Blind Eye

John's post Overstepping Bounds describes pharmaceutical companies turning a blind eye to the provenance of clinical data.

Strange as it may seem (in trust terms at any rate if not in commercial terms) authorities in the west readily accept results of tests done in the third world when it comes to licencing drugs. So boundaries become meaningless when the mega rewards of getting a new drug accepted in the west are at stake.

In my SOAPbox blog, I have just commented about the security services approach to Information Sharing, (as described by MI5 chief Dame Manningham-Buller in the House of Lords on Thursday) which involves turning a blind eye to the provenance of intelligence data.

Foreign agencies don't tell us whether detainees have been tortured, and we are too polite to ask.

Manningham Buller argues that:

the desire for context will usually be subservient to the need to take action to establish the facts, in order to protect life

Scribe (of the recently renamed Into The Machine blog) discusses some of the political implications of this statement in a long and insightful post Rhetoric vs Debate: A Truly Public Strategy.

To uphold the image of saintliness, and to admit the realities only internally, behind the scenes, is even more damaging than acknowledging the state of global affairs as it really is.

In the pharmaceutical context, the regulators are faced with real ethical dilemmas - safety versus saving lives, the interests of the trial subjects against the interests of possible beneficiaries of a successful drug. We may observe various kinds of oscillation in regulatory behaviour. (See my previous posts on Drug Regulation and Trust Cycles).

Both in pharma and in security, there are strong indications of double standards here. Certainly not conducive to trust - but that's pretty obvious I guess. And it's not difficult to find hundreds more examples of double standards in public life. The question is a deeper one - how do we tackle double standards from a trust perspective?

Overstepping bounds

originally posted by John

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Richard's blog Double Bluff raises, as he says, some interesting questions about the boundaries of trust. And while the topic of his blog, the technology of warfare, is of concern to us in these times of terror and insurgency, the boundaries of trust are all the while being eroded in many other aspects of our lives. And in pharmaceuticals, just as in war, transgressions of trust come back to bite us. Sometimes quite savagely.

In the west the bodies responsible for clinical testing define a discrete trust space in which tests must be carried out. The nature and aims of the test, the statistical methodology, control mechanism and review processes must all be made clear. The consent of those taking part must be fully 'informed'. There must be no coercion to take part, no 'undue' inducements to do so and no penalties for refusing to take part. Along with test-specific requirements, these, roughly, are the boundaries of the trust space for clinical tests in the west.

Needless to say the don't apply in the third world. Strange as it may seem (in trust terms at any rate if not in commercial terms) authorities in the west readily accept results of tests done in the third world when it comes to licencing drugs. So boundaries become meaningless when the mega rewards of getting a new drug accepted in the west are at stake.

In Kano, in northern Nigeria in 1996, in the middle of an epidemic of bacterial meningitis, Pfizer carried out a test on their new drug, Trovan. They used children with meningitis who were undergoing routine treatment. As a result in 1997 Trovan was approved by the US FDA (Food and Drugs Administration) but, oddly, not for use on children and not for epidemic meningitis. After less than two years' of highly profitable prescription, Pfizer removed Trovan from the market amidst reports that the drug produced 'hundreds of cases' of liver toxicity and 'several' deaths.

Third world tests, first world deaths. Drugs, like bombs, kill us just as readily as they defend us. The boundaries of trust are our only real protection.

See also: Marcia Angell's review of The Constant Gardener (NYReview, October 6th, 2005)

Off-label dog-whistles

originally posted by John

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Richard’s blog on off-label trust rings lots of bells for me. None though, until I read it, rang in the context in which it is presented (my prescribed product of choice being Bushmills). In a pharmaceutical context, Richard writes, Off-Label refers to uses of drugs that are not approved by the regulators and cannot therefore be printed on the product label or officially promoted by the drug company.

In view of the current state of political play in pre-election Britain, paraphrasing that opening rings quite a revealing bell: In a political context, Dog-whistle refers to uses of issues that are not approved of in terms of civilized politics and cannot therefore be printed in the manifesto or officially promoted by a serious party.

This is powerful medicine in every sense. Within the trust space, the informal, in both cases, takes precedence over the formal, the implied over the expressed and the unknown over the known. It is ‘trust me’ trust of a pretty abusive strain.

In the US electoral context, the political hygiene that got Mr Bush a second term, stemmed directly from successfully manipulating just such off-label trust. Unsurprising then that it should be being copied here.

Unlike politics, hygiene, it needs to be said, may not be the best description of outcomes in the pharmaceutical context.

