Cervarix related death in UK

A 14 year old girl in Coventry UK died after receiving a jab of the HPV vaccine Cervarix (GSK). While not acknowledging that the death was directly attributable to safety issues pertaining to Cervarix, the FDA has delayed its review of the safety and efficacy of the GSK vaccine. GSK has meanwhile voluntarily realled the batch of vaccine.

I have posted on the HPV vaccine before. HSA had ahead of the FDA approved the vaccine for girls/women between the ages of 9-26. The discussion then had been the off label use of the vaccine for women outside of this age range.

This latest fatal adverse event will make a signficant dent in GSK's attempt to compete with the Merck vaccine. The GSk vaccine apparently induces a stronger response because it containsthe controversial suqalene adjuvant AS03. Unlike the Merck vaccine which covers 4 strains, the GSK product covers only 2.

A second case of cholera??

A diarrhoeal epidemic (which appears to be fading) now 2 cases of cholera? What's happening?

Anything to do with the faecal contamination of waters off Pasir Ris?

Taming doctors' greed....?

Salma Khalik continues the doctor bashing in today's Straits Times with a report entitled "Tame doctors' greed and protect patients", essentially addressing the GPs' greedy right to make money through dispensing of medications. Hmmmm........

This is really not a new issue. From time to time, this gets surfaced.... the MOH suggestively indicates that we can change.... meets a brick wall of resistance, then it's back to status quo.

www.GeraldTan.com has done us the kindness of logging some of these public dicussions all the way through from 2005-7.

For me a number of things are obvious....

a] There is an enormous professional conflict of interest when doctors make money from dispensing. This is without doubt. The Singapore Medical Association, in all its protestations have never disputed that reality. I am not sure what the average proportion of a GP's revenue come from dispensing, but it must be substantial.

Given this conflict of interest, the burden of responsibility must naturally fall upon the shoulders of the profession to explain how the patient/consumer can know if the best and most cost-effective drug solution is being prescribed. I don't want to suggest how often this occurs, and it may well be limited to the practices of a few bad-hats, but it is clear that over-prescribing and inappropriate prescribing are certainly practices which litter the medical landscape.

b] The only real defence for maintaining the system is 'patient convenience'.

This controversy, to my mind, can be easily resolved if only the Singapore Medical Association can bring itself to face up to the reality that there is a real conflict of interest. There is nothing intrinsically wrong in GP clinics wanting to meet their bottom line, and for doctors to bring home the bacon. But the lack of separation between the doctor's role from that of a money-making dispenser potentially compromises the doctor's objectivity in prescribing. I think it would certainly allow the journalists at SPH (and me too) sleep a lot easier if the SMA itself devices a strategy to deconflict the situation instead of pretending the problem doesn't exist.

One such solution might be to financially decouple without physically separating the two functions. Make clinics lease out the dispensing space to a bona fide dispenser and make it illegal for doctor/proprietors to make money from the dispensing rights. This will remove the financial incentives that compromise medical objectivity, without taking away the patient's convenience of receiving their medicines at the clinics.

Slimming pills - The Sunday Times picks up the cudgel

The issue of slimming pills gets elevated to editorial status in today's Sunday Times. Entitled "GPs' Unethical Fat Gains", it screams that it is 'time to wield the stick!'.

But while I share in the sentiments raised, there are a number of problems.

Firstly, as the title of the editorial points out, this is essentially a problem of ethics. Prescribing slimming pills inappropriately is not really a problem of a legal wrongdoing. This is lack of professionalism and unethical behaviour, but not anything that can be easily whacked by a big stick. The HSA regulates the product, so it only goes after those who market products inappropriately, or who imports and sells unlicensed products. Correspondingly, it does not regulate medical practice.

The body that is supposed to regulate ethical and professional behaviour of doctors, is the Singapore Medical Council. This august body however, appears to have a reluctance to act against members for issues like this. Off-label prescribing is however, legally allowed, and unethical behaviour is much harder to prove. Yet, I believe, if the SMC wishes to retain its professional credibility in the eyes of the public, it will need to find some way to deal with problems like this. It cannot be that when the public can recognize a practice as unethical, that the Council would prefer to look the other way.

