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BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES Programme no. 5 - Side Effects
RADIO 4
TUESDAY 29TH JANUARY 2008
PRESENTER: MARK PORTER
REPORTER: ANNA LACEY
CONTRIBUTORS: NICK BATEMAN
JUNE RAINE
COLIN BAIGENT
SAUL BERKOVITZ
PRODUCER:Ìý HELEN SHARP
NOT CHECKED AS BROADCAST
PORTER
A few years ago the British Museum unveiled a new exhibit called "Cradle to Grave" - it was an artwork made up of the average British couple's lifetime consumption of prescribed medicines.
It included 28,000 pills and capsules - a figure that would have risen to over a hundred thousand if the artists had included non prescription medicines bought over-the-counter.
Cradle to Grave was a graphic illustration of just how dependent we have become on modern medicines, and the benefits they confer - everything from beating cancer, to easing the pain and stiffness of an arthritic joint. But, along with the benefits, come side-effects.
In today's programme I'll be finding out just how worried you should be by that long list on the leaflet that comes with your pills.
And those are often just the ones the manufacturer picked up in early trials before the drug was launched. The biggest test of all occurs afterwards when millions of people are prescribed the drug worldwide - and it's then, and only then, that some of the more unusual side effects become apparent.
Linda Hurcombe's daughter Caitlin's behaviour took a worrying turn after she was prescribed one of the later generation of antidepressants. With catastrophic results.
HURCOMBE
What happened in my personal case which was a tragic one and ended in my daughter's death by suicide was that she was visiting America and saw an ad on television, she was 17 years old at the time, for these new antidepressants that make you feel great, although I don't want to be flippant about my daughter Caitlin's particular first motives for wanting antidepressants, I'm telling the truth - this is what she came back home and said - I want these drugs. And in fact did go to the doctor a few months later, against my mild but uninformed advice, and said she was worried about college, she was furious with her boyfriend, she was having arguments at home, she was anxious and wanted to try antidepressants. And her GP did agree to that and said she should have counselling as well which she did. But I'm afraid her experience was something that I still shiver in horror, it's been eight years since Caitlin died but I still shiver in horror to think that I didn't recognise the immediate symptoms she had from this drug because she changed immediately and over 63 days on the medication descended into a chaos of self harm and eventually she hanged herself. And it's impossible to describe what that journey - it's of course changed the life of Caitlin and all of the many people who loved her. And in terms of my personal experience as her mother it ended up in trying to trace the issues surrounding medications that are now taken by 50 million people worldwide.
PORTER
Linda Hurcombe talking about her daughter Caitlin.
It's not clear whether the drug - a member of the Prozac like SSRI family - was definitely responsible for Caitlin's suicidal thoughts, but there have been numerous other reports of similar experiences. Reports that have since led to doctors being cautioned to be vigilant for suicidal thoughts in people who have recently started these drugs, and for all but one of them to be banned in anyone under 18.
My guest today is Nick Bateman, he's professor of clinical toxicology at the University of Edinburgh, and joins me from our Edinburgh studio.
Nick, before we get on to the systems in place for monitoring drug safety after a drug has been launched, perhaps you could give me an overview of the hurdles a medicine has to clear before a doctor can even start prescribing it?
BATEMAN
Well drugs, as you know, are developed by major pharmaceutical companies to a large extent and they do extensive studies in animals before any drug is given to man. This is for two reasons: first they just try and sort out what the drug is going to do and secondly, to ensure it's relatively safe when we start to give it to people. At that point if it looks like it's got a promising future studies are done in what are usually normal healthy volunteers to try and get some idea of what happens because until that point nobody's really quite sure what's going to happen when people take the drug. If that shows promise, and you may get some surprises at that time, but if it shows promise then smaller pilot studies are done in patient groups and then moving on to a larger clinical study, a formal clinical trial, at which point, if all goes well, the drug may then be considered for a licence to be sold more widely to the population.
PORTER
Nick, you mentioned surprises there, I mean not all surprises - I suppose you're referring to side effects - but not all side effects are necessarily bad.
BATEMAN
Well exactly and many of your listeners will be familiar with the drug Viagra, which has actually been developed for entirely different indication of angina when it was discovered to have a side effect which has now been of course made as a blockbuster in the world of pharmaceutical medicine. So that's one example. But sometimes of course it can go drastically wrong, as was the case in Northwick Park when unfortunately volunteers run into really serious ill health. So both and good and bad things can happen.
PORTER
What proportion of new medicines never make it through that process?
