning must be cited in all advertising as well as included in the package insert, is finalized.

Dec 26, 2005 — An unusually high quality new blog appears under the title “1boringoldman”. It starts out with primarily political commentary. As time goes on, the anonymous author is revealed to have medical knowledge and detailed understanding of events related to drug safety and conflicts of interest.

January 2006 — Lawsuit: William P. Williams brings an action on behalf of his son Kevin, files an amended complaint in the Northern District of California, alleging that William and Kevin suffered personal injuries as a result of Kevin’s ingestion of Paxil in March and April of 2003, when Kevin was 14 years old.

After being on Paxil for about four days, Kevin violently attacked his father. Kevin was then taken to the Contra Costa juvenile detention facility, where he later attempted to commit suicide by hanging himself in his cell, the complaint said.

March, 2006 — Lawsuit: A case is filed in the U.S. District Court in the Eastern District of Pennsylvania by the families of two young patients who had been prescribed Paxil. Eleven-year-old Trevor Blain was prescribed Paxil for “separation anxiety disorder” in October 2000. A month later, Blain allegedly attempted suicide by hanging himself with his dog’s leash. Blain survived the suicide attempt but remained in a coma and later died.

Seventeen-year-old Tonya Brooks, was prescribed Paxil in 2004. She allegedly started cutting herself soon after taking the medication and attempted suicide after five months on the drug. Brooks first attempted suicide by overdosing with Paxil and Ambien, a prescription sleep aid. She survived the overdose but was involved in a serious car accident the next day, allegedly while still under the effects of the medications. Three days after her first suicide attempt, Brooks “gouged a three-inch deep hole in her leg”, court documents said. This behavior, the plaintiffs alleged, ceased as soon as she stopped taking Paxil.

April 3, 2006 — Article: “The Flawed Basis for FDA Post-Marketing Safety Decisions: The Example of Anti-Depressants and Children” by Donald F Klein.

John Mann, MD, Co-Chair of the heavily conflicted ACNP Task Force notes in an accompanying news release that “Given that untreated major depression is the main cause of suicide in children and adolescents, and that suicide is the third leading cause of death among 15-to-24 year-olds, there is an urgent need for effective antidepressant treatments.”

May, 2006 — In response to an FDA requirement, GSK sends a “Dear Healthcare Professional” letter which states:

“Current prescribing information for paroxetine – and for all other antidepressants – contains information in the WARNINGS section …stating that “patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications… GSK has recently conducted a new meta-analysis… of suicidal behavior and ideation… Results of this analysis showed a higher frequency of suicidal behavior in young adults (prospectively defined as age 18-24) treated with paroxetine compared with placebo…”

This letter conveys the message that it is the depression, not the medication, that is the problem.

July 10, 2006 — Lawsuit: The family of Harold Garrison Jr, 16, who committed suicide on Paxil, launch a claim against Smithkline Beecham for failure to warn about the side effect of inducing suicidality, which was known to the company.

Aug 25, 2006 — Charles Nemeroff resigns as Editor of Neuropsychopharmacology:

“The editor of a leading psychiatry journal announced last Friday (August 25) that he was stepping down after he published a paper about a treatment for depression without disclosing that eight of nine authors – including himself – had financial ties to the company that makes the device. Charles B. Nemeroff, editor in chief of Neuropsychopharmacology, a publication of the American College of Neuropsychopharmacology (ACNP), will not serve another term as editor, the college told its members in an Email. The decision was made “in part, based on the recent adverse publicity to the journal and the ACNP…”

(See Nov, 2002, February 2003, Sept 26, 2003)

November, 2006 — FDA Psychopharmacologic Drugs Advisory Committee, Chaired by Daniel Pine, M.D., meets to:

“discuss the results of an ongoing meta-analysis of data on suicidality emerging from antidepressant trials. Historically, this has been an issue that has been examined by many organizations including the FDA in great detail over the last five or so years. The specific purpose is to look at newly available data that focuses on results compiled by the FDA in trials among adults where all the previous meetings we have spent time talking about data in children.”

November, 2006 — Shelly Jofre from BBC’s Panorama interviews Mina Dulcan, Editor of Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), on the question of the ethics of publishing Study 329.