So the ball is really in the SMC's court.

The related problem is that this is a really big ball to kick around, and nobody knows how the ball of yarn will unravel when you start tugging at the loose end. The problem is not just about slimming pills, but deeply entwined with a whole host of issues related to doctors offering treatments that have not been proven. I have posted extensively about this before. Off-labelling prescribing is just one manifestation of a range of unethical practices. Para 4.1.4 of the SMC ethical guideline makes its ethical position very clear :
"A doctor shall treat patients according to generally accepted methods and use only licensed drugs for appropriate indications. A doctor shall not offer to patients, management plans or remedies that are not generally accepted by the profession, except in the context of a formal and approved clinical trial."

Is it not apparent to the SMC that such practices are unethical?

So my challenge to the SMC is this - either amend your ethical guidelines, or find some way to deal with this. Looking the other way is not an option. The SMC should see that it has an increasingly critical responsibility to the public as Singapore gears up to be a medical supermarket.

Smoking in Singapore - time to stamp it out altogether?

The CNN recently highlighted some studies linking a fall in heart attack rates to the introduction of smoking bans in public places. Nothing really new.... it's kinda intuitive and has been shown in a number of previous studies.

Smoking is really another form of drug abuse. We've had smoking bans in public places for some time already, and have already begun to take it for granted to the extent when we visit countries without such bans, we wonder why they cannot do it.

In Singapore smoking is regulated by the HSA through the enforcement of the Smoking Act (no relation to the smoking gun!) and they regulate primarily(another quirky part of our history) the advertising and sale of tobacco. The control of smoking activities however is coordinated by the Health Promotion Board in partnership with the HSA (another quirky arrangement), through the National Smoking Control Programme.

"The NSCP aims to reduce smoking prevalence in Singapore through the following measures:

• Preventing the initiation of smoking among young people
• Educating, motivating and assisting smokers to quit smoking
• Promoting a climate conducive for non-smokers to remain free from the harmful effects of environmental tobacco"

All in all they have done a pretty good job, it seems that they may have hit a wall of sorts. Smoking rates, after hitting a nadir in 2004 seems to have turned around and have begun to creep up again.

HPB reports:
"Results from the National Health Surveillance Survey 2007 showed that the smoking rate among daily smokers aged 18-69 years increased slightly from 12.6% in 2004 to 13.6% in 2007. Compared to other age groups, the smoking rate was highest among young adults aged 18-29 years, from 12.3% in 2004 to 17.2% in 2007; in males the increase was from 18.2% to 25.4% and for females it was 6.6% to 9.1%."

My take on this is that it's time to really tighten the screws. Smoking is really an addiction. And time and time again we can see that the only effective way to reduce smoking is through legislation. A ban in public places was effective up to a point. After hitting the wall, it should be clear that if we are to reduce (no, not reduce but perhaps just to prevent the prevalence from going back up again) the prevalence of smoking, is to ban it completely. I say treat it as a drug of abuse, a problem of addiciton. Because that is what it is. A total ban. Move it into the domain of the CNB (Central Narcotic Bureau). Only then can we eliminate it from our society.

Too aggressive? Perhaps. But smoking comes with a considerable social and economic cost. It's time to put a stop to it.

MOH Weekly Infectious Disease Bulletin - cholera??

Actually I must congratulate the MOH for putting out their Weekly Infectious Disease Bulletin. It makes for fascinating reading, and I find it kinda gives me an idea of what is happening out there, away from the safe cocoon I inhabit.

For example, through the bulletin, I find out that malaria is pretty much past its spike, thanks to the efforts of the AVA. An chikungunya hasn't really gone away, though down to a very very low level. And dengue is pretty much under control. So the world's pretty safe at the moment...... except for that mysterious diarrhoea epidemic.

