Thursday, 18 May 2017

#ThinkSpeak & #PolitcalSpeak: a balancing act

Safety vs. rare, but life threatening adverse events. #ThinkSpeak #PoliticalSpeak

My oldest daughter recommended I watch the BBC Panorama programme about the HIV contamination of blood products in the 1980s. She is horrified by the Government's response to the crisis and has no doubts about who is to blame. 


It tells a harrowing story of people with haemophilia being saved but a technological advance (plasma Factor VIII concentrate) on the one hand and being exposed to, and infected by, HIV on the other hand. The story is not a simple one. It involves doctors trying to save lives, and improve the quality of life, of their patients with the latest innovations and the perceived slowness of public health officials and politicians to act on an emerging risk of HIV, and hepatitis C, from high risk blood donation practices in the USA. The documentary alludes to the dark arm of the Pharmaceutical industry who were processing, manufacturing, marketing and distributing the Factor VIII concentrate to be responsible, despite no evidence being presented to support the claim. Blaming Pharma seems to be the default position of Panorama. 

The programme raises very important issues about at what point in an emerging epidemic, AIDS in  people with haemophilia in the USA, do public health officials and doctors act? Scotland responded quicker than England and hence the rate of HIV infection in people with haemophilia in Scotland was half that of England. England is larger than Scotland and it was suggested that they couldn't respond as quickly because of a much greater demand and relatively lower supply of plasma donors in England. 

The story is relevant to MS. When PML emerged as a risk factor for pwMS on natalizumab treatment, Biogen withdrew natalizumab from the market and did a risk assessment. Biogen then relaunched natalizumab with a 'black box' warning and regulators restricted natalizumab to a group of pwMS with very active disease (rapidly evolving severe). Despite the risks neurologists and pwMS continued to use natalizumab with a resulting epidemic of PML that as of the 1st December 2016 there have been 698 confirmed cases of PML (695 with MS and 3 with Chron's disease) with 161 deaths. Who is responsible for these deaths; Biogen for relaunching natalizumab, regulators for allowing natalizumab back on the market, neurologists for prescribing it or patients for choosing natalizumab over other, albeit limited, options? In my opinion no one is to blame. The relaunch of natalizumab allowed people with very active, and disabling MS, to be treated,  the risk of PML to be better defined and for natalizumab to be derisked. In 2017 there should be very few new cases of natalizumab-associated PML. From a public health perspective the above process saved natalizumab for future generations of pwMS. The sad side of the story is that over 160 people had to die for us to get to where we are today. In the case of the haemophilia-HIV story lessons were learnt and heat-inactivation was rapidly shown to destroy the HIV virus rendering the Factor VIII concentrate safe from HIV. Plasma derived Factor VIII has subsequently been superseded by the development of recombinant factor VIII. 

Are there lessons to be learnt? Yes, transparency and honesty is needed. The Government was not, and subsequently has not been, transparent in relation to haemophilia-HIV epidemic. May be someone in the Department of Health should study the natalizumab-PML story as a case study on how to manage an emerging healthcare crisis. 


We will almost certainly have other crises like this going forward. In the MS space we don't really know what the risk of secondary malignancies is from the various licensed, or to be licensed, MS DMTs. What will happen if in the future a well-defined cancer risk emerges with one of the MS DMTs? Who will be to blame? Sometimes risks only become clear with time and provided we all admit that the risk can't be defined at present and we make sure that all parties are aware of this and then we collect the data and act on it in a timely fashion no one will be blamed and everyone will benefit. 

I have been hypercritical of Genzyme and the emerging Listeriosis crisis with alemtuzumab for similar reasons. It is clear that Listeriosis is a problem with alemtuzumab. However, we have been kept in the dark about the number of cases and the mortality associated with Listeria infection in alemtuzumab-treated patients. The only reference to the number of cases is in the small print of a poster at the AAN that stated the incidence of Listeria to be 0.26%. What we don't know is how many cases have there been and what is the mortality of alemtuzumab-associated Listeriosis. How many cases had Listeria meningitis and how many systemic Listeriosis? If only Genzyme could learn from Biogen's experience we would all be in a better place. Genzyme have no idea how difficult they are making if for neurologists on the coalface. What do we tell our patients? Wouldn't it be better if we had hard facts? I would urge Genzyme executives to watch 'Contaminated Blood' and imagine themselves as a patient with MS trying to weigh-up the risks and benefits of the various treatments on offer. Genzyme should also be leading on derisking alemtuzumab. Listeria infection, like PML with natalizumab, is preventable. 


BBC Panorama. Contaminated Blood: The Search for the Truth. First shown: 10 May 2017

It has been called the worst treatment disaster in the history of the NHS. More than 2,000 people died and thousands more were infected with HIV and Hepatitis C after being treated with contaminated blood products. All the victims were infected over 25 years ago, but even now new cases are still being diagnosed. Survivors and their families are trying once more to persuade the government to hold a UK public inquiry.

Panorama examines recently released documents, and asks if the government could have done more to save lives. The film hears the heartbreaking testimony of some of the victims and their families and explores the dilemmas of doctors who had to carry on treating their patients through the unfolding crisis.

13 comments:

  1. Prof G the poster estimates the cytomegalovirus infection rate of 0.13%. What does this mean?

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  2. Panorama are all aware of the MS drugs and whos died on them all and whats really going on in MS in the UK .

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    1. Unfortunately, the BBC likes a story. We approached them about making a documentary about high-cost drugs in MS and the global unmet need, but as they had the HSCT programme on the slate they said no.

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    2. Careful Gavin, you're feeding the tr** ;-)

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  3. "In 2017 there should be very few new cases of natalizumab-associated PML."