December 13, 2006 — FDA Psychopharmacologic Drugs Advisory Committee, Chaired by Daniel Pine, M.D., meets to:

“discuss the results of an ongoing meta-analysis of data on suicidality emerging from antidepressant trials. Historically, this has been an issue that has been examined by many organizations including the FDA in great detail over the last five or so years. The specific purpose is to look at newly available data that focuses on results compiled by the FDA in trials among adults where all the previous meetings we have spent time talking about data in children.”

January 29, 2007 — BBC Panorama broadcast ” Secrets of the Drug Trials ” . In the last of the 4 episodes on paroxetine (Seroxat), Shelley Jofre tells the story of how the facts about this drug were suppressed, even though they had been known to GSK and its predecessor companies from the outset. The episode shows how company officials cynically promoted the drug for young people, knowing that it was neither effective nor safe.

In this episode:

Jofre asks JAACAP Editor Mina Dulcan a question:

“JOFRE: Do you have any regrets about publishing this study?

DULCAN: Oh, I don’t have any regrets about publishing at all. It generated all sorts of useful discussion which is the purpose of a scholarly journal.”

Dr Healy is quoted as follows:

“We ‘re in a situation now where people who are ill generally have been deeply betrayed by the whole process, deeply betrayed by the pharmaceutical companies and by all the experts that have been willing to actually lend their names to the process…””If you’d heard the experts talk, they all say the drug was extremely safe and very effective. We were all hoodwinked, misled, duped. They produce these clinical trials which appear to be evidence and they aren’t, they’re adverts.”

May 2, 2007 — The FDA proposes that makers of all antidepressant medications update the existing black box warning on their products ‘ labeling to include warnings about increased risks of suicidal thinking and behavior (suicidality), in young adults ages 18 to 24 during initial treatment (generally the first one to two months).

June 12, 2007 — FDA Hearing on “Use Of Medication Guides To Distribute Risk Information To Patients” hears that despite the FDA requirement, introduced as part of the required warnings on SSRIs (finalized Feb 3, 2005), medication guides are not being distributed when antidepressant medications are dispensed.

Aug 10, 2007 — Report: In January, a federal judge dismisses the lawsuit O’Neal v SmithKline Beecham, re: the Paxil suicide of 13-yr-old Benjamin Bratt, on the basis of the Bush Administration’s new pre-emption policy. The firm of Baum, Hedlund, Aristei & Goldman had been retained as counsel for this suit.

By this time Baum Hedlund is one of the leading law firms dealing with SSRI damage claims. This is because of their groundbreaking role in the early cases of Fentress vs Eli Lilly, Forsyth vs Eli Lilly, Tucker vs GSK, etc. Their primary pharmacology expert in these cases is Dr David Healy. By the mid-2000’s, the firm is writing articles on this kind of case, (e.g. the Cure Worse than the Disease). Cindy Hall, at that time a Senior Paralegal at the firm, prepares a comprehensive report for the O’Neal case based on Dr Healy’s work. Presumably to have an American expert associated with the report, Baum Hedlund engages Dr Joseph Glenmullen of Harvard to prepare the final draft and put his name on the report. This report is unsealed on January 18, 2008.

In this report, the early evidence on adult safety of Paroxetine is reviewed, including the 1989 data that Dr Brecher reviewed in 1991. The report concludes that most of the suicides that SKB/GSK does not attribute to Paxil, and which are thus omitted from the data, are clearly caused by Paxil. After the data are reclassified and re-analyzed, the conclusion in the report is: “It is my opinion…that Paxil increases the risk of suicidality in adults. In addition, GlaxoSmithKline was aware of this risk, but hid it.”

Senator Grassley obtains a copy of this report and writes to GSK asking how it is that GSK knew of the dangers of paroxetine in 1989, but the first the public heard of it was the May, 2006 “Dear Health Professional” letter.

Sept 6, 2007 — Senators Charles Grassley (R-IA), the ranking member of the Committee on Finance, and Herb Kohl (D-WI), chairman of the Special Committee on Aging, introduce the Physician Payments Sunshine Act – so named because it aims to ” shine a much needed ray of sunlight on a situation that contributes to the exorbitant cost of health care, ” according to cosponsor Senator Charles Schumer (D-NY). The bill would require manufacturers of pharmaceuticals and medical devices with annual revenues of more than $100 million to disclose gifts or payments to physicians in any form, whether cash, trips, etc.