Then my eyes catches on single report of cholera........ yes, there was one case last week. The last case was sometime in April. Where, I wonder, did this come from? Was it imported? The guy must have been pretty sick while travelling? Or was this picked up from a local contamination? If so, where? Perhaps all that sewer contaminated water off Pasir Ris?

Who knows....

It probably is of pretty much academic interest since cholera for us shouldn't be too much of a problem to deal with. I have posted about cholera before. But it is more of an indicator of our ability to manage faecal contamination of our food and water.

So we'll find out if more cases emerge.

The great diarrhoea mystery

So the diarrhoea cases continue to baffle us all. For four weeks running it has reared its head above the epidemic threshold. And yet the Ministry of Health maintains its stony silence as if nothing is happening. Salmonellosis remains high (29 cases) but not high enough apparently to explain the diarrhoea epidemic.

Curiouser and curiouser, to say the least.

Death rates versus junior doctors.... alarming though not surprising

Here's a really interesting though alarming bit of news:

A small but statistically significant number of patients die each year when junior doctors start work in August, an Imperial College London study suggests.

Researchers looked at 300,000 patients admitted as emergencies to English hospitals between 2000 and 2008.They compared death rates between the first week of August, when new doctors arrive, and the previous week in July.After adjusting for various factors, they report in PLoS One that the August patients were 6% more likely to die.The period when an influx of newly qualified doctors enter the wards has sometimes been dubbed the "killing season", but studies to establish whether there is any truth to this have been inconclusive.

The researchers from Imperial College London stressed they were unable to draw firm conclusions about the reasons for the increase, but that it was significant, if small.

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

This piece of news when taken together with recent concerned postings from young doctors at Singapore M.D. about their apprehensions and lack of preparedness when they graduate.... and more recently about the rush to place them into residency programmes... must however, give us cause for concern. We have no local data, but I cannot imagine that our situation here is any better than that of the UK.

Perhaps the MOH should commission a similar study before embarking on these massive and rapid changes to our system?

IVF mistakes - what is the extent of the problem in Singapore?

CNN reported recently of an IVF mistake occuring in an Ohio clinic in the US, where an embryo was wrongly implanted into a woman. This is not an isolated problem as such mistakes have been increasingly reported. Just last month, the BBC reported on a whistle blower embryologist Ms Pavlovic who highlighted neglected procedural safeguards at the Guys and St Thomas's hospitals. As she had detected the mistakes by accident, she queried if there had been other mistakes that have gone undetected and unreported.

We really don't know how many such errors have occurred in Singapore (see previous post). None have ever been reported to my knowledge, but this silence does not necessarily mean we are error free. Perhaps many have just not been detected.

But what can we do about it? For one thing, IVF clinics have to be more stringent in their procedural disciplines. How do embryos get labeled and tracked? Are we still depending on handwritten scribbled information of sample labels, or can we move on to electronic tagging as one major clinic in the UK has done. With IVF, even one error is one error too many.

As a footnote, I would welcome any reports or IVF errors in Singapore if you are aware of any such problems. Just drop me a note. You don't have to name names or identify clinics if you are not comfortable.

The problem with slimming pills.....

The Straits Times recently reported on the problem with slimming pills. Strangely it is reproduced in full only in the Malaysian Insider.

But the report confuses a range of issues. Firstly there is the problem with the illegal selling on such pills. This is a relatively straightforward legal issue. People who buy such pills online are pretty dumb anyway and shouldn't be crying too much if anything happens to them.

Of more concern to me is the participation of doctors in the wanton prescribing of such medications to patients who do not really require them. This to me, is unscrupulous exploitation of patient's anxieties by medical professionals who should know better. There is an ethical (or lack of) dimension here, which the Singapore Medical Council seems reluctant to wade into.

Can it be regulated?

Unfortunately not at the moment. Such practices, unsavoury though they may be, are perfectly legal. This is an perfect example of how the loophole with respect to off-label prescribing can be exploited for crass commercial returns.

