Following a media feeding frenzy in the wake of an FDA Panel on SSRIs in Pregnancy – see Unsafe Safety Systems – another feeding frenzy erupted with an HHS (Health and Human Services ) statement that it was reviewing the use of Tylenol in Pregnancy and possible links to Autism.
This post engages with both of these frenzies. It is partnered with an ideally read first post on RxISK Health News Reviews SSRIs and FDA which features another post FDA’s Makary stacks the deck with conflicted expert panels.
In 2014, a well-conducted epidemiological study by Zeyan Liew and colleagues from Yale, published in JAMA Pediatrics, linked neuro-developmental delay (NDD) to the use of Tylenol, then marketed by Johnson and Johnson and now by Kenvue – a linked company.
Acetaminophen is a non-branded version of Tylenol. Both are generic and available Over-the-Counter (OTC). Both Tylenol and acetaminophen are sometimes shortened to APAP. To add to the confusion, in Europe the common name is paracetamol.
Neurodevelopment delay is how the problem should have been pitched but when the children who are affected come to clinical attention they are more likely to end up diagnosed as Attention-Deficit-Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD). Linking Tylenol to ADHD or Autism was also always more likely to capture media interest than a link to NDD.
Prior studies had pointed to a linkage but the 2014 Liew et al study turbo-charged the issue and called for a response. The slides here tell an obvious story about how companies respond in situations like this.
However much we might want to cheer a little sling-shooter, Goliath (Johnson and Johnson) and any pharmaceutical company have little option but to defend their product in the interest of their share-price and profits of more than $ 1Billion per annum, but also to mount a defense of the product in the interests of its takers, and in this case pregnant women.
As originally conceived, science moves forward when points are contested and participants in an effort to reach consensus are challenged to look closely at observable data.
In contrast slides to this characterization of science, in communications these days to their workforce, or a friendly audience, companies will inevitably say that readers have only been exposed to one take on the science. To adapt Kellyanne Conway’s immortal 2017 phrase, they are not been given our ‘alternative science’.
For companies, science is about a media battle rather than a scientific process.
Tylenol and acetaminophen are available over the counter (OTC). They constitute the most commonly taken drug in pregnancy in part because of messaging that paints them as the only safe analgesic to take in pregnancy. They were once billed as anti-inflammatory but it is now accepted they are not anti-inflammatory. They are still billed as being anti-pyretic (fever reducing) which has some truth to it but no more than cold sponging or showering.
Their analgesic credentials are under fire. In my opinion, like SSRIs, Tylenol has analgesic properties for some of us but not all of us, which means that the average analgesic finding in clinical trials may look minimal or debatable. Some of us know the drug works for us. Some know it doesn’t work of us. Should the roughly half of us who know it doesn’t work for us be told that the only thing we can take is Tylenol – acetaminophen?
Pharmaceutical companies view science as there to defend the brand. Company RCTs are designed to get a license and establish market positions – not to inform clinical practice or to help us understand ourselves or the universe. These ‘trials’ are commercial rather than scientific exercises. The ‘science’ is used in much the way it might be used in adverts for Washing Powders.
It also used in Doubt is our Product strategies along with False Balance Strategies. Doubt is our Product is well-known from company efforts to manage the debate around smoking and lung cancer.
False Balance is the mirror image of Doubt is our Product. In 2010, Brian Cox a physicist in a BBC program debunked horoscopes and complaints were lodged with the BBC. In response to the complaints Cox wrote:
“I apologise to the astrology community for not making myself clear. I should have said that this new age drivel is undermining the very fabric of our civilisation.”
Groups like Sense about Science – see multiple Sense about Science posts on DH – appear to have been set up to encourage – among other things – medical organizations and regulators to agree that once an RCT has shown a benefit and no statistically significant adverse effects that it would be False Balance to publish any Case Reports of Adverse Events on a treatment.
See War on Science and War on Civilization.
Pregnancy is fertile ground for companies. Unlike most other harms happening to us, no injury can be obviously seen happening to an infant and there may be a considerable length of time between a potentially harmful event and evidence of harmful consequences.
This opens a door for companies to claim that multiple other factors have confounded simple claims linking their drug to the problem.
It is relatively simple to fish around for confounders and with statistical sleights of hand create a statistical morass. Few doctors, female or male, or women contemplating a pregnancy will be able to tell with confidence which Cup the Coin is under and most will leave it to ‘experts’ – who in fact are no better placed to tell. The experts, and the rest of us, are more likely to figure there must be a valid point here if the article denying a link has a appeared in a ‘good’ journal – which is why companies preferentially colonize good journals rather than hide in the shadows.