Feb 29, 2008 — Lawsuit: Cunningham v. Smithkline Beecham, US DISTRICT COURT NORTHERN DISTRICT OF INDIANA HAMMOND DIVISION

This lawsuit arises from the suicide of 14-year old Scott Cunningham in March 2001. In their complaint, the plaintiffs, Scott Cunningham’s mother, father, and brother, allege that his suicide was caused by the prescription anti-depressant marketed under the name Paxil and manufactured by the defendant Smithkline Beecham (GSK).

The plaintiffs allege that beginning in 1994, Glaxosmith-kline (Smithkline) became aware that Paxil was ineffective for the treatment of depression in adolescents and that the drug increased the risk of suicide in adolescent patients. The plaintiffs further contend that Smithkline knew that, despite the lack of approval for use in treating adolescent depression, so-called “off-label” prescriptions of Paxil were sufficient to make the drug the second most prescribed anti-depressant for children and adolescents. The plaintiffs allege that through a series of conferences, articles, and other promotional efforts, including the use of paid “opinion leaders”, Smithkline promoted the use of Paxil for children.

April, 2008 — Senator Chuck Grassley starts to investigate payments from pharmaceutical companies to prominent academics, prompted by the discovery that GSK has not been honest about the risks of Paxil. He learns that many high ranking academic physicians are receiving payments for speeches, and research far in excess of the usual limit prescribed by university conflict of interest policies ($10,000).

His investigations are aimed at the following psychiatrists, along with a few doctors in other specialties: Melissa DelBello (U. Cincinnati) Joseph Biederman (Harvard), Tim Wilens (Harvard), David Brent, Jeffrey Bridge, Daniel Casey (VA Medical Center in Portland), David Dunner, Graham Emslie, Daniel Geller, Robert Gibbons, Frederick Goodwin, Martin Keller (Brown), Andrew Leon, John Mann, John March, Charles Nemeroff (Emory), Augustus John Rush (U Texas), Neal Ryan, David Shaffer, Alan Schatzberg (Stanford) and Karen Wagner (U Texas).

July 12, 2008, the New York Times reported “But now the profession itself is under attack in Congress, accused of allowing this relationship to become too cozy. After a series of stinging investigations of individual doctors’ arrangements with drug makers, Senator Charles E. Grassley, Republican of Iowa, is demanding that the American Psychiatric Association, the field’s premier professional organization, give an accounting of its financing.”

Note that:

Daniel Casey chaired the 1991 FDA hearings which resulted in no warning for SSRIs at that time. David Dunner and John Mann were also decision-makers in these hearings; Graham Emslie, lead on the 1997 and 2002 fluoxetine (Prozac) studies, and one of the listed authors on Study 329, was Co-Chair of the ANCP task force that kept insisting in 2004 that the suicides of young people on SSRIs was due to depression. John Mann was the other Co-Chair. Frederick K Goodwin, Andrew C Leon, Neal D Ryan, David Shaffer and Karen D Wagner were ANCP Task Force members. Martin Keller was the lead on Study 329, as well as a similar study for sertraline (Pfizer). Neal Ryan was originally selected to lead Study 329.

April 11, 2008 — Article: Clinical trials and drug promotion: Selective reporting of study 329, by Jon N. Jureidini, Leemon B. McHenry, and Peter R. Mansfield describes the practice of selective reporting of study trial data that cannot be identified without access to internal company documents.

June 11, 2008 — Letter: Senator Chuck Grassley writes to Michael O. Leavitt, Secretary of the U.S. Department of Health and Human Services. He requests that the FDA look into whether safety information had been withheld in the US:

“I have recently received an expert report prepared for litigation by Dr. Joseph Glenmullen, a professor at Harvard University. Based on documents from GlaxoSmithKline (GSK) and the FDA, Dr. Glenmullen concluded that GSK officials knew back in 1989 that Paxil is associated with an increased risk for suicide. I have attached his report* for your review and consideration. Furthermore, I have learned that Britain’s Medicine’s and Healthcare Regulatory Authority (MHRA) concluded a four year investigation of Paxil. That report found that GSK had been aware since 1998 that Paxil was associated with a higher risk of suicidal behavior in adolescents. However, the British government did not move forward with criminal prosecutions because the laws at the time were not clear enough as to whether GSK should have informed the regulatory agency.