Off-Label Trust

One of a series of posts about Off-Label

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In a pharmaceutical context, Off-Label refers to uses of drugs that are not approved by the regulators and cannot therefore be printed on the product label or officially promoted by the drug company. More generally, it refers to any unauthorized or emergent use of a product or service. In this blog posting, I shall explore the implications of off-label for trust.

There is a regulatory process that is supposed to allow medical practitioners and their patients to trust pharmaceutical products. Under certain conditions, trust in the regulatory process (authority trust) generates trust in particular products (commodity trust). One of these conditions is strict adherence by all parties to the label.

• Users must confine themselves to using the product as specified on the label.
• Providers must confine themselves to promoting the product solely as specified on the label.
  

Whether the drug company sales force is permitted to hint at off-label uses of a given product or not, this sets up a transference in which the nudge/wink (or enforced silence) of the salesman replaces the bureaucratic authority of the FDA.

Meanwhile, samizdat off-label information may circulate in the medical community, possibly based on direct/indirect trial/error experience by medical practitioners. This is a form of network trust.

Off-Label as Samizdat

One of a series of posts about Off-Label

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In a pharmaceutical context, Off-Label refers to drugs being used in ways that are not approved by the regulators and cannot therefore be printed on the product label or officially promoted by the drug company. More generally, it refers to any unauthorized or emergent use of a product or service. In this blog posting, I shall explore the implications of off-label for knowledge management.

Robert Stern describes some of the difficulties involved in disseminating Off-Label research data. There are clearly some potential conflicts of interest, and doubtless sometimes there is natural suspicion of the motives of the drug companies. However, the result is that data describing the behaviour of certain drugs in certain contexts are not available.

This means that many good uses of drugs may be suppressed by regulators, or self-censored by drug companies in order to get speedy approval. In a separate post, Robert Stern quotes a physician as saying "Often the drug companies will under-dose their labeling to get it through the FDA." So does the physician have some other way of finding out an appropriate dose, or is it all done by trial and error?

If the official channels are blocked, how does the medical community share practical knowledge about Off-Label. Is this all done by unofficial samizdat and word-of-mouth?

There is a newsletter for sceptical patients called What Doctors Don't Tell You. Perhaps there should be, if there isn't already, a newsletter for doctors called What Drug Companies Don't Tell You.

Off-Label as Innovation

One of a series of posts about Off-Label

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In a pharmaceutical context, Off-Label refers to uses of drugs that are not approved by the regulators and cannot therefore be printed on the product label or officially promoted by the drug company. More generally, it refers to any unauthorized or emergent use of a product or service. In this blog posting, I shall explore the implications of off-label for innovation and technological change.

According to Alexander Tabarrok and Daniel Klein, Off-Label Drug Awareness Saves Lives (Independent Institute, Feb 2003). "Off-label prescribing is a vital aspect of modern medicine because it often happens that new and important uses are discovered for old drugs."

For some drugs, it seems there is more off-label usage than on-label usage. The medical state-of-the-art can be found in off-label use of drugs, and professional presentations that restrict themselves to on-label uses may lack medical credibility. Robert Stern describes a communication event that was poorly attended, because it was thought to be on the side of the official label, rather than on the side of emergent practice.

Many good uses of drugs may be suppressed by regulators, or self-censored by drug companies in order to get speedy approval. Robert Stern quotes a physician as saying "Often the drug companies will under-dose their labeling to get it through the FDA."

But drug companies are not permitted to promote off-label uses of drugs. This apparently extends to the dissemination of research data concerning possible off-label uses. See Litigation Threatens Off-Label Pharmaceutical Sales, by Kenneth J. Nolan (HealthLeaders News, January 21, 2004)

Off-label eventually becomes on-label. A well-known example is the use of aspirin for heart conditions. Regulators resisted this use of aspirin for years; it is now widely accepted. This provides us with an important pattern of technology development and dissemination.

[Update] Going beyond pharma, we can see similar innovation processes elsewhere. There's a very familiar example in telecoms. Telephone companies were originally oriented towards providing voice services. Computer users started to use modems, which were designed to extract added value from a voice connection by using it to transmit data. With Voice Over IP, we have now come full-circle: VOIP is designed to extract added value from a data connection by using it to transmit voice. These services are now officially sold by the telephone companies - off-label has become on-label.

Trust Cycle

Interesting press release from researchers at the University of California at San Diego.



Pharmacy dispensing volumes spike at the start of each month, because of the timing of government assistance payments . This leads to a spike in medication errors, resulting in a spike in mortality.



Thus trust goes in cycles. At some times of the month you get a rushed service, with little opportunity for personal (authentic) interaction. At other times, the pharmacist may be able to spend a little more time on each item, not just checking the technical correctness of the medication but also relating to the patient as a person.