Depression Rating Scales, like the Ham-D for instance, are essentially Quality of Life scales on which women who are living in poverty, isolated from a supportive network, under severe stress or otherwise disadvantaged will all have much higher ‘depression’ scores than more fortunate women – without being depressed.
Before the advent of antidepressants, depression was much less common. Women on the ‘verge of nervous breakdowns’ were viewed as anxious rather than depressed. A woman had to clearly have a severe affective disorder unlinked to social stressors to be diagnosed as depressed and the diagnosis was made by a judgement call not by rating scale. Back then, there was no evidence these untreated depressions caused neurodevelopmental delay or birth defects. But now the kitchen sink can be thrown at any claims linking an antidepressant (or Tylenol) to birth defects.
Slide
A naming names slide is not fair.
It is well known that companies have advisory boards and route their marketing through key opinion leaders (KOLs). I have been on company advisory boards. I may have been viewed as a KOL – I was certainly invited to speak at company sponsored meetings. This has left me well placed to offer a view that advisory boards with their meals in lush restaurants and stays in the best hotels are more ways to make friends for the company, profile potentially problematic folk or generally make it hard to raise concerns about company products.
Marketing departments only listen closely to one or two advisors – they don’t do things by committee.
Advisory board members and KOLs are useful links to journals and to have as authors on articles giving the impression these independent articles from authoritative figures whose (ghostwritten) views need taking seriously.
As senior figures in professional bodies, like the American College of Obstetricians or Gynecologists (ACOG) or the Society of Maternal and Fetal Medicine (SMFM), they are also well-placed to suggest a position paper on controversies – such as Tylenol or SSRI use in pregnancy. When the professional body agrees, the KOL will offer to draft one, which will be reasonable enough to be approved by a committee, especially one convened in the absence of members of the awkward squad.
Position papers or Guidance are then published and all of a sudden it will look like all 60,000 members of ACOG agree on the absolute safety of Tylenol or SSRIs in pregnancy and of course on the need to stop alarming women.
This partnership image showing the logos of organizations featuring in a company distribution channel needs no comment. Gary Schwitzer used the ACOG and SMFM logos to illustrate his Stacking the Deck post.
There are a host more logos in this slide from women’s organizations to Autism organizations (ASAN)
and other professional bodies like the American Academy of Pediatrics.
Bob Whitaker and others regularly mention the Guild interest of bodies like the American Psychiatric Association (APA) giving the impression that these bodies rather than Pharma are the dominant players when it comes to shaping healthcare. The slide above along with the one below convey the impression that these professional bodies are bit players, no more substantial than the patient bodies Pharma set up.
These final slides illustrate elements of company modus operandi. As outlined in Back to the Future of Personal Care, what we call Big Pharma is perhaps better called Big Propaganda.
Companies claim to be concerned about Science and encourage doctors (HCPs these days) and the rest of us to Follow the Science, when they mean follow our alternative science. The slide above shows that articles have been written – compendious articles with distinguished names – that will be brought along to any conversation with partners.
It would be a remarkable partner who would be able to challenge this material – even though some of these articles got rejected serially on peer review. Remarkable not because the articles are full of genuine science but because aim at confounding with statistical non-sense.
Companies have no interest to contribute genuinely to establishing facts. Their concern is to gauge how well placed they are to prevail in legal actions – taking into account their ability to hire the best lawyers and experts and abilities to scare any HCPs from daring to suggest the Emperor’s outfit might not be quite perfect.
So much are companies in control of these meetings with partners that as the Health News Review post ends by pointing out, there is almost nothing FDA can do that companies can’t turn to their advantage and our disadvantage.
Having made these points, consider this. While birth defects and neurodevelopmental delay pose challenges for professionals and the rest of us in terms of establishing a link to a treatment, as mentioned at the FDA July 21st Panel meeting, both Tylenol and SSRIs act on the serotonin system and mute sensory input. Sensory input is the major driver of brain development in utero and early infant life.
Muting sensory input is the core action these drugs have. This muting may be useful to some of us in later life. Biology is first of all about function. Neurotransmitters may play a part in delivering a function but once born we find ways to ensure we can function even when we are missing arms – if I have been damaged by thalidomide and want to play the piano I may do so with my toes.
Against this backdrop, step back from confounding and neurotransmitter biobabble for a moment and ask how much sense does it make to turn down or off the sensory input that drives brain development?
This point is not aimed at casting SSRIs or Tylenol into outer darkness. Agents that inhibit important functions in utero can often contribute in surprising ways later in life – rather like isotretinoin (Accutane), SSRIs for instance have anti-cancer properties.
The point is that this is such a dangerous thing to do, how come we end up with studies finding the obvious consequences and others claiming there is no evidence for any problems – except for valproate (which is beyond saving) which these other studies neglect to mention shares epigenomic and other effects with Tylenol.
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