International Day in Memory of SSRI Fatalities

Motivated initially by the death of Traci Johnson, a healthy volunteer in a Cymbalta trial, at one of Eli's facilities, Ana has chosen the 6th anniversary of Traci's suicide by hanging to inaugurate a day in memory of all those who have suffered such extreme adverse reactions to this class of psychoactive drugs that they have taken life - either their own, or that of others. I'll leave Ana to explain the full rationale behind the Event:

February 7 - International Day in Memory of SSRI Fatalities

You can link to the Bloggers Unite Event page via the link, below, or by clicking on the ribbon in the sidebar, at the top of this page. You will need to join Bloggers Unite as part of the process of joining the Event (a 30 second operation, if my experience is anything to go by).

Bloggers Unite - International Day in Memory of SSRI Fatalities

I am aware that the standard line in such cases is to blame these reactions on the underlying condition of any given patient, but plenty of these cases have been acknowledged by official sources as being at least exacerbated by drugs - the Donald Schell case, for example, which involved Paxil (Seroxat). Be under no illusions: there is an issue, here, and it's regrettable that post-marketing reports of adverse reactions tend to be treated with the same kind of selective approach as those emerging during clinical trials.

Recording: British Paxil Users Meet With Brit FDA

Furious Seasons has posted the audio recording of the recent meeting between representatives of the Nine Elms Massive and patient advocates. I've made a couple of comments on there, if you're interested (and even if you're not interested, I've still made a couple of comments), but the upshot is that the Establishment has decided to defend its position - there is no attempt being made to address the issues with the industry that several commentators and patient advocates have raised. It seems to be about justifying the status quo, when the status quo is shit.

I listened to the recording for 36 minutes, and I was so disgusted with the whole fucking thing that I refused to expose myself to it, any further. It sounded very much like a PR exercize, nothing more. If the MHRA was really listening, it would be including its biggest (or at least most vocal), critics in the discussion and it would be addressing the issues that they raise, instead of justifying the machinations of the system, which, in their totality, I argue achieve precisely the opposite of what it is argued is being achieved.

What is being done to address the way in which companies have complete control over the trial of drugs, statistical analysis and writing of papers? What is being done to establish regulatory rules and guidelines, which fill the gaps left by legislation? Will the UK regulator address the question of its apparently flimsy assessment process - for example, why does it accept those dodgy academic papers as valid evidence of safety and efficacy, when there is evidence that this business of "information laundering" renders academia unreliable, to say the least?

Oh, it's all bollox - the halfwits don't want to change a damn thing, because it's not in their interests to change anything, and because they don't know how.

Matt

Clinical trials and drug promotion: Selective reporting of study 329

A paper by Jureidini, McHenry and Mansfield on the subject of Protocol 329. Dr Jureidini, you may remember, was one of the original critics of the paper that the Great Genius Who Is Professor Martin Keller "wrote," back in 2001. The paper is available on Healthy Skepticism, but has attracted attention from Fidders and Clinical Psych, the latter making the particularly pertinent observation that the various statistical shennanigans that took place in order to turn, quite magically, Paxil from a pile of kak into a pile of kak with a bow on top is anything but an isolated incident (although, I find that all magic is based on sleight of hand).

I'm not a statistician, and so I don't fully understand the nature of the argument, although I do understand that changing what one claims to have been looking for, after one has the results in front of one, probably isn't very scientific. No, to quote the Great Genius Who Is Professor Martin Keller, "I'm better with words"! And I'm still struck by the need that James McCafferty (the Paxil Phase 4 project manager, and a SKB employee), perceived to tell Sally Laden (the ghostwriter) that she oughtn't to be making grand claims as to safety, when she was also documenting lots of adverse events.

McCafferty and Rosemary Oakes, a senior statistician at SKB, who worked on the project, got their names on the paper, when it was published. Call me old-fashioned, but I should have thought that having the Company run the trial, crunch the numbers, and then write the paper, informing people of what the numbers meant, before using that paper as an adjunct to a marketing authorization application (and have the regulator accept said paper as valuable evidence), is probably open to abuse. What? Oh, yeah: it was abused, but I should state for legal reasons that it is only my opinion that this was abused. As such, it is merely my opinion that I cannot conceive of a more flagrant fraud.