In response to the MHRA report, Britain’s public health minister, Dawn Primarolo, told the Guardian newspaper, “Companies that conduct clinical trials should not compromise people’s health by withholding information.” The Guardian also reported that the British government plans to introduce new legislation later this year to make clear that drug companies should not withhold safety information. In light of this investigation by the MHRA, I would like you to take a look at the information that agency gathered and determine if the company has withheld safety information here as well. I also request a briefing for my staff on whether or not a review is being conducted by HHS or any of its departments/ agencies regarding whether or not GSK withheld information from the FDA.”

*see August 10, 2007

Sept 24, 2008 — CBS news reveals that Dr Martin Keller has been targeted by Senator Grassley:

(UWIRE) – Investigators from the U.S. Senate Finance Committee are scrutinizing Brown University over disclosure of conflicts of interest in clinical research, Provost David Kertzer confirmed Thursday.

Though university spokespeople would not comment on the details of a letter of inquiry from ranking committee member Sen. Charles Grassley, R-Iowa, a source familiar with the investigation has confirmed that the letter names Professor of Psychiatry and Human Behavior Martin Keller, the chairman of the psychiatry department at the Alpert Medical School.

Keller has gained notoriety for authoring a controversial clinical study of the antidepressant drug paroxetine – marketed as Paxil in the United States – which concluded that the drug was safe and effective in adolescents. Keller and some of the study’s co-authors have been accused by doctors, lawyers and journalists of having the 2001 study ghostwritten, earning large sums of money from Paxil’s maker, GlaxoSmithKline. In addition, some say the researchers manipulated and suppressed data – including those showing increased suicidal tendencies in children taking the drug.

Study 329, as it is referred to by GSK, went on to become one of the most-cited articles in medical literature supporting the use of antidepressants for adolescent depression. At the time, GSK jumped on the favorable results, seeking to promote the use of its product among children, a largely untapped market for antidepressants.

In recent years, new studies and secondary research using old data have demonstrated that Paxil can lead to increased suicidal tendencies in children.

Keller would later acknowledge in a 2006 deposition that he had been accepting tens of thousands of dollars in consulting fees from GSK and Scientific Therapeutics Information – a company acting on GSK’s behalf – during and after the years he was conducting crucial research on the efficacy and safety of Paxil in children.

…Alison Bass, a former reporter for the Boston Globe, said Keller may have earned more than he acknowledged in tax returns. In a 1999 article for the Globe, Bass reported that Keller had earned a total of $1 million in consulting fees from various drug companies over the fiscal years 1997 and 1998, according to his tax returns from those years.

According to Bass, the tax returns show that Keller received $218,000 from Pfizer and $77,400 from Bristol-Myers Squibb during the same year he was praising Pfizer’s Zoloft and publishing positive conclusions on BMS’s Serzone. Missing from his tax returns, Bass told The Herald, was the money Keller acknowledged earning from GSK.

October 3, 2008 — Among the most serious violations uncovered by Senator Grassley’s investigations is the following:

“A prominent Emory University psychiatrist received at least $2.8 million in consulting fees from companies whose drugs he was evaluating and failed to report a third of it, congressional investigators studying medical conflicts of interest said Friday. The allegations against Dr. Charles B. Nemeroff, the latest in a series of such charges, are the most striking to emerge from the probe, which seems likely to alter the cozy relationships between prominent academics and the drug industry.

Nemeroff received the money from GlaxoSmithKline between 2000 and 2007 while he was the principal investigator on a $3.9 -million National Institutes of Health study of five Glaxo drugs for treatment of depression, Sen. Charles E. Grassley (R-Iowa), who initiated the investigation, said in a letter to Emory published Friday in the Congressional Record. Nemeroff continued to receive large amounts of money for delivering talks to other physicians even after he signed university documents pledging to accept no more than $10,000 a year from any one company, the inquiry found.”

