Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Author Archive for David Healy

File under Phile: Anecdotes are not Science

civil_2830627b

Editorial Note: The Post-Truth Rumorology post attracted a comment by Annie that deserves featuring.

She cites a really good Daily Mail article in which Melinda Messenger talks about intervening when her daughter is scheduled to have the HPV vaccine. The DM article drew this response from Dr. David Robert Grimes – a physicist at the University of Oxford – “Mothers should listen to the experts”.

Grimes: Mothers should listen to the experts not Dr Google

Cervical cancer is one of the few cancers we can prevent, which is why this vaccination program is so important and why all parents should ensure their daughters receive this potentially life-saving inoculation, writes Dr Robert Grimes, Science Writer and Cancer Researcher at the University of Oxford.

Gardasil, the form of the vaccine currently used in the UK, has been extensively tested for years and recipients constantly monitored for potential adverse effects.

More than 200 million doses have been administered over the past ten years, with research and trials dating back to 1991. The vaccine has proved to be a safe and effective intervention with an extremely low complication rate.

Only last year, a report based on data from more than a million recipients concluded the vaccine had a ‘favourable safety profile’. But still claims of ‘vaccine damage’ continue to circulate online, to be stumbled upon by the many who daily consult Dr Google, instead of turning to highly trained health professionals for advice.

Much of it comes from anti-vaccine campaigners, not content with the damage already done by the discredited, downright dangerous claims linking the MMR vaccine to autism. Among the groundless assertions are that the HPV vaccine causes thrombosis and chronic fatigue.

I cannot blame anyone whose child becomes ill or permanently exhausted for searching for an explanation and cause.

However, if you are giving a medical intervention to everyone at a certain age, as in this case, it is a medical certainty that some people get sick in the days, weeks or months afterwards. It would, of course, have happened whether or not they had received the treatment. It is merely coincidence.

Perhaps another issue with the vaccine, for some parents at least, is having to face up to the fact that their children will likely become sexually active in the not-too- distant future.

But, although pretty natural, such squeamishness doesn’t give you the right to deny your child, or the people they may become intimate with, the protection provided by this vaccine.

This most recent scaremongering, from the American College of Paediatricians concerning a risk of premature menopause, is equally without merit.

This is not some august medical body (in fact, that’s the American Academy of Paediatricians), but rather a group of conservative activists opposed to abortion rights, gay marriage and pre-marital sex.

Their claim is motivated more by ideology than by any evidence, and is simply not supported by the overwhelming weight of scientific evidence. There is no link between the HPV virus and premature ovarian failure, so it makes no sense to suggest that the vaccine may cause this condition.

Yet still, there have been a number of legal challenges mounted against the manufacturers of Gardasil, supported by the ‘Regret’ group in Ireland.

The case made it all the way to the Irish High Court, and although it was refused, the movement shows no signs of abating.

We need only cast our minds back to the damage done by scare stories about the MMR vaccine to be reminded how dangerous this can be.

Those who are not vaccinated against the HPV will have a much higher risk of contracting cancer than they would have of becoming ill as a result of having the jab, so, from a parenting perspective, it’s a no-brainer.

What we must avoid at all costs are these tales of personal misfortune, which are ultimately unrelated to the vaccine, getting in the way of an inoculation programme that could save many thousands of lives.

Editorial Note: Dr Grimes is not a doctor. He is closely linked to Sense about Science for whom vaccinations can do no harm.

Twittersphere

Annie also picked out some DRG Tweets. In response to Caron Ryalls

(a) No idea who you or your daughter are (b) Going to go out on a limb & say no medical records say HPV vaccine caused ill health

Caron Ryalls‏@caronryalls

U publicly claim my daughter’s ill health is unrelated 2 HPVvax but U hv no access 2 her medical records @drg1985!

Linked to the Daily Mail article: David Robert Grimes ‏@drg1985

The @DailyMailUK just ran page 3 model’s fears over HPV vaccine. Utter drivel. I was quoted in reply, w/ name mangled. Not linking.

..it’s utterly irresponsible of @DailyMailUK to run this crap, especially as I clearly stressed dangers of false balance to DM reporter.

And the sad thing is, the ramblings of a celebrity will garner far more press and panic than me or any scientist. Do better, @DailyMailUK

..it’s precisely this kind of thing that makes scientists weary about talking to the press; science is an afterthought. @DailyMailUK

Age of consent

The Messenger article was well done. Neither Motivation nor Expertise are always right, we ideally need both. But if forced to choose between them, and in particular when motivation is linked to a mother looking after her children, in our current post-truth world of which pharmaceutical companies are the masters – as Study 329 demonstrates, I personally would lean toward motivation.

What was a surprise for me in the article was that while Messenger was sent a consent form by her daughter’s school and made it clear she did not consent, on the day the vaccinators are there if a 12 or 13 girl consents the vaccinators can over-ride a parent’s objections.

The Victoria Derbyshire show last week also featured a pre-teen who figured they were in a mis-sexed body. They were looking forward to being 13 when they could essentially demand the alt-hormones.

But if a teenage girl walks into a beautician in Britain and wants her ears pierced, unless she is 16 nowhere will do it without parental consent, and in Scotland it would be illegal.