Matt

Lying through your teeth

Fidders has put together a video, which is very nicely done - lots of very useful information, with a musical accompaniment:

More opaque than an opaque thing... Part IV

I thought I might as well go through all the hoops and mail the Head of the absurdly-named Intelligence and Enforcement Unit, at the MHRA. This to Michael Deats, copied to Woods, Breckenridge, Vara, Johnson and the CPS:


Dear Mr Deats,

I am currently engaged in a discussion with Professors Woods and Breckenridge and the CPS (please see below) on a question over the application of Regulation 50 of the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended).

Would it be your position, as Head of the Intelligence and Enforcement Unit at the MHRA, that where trials have been carried out on a drug, and those trials have produced negative results, and that there are also trials of that same drug that have yielded results that are interpreted as positive, and it is subsequently only the positive results that are submitted in support of a marketing authorization application, that the presentation of only the positive data (owing to the suppression of the negative data) amounts to the provision of "false or misleading" information, under Regulation 50?

Best regards

Matthew Holford

More opaque than an opaque thing... Part III

I'm a bit disappointed with the feedback I'm getting from the MHRA, just now, so I thought I'd try a different angle. This was sent to Breckenridge and Woods, copied to Johnson, Vara and the CPS:


Dear Professors Breckenridge and Woods,

My apologies, I should have copied you in on this, earlier. There appears to be a consensus amongst the (disinterested) scientific community that the withholding of data on drugs is unscientific. I would argue that it is unlawful, although I am interested to understand whether that view is shared by the Establishment.

Either way, the practice of suppressing negative data has contributed significantly to the Seroxat farce, in all its ignominy. To date, the MHRA has done nothing to ensure that that does not happen again. I would hold that that is incompetence of the highest order, and I can only imagine that it is not doing anything, because it is not in the interests of the Worshipful Company to do anything. That is corruption, if it be true. Are you corrupt, gentlemen?

Best regards

Matthew Holford

*************************



Dear Sir or Madam,

I am currently engaged in a discussion with the MHRA, concerning the application of the Medicines for Human Use (Clinical Trials) Regulations 2004 (please see below). It appears that the MHRA is unable to provide an opinion, for whatever reason that it might have.

Is the CPS positioned such that it may provide definitive guidance as to the nature of conduct that would constitute a contravention of Regulation 50?

Best regards

Matthew Holford

********************************

I see a sign... it is a good omen!

The MHRA was kind enough to follow up on a matter that I raised with it a little while back. I'm not sure that it says anything new, particularly, but it's always good to hear from somebody different. The MHRA's correspondence is emboldened, as usual:


Dear (redacted),

I have had an opportunity to read through your letter, for which, again, many thanks. I have the following comments/questions:

I believe the hypothetical scenario relates to a question that I put regarding the investigation into the GSK vaccine business, in Russia. As far as I know, there have been no decisions made as to GSK's culpability, as yet, and as such I understand that you would not wish to speculate on such a matter. In the event, one of the GSK shareholders in the House was kind enough to refer the matter to the then Secretary of State for Health, Patricia Hewitt. The DoH advised me, via the shareholder, that the MHRA does not concern itself with matters that relate to events in other jurisdictions. As such, I feel that I am as well informed on this matter as I care to be.

As to risk/benefit assessments, I believe that that very precise figure of 83 trials relates to a paper that I had read. If I remember aright, it was a piece by Peter Breggin. I regret that I do not have specific details of the trials to which (I presume) Dr Breggin was referring.

However, while I understand from your comments that the MHRA's risk/benefit analysis is perhaps more subjective than objective, I was rather more interested in the procedure involved? I see that 50 trials were held to demonstrate the efficacy of the drug - did any of these involve a review of the raw data, or were statistical summaries only provided?

