Hypothetically speaking

Working on past experiences, like when weight-loss drugs had to be withdrawn when they caused heart attacks for instance, what if a top earning drug designed to save lives actually had harmful side-effects such that the overall mortality rates showed little significant improvement? Just suppose the NHS was engulfed in an inertia of prescribing such drugs, whereas an inexpensive alternative was available that was more effective? How would this be regulated, if multiple drugs were commonly prescribed for instance? What could be done to correct the practice?

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  • One of the reasons NICE was set up was to make sure that the NHS was not only prescribing drugs that worked, but that made some sort of financial sense - in other words, there was not a better way of doing this that cost less.

    However, this can be very controversial, especially with treatments that either offer prevention or might slow down a progressive condition. The effectiveness of these can be much harder to measure (especially over the short term) and NICE can be a little risk adverse sometimes when it comes to adopting some of these drugs which can be very expensive. Drugs for the treatment of dementia are probably the best known in this area with support for their early adoption from people like Terry Pratchet (quite understandably).

    It is an impossible choice sometimes I suspect.The NHS has a fixed budget in this respect - it is not like private insurance based services where you can negotiate with the insurance company or directly with the patient whether they want to spend the money - and NICE can only licence what it can pay for. It is inevitable that it will always get criticised by someone.

  • You mean, like statins?? It's disgusting.

  • Thinking about the first part of your question, I’ve pulled out some insights from our Making Sense of Drug Safety Science guides:

    "Clinical trials test both the efficacy and safety of the most promising drug candidates, providing initial data about the new drug, which can be used to decide whether its benefits are likely to outweigh its harms. After Phase 3 clinical trials, if the outcomes are good, regulators have to decide whether to license the drug. Drugs with side effects can be licensed but the beneficial effects must outweigh the risks of harms.

    Even after a drug is in widespread use, Phase 4 trials are carried out to find out more about the side effects and safety of the drug, what the long term harms and benefits are and how well the drug works when it is used more widely. If a drug is later found to cause severe, rare side effects whether it continues to be prescribed depends on the nature and severity of the disease and the availability of other treatments. If the effect is not severe and is understood, doctors will be informed of the potential problem so that they can decide whether the drug is suitable for individual patients and information is added to the medicine’s label. However, almost all cases of rare side effects reported at this stage are not predicted from the mechanism of the drug or from the pre-clinical toxicology and human volunteer studies. They are generally severe, even life-threatening, reactions- these drugs get withdrawn."

    You can read more at Making Sense of Drug Safety Science at: senseaboutscience.org/data/...

  • I don't find it overly reassuring. I read it as there's a kind of assumption that drug companies will be upfront and/or GPs will notice and be able to associate side-effects.

  • Patients can themselves report suspected side effects, via the Yellow Card system at yellowcard.mhra.gov.uk/

  • Thank you Lauren. I didn't know that. I would suspect a lot of other people don't either, and that side-effects are under reported.

  • Hello,

    I’m a pharmacist with over ten years experience in the drug safety field. You are correct in thinking side effects are under-reported. A large review of studies of the reporting rates showed that 1 in 20 detected side effects were reported by healthcare professionals. It does depend on the drug and the side effect. Serious side effects are more likely to be reported, as are side effects to new drugs – reporters are aware that regulators are particularly interested in new drugs. As new drugs have only been tested in a relatively small population before they are marketed, it is only when they get to market that we can fully find their side effect profile. Such drugs are marked with an upside down black triangle symbol in Europe (the UK was ahead of this, putting the symbol on new drugs from the mid-1980s after the Opren scandal).

    The UK’s Yellow Card scheme was started in 1964 after the thalidomide scandal. It was initially restricted to doctors, but falling numbers of reports in the 1990s led to its extension to other professions. Patient reporting became an increasing political issue in the early 2000s, and was announced as policy in 2004. The recent fall in patient reporting of side effects is regrettable, but in part is probably due initial high levels of reporting due to news articles at the time and a pulse of reports from pent-up demand from patients who had been demanding patient reporting. It should be remembered that doctor reporting took time to be established.

    There’s an excellent report on patient reporting at the HTA site (link journalslibrary.nihr.ac.uk/... ) which is a good read if you are interested.

    Reports like these are called “spontaneous reports” and the Yellow Card scheme is an example of a “spontaneous reporting system”. It’s important to understand how these schemes work and what they are to put under-reporting in perspective.