Oct 3, 2008 — Under the Title: “Busted…” 1boringoldman, a.k.a. Dr Mickey Nardo, with respect to the revelations about Charles Nemeroff that have just hit all the major US news outlets, blogs:

“In the mid 1980’s, I was on the full time faculty at Emory in the Department of Psychiatry in charge of the Residency Training Program under an aging Chairman – a man who had founded the Department in the late 1950’s. I was and am a Psychiatrist and Psychoanalyst, so my own interest was in psychotherapy/analysis, but we had a well- rounded program – or so I thought. When a new Chairman came from Duke, I liked him, but it became quickly apparent that whatever he thought Psychiatry was, it wasn’t what I thought. After a year of being a fish out of water, I resigned, staying for a year to give myself time to figure out where to go next. I had tenure, so I had that luxury. After I left, this new Chairman became Dean of the Medical School and hired his friend Dr. Charles B. Nemeroff as Chairman of Psychiatry. The National Institutes of Health have strict rules mandating that conflicts of interest among grantees be managed or eliminated, but the health institutes rely on universities for oversight. If a university fails, the agency has the power to suspend the school’s entire portfolio of grants, which for Emory amounted to $190 million in 2005. But this step is so draconian that the health institutes almost never take it.

Dr. Nemeroff was the principal investigator for a five-year, $3.9 million grant financed by the National Institute of Mental Health for which GlaxoSmithKline provided drugs. Income from GlaxoSmithKline of $10,000 or more in any year of the grant – a threshold Dr. Nemeroff crossed in 2003, 2004, 2005 and 2006, records show – would have required Emory to inform the health institutes and manage the conflict or remove Dr. Nemeroff as the investigator. Repeatedly assured by Dr. Nemeroff that he had not crossed this income threshold, Emory did nothing.”

October 13, 2009 — Legal Judgement: GSK is ordered to pay the family of Lyam Kilker $2.5 million when a jury decides that Paxil is responsible for his birth defects.

“Oct. 13 (Bloomberg) — GlaxoSmithKline Plc must pay $2.5 million over claims that its Paxil antidepressant caused birth defects, a Pennsylvania jury concluded in the first of 600 such cases to come to trial.

Jurors in state court in Philadelphia deliberated about seven hours over two days before finding Glaxo failed to properly warn doctors and pregnant users of Paxil’s risk. The panel awarded $2.5 million in compensatory damages to the family of Lyam Kilker. The 3-year-old was born with heart defects his mother blamed on the drug…

It’s the first time a jury has considered claims that Glaxo, the U.K.’s largest drugmaker, knew Paxil caused birth defects and hid the risk to increase profits.” “The company disagrees with the verdict and will appeal, Kevin Colgan, a spokesman, said in an e-mailed statement.

“While we sympathize with Lyam Kilker and his family, the scientific evidence does not establish that exposure to Paxil during pregnancy caused his condition,” Colgan said.”

Dec 14, 2009 — Article: Glaxo Said to Have Paid $1 Billion in Paxil Suits estimates damages paid by the company to date related to suicides and birth defects.

“The London-based company hasn’t disclosed the settlement total in company filings. It has made public some accords. Glaxo’s provision for legal and other non-tax disputes as of the end of 2008 was 1.9 billion pounds ($3.09 billion), according to its latest annual report. This included all legal matters, not just Paxil…

About 450 suicide-related Paxil cases were settled. Only about a dozen haven’t been, the [Glaxo spokespeople] said. The $1 billion total doesn’t include more than 600 claims that Paxil caused birth defects.

Based on the outcome [in the Lyam Kilker lawsuit], an analyst estimated the company may potentially face additional verdicts in birth-defect cases waiting to be tried in Pennsylvania.”

DATE — March 23, 2010 US Senators Grassley and Kohl’s Physician Payment Sunshine Act is finally enacted as part of the Patient Protection and Affordable Care Act (see Sept 6, 2007). Key Dates:

• August 1, 2013: Manufacturers are required to begin collecting payment information.
• January 1, 2014: CMS target date for launching its physician portal, whereby every physician can sign up to be notified when his/her individualized report is available for review.
• March 31, 2014: Manufacturers and GPOs report the payment/ownership data for August 1 – December 31, 2013 to CMS.
• June 30, 2014: CMS target date for providing physicians access to their individualized August 1 – December 31, 2013 report. Through the CMS portal, physicians will be able to contact manufacturers/GPOs if corrections are necessary.
• September 30, 2014: CMS date for release of the data via a publicly available and searchable website.