Either way, I would be interested to understand how "efficacy" was demonstrated, given that Mr Goldfinch has advised me to the effect that it was not necessary for an applicant to demonstrate the level of efficacy, merely that there was efficacy. I must confess that I am struggling with this one, because if one doesn't have a frame of reference, then it will not be possible to judge whether a drug is efficacious, or not, I should have thought. Indeed, unless placebo and drug's performance are measured against the same scale, then any amount of numbers will be meaningless, irrespective of what the applicant says that the summary demonstrates. Furthermore, one may not say with confidence (nor with the conviction of truth) that a drug is better than placebo, if one does not know what the drug scored, relative to the placebo. Nor will it help if one is unaware as to what the placebo scored.

In summation, then, I am keen to understand the procedure followed in the assessment process, including the risk:benefit analysis, however mercurial the latter element may be?

Best regards

(redacted)

--------------------------------------------------------------------------------
From: (redacted)
To: (redacted)
CC: (redacted)
Subject: FOI 07/088 Seroxat
Date: Wed, 5 Sep 2007 15:56:57 +0100


Dear (redacted),

Please see attached response to your previous query, and please accept my apologies for the considerable delay in responding.

Kind regards

(redacted)
Licensing Division
MHRA
Tel 0207 084 2391
Fax 0207 084 2323

Attachment:
FOI 07/088

Dear (redacted),

Regarding you enquiry back in 9 March 2007, I regret that this was not addressed at the time, however I am able to address your queries which was as follows:

“I understand that the MHRA may have issues commenting on legal matters, particularly when such matters pertain to a jurisdiction outside its own. What would be its response, in the event that an (unnamed) pharmaceutical company were found to have breached a law in another jurisdiction, which also happened to be a law in the UK?”
The MHRA is unable to comment on a hypothetical scenario.

“I am interested to note your comment, concerning risk/benefit assessment. I understand that 83 trials were carried out on Seroxat, during the period 1980-91. What fraction of these did the MCA/MHRA view the results of? Indeed, I would be most interested to understand the technicalities of the MHRA's risk analysis. Perhaps you could advise me, on this point.”

Without a list of the 83 trials to which you refer it is not possible to say which of those trials the MHRA has viewed the results of. However, I have been able to ascertain the following information from the original assessment report:

Human Pharmacology: 59 studies were analysed and presented Pharmacokinetic data was obtained from over 60 studies; Drug interaction data was obtained from 30 studies; Efficacy data was supported by over 50 studies (11 Placebo controlled studies; 16 comparator studies; 4 double blind comparator studies, 5 long term efficacy studies; 19 open studies). Safety data will have been obtained from the above mentioned trials.

Regarding the technicalities of the MHRA’s risk analysis. There is no magic formula that can be used to weight the risk/benefit analysis, it is purely a case of considering the benefit(s) that the patients in the trials have experienced against the potential and demonstrated adverse reactions reported in the trials. Obviously the severity and the reversibility of reported adverse reactions need to be carefully balanced against the benefit to the patient of taking the product. The quality of life of the patient if untreated is also a factor that has to be taken into consideration. For some products it may be very easy to establish risk/benefit, however, there are those where the risk/benefit is less clear cut. This is one of the reasons why all new chemical entities (medicinal product) are considered by the Commission on Human Medicines (previously the Committee on the Safety of Medicine) and it subcommittees before a marketing authorisation is granted. It is also the reason why all new drugs have a black triangle for at least 3 years following the initial granting of a licence, to warn prescribers to be vigilant as this is a new product for which there is only limited experience.

If you have a query about this letter, please contact me. If you are unhappy with our decision, you may ask for it to be reviewed. That review will be undertaken by a senior member of the Agency who has not previously been involved in your request. If you wish to pursue that option please write to the Communications Directorate, 10th Floor, Medicines and Healthcare products Regulatory Agency, at the above address quoting the above reference. After that, if you remain dissatisfied, you may ask the Information Commissioner at The Information Commissioner's Office Wycliffe House Water Lane Wilmslow Cheshire SK9 5AF to make a decision on whether or not we have interpreted the FOIA correctly in withholding information from you.