    Up to March 6, there have been 16 new PML cases. The rate has fallen, but not considerably.
    Source: chefarztfrau.de

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    1. I agree 16 is too high. We have some patients who are JCV+ve who want to remain on natalizumab despite the risks. We are trying to get them off natalizumab; some are saying yes now that we have daclizumab available. I suspect most will switch once ocrelizumab becomes available.

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  4. This sounds like as good an argument as any for a pharmacovigilance register. Any thoughts?

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  5. "We will almost certainly have other crises like this going forward. In the MS space we don't really know what the risk of secondary malignancies is from the various licensed, or to be licensed, MS DMTs. What will happen if in the future a well-defined cancer risk emerges with one of the MS DMTs? Who will be to blame? Sometimes risks only become clear with time and provided we all admit that the risk can't be defined at present and we make sure that all parties are aware of this and then we collect the data and act on it in a timely fashion no one will be blamed and everyone will benefit."

    What a funny question – who is to blame?

    “Sometimes risks only become clear with time” – if the pharma and the neurological community knew that tysabri and gilenya work by preventing cells from entering the CNS, then why was it not reasonably foreseeable that stopping treatment could lead to rebound?

    And if we agree that there was no way to foresee rebound before withdrawal of Tysabri from the market, then why did we not foresee the same when we stop gilenya?

    It’s easy to blame the pharma for this. Why would the pharma want to focus on stopping treatment – it is far more in its interest to ignore cessation of treatment and convince prescribers (neuros) that the treatment shouldn’t be stopped (do you know how times I’ve heard the question “WHY would you want to stop tysabri”).

    Who is to blame?

    From my point of view, pharma is to blame yes, but so are the prescribes – neuros as a community - should have done a bit more critical thinking to protect their patients. Neuros are supposed to be critical thinkers, not regurgitators of pharma spin.

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    1. RE: "...but so are the prescribers – neuros as a community ...."

      Is this a criticism levelled at us? A few of us in the community predicted PML and rebound; it was based on scientific principles of how natalizumab worked.

      Some of us are also predicting a secondary malignancy risk; it is based on the mode of action of the DMTs. Almost all immunosuppressive therapies, particularly continuous immunosuppression, are associated with a secondary malignancy risk. The risk is proportional the intensity and duration of immunosuppression and co-factor such as excessive UV-light exposure in the case of skin cancer.

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    2. It is a criticism aimed at the neurological community in general, not Barts or its practitioners in particular.

      Based on what I see (as a non patient), I would exempt Barts practitioners from that criticism, as I would 2 Australian neuros I know.

      But you and them are far in between.

      I agree that you as an individual cannot possibly be doing more than you are and are doing far more than most.

      Your colleagues read this too, as you mention from time to time.

      With so many DMTs around for a chronic condition, why on earth would a clinician who treats people be asking "Why" would someone want to come off tysabri (etc). They should have been asking how patients would come off tysabri (etc) - they should have been asking this from the moment they started infusing patients with it.

      I hold the same view about anti depressants.

      We rely on clinicians to be our mouth pieces in the political games with powers to be, such as the government and the pharma. But I often feel clinicians let us down in that respect and dispense the official line rather than help me critically interpret it.

      I don't have ms personally.

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    3. As a patient I disagree with you Anonymous.

      Sure our neurologists and pharma have responsibility to inform us of the risks. But I know as a patient that that there are risks and I gladly choose to take them over brain damage. I very happily take reducing brain damage in return for theoretical cancer risk and I am comfortable with the known risks. Personally I would rather a short life with more quality. I think all of us know that there are unknown risk. Each patient has a different risk tolerance and I know more than one person who has chosen the safest option (partly because of the history). One of those people though has progressed rapidly and is now choosing a much much more aggressive DMT option because the reality of degeneration has hit hard.

      Each patient also has a different level interest in looking at all the issues critically. Many very much want their neurologist to just tell them what to do. I happen to run a support group and this was a surprise to me because I'm the polar opposite (hence my reading this blog). While not all neurologists are great neurologists I do believe that the vast majority of them really do have their patients best interest at heart. As well as wanting to guide our own decisions most of us as patients also make no attempt to have a political voice. Our lack of voice is more our fault than anyone's. I don't think most (if any) neurologists or researchers got into this because they were remotely interested in the politics of it, so we can't exactly hold them to account for not being great at it. I personally thank them for the work that they do on this front.

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  6. What will happen if in the future a well-defined cancer risk emerges with one of the MS DMTs?
    Heh. While seeking opinions on HSCT, neuros were so wanting to talk my partner out of HSCT that they presented DMTs as safe in terms of future malignancies (with the exception of Lemtrada), while they talked up the safety of DMTs. As my partner has a breast cancer history, she was concerned – one esteemed neuro even tried to tell her that tysabri is safe and unlikely to lead to future malignancies, whereas hsct reconstitutes the nervous system and could cause her breast cancer to come back (her oncologist, breast cancer surgeon and heamo all disagreed with that ‘opinion’).

    If there is a future malignancy risk associated with DMTS you can see where my blame would lie. Not because neuros are responsible for the risk – but because they are giving advice that something is safe far too easily. Not all neuros, not even all your neuro friends, actually give the advice that risk associated with the the long term use of DMTs, including malignancy risk, is not really known because we haven’t been using the drug long enough.

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  7. Genzyme have no idea how difficult they are making if for neurologists on the coalface. What do we tell our patients? Wouldn't it be better if we had hard facts?”

    Genzyme is a regulated capitalist market player with a lot of power.

    You are supposed to protect MS patients.

    Why not talk to oncologists who have been using the drug for far longer than neuros: they might be able to give you some help?

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