Medawar's breakdown of MHRA/CSM 'findings'

December 30, 2004

" Review:

Report of the CSM's Expert Work Group on the Safety of Selective

Serotonin Reuptake Inhibitor antidepressants

http://www.network54.com/Forum/message?

forumid=281849 & messageid=1104373529

1. The launch

Here was a 235-page manuscript report, full of technical jargon and

charts, along with tables, diagrams and many references to learned

works. The report was presented as the output of a meticulous

scientific enquiry that had lasted over eighteen months – about

ten

times longer than it takes to screen a new drug application.

But the report was released only to journalists, and four days after

the launch, copies of the report are still not generally available.

Nor is there yet any reference to it on the website of the Committee

on Safety of Medicines (CSM), in whose name this review was done.

Only the recommendations have been reported, so peer review will

take time.

The report was launched at a press conference organised by the

Department of Health (DoH), at 10.30 on the morning of Monday 6

December. None of the journalists I have spoken to (n=6) had

received their (confidential) invitations from the DoH before 5.00pm

on the Friday before. One of them charitably suggested that perhaps

the authorities were waiting for the London Stock Exchange to close.

However, the global stock market never actually closes, and `news

management' probably comes closer to the mark – but yes, I

have an

axe to grind. Not for the first time, the DoH refused me admission

to this briefing on the technically defensible grounds that I am not

a member of the press. I have written extensively about the safety

of SSRIs for many years, was invited to give evidence to the Working

Group, and regularly brief journalists on drug policy and safety

issues. I was even for some years a member of the National Union of

Journalists - but yes, I no longer carry quite the right cards.

The same exclusion applied to my distinguished colleague, Dr

Herxheimer. He did manage to buttonhole Professor Kent Woods to

request admission – but Woods tersely denied any responsibility.

He

is Chief Executive of the MHRA (Medicines & Healthcare products

Regulatory Agency) and was the front man that morning. The DoH is

like any other supertanker or juggernaut: changing course requires

teamwork and planning. Woods has been in the job for less than a

year, easily long enough to appreciate the triumph of process over

individual initiative and common sense.

It was a bit cold, but and I spent a productive several hours

on the forecourt of Richmond House (HQ of the DoH), talking to

journalists and doing a few interviews. Here we were fortunate: the

journalists all trouped out of the briefing about 15 minutes after

they'd all filed in. A fire alarm had gone off, so everyone

evacuated the building and milled around on the pavement outside for

the best part of an hour.

News management? Apart from the decision to engineer a headline

response by offering the report only to the press, the presentation

was organised to focus strictly on the use of antidepressants. The

other two key figures on the podium had not been directly involved

in the CSM Review. Their presence would have discouraged questions

about the big underlying issue – the performance of the drug

manufacturers and regulators themselves.

Alongside Woods was Dr Dillon, Chief Executive of the

National Institute for Clinical Excellence (NICE), whose new

guidelines for the treatment of depression were being published that

same day. The other was Professor Louis Appleby (National Director

for Mental Health), whose main concern would be about the risk of

suicide and the need for effective treatment of depression:

" The CSM has delivered one of the most comprehensive reviews of a

class of medicines ever to be completed and it has been painstaking

work, examining evidence from literally hundreds of clinical trials.

What's important now is that their advice is put into practice.

Publication of the NICE guidelines gives us the tools to do the job

so that patients and prescribers can together make the best informed

decisions. " (DoH press release, 2004/0433)

The lack of other key players was notable. Where was Professor

Gordon Duff, Chairman of the Committee on Safety of Medicines, which

had supposedly initiated this review – and in whose name a

warning

letter to prescribers would be published that same day? Why was

there no sign of Professor Ian Weller, Chairman of the CSM's

Expert

Working Group whose report was being released? And what had happened

to Professor Sir Alastair Breckenridge, Chairman and `public

face'

of the MHRA and former Chair of the CSM? He was a key figure in this

affair and for many years a consultant to the manufacturers of

Seroxat (paroxetine), the troublesome drug that prompted this view.

In The Guardian, the redoubtable Boseley pointed also to the

absence of any representative of the Royal College of Psychiatrists

or the mental health charity MIND. Brook, its chief

executive, had resigned from the expert working group in March.