Yours sincerely



(redacted)
Licensing Division
MHRA

--------------------------------------------------------------------------------

From: (redacted)
Sent: 09 March 2007 17:21
To: MHRA Information Centre
Cc: The Four
Subject: RE:


Dear Sir or Madam,

Thank you for your kind reply.

I understand that the MHRA may have issues commenting on legal matters, particularly when such matters pertain to a jurisdiction outside its own. What would be its response, in the event that an (unnamed) pharmaceutical company were found to have breached a law in another jurisdiction, which also happened to be a law in the UK?

I am interested to note your comment, concerning risk/benefit assessment. I understand that 83 trials were carried out on Seroxat, during the period 1980-91. What fraction of these did the MCA/MHRA view the results of? Indeed, I would be most interested to understand the technicalities of the MHRA's risk analysis. Perhaps you could advise me, on this point.

Best regards

(redacted)

The letter of the Law (but what of the spirit?)

In the light of the previous post, I thought it might be worth reminding everybody just how excoriating (if one was paying attention) some of the commentary of the Health Select Committee's report into the influence of the pharmaceutical industry was. It's a riveting read, if you're into that sort of thing...

The Report is available at http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf, if any readers feel inclined to trawl through the 100+ pages for themselves. Pertinent extracts, in support of my last post, follow:


282. The relationship between the industry and the MHRA is naturally close. There are regular interchanges of staff, common policy objectives, agreed processes, shared perspectives and routine contact and consultation. Many of the senior staff of the MHRA have previously worked with the industry, the main exception being Prof Woods, who became chief executive of the MHRA in 2004. Overwhelmingly, the different parties appeared to speak the same language, with companies determined to observe the letter of the law and the regulators determined to uphold it. Dr Herxheimer stated:

…when the agency was hived off from the Department of Health…the culture became confirmed that the industry is the client and the client must be looked after: quick service, good service, easy contact, etcetera - so it is a closed community in a sense.

283. Such closeness provides the basis of the trust that the MHRA said it relied on as an integral part of the regulatory process. The MHRA Chairman suggested that trust underpinned the stance of the MHRA towards the companies they regulate [my emphasis]. We inferred that this extended to the routine acceptance of companies’ summaries of the results of tests on their drugs as true reflections of the raw data on which they were based.

284. Trust is critical in the relationship between regulators and industry. However, at the heart of this inquiry are the concerns of those who believe that the MHRA is too trusting. Trust should be based on robust evidence; it should be earned rather than presupposed. The evidence indicated that the MHRA examined primary (raw) data on drug effects only if it suspected some misrepresentation in the summary data supplied. It was argued that such trust in regulated companies goes too far: reliance on company summaries is neither sufficient nor appropriate, in the absence of effective audit and verification of data that companies provide. The secrecy surrounding this information is also unacceptable, as Sir Iain Chalmers [co-conveners of the James Lind Alliance] commented:

Denial of access to information held by the [MHRA] puts the interests of pharmaceutical companies ahead of those of patients and prescribers. This is particularly indefensible in the light of evidence that regulatory agencies, supposedly established to protect the public, are acquiescing in biased later publication of the information they hold.

285. Regulatory inertia was clearly illustrated through publication of the findings of the UK’s first ever public investigation into a drug safety problem: the December 2004 report of the CSM’s Expert Working Group (EWG) into the safety of SSRI antidepressants. The Group’s main findings pointed to lack of evidence of risk (rather than risk itself) not least because a number of essential studies had never been performed...

Abuse of Trust IV - Russia charges 3 doctors over Glaxo vaccine tests

""Many of the children sent for trials had been diagnosed with diseases. They (GSK) had no right to put children with health problems through these clinical tests. It can lead to a deterioration in the child's condition, which has happened in the case of some of these children.”

...A company spokeswoman said its own internal audit showed informed consent had been given by all parents and doctors involved in the trial."

