Fraud in SSRI drug trials - The Gathering Storm Part II

Sometimes there is no other way to say it than through humour. We have taken the most vulnerable in society, and we have lied to them. We have lied as a profession. We have allowed our "regulators" to lie and to collude with lying. The best and most intelligent of our profession have remained silent.

This is the classic description of the research method in these trials:
Monty Python: The Gathering Storm - Part II


"Who's gonna investigate the man who investigates the man who investigates me" was the refrain of "The Investigator's Song", words and music by Harold Rome/Zero Mostel in 1947. The song's final line: "One more problem puzzles me; Pardon my strange whim. But who's gonna investigate the man who investigates the man who investigates... him?"
(The People's Song Book, Waldemar Hille, ed., Boni & Gaer, 1948)

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You owe the General Medical Council £5 - the case of Sushant Varma

Although not about medical scientific misconduct, this is directly related.

The General Medical Council (GMC) is one of several bodies in the UK charged with regulating aspects of integrity in clinical medical research. It also registers and regulates other activities of doctors. The functioning of the GMC is therefore of considerable public interest.

Also of interest is the approach of the GMC to their requirement that doctors should be truthful.

In response to a request, the GMC recently confirmed that it spent £175,000 (approximately $350,000) on external legal fees pursuing one medical student/junior doctor, Dr Sushant Varma of Sheffield (my home city).

Our ref: IAT/F1314/EH

Dear ______

I write further to your request made in accordance with the Freedom of Information Act 2000, as set out in your email below.

I can confirm that this case has cost the GMC £175,000. I should add that this does not include the time spent by GMC staff on case administration. We are unable to quantify this as we do not record the amount of time staff spend on individual cases.

If you have any concerns regarding the handling of this request please address these to:

Julian Graves
Information Access Manager
General Medical Council
Manchester M1 6FQ

Given the convoluted machinations of the GMC in this case, it's internal expenses are likely to have been a further £175,000, and considerable expenses were incurred by the Medical and Dental Defence Union of Scotland (who provided some legal support for Varma). Given the number of registered doctors in the UK (~100,000) this single case will have cost each doctor around £5.00. Meanwhile, doctors have noted the recent hike in GMC fees (from £290/year to £390). The GMC states this is "not related to revalidation reform", but rather to other "accumulated expenses" such as those incurred in this case.

Varma is a colorful character, and has certainly told some trivial lies. For example he lied on his CV about an appearance on a television show (Blind Date). He has freely admitted to those lies. He may have told a more serious lie, but the evidence for that is far from clear. The GMC apparently declined to examine relevant evidence. Varma was erased from the medical register and his career was destroyed.

Of broader importance are the precedents raised by this case, and the consistency of GMC action:

1. When can a doctor lie?
2. Are all lies of equal importance?
3. Are the status and responsibilities of the lying doctor relevant?
4. From the point of view of medical regulation, is there a difference between lies told in clinical research, lies in clinical practice, and private lies (which might reflect on the credibility of a doctor)?

To paraphrase Frank Zappa, the GMC is a body of rules, badly written and randomly enforced. What happened to Dr Varma merits some examination, as do the motives that might have led the GMC to spend such a considerable amount of our money on this one relatively trivial case.

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Memory Hole (30 October): Junk science

Scientific Misconduct Blog Memory Hole: Events of October 30th

8 years ago today: Science versus quackery in SSRI drug trials

On 30 October 1999 an important, worrying and predictive article by Sarah Boseley appeared in the Guardian. This is about open, honest and properly represented science versus quackery. The problems are obvious.

An abbreviated version of the Guardian article is reproduced below:

They said it was safe, The Guardian Oct 30 1999

Since the launch of Prozac there has been a spate of disturbing accounts of violence and suicide committed by people prescribed the drug. Victims and families of killers have sued Eli Lilly but no cases had reached a verdict because Lilly settled out of court.