Later, he would tell Panorama: " I have little confidence that the

drugs they're licensing day by day are being licensed in a way I

would feel appropriate and what's even more concerning I have

very

little confidence in drugs that have been regulated in the past. "

So, one way and another, the headlines won the day. " Tighter

warnings on antidepressants " (Reuters); " Are anti-depressants over-

prescribed? " (BBC News); " GPs Told to Use Alternatives to Anti-

Depressants " (Scotsman); " New guidelines for prescribing

antidepressants (Medical News Today); " GPs giving Prozac to

thousands who don't need it " (The Times); " Curb handouts of the

happy pills, doctors told " (Daily Mail); and " Regulators Suggest

Restricted Use of Drug " (Associated Press)

To date, the regulators (and by extension the drug companies) have

managed to evade the scrutiny of their performance that is now

urgently overdue. Gloss and spin rule, OK? The authorities have

misinformed doctors and prescribers for many years, but now seem to

be blaming them.

CM, 10 December 2004

2. Major outputs

What is the major output of this report and what of its clinical

significance? The key to both is a two-page document that is neither

part of the Expert Working Group (EWG) report nor formally endorsed

by its members. It is a list of wording changes to the Summary of

Product Characteristics (SPC) for all SSRIs, proposed by the full

Committee on Safety of Medicines (CSM) on the basis of the EWG

report.

The SPC is an important document. It is the small print in the

implied contract between drug manufacturers and the regulator - as

proxy for prescribers and patients. It formally defines what a drug

should be used for, spells out the approved drug dosages and

identifies known and suspected hazards. It used to be called

the `data sheet' but is now the SPC and applies across the

EU,

as `the label' does in the USA.

It seems most unlikely that UK prescribers often refer to the SPC.

These days, with many other sources of information, the SPC only

masquerades as a set of prescribing instructions. Its overwhelming

significance is as a set of rules for manufacturers – right down

to

the wording they must use in the tiny-print `health warning'

section

of drug advertisements. The SPC is part of the product license and

legally determines what drugs should be used for, and how

manufacturers may and may not promote them.

Generally, companies write their own SPCs, which they then submit

for regulatory approval – and when it matters, company lawyers

fight

hard for the wordings they want. In marketing terms, the wording can

make or break a drug. So it is unusual – especially over a decade

down the line – for the regulators to publish in advance the new

SPC

terms they propose. On this occasion, however, I would expect the

SSRI manufacturers to comply with alacrity, once they have stopped

jumping for relief and with joy.

Even before you take stock of the proposed SPC changes, this was a

dismal end to the hard work of the EWG, and it seems a disgrace that

the CSM allowed it. These proposed SPC changes were publicly

presented as " advice " from the Committee on Medicines as a whole -

supposedly a distillation and encapsulation of the findings of its

expert working group. In practice, the proposed new wordings reduce

the EWG's main output to some minor small print changes - no

doubt

rubber-stamped by the CSM on the basis of proposals made by the MHRA.

Aside from the paucity of the SPC proposals – see below – the

immediate point is that the CSM appears to be either impotent or

oblivious to the limitations of the regulatory process, including

the seamy side of the relationship between companies and regulators.

The CSM was arguably compromised from the moment it agreed that the

working group should be lumbered with impossibly restrictive terms

of reference, but here the Committee missed its last opportunity to

reflect on the obvious wider implications of this affair.

Individual CSM members are overwhelmingly clever and utterly decent

people but, collectively, it would misrepresent them to say they

ducked. As a decision-making organisation, the CSM has been squeezed

out of existence – compromised by industry influence and lack of

public confidence, comprehensively manipulated by the MHRA, and

effectively cowed.

It seems extraordinary and more, that the companies themselves were

asked to provide and analyse the main data that informed the EWG

review. The EWG largely ignored the raw data; they relied instead on

the clinical summaries that companies had prepared. Yet throughout

this 18-month enquiry, all kinds of evidence came to light of

critical omissions and opportunities missed. Is it not alarming, for

example, that prescribers have been given the wrong dosage

information for 15 years or more?

Part of the problem is the failure by regulators to contain a

corporate culture that positively relies on cut ethical corners and

games of hide-and-seek. Relationships between companies and

regulators bring to mind captives/jailers and cats/mice or fox and

chickens, if you prefer.

Within a few weeks of its establishment, the EWG found evidence of

lack of efficacy that led it to contraindicate paroxetine (Seroxat)

for depression in children – but this was from trials the

manufacturer had conducted years before. Earlier this year, a 1998

company memorandum surfaced that helped to explain this. Kline

Beecham thought:

" … it would be commercially unacceptable to include a statement

that

efficacy had not been demonstrated, as this would undermine the

profile of paroxetine " . (Medicines out of Control? p.202)

Then there was this, from a 1999 Pfizer memorandum about how to

respond to a request from the US Food & Drug Administration for

adverse drug reaction (ADR), presumably data for sertraline

(Zoloft/Lustral), now the leading SSRI.