Slimming pills are not without toxicities, and their use is generally directed only to those situations where diet and exercise regiments have been ineffective, or where co-morbidities make weight reduction a medically (relatively) urgent procedure. But their off-label use for indications that are relatively trivial, is not prohibited by law. It is only unethical because it is exploitative and not usually in the patient's interest. Otherwise there is more than an element of caveat emptor in the process.

So what can do we do about it?

Not much really. Caveat emptor. Perhaps if more exploited patients take their doctors to court, ... but more likely it will just up the cost of medical practice insurance.

Selamat Berhari Raya

The one thing I like about Hari Raya is that the focus is very much on relationships, forgiveness and reconciliation.

So to all my muslim friends,
Selamat Hari Raya Eid ul-fitr untok semua kawan kawan.
Maaf zahir dan batin

Here is an old song from Rahimah Rahim. Don't see or hear from her very much nowadays, but she is still very much loved.



Have a nice long weekend all!

H1N1 vaccine - areas of concern

So the MOH has clarified that the vaccine will be offered pretty much at cost and for about the same price as the seasonal flu vaccine. Channelnewsasia reported price range of $22-38. Which is somewhat more than my earlier 'rojak' estimate of $10 per shot. But it's still affordable.

What MOH needs to clarify though is whether the GSK vaccine requires the squalene based AS03 adjuvant. The safety of the AS03 adjuvant, like the Novartis MF59, has been in question for some time. These adjuvants serve the purpose of heightening the immune response, resulting in the necessity of using a smaller amount of antigen. It was deemed necessary only because anitigens were difficult to produce in large quantities. The problem is that, theoretically the immune stimulation may induce the body to react against its own tissues. One of the suspected consequences has been the development of the Guillain Barre syndrome. This is a rare possible adverse event associated with the use of these vaccines. Whether this is a real consequence or not is hard to determine as these tend to develop over years after the vaccination event, and hence the causal link is hard to establish.

The US FDA has not yet licensed the use of these adjuvants, although it seems to preparing for their use should an H1N1 emergency arise. It has also not yet authorized the emergency use of these adjuvants.

Recent studies have shown that single doses of the un-adjuvanted vaccines are adequate to produce the antibody levels required for protection. So theoretically, we should not need the adjuvants.

Although the risk of Guillain Barre syndrome, even if real, is very low. It is nevertheless necessary to consider the risk when exposing children to vaccines containing these adjuvants. We need to appropriately balance the benefit of protection against a potentially fatal HiN1 infection, and the potential risk for a vaccine-adjuvant related auto-antibody response.

Parents do need to be aware. The MOH should also be mindful of parent's concerns and be transparent about whether such vaccines contain the squalene adjuvants. Patients do have a choice, and should be empowered to make a decision about the risks they are prepared to take.

There is a fairly decent review here:
http://www.slate.com/id/2228700/

A related question, and something that I have found difficulty in getting information about is, how the HSA regulates something like this? Does it have a policy about squalene adjuvants? How does it regulate such novel vaccines in a 'not sure if there is a pandemic' situation?

Farewell Mary Travers - Requiscat in Pace

Mary Allin Travers (November 9, 1936 – September 16, 2009) was an American singer-songwriter and member of the folk group Peter, Paul and Mary, along with Peter Yarrow and Noel "Paul" Stookey. Peter, Paul and Mary was one of the most successful folk-singing groups of the 1960s.

In 2005, Travers was diagnosed with leukemia. Although a bone-marrow transplant was apparently successful in beating the disease, Travers died on September 16, 2009, at Danbury Hospital in Danbury, Connecticut, from complications arising from chemotherapy. She was 72 years old. (Wikipedia)

H1N1 vaccine - we give it to GSK!

So MOH has secured 1 million doses of the GSK vaccine. I wonder how much the windfall was for GSK.

Canada apparently bought 50 million doses for more(?) than Can$400 million. So I guess we'd be looking at something in the region of about S$10 million?

I wonder if these vaccines come with AS03, the controversial squalene loaded adjuvants?