BATEMAN
Well a very high proportion of course because it's often only at that stage you really begin to realise what the drug does when you give it to people. So many hundreds pass by the wayside before they get to that stage.
PORTER
And how many people would be involved in a typical drug trial before a drug is licensed?
BATEMAN
It depends on the indication, if it's for a relatively common disease - may be a few hundred to a thousand - for rarer diseases smaller numbers.
PORTER
So looking at the side effects that are listed on the leaflet that comes with the drugs that everybody gets now, those are the ones that have surfaced during the early trials, does that mean they're very common?
BATEMAN
Well the issue of commonality is quite difficult isn't it. We obviously when we give a drug a licence have to bear up two things - weigh up two things - this is the effectiveness of it and its adverse effects and understanding that balance is critical to how you get a drug into the marketplace and how safe it is. So frequency will be taken into account in terms of the safety and indication. So a headache in an anti-cancer drug you might not worry about. A headache in a drug that was used for headaches would be a big problem.
PORTER
But rarer side effects, ones that occur in say less 1 in 3,000 people are unlikely to be picked up, you often don't have that number of people in the initial trial.
BATEMAN
Exactly and that's the reason that increasingly we're needing to monitor the effects of drugs after their licence and this has been not a new problem and there are lots of new initiatives in this area which I'm sure we'll talk about today. But it's important to realise for patients that when you see a headline in the newspaper - New wonder drug - at that stage it's often very difficult to be sure of its full safety profile.
PORTER
So what does happen after a drug is launched and taken by millions of people, rather than those few thousand? Well the Medicines and Healthcare Products Regulatory Agency - the MHRA - is the government body charged with protecting the public by ensuring that medicines are safe. Dr June Raine is Director of Vigilance and Risk Management at the agency.
RAINE
Once a drug is launched we move forward very promptly with robust monitoring systems and central to this is the yellow card scheme. This is a scheme where health professionals can report to us, on a readily accessible form, it's there in the back of the British National Formulary, to tell us what they have observed, they don't have to prove that the association is a causal one, just to tell us their suspicions.
PORTER
So if they - if a doctor suspects a side effect in a patient he or she will send you a yellow card but how many do you get - that depends on them spotting the side effect, drawing the association and then sending the form and they're busy people and you could see that things don't always get sent like they should.
RAINE
We receive about 20,000 every year and of course we could always wish for more, we encourage health professionals, we urge them to report their suspicions and we remind them at every possible opportunity. But we're pleased that the ability to detect new signals in the UK we believe is second to none, we have a system that has picked up really quite rare side effects quite promptly and really I think that's the tradition of the yellow card scheme ever since the thalidomide tragedy where a very unusual side effect - focamelia, the limb deformity in babies born to mothers who'd received thalidomide in pregnancy - only was picked up after about 10,000 exposed foetuses. Nowadays we would pick this up with as few as four or five.
PORTER
So you're looking for trends which you then investigate. How do you act on the data that you get from the yellow card system, say something - you spotted a pattern that may be worrying, what do you do next?
RAINE
If we believe that the pattern is disproportionate to what we would have expected, taking into account what was seen in clinical trials, what might be expected from the way the drug acts, we immediately look carefully at the series of cases and we conduct a risk assessment. We may then look to other sources of data such as large epidemiological studies, studies in large populations of patients, or indeed further clinical trials.
PORTER
Where's the patient's role in all of this - if I'm on a drug and I'm worried that it's giving me a side effect can I directly report it or do I need to go through my health professional?
RAINE
Yes you can report to us direct. We really do want to hear from patients, we're wanting to know what their experiences are, we've been piloting patient reporting over the last two years, I'm delighted to say we've had about 7,000 reports in total. And these are an equivalent level of seriousness to those from health professionals. We particularly welcome hearing what patients tell us in the way of details on their life and their activities which may have been affected by an adverse reaction. So if you're listening out there we really are interested in hearing more about any side effects you may have experienced.
PORTER
And where does the pharmacist fit into all this?
RAINE
Pharmacists themselves are able to report, they are able to report to the yellow card scheme, whether they're community pharmacists or they're in hospitals. But in the middle of February we are particularly looking at pharmacists to support our extension of yellow card reporting by patients by being the home of adverse reaction reporting. We'll be launching special information packs that will go to pharmacies throughout the UK and we will be also in parallel opening up a web enabled form that's been streamlined and made much easier to use.
PORTER
Dr June Raine talking to me earlier.
You are listening to Case Notes, I am Dr Mark Porter and I am discussing drug side effects with my guest clinical toxicologist Professor Nick Bateman.