There are three types of risk that may be affected by this cycle.

• Implementation risk - is this correctly dispensing what was prescribed?
• Composition risk - how does this medication interact with anything else the patient is doing/taking?
• Intention risk - is this the right prescription for this patient?

Trust is not reduced to a matter of technical competence, but embraces the human interaction (or lack of it) between the pharmacist and the patient.

original press release (January 5th, 2005)

relayed in ScienceDaily and in LeaderLog

POSIWID thinkers may note that the negative impact of this phenomenon falls disproportionately on those dependent on government assistance, thus effecting a kind of triage. God forbid there is any purpose in here.

Drug Regulation

Dr David Graham, described by the FT as a safety official, told US senators last week that the FDA system was broken because of a conflict of interest.



According to the Financial Times, the FDA once enjoyed a high reputation. Few consumers challenged its judgement. The FT writes: "Such trust is one reason why the US public has been more willing than Europeans to accept foodstuffs containing genetically modified organisms."



So what has eroded this authority trust? The FT identifies two factors that may be relevant.

1. One can detect a regulatory cycle in drug approval. Testing standards became tougher after Thalidomide, were relaxed when AIDS stimulated demand for new and experimental drugs, and so on.
2. Division of responsibility and inconsistent handling of drugs at different stages of the innovation lifecycle. Approval follows one process; monitoring of approved drugs is done by a different department and follows a different process.
   
   

Oscillation and internal contradiction are both natural phenomena of complex systems, and tend to have a destabilizing effect on trust. One obvious response to this is to distrust complexity. But denial of complexity may merely create a false illusion of trust. Authentic trust may just have to accept oscillation and contradiction.



So whither the FDA - towards a restoration of authority, or towards an engagement with authenticity (if we can believe that)? Either way, a more intelligent and honest attitude to risk (as recommended by the FT) will be useful.



Source: FT Editorial No Pain-Free Option (November 20, 2004)

Clinical Validation

Hypotheses are checked not against impersonal trials of their adequacy but against testimonials, case studies and assessments of success made by parties with a stake in their outcome.

Frederick C. Crews, Out, Damned Blot! New York Review July 15 2004

Drug companies only publish the results of favourable trials. Some people argue they should be forced to publish all results, whether favourable or otherwise. However, this could simply cause the drug companies to engineer the trials more carefully in advance, to reduce the risk that the trials might reveal anything inconvenient to their commercial agenda.

Marcia Angell, The Truth About the Drug Companies, New York Review July 15 2004

Publicness and uncertainty

originally posted by John

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To trust is to rely on someone or something to take care of our interests. We are free to choose it or not choose it. And while the benefits of trust are huge it is never a risk-free choice. Publicness is the antithesis of trust. ‘Trust me,’ publicness misguidedly pleads, and then reinforces its plea with actions intended to remove any lingering uncertainty there might be around ‘trustworthiness’. The reality is that trustworthiness has practically nothing to do with trust. So publicness is almost always misguided.


That said, publicness is all around us all the time. Coca-Cola avowed that it would never dream of poisoning consumers of its products and to prove it it delayed the re-launch of its Sidcup water (aka Dasani). The French government’s recent decision to ban hijab in government-controlled buildings is as much an act of publicness as is the banned dress code itself. Publicness works on many levels and does weird things to trust relationship at both a micro and a macro level.


When a pharmaceutical company ‘discovers’ a new drug its most important consideration instantly becomes making money out of it. This requires diagnoses that enable the drug to be prescribed. Very often this leads to what have been tagged ‘designer depressions’ becoming defined (the ‘psycho’ sector of the drugs industry is where the really big money is currently) with ‘sufferers’ being given a badge-set of symptoms treatable only by this 'trust me' wonder drug.


We can see an even scarier (and literal) badge of publicness right now in US politics. Everyone who’s anyone is required to wear the national flag as a ‘trust me’ lapel badge. The US is a highly conformist society (how else could there have ever been un-American activities?) and no one dares to appear in public without displaying his publicness. That’s bad enough but this year there’s going to be an election and one of the candidates speaks French and German (the languages of UN-supporting foreigners). Although he always wears his badge, the polyglot’s opponents never fail to refer to him as ‘Frenchified’ or ‘Exotic’ in an effort to undermine his ‘trustworthiness’.


His response (sadly) drives publicness into a vicious downward spiral. ‘Trust me,’ he pleads while assuring voters that he has disavowed eternally everything ‘foreign’ and pledged to speak only ‘American’ from here on.