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

Fluoxetine - Part II

God, I'm bored. The MHRA's mail is in bold, as usual:


Dear Sir or Madam,

I have had the opportunity to scan the excellent and informative documents that you linked. I am particularly interested in the second of these:

Making Regulatory Decisions about Medicines and Medical Devices

and most particularly Section C., paras 1/2:

1 Does the product work and offer useful clinical benefit if used in its specified way? [my emphasis - was this rider included by a scientist, or a lawyer?]

Is there robust evidence that the product will do what the company says it will do?

2 What impact will the product have, or is it having, on both the quality and length of life in those patients who are treated with it or on whose behalf it is used?

Are you able to expand, at all? I think that these questions, in combination, essentially ask the same question that I put to you, initially - ie, "what is the benefit of fluoxetine?". So, perhaps you could detail what "robust" evidence amounts to, and what evidence would be sufficiently robust, such that it demonstrates that which is claimed of a drug? I am particularly interested, in this context, on the question of "quality of life," alluded to in para 2 - presumably the "impact" spoken of is intended to refer to a positive/beneficial impact? In which case, what "robust" evidence would demonstrate the same beneficial impact claimed of a given drug by the manufacturer?

Please feel free to use fluoxetine as a case study, when answering these questions - I imagine that this would assist my understanding.

Best regards

Matthew Hoford

***********************************
Subject: FW: FOI 08/064 - FW: Fluoxetine
Date: Wed, 19 Mar 2008 12:06:56 +0000
From: info@mhra.gsi.gov.uk
To: [redacted]@hotmail.co.uk


Dear Mr Holford,

Thank you for your recent enquiry to the MHRA.

Please find attached a response to your enquiry.

Please contact us again if you need further assistance with this, or any other queries.

Kind Regards,

Central Enquiry Point
Information Centre
Medicines and Healthcare products Regulatory Agency
Tel: 020 7084 2000

Attachment:
Thank you for your e-mail dated 18 February, 2008, concerning fluoxetine. In particular, you wish to conduct you own risk:benefit analysis using the MHRA’s methodology. You will not be surprised to know that the risk:benefit analysis does not consist of a magic formula. We do however outline our approach to weighing up risks and benefits for medicines in a document on our website called "Medicines and Medical Devices Regulation: What you need to know http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con2031677.pdf, particularly in the box entitled "When is a product acceptably safe?" on page 2). There is further detail in another document on our website titled "Making Regulatory Decisions about Medicines and Medical Devices"

http://www.mhra.gov.uk/home/groups/comms-sp/documents/websiteresources/con2030689.pdf

These documents should give you some insight into the way we make decisions and the factors and considerations that go into the risk:benefit analysis.

You have also asked us to explain the benefit of fluoxetine, this information can be obtained from the Summary of the Product Characteristics for fluoxetine which you can access through the Electronic Medicines Compendium (http://www.medicines.org.uk/searchresult.aspx?search=fluoxetine)

I hope the above information is helpful and answers your query.

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...

Re: FOI 07/118

I received a response from the MHRA to a query I put to it back in April, but which it overlooked, at the time. Much as it galls me, I've had to type it up, because I can't work out how to drop in the original Acrobat document, which was attached! My original 'mail is immediately below and my reply is beneath the MHRA's missive, which I've emboldened, for convenience. Make of it what you will, although I would like to draw your attention to the MHRA's "catchphrase," which is "Safeguarding Public Health."

Matt

From: Matthew Holford
Sent: 12 April 2007 15:51
To: MHRA Information Centre
Cc: [redacted]@gsk.com; [one of the Four]@parliament.uk; [one of the Four]@parliament.uk; [one of the Four]@cix.co.uk; [one of the Four]@parliament.uk; [my MP]@parliament.uk
Subject: FOI 07/118 - Medicines regulation and the pharmaceutical industry