December 7, 2010 — Article: “The Rules of Retraction”, by Melanie Newman discusses the attempts to get the publication of Study 329 retracted.

January 31, 2011 — Article: “Conflicted Medical Journals and the Failure of Trust” by Jon N. Jureidini Ph.D.M.D. & Leemon B. McHenry Ph.D., is published.

This article summarizes the flaws in the original 329 study. The Abstract is reproduced below:

“Journals are failing in their obligation to ensure that research is fairly represented to their readers, and must act decisively to retract fraudulent publications. Recent case reports have exposed how marketing objectives usurped scientific testing and compromised the credibility of academic medicine. But scant attention has been given to the role that journals play in this process, especially when evidence of research fraud fails to elicit corrective measures. Our experience with The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) illustrates the nature of the problem. The now-infamous Study 329 of paroxetine in adolescent depression was negative for efficacy on all eight protocol-specified outcomes and positive for harm, but JAACAP published a report of this study that concluded that “paroxetine is generally well tolerated and effective for major depression in adolescents.” The journal’s editors not only failed to exercise critical judgment in accepting the article, but when shown evidence that the article misrepresented the science, refused either to convey this information to the medical community or to retract the article.”

August 2, 2011 — Article: Legal Remedies for Medical Ghostwriting: Imposing Fraud Liability on Guest Authors of Ghostwritten Articles.

Simon Stern and Trudo Lemmens from the University of Toronto make the following points about ghostwriting:

“Summary Points:

• Ghostwriting of medical journal articles raises serious ethical and legal concerns, bearing on the integrity of medical research and scientific evidence used in legal disputes.
• Medical journals, academic institutions, and professional disciplinary bodies have thus far failed to enforce effective sanctions.
• The practice of ghostwriting could be deterred more effectively through the imposition of legal liability on the “guest authors” who lend their names to ghostwritten articles.”

Oct 4, 2011 — A group of 24 physicians, academics and journalists send a letter to President of Brown University, President Ruth J. Simmons, asking her to contact Dr. Andrés Martin, Editor of the Journal of the American Academy of Child & Adolescent Psychiatry, to request retraction of the published 329 study.

June 30, 2012 — Martin Keller, lead Author of the original published study, retires from Brown University. A Sept, 2012 post by the staff writers at Drug Watch notes:

“Study 329 has never been retracted, however, and its authors did not face sanctions. The universities they represented did not even issue a public acknowledgement of the danger their academics created when they published a fabricated study. Furthermore, the lead author of the study, Martin Keller, was allowed to quietly retire from his academic position at Brown University at the end of June and maintain the title of emeritus professor of psychiatry and human behavior.”

July 20, 2012 — Dr. Jureidini requests the Editor of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) to retract the original 329 study.

2012 — Throughout 2012, the 1boringold man blog of retired psychiatrist and statistician Mickey Nardo, records insights and observations about the growing debate over data integrity and access, describing the efforts of David Healy, Jon Jureidini, Peter Doshi, Tom Jefferon, Peter Gøtzsche and others.

Oct 11, 2012 — GlaxoSmithKline announces plans to make data from clinical trials of drugs available to researchers beginning in 2013. Under the new policy, GSK will establish an independent panel of experts to review information requests submitted by researchers, which will be evaluated on scientific merit. The company then will make that data available to scientists on a secure website.

The policy will apply to global clinical trials dating back to 2007, as well as all clinical trials for drugs that have completed the approval process or have been abandoned starting in 2013. Following this announcement questions arise such as who will count as a qualified researcher? and exactly what data will be released?

As Micky Nardo notes Oct 9, 2013 (The Wisdom of the Dixie Chicks): “Having looked at GSK’s proposed process for access myself, it gives GSK the choice of releasing the data based on the credentials of the applicant and GSK’s opinion of the worthiness of their research proposal. I don’t want access to their IPDs to do further research. I want it to check and see if they’re cheating again like they’ve done countless times before.”