Minister of Health's Blog

It was great to see Minister appearing on his own blog. Congratulations, Sir!

My only grouse is that you do not allow direct comments on your blog. To comment, one has to have a Facebook account to access the Ministry of Health Facebook. Sir, not everybody wants to be on Facebook. So sadly, I will have to pass on commenting on issues on your site.

But still, it's a great start!

Off-label stent use - risky venture

The risk of definitive stent thrombosis is increased after “off-label” stent implantation irrespective of drug-eluting stent or bare-metal stent use

Rainer Hoffmann, Helene Klinker, Malte Kelm and Rüdiger Blindt
Department of Cardiology, University Hospital, Aachen, Germany
Medical Clinic I, University, Aachen, Germany
University Clinic Aachen, Aachen, Germany

Published online: 11 August 2009 Clinical Research in Cardiology

Abstract

Introduction
A limitation of drug-eluting stent (DES) use to FDA-approved indications has been suggested to reduce the risk of stent thrombosis. This study evaluated predictors of stent thrombosis in clinical practice after the use of drug-eluting as well as bare-metal stents (BMS), including adherence to the FDA indications for DES.

Methods
Between July 2002 and October 2006 percutaneous coronary intervention (PCI) was performed on 5,945 patients using BMS (68%) or DES (32%). Patients had 1-year follow-up for definitive stent thrombosis (ARC criteria). 76 patients (1.27%) developed definitive stent thrombosis. Clinical, procedural, and angiographic parameters were related to those of 786 patients without stent thrombosis to define predictors of stent thrombosis. Off-label or on-label implantation of stents according to the FDA-approved indications for DES was included as parameter in the analysis.

Results
In 434 patients, stent implantation was performed within FDA-approved indications and in 428 patients outside of FDA-approved indications for DES. Predictors of stent thrombosis were PCI in acute myocardial infarction (OR = 4.51, P < or =" 4.43,">P < or =" 1.07,">P < or =" 3.67,">P < or =" 6.13,">P < or =" 2.56,">P = 0.014), LV-EF < or =""> P < or =" 3.65,">P = 0.004), stent length in mm (OR = 1.04, P = 0.015), and implantation of multiple stents (OR = 2.64, P = 0.002) remained predictors of stent thrombosis. Off-label stent implantation was no independent additional predictor as it is a combined parameter of the above-mentioned predictors.

Conclusions
Implantation of coronary stents outside of the FDA-approved indications for DES is associated with an increased risk of stent thrombosis using DES and BMS.

The Transplantation Ethics Committee (TEC)

The Minister's clarification about hospital transplantation ethics committees (TEC) was assuring, but I think inadequate.

Reassuring because they will be properly trained people. Trained by the NUS Centre for Biomedical Ethics no less. This will be whole lot better than the 'training' for members of the current hospital clinical research ethics committees. Minister says the TEC will comprise 3 members - one lay person, one medical person....and the third, one of the doctors from the hospital.

But I am a bit concerned about the size of the committee. One of the important features of an ethics committee is that it should be able to represent as much as possible the breadth of opinions from the society. The current hospital ethics committees, as mandated by GCP-ICH is a minimum of 5 members. Even so, I feel 5 is probably not adequately representative. Reducing the quorum to 3 further restricts the variety of opinions and depth of discussions.

Furthermore, to ensure representativeness of the committee, I believe it is mandated by GCP-ICH that the committee must not comprise all doctors, members of the same gender, or same ethnic group.

By these expectations, Minister's composition for the TEC will be very narrow based indeed. Expedient, but too narrow for my liking.

Admittedly you can play the mathematics and still satisfy the conditions (after dinner mental maths for you?), but I think the quality and breadth of the opinions expressed and the related discussions will be much less representative of Singapore society.

Also apart from the composition of the committee, it is perhaps more important to specify the procedural aspects of how the committee will function. I hope this will be forthcoming soon.

Pneumococcal stats - my mistake!

Haha ... yes...I did make a mistake about the stats. The MOH bulletin reports all cases, whereas the cited figure of 70 is for children under 5 years.