" The actual task of generating a list of events with a report rate

for each event is a fairly easy task, the main question is do we

want to provide FDA with a simple straightforward report (report

28C) or do we want to give them a complicated and confusing one

(report 28)? "

The ambiguity here makes it just conceivable that the company wanted

to be as helpful as possible, but the overall context suggests not.

For example, another series of Pfizer memoranda (1996) described as

follows the company's position in dealing with the Norwegian drug

regulators:

" We should not volunteer to describe the withdrawal symptoms, but

have an agreed list prepared in case they insist " …. " We need to

be

careful about this, bearing in mind label harmonisation. Ideally we

agreed we should keep symptoms of withdrawal out of the label. "

Further evidence recently emerged suggesting that the regulators

actively engage in the duck and weave. How have the SSRI

manufacturers satisfied the regulators' requirements for proof of

efficacy from trials of active drug against placebo? They have

submitted evidence from trials that give positive results, ignoring

the ones that didn't. Pfizer's antidepressant, reboxetine was

licensed in Europe (in 1997) on the strength of one positive trial

result from the eight that were done – still not quite enough to

get

it a license in the USA (Lancet, 19 June 2004, 2087).

The gaping hole in the EWG report is the lack of focus on the modest

efficacy of SSRI drug treatment – and the same might be said of

the

NICE guidelines for the treatment of depression that were informed

by the EWG review. Yes, the Group did quickly establish the lack of

antidepressant efficacy in children, because the data were limited

and therefore manageable. But in relation to adults, the EWG seems

to have inferred efficacy mainly on the grounds that not treating

depression may be more hazardous than doing so. The point is

debateable, depending largely on the nature of depression, and the

source of information:

" Suicide is rare, even amongst people with depression " (EWG, p. 68).

Alternatively, " when people with depression are left untreated, 15%

will actually commit suicide " (Spokesman for Eli Lilly, the makers

of Prozac (fluoxetine), quoted by BBC News, 12 December 2004). See

also Medicines out of Control? p. 47 FN 2)

The EWG did not directly assess antidepressant efficacy in adults;

instead, its report includes a chapter on `Burden of Depressive

Illness and Self Harm " . Nevertheless, the CSM Chairman represents

this as the key conclusion: " SSRIs are effective medicines in the

treatment of depression and anxiety conditions " . And that is what

matters, above all, in the SPC.

The new NICE guidelines for treating depression tackle the efficacy

issue to the extent of recommending non-drug alternatives for mild

to moderate depression – but the CSM's proposed revisions for

the

SSRI Summaries of Product Characteristics (SPCs) do no such thing.

Subject to additional small print warnings, the manufacturers will

be able to promote SSRIs exactly as they do now – notably

with `disease awareness' campaigns, orchestrated by PR

agencies who

target the " authoritative third parties " who communicate with you

and me.

The new small print warnings for SSRIs relate to the risk of

suicidality and drug withdrawal reactions. To exaggerate slightly,

in the interests of brevity and clarity, they merely tweak the

existing wordings. They say virtually nothing that could not have

been said years ago, and should have been. Moreover, the CSM has

proposed no change to the SPC to reflect the EWG's one new

finding –

that venlafaxine (Efexor/Effexor) should in future be prescribed

only by specialists.

The proposed new SPC does, however, include one obvious

`exclusion

clause'. It is buried deep in the verbiage and all but drowned at

the end of a long paragraph that begins thus: " Depression is

associated with an increased risk of suicidal thoughts, self-harm

and suicide (suicide-related events). This risk persists until

significant remission occurs " . No attempt is made to distinguish

between more and less severe depression, and remission due to drug

or other factors.

This exclusion clause is a fragment of text that will no doubt allow

the drug regulators to say at some time in the future, that they did

indeed warn of the risk of antidepressant-induced suicidal

behaviour, back in 2004. The small print says: " Furthermore, there

is evidence that in a small group of people, antidepressants may

increase the risk of suicidal thoughts and self-harm " .

But for the time being, the regulatory machine is relying mainly on

the " good evidence " that points to another finding, " that there is

no clear increase in the risk of suicide from SSRIs compared to

other antidepressants " . The lack of reference to paroxetine

(Seroxat/Paxil) is conspicuous, but no justification for either

relief or joy.

CM, 17 December 2004

To be continued "

http://www.socialaudit.org.uk/6040000.htm#New

December 30, 2004