Nick, you are Head of the Yellow Card Centre in Scotland, are reports from the public given the same weight as those from doctors and pharmacists?
BATEMAN
Yes they are now. When this scheme first started in the UK there was concern about whether the reporting level would give us the same information but as June Raine mentioned in that interview it seems to be that it does and that's very encouraging because it gives us a new source of information for our network of pharmacovigilence.
PORTER
And what sort of information is useful - do you want to actually hear reports of things that are already on the leaflet that came with the drug, for instance, indigestion on someone taking an anti-inflammatory?
BATEMAN
No not really, I mean there are two types of things that we're interested in, in particular. One is an unknown side effect, something that's not on the label that the patient gets with the tablet box. And secondly, is more serious side effects that affects their lifestyle, their quality of life or may indeed result in a hospital admission or prolonged time off work. That sort of thing, which is new and important to them.
PORTER
Talking about new side effects, it must be very difficult to eliminate coincidence, there's an awful lot of people out there taking medicines and an awful lot of things happening to them, how do you know if the drug is to blame?
BATEMAN
A good question and a very difficult one to answer. Basically one has to acquire, as Dr Raine said, a group of data about a particular drug, compare that data to the background rate of that condition in the community at large, and see whether there's an excess in the patients who've received the drug. We also, of course, can now look at the reports from patients as a whole to the whole database that Dr Raine referred to and that gives us a very powerful statistical tool to try and detect unusual reactions. But of course unless you have a report from a patient or a doctor or a pharmacist or a nurse you can't get a signal.
PORTER
Put the whole post marketing thing into context, how many drugs are likely to get withdrawn after launch because of problems detected by the yellow card scheme or their equivalence elsewhere?
BATEMAN
It's difficult to give you precise numbers but we get about 10-20 new compounds a year on the market and probably at least one a year tends to have some serious problem that we detect. There are obviously lots of other less important things that don't hit the headlines but which are included in the datasheet as we get to know more about the drug.
PORTER
So it's not just about withdrawing the drug, you might change the advice that you give to doctors about how they use it?
BATEMAN
Absolutely and as you as a doctor will have had letters from the committee saying please change your pattern of prescribing to account for this problem.
PORTER
Well the anti-inflammatory Vioxx was one of those drugs that was withdrawn. It was one of a new breed of non-steroidal anti-iflammatories - known as Cox-2 inhibitors, or coxibs. They were designed to ease pain and stiffness in arthritis, while being kinder on the stomach than existing NSAIDs or anti-inflammatories like aspirin, naproxen and ibuprofen. But it wasn't long before an unforeseen problem emerged. Professor Colin Baigent is an epidemiologist at the Clinical Trials Service Unit at the University of Oxford.
BAIGENT
The trouble started with the first big trial that was comparing the drug rofecoxib which of course we know as Vioxx against the drug naproxen, which is an old fashioned NSAID. And what happened was although the coxib Vioxx was quite easily able to prevent pain, so in that respect it was highly acceptable, and was also able to prevent or reduce the stomach of stomach ulceration, something unexpected happened in that there was an excess of heart attacks in people who were allocated to Vioxx. And that of course caused a great deal of concern. But there was a twist and that is that naproxen is a bit like aspirin in that it can prevent heart attacks. So we didn't really know for certain whether it was the case that Vioxx was causing heart attacks or naproxen might be preventing heart attacks. So it was one or the other or possibly both and it was necessary to sort that out.
PORTER
Comparing Vioxx against placebo - a dummy drug - would be the best way to reveal any increased risk of heart attack. But that's difficult, and cruel, when Vioxx is prescribed to people who are in pain because of arthritis - as it mostly was. Fortunately there was another study going on that wasn't looking at the drug's pain killing benefits - but a possible protective effect against cancer of the bowel.
BAIGENT
The ability to sort all this out was actually really almost serendipitous really because it so happens that it had been suggested that the Cox 2 enzyme might be responsible for the development of colon cancer and so there were randomised trials in progress comparing a Cox 2 inhibitor versus placebo - that is to say an inert substance. And as a result of this there were trials available in which we could see very clearly whether Vioxx or a similar drug was causing heart attacks. And in fact when those big trials did report their results it became really clear that Coxibs do cause an increased risk of heart attacks.
PORTER
Concerns over that link between Vioxx and heart attack led to the manufacturer MSD withdrawing the drug in 2004. But the story doesn't end there.