Presumably the numbers will be compatible if approximately 28% of reported cases are less than 5 years old.

My apologies. My mistake. Missed my coffee this morning!

The Pneumococcus vaccine - I am confused and alarmed, but a bonus for Pfizer-Wyeth or GSK?

So Minister has now agreed to putting the Pneumococcal vaccine into our National Childhood Immunization Programme, despite being resistant to the idea 2 years ago. At that time MOH said the situation did not warrant it.

"The ministry has reviewed our local situation and has decided not to incorporate the pneumococcal vaccine into the National Childhood Immunisation Programme at this point in time," said an MOH spokesperson. This is because the hospitalisation rates for invasive pneumococcal disease in children in Singapore declined from 38 per 100,000 people aged five years and below in 2004 to 26 per 100,000 people last year."

The latest figures Minister cited yesterday was that the annual number of cases was about 70.

I have to say I am somewhat puzzled. Did the situation deteriorate so rapidly over a mere 2 years? I mean we were in the pink of health 3 years ago, and then suddenly things appear to have worsened to the extent that now we need to immunize.

I did a quick check of the MOH epidemiological stats. Strangely MOH didn't publish any invasive pneumococcal stats until 2009..... so I am presuming MOH did collect data except that they did not publish. The 2009 data is however very interesting in that in the first 36 weeks, MOH logged an even more astounding 183 cases of invasive pneumococcal disease. Extrapolating to the full year, we might be looking at something like 250 cases!!! This is more than 3 times the estimate of 70 that Minister Khaw cited.

Quite frankly, I find the figures rather confusing. Do we have a problem or do we not have a problem? We had a declining incidence of 26 per 100000 per year in 2006. Minister cites 70 cases per year. And the MOH bulletin reports an approximate annual incidence of invasive pneumocaccal disease of 250 for 2009. All in a space of 3 years. Mind boggling to say the least. Or did I make a mistake with the figures?

Meanwhile Pfizer-Wyeth must be rubbing their hands rather gleefully if MOH implements the programme. Pfizer was rumoured to have bought Wyeth because (at least one of the reasons) because of the Prevnar vaccine that Wyeth had, plus the new 13 strain vaccine that is about to come on board. The size of the Prevnar market for Wyeth has been estimated to be about US$2.4 billion, and that of the new vaccine will probably exceed that.

But Pfizer-Wyeth has competition in the wings, as GSK has set up a S$600 million plant in Tuas to make pneumococcal vaccines!! This will be ready in 2011.

So the market hots up. I wonder who MOH will choose to supply the vaccines for the NCI Programme? I wonder who will get the cake?

Meanwhile parents have to be prepared to fork out approximately $700 for the vaccines ($170 per dose x 4 doses). And yes, taking from Medisave is still paying for it.

Diarrhoea - the mystery continues

There was a total of 2716 reports of acute diarrhoea last week. Only 27 was reported as salmonellosis. One has to assume the bulk of cases were not tested, or of unknown aetiology.

Stents and prostheses - are they regulated?

One of the quirky consequences of the way our medical environment has developed is the fact that while pharmaceuticals are regulated to the nth degree, surgical procedures and the stuff surgeons stick into our bodies (e.g. stents and prostheses etc) are hardly regulated at all.

In 2007 the Health Products Act was passed, which to some extent rationalized the regulation of stents and prostheses (collectively called 'medical devices'), but regulation of these things remain, by comparison to pharmaceuticals, barely regulated. The regulations for these medical devices are to a large extent limited to registration, manufacture, supply and advertising. There is minimal expectation of any proof of safety and efficacy.

In otherwords, cardiologists and surgeons are pretty free to stick in any device into our bodies so long as these devices are registered at the HSA. The patient consumer really has no way to determine if any of the very many brands of devices being used have been proven for the disease, or have any reliability with respect to their longevity in the body, or their safety over long periods of time.