Oct 26, 2012 — The U.S. Department of Justice brings an action in U.S. District Court to recover damages and civil penalties from GSK under the False Claims Act, and damages and other monetary relief under common law and equity for causing the submission of false of fraudulent claims to federal health care programs. The action was brought on behalf of the Department of Health and Human Services (the FDA is under this) and the Centres for Medicare and Medicaid Services (CMS). The claims relate to 3 drugs: Wellbutrin, Avandia, and Paxil.

Nov 19, 2012 — Dr David Healy posts a brief history and status review on the quest for transparency in drug clinical trials.

Dr Peter Gøtzsche takes on the EMA over the issue of access to study reports the weight loss drugs rimonabant and sibutramine.

“The other driving force came from Peter Doshi and Tom Jefferson’s efforts to conduct a Cochrane review on Roche’s antiviral for influenza – Tamiflu. … governments around the world stockpiled billions of dollars worth of this under the impression it saved lives by reducing transmission, kept people out of hospital and got them back to work faster … Doshi and Jefferson asked Roche for access to the data – they agreed – but never delivered. The BMJ have picked the issue up as the most clear cut case on which to campaign for data access.”

November, 2012 — GSK agrees to pay $US 3 billion to settle the U.S. Department of Justice lawsuit. This is the largest settlement ever.

The settlement includes $1 billion in criminal fines and $2 billion to resolve civil liabilities owed to the federal government and the states, the Justice Department said.

Dec 21, 2012 — Dr Andres Martin, Editor-in-Chief of JAACAP responds to Dr. Jureidini’s request for retraction of the 329 study article, claiming that the Editorial Board did an extensive review. He states that there is no basis for retraction or other editorial action.

April 26, 2013 — Letter: Dr. Jureidini writes to GSK CEO Sir Andrew Witty asking GSK to request retraction of the original 329 study article.

May 3, 2013 — Reply: Dr. John Kraus responds on behalf of Sir Andrew/GSK declining to request retraction, refuting the suggestion that the reported findings were fraudulent, and noting that the authors had refused to request retraction and the journal had refused to retract.

June 13, 2013 — Article: Peter Doshi, Kay Dickersin, David Healy, Swaroop Vedula, and Tom Jefferson publish in BMJ: “Restoring invisible and abandoned trials: a call for people to publish the findings”, or RIAT, as a way of clarifying the true value of treatments. Dr David Healy describes the implications of RIAT:

“Experts are today calling for all unpublished and misreported trials to be published or formally corrected within the next year to ensure doctors and patients rely on complete and accurate information to make decisions about treatments. The BMJ is backing their call as part of its “Open Data” campaign – to ensure clinical trial data is publicly available for independent scrutiny – and will discuss it in more detail at a meeting in London on Friday 14 June 2013.

Unpublished and misreported studies make it difficult to determine the true value of a treatment. Around half of all clinical trials for the medicines we use today have never been published – and a whole range of widely used drugs have been represented as safer and more effective than they are, putting patients at risk and wasting public money. The authors of the declaration… will contact manufacturers of trials, asking them to signal their intent within 30 days to publish previously unpublished trials and formally correct previously misreported trials (i.e., to restore abandoned trials). They propose that if anyone who declares an intention to publish or correct does not do so within one year, all publicly available data for such trials should be considered “public access data” that others are allowed to publish…

New freedom of information policies mean the public, and the authors, have access to around 178,000 pages of previously confidential trial documents and clinical study reports for widely used drugs for depression, heart disease, epilepsy and influenza. Some trials remain unpublished years after completion, while others have been published but have been shown to contain inaccuracies.”