However in 1999 for the first time, Lilly came up against a family in the US who would not settle. The Forsyths wanted a hearing. Internal documents belonging to Lilly were produced in court, and these "showed that Lilly knew as long as 20 years ago that Prozac can produce in some people a strange, agitated state of mind that can trigger in them an unstoppable urge to commit suicide or murder".

Lilly's own internal documents show it was identified as early as 1978. On August 2 of that year, when only three trials were under way, minutes of a meeting of the Fluoxetine (Prozac) Project Team run thus: "There have been a fairly large number of reports of adverse reactions... Another depressed patient developed psychosis... Akathisia and restlessness were reported in some patients." A similar meeting 10 days earlier had noted that "some patients have converted from severe depression to agitation within a few days; in one case the agitation was marked and the patient had to be taken off [the] drug."

The minutes further state that "in future studies the use of benzodiazepines to control the agitation will be permitted". So, from that point on, Lilly's trial subjects would be put on tranquillisers to get them over the akathisia experienced by some in the early days on the drug. Yet once Prozac was on the market, there was no warning to doctors that such action might be necessary.

Those who developed akathisia or who had any suicidal tendencies were excluded from the trial data on the basis that they would otherwise obscure the results of the drug's success in treating depression. Yet the German licensing authority, the Bundes Gesundheit Amt (BGA), on scrutinising the results, expressed concerns about the drug's safety. On May 25, 1984, according to Lilly's internal documents, a letter from the BGA stated: "During the treatment with the preparation [Prozac], 16 suicide attempts were made, two of these with success. As patients with a risk of suicide were excluded from the studies, it is probable that this high proportion can be attributed to an action of the preparation [Prozac]."

During the licensing process in the US, however, Lilly did not tell the Food and Drugs Administration (FDA) of the German concerns. Some of Lilly's own scientists had reservations about this.

One of them, John Heiligenstein, wrote in an internal memo on September 14, 1990: "We feel caution should be exercised in a statement that 'suicidality and hostile acts in patients taking Prozac reflect the patient's disorder and not a causal relationship to Prozac'.

A memo from Thompson ran: "I hope Patrick [probably a Lilly employee, but not identified fully in the memo] realises that Lilly can go down the tubes if we lose Prozac, and just one event in the UK can cost us that."

A memo from the German office to Lilly's US headquarters in that November indicates that Lilly was keen to root out the word "suicide" altogether from its database record of side-effects experienced by patients on the drug: Claude Bouchy and Hans Weber in Germany were alarmed by suggestions from their US superiors that, when GPs reported a suicide attempt on Prozac to them, they should record it as "overdose" (even though it is not possible to kill yourself by overdosing on Prozac), and that a GP's report of "suicidal ideation" should be recorded as "depression" - "Hans has medical problems with these directions and I have great concerns about it," runs a memo from Bouchy to Thompson. "I do not think I could explain to the BGA, to a judge, to a reporter or even to my family why we would do this, especially on the sensitive issue of suicide and suicide ideation."

Something had to be done. Lilly finally agreed to undertake the study suggested by the FDA, and look at the suicide rate among UK patients on Prozac, but it didn't. Instead, the company put together a "meta-analysis". Lilly's own scientists, led by Charles Beasley, did the work.

Beasley's study was published in the British Medical Journal in 1991. It had "the appearance of scientific rigour", says Dr Healy, but it is clear, he says, in the light of the documents that emerged in the Forsyth case, that the so-called meta-analysis had included only 3,065 patients out of around 27,000 involved in the trials and that it had also included data that the FDA had rejected during licensing. Among those excluded from Lilly's study were the 5% of patients who had shown akathisia-like symptoms during the clinical trials and had dropped out, and also the 13 or 15 suicides. Nor was there any mention of the fact that a considerable number of patients had been put on benzodiazepines to suppress the very problem that Lilly was claiming did not occur.

Is this science?? Has the Beasley paper been retracted or corrected? We cannot claim to prescribe under the banner of science if we fail to deal with this.