    Let’s imagine a new drug is released called xamaldaby. Over the first month of its release on the market, 200 Yellow Card reports are submitted by doctors, pharmacists, and patients. All of those reports are classified into the type of side effect. Cards are reviewed by the MHRA, but also highly complex statistical methods are used to compare xamaldaby to the other drugs in the database. In simple terms, the proportion of each type of side effect of xamaldaby is compared to the same side effect of all the other drugs combined.

    If the side effect for xamaldaby is disproportionately reported compared to the other drugs in the database, then that is “signal” that something is worth investigating further (like the dust rising over the horizon from an approaching army). Sometimes, individual cards might provide such strong evidence that action can be taken on that alone (the army is storming your castle). In other cases, warnings may be issued to prescribers and patients or further studies ordered to investigate if the side effect is real (sending scouts out to check out the dust cloud). Not all signals are real (it was just a gust of wind blowing up the dust over the horizon).

    To find a signal of a potential side effect, it isn’t strictly necessary to obtain all cases of a side effect. Despite the fact that under-reporting is common to the Yellow Card scheme, and historically it has only ever had a minority of actual side effects, it still manages to find suspected side effects because it uses disproportionality to find the side effects. Even with only 5% of side effects disproportionality can be found . Obviously if no-one ever reported the scheme wouldn’t work at all, but there will always be under-reporting. Doctors, pharmacists, dentists, nurses and patients all need to be encouraged to report to make the scheme continue to be useful. It’s also worth noting that it isn’t the only data regulators use to make judgements on safety.

    If you think you have a side effect, report it at the Yellow Card website, and “If in doubt, fill one out”. Pharmacists are also well placed to advise you if you have concerns about side effects, and can report on your behalf as well.

    Kind Regards

    Dr Anthony Cox, English National Board Member, Royal Pharmaceutical Society

  • I had a severe and terrifying reaction to steroids and when I discussed it with my GP he shrugged!! I almost killed myself as a result of this and the doctors didn't want to know. I wish I had known about the yellow card scheme then.

  • Yes, this is a real problem. According to the MHRA- reports from members of the public have declined from a high of 3,584 in 2006 to 1,789 in 2012. They are trying to highlight the Yellow Card Scheme: mhra.gov.uk/NewsCentre/Pres...

  • Hi Emily, as someone that has been involved in promotional videos for 35 years, that one is truly dreadful. Aside from unforgivable sound issues on the first segment, it is as boring as hell and at eleven minutes long completely useless for even pharmacists, let alone consumers. It is not surprising that it has only had 800 views since Feb 2013 on YouTube.

    This highlights a continuing problem - often companies/government/concerned bodies simply do not have the knowledge to promote properly initiatives like this, but if they go to the advertising industry (my world) for help, they get ripped off price wise or taken down an over the top creative route that is too expensive and complicated to keep going.

    To promote this idea pharmacists should be encouraged to:

    1. Put a big yellow notice on the wall behind the counter saying "Is your medicine making you feel worse? Tell us - we need to know"

    2. Put a concise, useful yellow slip into packets saying something similar and saying what the yellow card scheme is.

    3. Replace the ridiculous legal advice slip that comes with medicines with something that is written for ordinary people (and in bigger print).

    If at its height there were 3,584 reports in 2006, considering the millions of does taken in that year by millions of people, that is a very, very low figure.

  • Hi Joss

    Just came across this MHRA yellow card system video on YouTube, that's new since we last discussed the Yellow card system:

    Cheers

    Emily

  • Hi Emily - that is a lot clearer. (though it would be better if they had child actors who could speak clearly, and I hope they have done this multi-lingual)

    It doesn't say who the MHRA is, which many people won't know and that is a pity.

    The actual Yellow Card website looks quite clear and straightforward, which is good, though it is not responsive, so difficult to use on mobiles or small tablets

    The problem with anything like this is that there is rarely any unified approach. But this is a start.

  • I am currently reading "Bad Pharma" by Ben Goldacre and it covers this and related issues in a very accessible way. I would recommend it.

  • There is a GP called Malcolm Kendrick who has a fascinating website (http://drmalcolmkendrick.org/) with much very thoughtful and well researched information around drug companies, drug trials and misinformation. The latest blog entry is about the companies Takeda, and Lilly who have just been fined $9bn by the US courts for suppressing data.

    rsc.org/chemistryworld/2014...

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