Read on: http://glaxosmithklinenews.blogspot.com/2007/03/uninformed-consent.html

This is a relatively old story (5 or 6 months, or so, and there doesn't appear to be anything new on it, judging by my Google search). This was the case that I contacted the DoH (and the MHRA) about, and it is the case that the One of the Four contacted me about ("Delighted to engage GSK shareholders" (below)). I was told that the MHRA knew no more about it than what was avaialable in the press.

What a bunch of jobsworths!

Matt

Abuse of Trust III - New York's HIV Experiment

"In fact it was the drugs that were making the children ill and the children had been enrolled on the secret trials without their relatives' or guardians' knowledge."

Read on: http://news.bbc.co.uk/1/hi/programmes/this_world/4038375.stm

Yes, there's a common theme here, all right. The question is "why?" Because people think that they can get away with it? I suppose that if one wishes to find out what people are capable of, one has to put them in a position where they believe that there will be no repercussions from their conduct, irrespective of how low the motivation was for that conduct.

Matt

Abuse of Trust I - U of Iowa Pays $1 Million to Settle "Monster Experiment"

"Whatever the culpability borne by the academic researchers involved in this 1939 experiment, their colleagues in academia put their head in the sand, failed to recognize the immoral nature of the experiment, and thought only of career ramifications: "the other professors at the time told [Johnson] that it would ruin his reputation to publish the data."..."

Read on: http://ahrp.blogspot.com/2007/08/u-of-iowa-pays-1-million-to-settle.html

Something about this piece on the Alliance for Human Research Protection attracted my attention. So much so, that I 'mailed it to Alan Johnson. It's obviously a grotesque abuse of power, but something tells me that it's indicative of a certain mindset, rather than an isolated incident, limited to one rogue "scientist". Naturally, evil machines (I've had this accusation levelled at me, so I have no compunction in forwarding it), such as Dr Johnson, who appears to have been pursuing his research for his own, private purposes, perhaps even with a view to repairing himself, are few and far between. I don't doubt that the vast majority are geared towards the serving of the Greater Good, whatever that might be.

Matt

Re: FOIA 07/040

I just thought I'd put the previous two posts into context:

Sent: 01 February 2007 01:53
To: MHRA Information Centre
Subject: Panorama: Secrets of the Drugs Trials

Dear Sir or Madam,

I note from the BBC's reportage that the MHRA initiated criminal proceedings against GSK, presumably with respect to its (GSK's) claims and misrepresentations about its anti-depression drug, Seroxat (Paxil, in the US):

http://news.bbc.co.uk/1/hi/health/6308871.stm

I note that this case is some three years old, and wondered what, if any, progress had been made? For what it's worth, the allegations have caused consternation, anger and resentment amongst the "depressed community", if commentary on the internet forums that I post on are anything to go by. If you were able to disclose the status of the investigation, I imagine it would be a benefit to a lot of people to know that this matter is being taken very seriously indeed by those in a position to regulate the drugs industry, and to punish those who take advantage of the desperation of people, who have little choice but to take drugs owing to the paucity of alternatives offered, generally-speaking.

Please note, for your information, that I have discussed this matter (in the context of corporate manslaughter/gross negligence manslaughter) with my local police force, and it is currently logged as an incident.


MHRA Reply

Sent: 21 February 2007 15:19
To: @hotmail.co.uk
Cc: MHRA Information Centre
Subject: RE: FOI 07/040 - FW: Panorama: Secrets of the Drugs Trials

Dear

Thank you for your e-mail of 1st February concerning reports of an MHRA investigation into GSK with respect to claims and misrepresentations concerning its anti-depression drug, Seroxat.

MHRA has considered your request under the provisions of the Freedom of Information Act 2005 and I am pleased to be able to provide the following response. The MHRA has a duty to protect public health and takes seriously any report of a suspected breaches of medicines regulations.

The MHRA investigation into GlaxoSmithKline and its alleged failure to supply pharmacovigilance information to the MHRA relating to the paediatric use of Seroxat (paroxetine) commenced on 1st October 2003. The investigation is still in progress and will continue until the relevant lines of enquiries have been concluded. No decision has yet been made on whether or not to prosecute GSK.

I hope this clarifies the position.