Dear Sir or Madam,

I was interested to read the article, by your esteemed Chairman and CEO, respectively, Prof Breckenridge and Kent Woods:

http://www.bmj.com/cgi/content/full/331/7520/834

I must confess myself surprised and delighted to discover that the MHRA charges companies, for the purpose of licensing trials. As such, it is presumably aware of any trial, for which it has granted a licence, and for which it does not receive trials results, including details of elements of that trial conducted in other countries? Does the MHRA keep records of any such failure to notifiy, or is its interest limited to collection of the trial fee? If it does, may I ask from what date it began keeping this information? Also, may I ask what percentage of authorized trials do not have the results notified to the MHRA? May I ask what action it takes, in the event that a failure to notify has taken place? Indeed, may I ask what period of grace, after the end of the trial, does the MHRA permit companies, before commencing legal action, under the relevant legislation (The Medicines for Human Use (Clincial Trials) Regulations 2004 (http://www.opsi.gov.uk/si/si2004/20041031.htm#28))?

Finally, I note that the offences, identified under ss49-50, shall be subject to a fine or a maximum period of imprisonment not exceeding two years (ie, they are considered not to be a serious arrestable offences), upon conviction on indictment. The maximum fine, which is defined by statute, is currently £5,000, I believe. To what extent does the MHRA understand these penalties to be an adequate deterrant to non-compliance with the Law?

Best regards


Matthew Holford

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

22 August, 2007

Dear Mr Holford

It has been brought to my attention that you have not been provided with a response to your request for information under the Freedom of Information Act (FOIA) made on 12 April 2007. I apologise for this oversight and I provide a response below:

The Clinical Trials Directive 2001/20/EC and the UK implementing legislation (SI 2004/1031) refer to the sponsors' liability to notify the competent authorities of concerned Member States of the end of a trial within 90 days of its completion. There is no reference however to notification of trial results.

The implementing European Commission guidance ENTR/F2/BL/D 2003 Revision 2:

Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial. [MHRA's emphasis]

refers in section 4.3.2.4: Clinical Trial Report: "The sponsor should provide a summary of the clinical trial report within one year of the end of the trial to the competent authorities of the concerned member states..."

The above legislation and guidance came into effect on 01 May, 2004. In the UK prior to that date the clinical trial legislation placed no obligation on trial sponsors to notify the competent authority of the results from clinical trials, at the end of the trial.

The MHRA has therefore to date, not kept records of where trials results have not been notified to it, following completion of clinical trials in the UK.

I hope this is helpful and once again I apologise for the delay in replying.

Yours sincerely

[redacted]
Clinical Trials Unit

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

Dear [redacted]

As you may appreciate, I'm not fully conversant with the way in which the various pieces of legislation "mesh". If I understand correctly, then, a clinical trial must be licensed in order to proceed. Upon completion (or presumably early termination) this must be communicated to the MHRA (in the UK), within a certain specified period of time, with failure to do so being a criminal offence. It is also my understanding that the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended) provide that information must not be provided that is false or misleading. Regulation 50 provides, if I remember aright.

From your comments, it is apparent that a sponsor may, if it so wishes, not provide the results of trials that have been completed and such completion presumably properly reported. If received wisdom is to be believed, this will be because a trial has "failed". In any event, results data is regarded as proprietary within the industry, and a company may not be compelled to give it up. Indeed, if I understand correctly, trials data is not generally given up, even where a trial is deemed "successful" and used in the marketing authorization application portfolio to demonstrate the "efficacy" of a drug, even where, as is apparently the case with Seroxat, the level of efficacy has not been demonstrated. Instead, a statistical analysis is usually provided. None of this sounds terribly scientific to me, but then I'm a compliance professional, not a drugs regulator.

I would be interested to understand how the MHRA views this withholding of data? We know that certain Seroxat trials "failed", and the results were not made public. Others were held to demonstrate efficacy, and a statistical report based on the successful trials was presumably made available to the MCA/MHRA with the licensing portfolio. This presumably purported to demonstrate efficacy (although not very precisely, as I understand it), safety and quality, or else the product would not have been licensed.

If something similar were to happen today, would this withholding of data be deemed to amount to an offence under Regulation 50 by the MHRA? That is, if a company provides less than all the information about a drug, and the information withheld is negative, then the information that is provided is presumably false, or misleading. Also, does the MHRA endeavour to ensure that it has, at least, a statistical report from all trials conducted on a particular drug, in the event that a marketing authorization is sought for that drug?

I would be interested to read of your views.

Best regards

Matthew Holford