June 13, 2013 — The same day that the BMJ published the RIAT article, Micky Nardo blogs that the RIAT team is a broad coalition, of which he is a member:

“a bold remedy…

To every thing there is a season, and a time to every purpose under the heaven… Ecclesiastes 3:1, Corinthians II 6:2″ “In the story of every tension, there’s a time for reflection and understanding, and then there’s a time for action… The time for just decrying the shameful abuse of clinical trials in psychiatry and the rest of medicine has passed… The Cochrane Collaboration, Peter Doshi, and Tom Jefferson have been playing hard chess with Roche around the billion dollar efficacy questions with Tamiflu. Healthy Skepticism and others have dogged the JAACAP over Paxil Study 329 for a decade. Dr. David Healy’s Pharmageddon and Rxisk database have taken on trials as well as adverse effects in general. Now comes RIAT [Restoring Invisible and Abandoned Trials] backed by a broad collaboration proposing a plan to add some teeth to the demands for clinical trial reform, focusing on missing and jury-rigged studies. The plan was announced today…”

June 28, 2013 — Despite its own advisory group recommending against it, the FDA approves Paroxetine for treating symptoms of menopause. The advisory group conclusion, by a vote of 10 to 4, is the overall benefit–risk profile of Brisdelle does not support approval. Noven gets Brisdelle approved despite reported efficacy barely higher than placebo.

A New England Journal of Medicine Article explains why the FDA approved this drug against the advice of its own advisory Committee. The logic behind the approval seems to be that hormonal options have fallen out of favour and it is necessary that some medication be available. The article repeats the myth that paroxetine has a proven safety profile.

Article: FDA Approval of Paroxetine for Menopausal Hot Flushes

“The efficacy of Brisdelle was established in two randomized, double-blind, placebo-controlled, multicenter clinical trials. Among a total of 1184 menopausal women who had a median of 10 moderate-to-severe hot flushes per day, Brisdelle was shown to provide modest relief in comparison to placebo. For example, at week 12 in one study, there was a median reduction from baseline of 5.9 moderate-to-severe hot flushes per day with Brisdelle as compared with a median reduction of 5.0 per day with placebo (median treatment difference, 0.9; P<0.01). At week 12 in the second study, there was a median reduction from baseline of 5.6 moderate-to-severe hot flushes per day with Brisdelle as compared with a median reduction of 3.9 per day with placebo (median treatment difference, 1.7; P<0.001). Despite this modest effect, more women who used Brisdelle than women who used placebo considered the reduction in frequency of their hot flushes to be clinically meaningful. In addition, Brisdelle remained efficacious at 6 months, the latest time point assessed. This is an important finding, because a lack of efficacy at 6 months after treatment initiation would call into question its usefulness for this fairly chronic condition.

The safety profile of paroxetine, when used at higher doses to treat psychiatric disease, is well-established.”

Sept 4, 2013 to Nov 8, 2013 — (See correspondence with GSK re: Data) In a series of letters and e-mails to GSK, Dr. Jureidini requests access to the Case Report Forms, or CRFs, showing anonymized patient-level data and making reference to GSK stated support for RIAT. The company declines to make the CRFs available to Dr. Juriedini.

Nov 12, 2013 — Feature Article: “Putting GlaxoSmithKline to the test over paroxetine” by Peter Doshi

“Blockbuster antidepressant paroxetine is no stranger to headlines. The drug is now back centre stage as requests for clinical data from one of its trials are testing manufacturer GlaxoSmithKline’s commitment to full transparency.

GlaxoSmithKline is leading the pack in its efforts to liberate access to its clinical trial data. It was the first major pharmaceutical company to sign up to the international AllTrials petition calling for all trials to be registered with the full methods and the results reported… But one group’s request for data is testing the limits of GSK’s commitment to full transparency. Jon Jureidini, clinical professor of psychiatry at the University of Adelaide, is leading a team to reanalyse and republish the results of GSK’s study 329.”

Sept, 2014 — A video clip is released of Dr. David Healy reviewing the history of Study 329 in a lecture in Cardiff, Wales.

Sept 3, 2014 — Study 329 is re-written. The re-write reflects the results actually indicated by the data. Entitled: “A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression: Restoring Study 329” is submitted to BMJ.

The authors are: Joanna Le Noury, School of Medical Sciences, Bangor University; John (Micky) Nardo, Psychiatry (retired), Emory University; David Healy, School of Medical Sciences, Bangor University; Jon Jureidini, Paediatric Mental Health Training Unit, University of Adelaide; Melissa Raven, Discipline of Public Health, Flinders University; Catalin Tufanaru, Joanna Briggs Institute, University of Adelaide; Elia Abi-Jaoude, Psychiatry, University of Toronto.