BAIGENT
Back at the beginning of 2005 we set about trying to bring together all the evidence from the randomised trials that had been done, there were quite a lot of them, over 140 trials, and we crunched the data to look at this in more detail. And what we found was that as far as the evidence can tell us, and it is still very limited, the coxibs all seem to have some hazard when they're used in the doses that were studied and in the trials. It's always more complicated than it looks of course and it may be that lower doses of coxibs are more safe than higher doses but we don't really know that for certain. The other thing that came out of that study, which was very important, is that the old fashioned NSAIDs they are not any safer from the point of view causing heart attacks than these new drugs. So although there was a great public concern about the Cox 2 inhibitors and it was all over the press when Vioxx was removed from the market, in fact it's very important to remember that not only do they cause heart attacks at least when they're used in high doses but they also cause a higher risk of stomach ulcers. So with the old fashioned drugs you're getting the worst of both worlds.
PORTER
Professor Colin Baigent.
Nick, Colin makes an interesting point there. But other Cox 2 drugs survived, and, as, Colin pointed out some of the older anti-inflammatories are linked to heart attack too. So why was it Vioxx that bore the brunt of the blame?
BATEMAN
I think it bore the brunt of the initial blame because it did such a good study that showed quite clearly the cardiovascular risk with that agent. And when one compared the dangers with Vioxx versus the other drugs at that time it did not seem that they were as hazardous in the patient groups being studied. Now whether that's true is still a matter of debate and there are ongoing academic discussions, as you've heard from Colin, about this topic. It's not an easy one to sort out.
PORTER
But this is an interesting case where one drug metaphorically fell on its sword and actually changed the way or changed our appreciation of the dangers of using a host of other related drugs.
BATEMAN
It is and it shows you that you still have to keep an eye on the drugs and he says non-steroidals, these other drugs like naproxen, ibuprofen, have been around for 20, 30 years and now we're still discovering new problems with them after such a long time because of the interest in the adverse effects of a different class of drug.
PORTER
OK. I want to move on to another area that's not quite so well regulated - supplements and complementary therapies. Just because something is natural, doesn't mean that it's side effect free - or that it won't interact harmfully with prescribed medicines. The herb St John's Wort - a popular over-the-counter remedy for mild depression - being a case in point. As our reporter Anna Lacey discovered when she met Dr Saul Berkovitz at the Royal London 91Èȱ¬opathic Hospital, where he runs the only hospital-based herbal clinic in the NHS.
BERKOVITZ
The main issue that's arisen with St John's Wort is interactions with orthodox drugs and the problem with St John's Wort is that it affects an enzyme in the liver which breaks down many important drugs and it's known as an enzyme inducer, the liver's naturally there to break down drugs and it enhances that process, so it therefore can reduce the effects of these orthodox drugs.
LACEY
So can you give me some examples of orthodox drugs, as you call them, that might be affected if you're also taking St John's Wort?
BERKOVITZ
Well one of the most important is a blood thinning drug called warfarin. Warfarin is widely used, for instance, if you've had blood clots or to prevent strokes and obviously it's important to thin the blood to the appropriate degree. Now if you're also taking St John's Wort you can reduce the effect of warfarin and therefore the blood won't be as thin as it needs to be and this can lead to failure of treatment. Another important drug interacting with St John's Wort is called cyclosporin and this is a drug that's used to suppress the immune system often if you've had a transplant and clearly if that fails that can lead to transplant rejection. There are other drugs, for instance, drugs used for HIV, some epilepsy drugs, there's another important interaction with the contraceptive pill and obviously you don't want failure of contraceptive either. So these are important drugs that interact with St John's Wort.
LACEY
You just gave me a whole range of drugs there but people might be taking any number of other drugs, how do they know if it's going to be safe or not?
BERKOVITZ
The only way to find out is to get advice from a trained professional. This might be your doctor, either your hospital doctor or your GP, or your local pharmacist and in recent years pharmacists have developed expertise because they sell a lot of herbs so they should be in a position to tell you. Unfortunately the advice you get from a lot of health food stores I would say is not reliable. And it's important to realise that you don't often get the information on the bottle of herb or as a package insert as you do with many drugs which warn you about the interactions.
CLAUDIA
This one is St John's Wort in standardised preparation.
LACEY
So tablets?
CLAUDIA
Yes in tablet form. My name's Claudia Avalona and I work as a pharmacist at the Royal London 91Èȱ¬opathic Hospital and we are now entering the pharmacy. At the moment what we find in the marketplace are three different classifications of herbal products. We have unlicensed the herbal products, we do have licensed herbal products and we also have herbal products which are registered as food supplements. Among these ones only the licensed herbal products are regulated which means that they've been assessed for safety and efficacy.