One would expect that hospital and clinics performing these procedures (and perhaps the MOH as well) should be collecting data on the outcomes of these procedures where devices are implanted into the body, but this is almost never done. So the patient consumer is really in a very vulnerable position.

To compound the problem, these medical devices are very often used in off-label indications.

Salmonellosis and diarrhoea epidemic in Singapore

The diarrhoea epidemic continues. I am told the polyclinics have been somewhat overloaded with diarrhoeal cases. I am assuming that this has been salmonellosis because that's what the MOH stats appear to suggest.

But MOH and AVA have persisted in their silence and one wonders what's going on.

Meanwhile, the latest 'hot-off-the-press' nationwide recall in US because of salmonella are chocolate covered nuts made by Kilwin's. I wonder if any of these chocolate products have made their way into Singapore.

See http://www.fda.gov/Safety/Recalls/ucm182067.htm

Salmonellosis epidemic in Singapore - strange silence from MOH and AVA

I posted about the spike in diarrhoeal disease 2 days ago, not knowing a report was coming out in Straits Times the very next day. Technically the numbers being seen at polyclinics indicate an 'epidemic' in Singapore. Yet MOH and AVA has been strangely silent about this. Is this food poisoning? Where are the clusters? What's happening? We are all in the dark!

Dr Paul Ananth posted a comment refering to the recent recall of some salmonella contaminated product. In 2007, there was a similar recall of Peter Pan peanut butter in Singapore for salmonella contamination.

So what's happening, AVA? Is this some contaminated food that we should be aware of?

One dose H1N1 vaccine - No need for adjuvants

So an Australian study has demonstrated that with the new crop of H1N1 vaccines, a singlae dose is all that's required. No adjuvants are required. This data confirms what the China vaccine had earlier showed.

The importance in these findings is that firstly, it means the amount of vaccines available can reach twice as many people; and secondly, more importantly, we do not need to use any fancy adjuvants.

One of the major concerns of vaccine technology is the need for adjuvants. Adjuvants are often used to heighten the body's antibody response. This is often needed as the antigen is used in low quantity or does not by itself elicit a strong immune response. The problem with adjuvants is that the hyper-stimulation of the body's immune response (theoretically at least) may induce an unwanted immune response to the body's own proteins. The Guillain - Barre syndrome emerged as one of the problems associated with the US mass vaccination in 1976-77.

Of recent concern has been the use of squalene in commercial adjuvants such as the AS03 (GSK) and MF59 (Novartis). These adjuvants have not been approved for use in the US.

The one dose vaccines (sans adjuvants) should ameliorate these concerns.

Spike in diarrhoeal diseases? What's happening?

Unbeknownst to many, and almost slipping under the radar screen, is this spike in diarrhoeal diseases over the last 2 weeks. I wonder what's going on?
The MOH report just indicates salmonellosis as the bug; 26 over the last week. No new reports of specific food poisoning outbreaks in the media. But we've crossed the epidemic threshold for 2 weeks already.

Someone tell us something!!

H1N1 - second wave?

I found the recent report in the Straits Times that the hospitals were gearing up for a second wave, somewhat intriguing

The report had cited an estimate that about 700,000 had already been exposed to H1N1 and was likely to have immunity. This estimate was based on a back calculation from WHO's estimate of case-fatalities, which was in all likelihood an overestimate, which means the 700,000 is probably an underestimate. But let's say that that represents a decent estimate.... the extrapolation would mean that based on a total population of 4.8 million, there remains another 4.1 million residents and non-residents without immunity.

So a second wave is not an unlikely event.

But as I pondered this with my mathematically challenged mind,.... I couldn't help wondering if the second wave may be reasonably expected to be greater or lesser than the first wave. It just seemed to me that all things being equal (i.e. that the virus hasn't changed) that a wave resulting form exposure to 4.1 million individuals with no immunity might be expected to be lesser than that arising from exposure to 4.8 million naive individuals. And if we had underestimated the numbers who have been exposed to the first wave, the numbers who remained vulnerable would be less ..... and the size of the expected second wave would be correspondingly muted.