Sources: They said it was safe, The Guardian Oct 30 1999
Related patient blogs: Furious Seasons, Soulful Sepulcher

2 years ago today: UK Drug regulator undeclared links with Syngenta

On 30 October 2005 Britain’s drugs safety watchdog (the MHRA) was "forced to declare an interest in one of the world’s largest pesticide companies, following an investigation by the Sunday Herald". Sir Alasdair Breckenridge, the chairman of the MHRA "changed his mind only after responding to a series of allegations about potential conflicts of interest". He formally declared his involvement with Swiss agrochemical giant, Syngenta. The revelation has prompted fierce criticism.

"This was also not the first time that Breckenridge had been caught up in controversy about an alleged conflict of interest". There have been calls "for Breckenridge’s resignation over alleged failings in regulating anti-depressant drugs". "From 1992 to 1997, Breckenridge was a scientific adviser to SmithKline Beecham (now GlaxoSmith-Kline), which manufactured one of the drugs, Seroxat". Three other members of the MHRA’s committee on the safety of medicines – professors Chipman, Park and Griffiths – declared interests in Syngenta in 2004. Ian Kimber, head of research at Sygenta’s central toxicology laboratory in Cheshire, is a member of the MHRA’s committee on the safety of devices.

So much for that stated "independence".

Source: Drugs watchdog linked to pesticide company - Sunday Herald 30 Oct 2005

2 years ago today: The purpose of a University

On 30 October 2005 the Times newspaper and BBC revealed that a lecturer at Southampton Solent University in the UK secretly filmed meetings with senior academics at which she was put under pressure to pass students whom she believed should have failed. “As a new lecturer I was under huge pressure to pass the students. The college was financially driven. It was a pure bums-on-seats policy. It wasn’t about education at all.”

A colleague stated on film: “Essentially, in the end you have to fit with the system. It’s as simple as that.”

Source: Lecturer reveals university pressure to pass poor students Times Online Oct 30 2005

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Memory Hole (16 October): Merck probed over "agreement" with FDA and data analysis

3 years ago today: Probe of Merck "arrangement" with the FDA and data analysis

On 16 October 2004 the Financial Times of London and the Washington Post reported on a probe of the FDA and its relationship with Merck. Vioxx had been withdrawn two weeks previously. The FT discussed a secret deal with US regulators that made Merck privy to government studies on its drugs. An FDA E-mail, suggested regulators discussed a notification agreement with Merck. In a May 14 2002 e-mail, Ann Trontell, FDA deputy drug safety director, warned colleagues that a Merck official had reminded her that "there had been an agreement that Merck would be informed prior to any FDA publication about one of their drug products".

The Washington Post reported that "Merck officials faced a difficult decision about how to handle the catastrophe". "The whole saga, industry experts said, raises unsettling questions about aggressive consumer marketing of drugs before their long-term safety has been proven."

"researchers had been warning about the drug's possible cardiovascular risks since 2000". "Data from a company study found then that users had four times as many heart attacks and strokes". Merck "repeatedly reassured the medical and financial communities that Vioxx was safe". Eric Topol said "Why didn't they stop the DTC [direct to consumer] marketing?". "That's the tragedy here."

"The FDA safety officer in charge of the report, David Graham, concluded that Vioxx posed much greater cardiovascular risk than the other major drug in its class" In an E-mail "a Merck official complained that the FDA had not lived up to a prior agreement to alert the company before releasing any negative information about its products."

Clinical trials include independent safety monitors. "The four monitors, along with a Merck statistician were the only ones with full access to information about the trial, including which patients were getting Vioxx and which were getting the placebo."

(For a glimpse into the way in which data and analyses can get combobulated under such incestuous high-stake conditions a single example will suffice. Therein lies a great deal of the problem.)



Merck is I believe one of the more ethical pharmaceutical companies. Who sets the standards?

Sources: Financial Times, 16 Oct 04, Merck under spotlight for 'deal' with US drug regulators; Washington Post, 16 Oct 04, Painful Withdrawal for Makers of Vioxx

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