LACEY
But if somebody's walking into a shop how will they tell the difference, is there some kind of mark on the box for instance?
CLAUDIA
Yes, the way of recognising herbal products which have been licensed is to look for an initial THR, which stands for traditional herbal registration, and beside these initials there's a number which is basically the licence number.
LACEY
In fact we've got a box here of some devil's claw root extract and then on the back here, down in the bottom right hand corner, there is this THR and a long number, so that means that this is a proper licensed product?
CLAUDIA
Yes as this product has been granted this licence it's sure to contain what the label claims.
LACEY
So Claudia will be able to find St John's Wort with this THR licence?
CLAUDIA
As far as I know there aren't any St John's Wort preparation at the moment which have been granted a traditional herbal registration.
LACEY
With so many unlicensed products you'd be forgiven for thinking that serious side effects are happening all the time. But in truth a lack of both public and medical knowledge about the possible side effects means that it's not clear if St John's Wort is a problem or not. Saul Berkovitz.
BERKOVITZ
Obviously herbs are in very widespread use but the number of actual case reports of significant harm is very low and surprisingly low. Now this may be due to under reporting where the patient may have suffered an adverse consequence but not linked it to the herb and neither has their doctor or it may be that in fact the level of significant reactions is actually low and perhaps the concern is overstated.
LACEY
But it's very difficult to know because there's not wonderful communication between patients and doctors about the use of herbal medicines. So what's your advice to people who might be taking St John's Wort, of course they might just be buying from their health food shop or self medicating, what should they do?
BERKOVITZ
Well I think it's important to realise that herbs are essentially drugs, they have physical effects on the body and they may interact with any other medication that you're taking. So the important advice really is to inform your GP and all your health professionals, if possible keep a list of all the herbs and vitamins that you're taking and the doses and if you're in any doubt as to interactions with drugs contact your pharmacist or your doctor.
PORTER
Saul Berkovitz talking to Anna Lacey.
Nick are we really as much in the dark as Saul is suggesting, he mentioned there that St John's Wort, for instance, can interact with the contraceptive pill and cause a failure of contraception, now that's theoretically a problem, do we have any evidence that it actually has a significant actual impact?
BATEMAN
I think the oral contraceptive I don't have the figures to show you definitely yes but certainly in the laboratory you can show it very clearly. One of his other examples, cyclosporin, which is an immunosupressant for liver transplant patients to prevent rejection there's very good evidence that some patients are actually losing organs because of taking this agent with the cyclosporin and lowering their blood levels, so it is - can be very, very serious if you get the wrong interaction. And the other point I'd make is that these agents, of course, as has been pointed out are not regulated in the same way as the drugs, so the quantity of active ingredient varies from product to product. So for the patient it's quite difficult to know what the implication is going to be from a particular product when it's bought.
PORTER
But you're on the other end, would you like to see more people, healthcare professionals and the public, reporting side effects of these sorts of non-licensed supplements and remedies, would that be helpful to you?
BATEMAN
Yes it certainly would because as has been pointed out in that interview knowledge of this area is quite limited. Patients themselves are probably in the best position to know whether they've had a problem and I think in the past, and still today, many are reluctant to tell their doctor that they've been taking alternative medicine at the same time as prescribed medicine. So there's a need perhaps to let them do this without their health professional necessarily being aware and so they're not embarrassed.
PORTER
But that's the new yellow card system that patients can directly do it. I mean they can use that yellow card can they if they're talking about a non-licensed product, does that matter?
BATEMAN
Well if there's interactive with a licensed medicine certainly yes, the issue about non-licensed products is much more complex. And my view, personally, is that they should report these problems and in that way we may become aware of them. But of course from the point of view of the drug regulatory bodies they have a limited activity under the law which excludes some of these products from their responsibility.
PORTER
Professor Nick Bateman, thank you very much.
If you want more details of anything we have talked about today - including the yellow card scheme mentioned there - then there are some useful links on our website at bbc.co.uk/radio4. Where you can also listen again to any part of the programme, or download it as a weekly podcast. And if you don't have access to a computer then do try the Action Line on 0800 044 044.
Next week's programme is all about hospital acquired infections - like the so called "superbugs" MRSA and C.Diff. How much of a threat do they really pose to people going into hospital? What are your hospitals doing to protect you? And, just as importantly, what can you do to protect yourself? Join me next week to find out.
ENDS
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