So is a panic warranted? I hardly think so, especially since the first wave wasn't even quite the tsunami predicted.

Off-label use of drugs - why the concern

All modern pharmaceuticals are subject to rigorous testing before they are allowed to enter the market place. Pharmaceutical companies are required to show good evidence of efficacy and safety for the dosages used and for the specific clinical conditions they are meant to treat. Consequently, when they are finally licensed into the market place, they carry a product label listing the specific disease indications for which claims have been validated.

Off-label use of the drug occurs when drugs are used for indications that have not been tested for. Hence the implications are that there is really no evidence other than anecdotal ones, that using these drugs in off-label situations will be effective and safe.

Off-label drug use is not illegal, but the US FDA prohibits the promotion of off-label use. The reason for this relate to the concern that pharmaceutical companies tend to gain market access by initially testing their drugs in a very narrow and specific way and can therefore show that the drugs are sfae and efficacious. Once the drugs are licensed, a host of off-label uses are then directly or indirectly promoted. For many drugs, the off-label uses may be even more lucrative than the labelled uses. In this Canadian report, approximately 25% of all prescriptions may be off-label prescriptions. This number is however decptive as the actual figure may be higher in different clinical situations. It is particularly prevalent in paediatrics, oncology and psychiatry. It is particularly problematic for expensive prescribed drugs.

In recent times, some major players have been caught. In Jan 2009, Lilly had to pay out US$1.4Bn for promoting off-label use of their drug Zyprexa. In 2004, Pfizer itself pleaded guilty and had to pay out US$430million for promoting their drug Neurontin. I imagine these are but the tips of the iceberg in the pharmaceutical industry given the attractiveness of the off-label market.

But what, you may ask, is the problem with off-label use?

Well, the main problem is that every medicine we use have been licensed only for very specific conditions for which they have been extensively tested for safety and efficacy. This evidence is vitally important for the protection of the patient consumer. Off-label use of drugs imply that drugs can be marketed for conditions for which there is no evidence of safety or efficacy. If this level of ambiguity is acceptable for medical therapeutics, then why bother with drug licensing in the first place? Surely the patient-consumer has to be treated with more respect and consideration.

Doctors have a legally sanctioned ability to use drugs according to their clinical judgement, and in an off-label situation, but this practice should be covered by the SMC guidelines which make it clearly unethical if the doctor provides unproven therapies, other than part of a clinical research protocol.

The Pfizer US$2.3Bn fine,... and off-label use of drugs

I posted earlier on the ethics (or lack of) of off-label use of drugs. Now the latest news is that the pharmaceutical giant, Pfizer has just agreed to a payout of a massive US$2.3Bn for illegally promoting off-label use of its drugs. The chief target was Bextra, the painkiller that was withdrawn from the market in 2005, just barely 4 years after entering the market.

But this is unlikely to curb such unsavory practices. Pfizer, the largest research based pharmaceutical company (revenue of US$48.2Bn in 2008) has been cited as a repeat offender.

The incident highlights the growing pressures on pharmaceutical companies to push their drugs, often beyond the original proven indications just to grow the size of the pie. Drug development is a very scientific but expensive process and when drugs are licensed into the market place they are registered only to be used for the indications for which they have been tested. Companies often encourage doctors, indirectly and sometimes directly, to consider using their drugs for unproven indications. Use of the drugs in unproven situations, are termed off-label use. This is a very cheap and convenient way to generate better returns on their research investments, because you only need to invest in testing for one indication, but maximize returns by encouraging market use for a number of other unproven conditions.

So Pfizer was caught red-handed.

But what about other companies? I wonder what the HSA is doing about this problem. How does it police the pharmaceutical companies here in Singapore with respect to this? No point just citing the regulations. We need to know what is actually being done to curb this.

In my earlier post, I highlighted this as an ethical problem facing doctors. The SMC ethics guidelines specifically ruled against use of drugs for unproven indications. But we know it happens. And I don't think the SMC is really doing anything about it.