“Anecdotes are not science”

A common theme in comments like DRG’s is that anecdotes are not data or science.

The original phrase was the Plural of Anecdotes is Data. This was coined in 1969 by Raymond Wolfinger. It is at the heart of the Big Data industries. If this weren’t true Google and Facebook wouldn’t exist.

The idea that the Plural of Anecdotes is not Data appears to originate from the CEO of Nutrasweet after his company’s product became embroiled in a cancer scare. It has been the mantra of corporations defending products ever since. (Please let us know if you can find earlier uses).

The response “Anecdotes are not Science” to claims of harms came into existence earlier. It was being widely used by spokesmen for the Pedophile Information Exchange during the 1970s when they infiltrated the Gay Liberation Front and Britain’s National Council of Civil Liberties. The NCCL was then steered by figures like Patricia Hewitt and Harriet Harman, who feature in the photo above. Hewitt and Harman were later among the leadership of the Blair Government.

Statements that we haven’t proven harm to children offered the press a shooting-fish-in-a-barrel opportunity to go after the Loony Left.

The PIE also showed a mastery of the ability to split hairs and other tricks that are now part of the corporate armory – No pedophile ever harmed a child, they were busy telling us in the 1970s – it’s child-molesters that do things like that.

The upshot was caught in this constructed photo of Patricia Hewitt – a decent woman as far as I know – who probably never actually said this.  But she ended up years later being portrayed as taking the same position that all politicians on the Left or the Right take in response to drug induced injuries and occupational injuries or environmental toxicity – we can’t or haven’t proven harm.  In most of these cases, like environmental toxicities and drug induced injuries, it turns out the harms to children are even greater than to anyone else.

The Vaccine arguments portray children’s immune and other systems as still developing suggesting they are more able to overcome these challenges than older people.  This is Anecdotal.

10441006_10152768177769339_1532353414993405496_n

 

Post-Truth Rumorology?

The HPV Vaccination in Japan

Stopping the spread of Japan’s antivaccine panic

Following the post last week on MedWatcher Japan’s efforts to bring the issue of HPV vaccines to light, my attention was drawn to a recent Wall Street Journal article which stated:

“Japanese women’s health is increasingly at risk as public-health policy is driven by conspiracy theories, misguided political interference and bureaucratic caution. This is particularly evident in the government’s handling of the human papillomavirus (HPV) vaccine to protect against cervical cancer.

In June 2013, just two months after the HPV vaccine was included in the National Immunization Program, the Japanese government made the unusual and perplexing decision to keep the vaccine in the NIP but suspend “proactive” recommendations for it. This was evidently in response to highly publicized accounts of alleged adverse reactions.

The result was that girls in the target age group, from the 6th grade of primary school to the third grade of high school, stopped receiving the vaccine. Vaccination rates dropped to below 1% from about 70%….

The Vaccine Adverse Reactions Review Committee, a task force established by the Japanese Ministry of Health, Labor, and Welfare’s Health Science Council, has repeatedly concluded that no causal link exists between HPV vaccines and professed symptoms, and that most reported cases were likely psychosomatic. A study of 70,960 vaccinated and nonvaccinated adolescent girls from Nagoya also found no significant association between 24 alleged vaccine-induced symptoms and the HPV vaccines….

In Denmark, Kusuki Nishioka, the Japanese doctor who first suggested the HPV vaccine caused brain injuries, appeared on television. The vaccination rate there has since dropped to about 20% from 80%.

The antivaccination movement is gaining traction in Japan. On July 27, 63 young women filed lawsuits against the Japanese government and vaccine manufacturers in the district courts of Tokyo, Nagoya, Osaka and Fukuoka, demanding compensation for alleged side effects from HPV vaccines….

These events are reminiscent of the biggest vaccine scandal in history. In 1998, Andrew Wakefield published “scientific data” in the Lancet as evidence that the MMR vaccine for measles, mumps and rubella caused autism.

Mr. Wakefield’s data was later found to be manipulated, but it was not until 2010 that his paper was retracted and his medical license revoked. Earlier this year, Mr. Wakefield released a movie called “Vaxxed: From Cover-Up to Catastrophe.” Robert De Niro, whose son is autistic, tried to premiere this movie at the Tribeca Film Festival. This once again fueled antivaccine sentiment in the U.S.

We can’t afford to sit back and allow a similar situation to develop in which unscientific claims jeopardize lives around the world. The Japanese government should reinstate its proactive recommendation for the HPV vaccine and set a positive example before irrational fear of the vaccine gains further momentum in other countries”.

The vaccine business

Once upon a time it was public health doctors who decided what vaccines became part of national vaccination schedules. In Japan and elsewhere the introduction of HPV vaccines to the vaccination program was engineered by the makers of vaccines. Vaccination is a business as much as or even rather than a matter of public health. See HERE.

When concerns appeared in Japan and the government suspended the heavy promotion of the vaccine it triggered an international response with the Center for Strategic International Studies, a body set up in the Cold War “dedicated to finding ways to sustain American prominence and prosperity as a force for good in the world”, publishing a report on HPV Vaccination in Japan authored by Heidi Larson and others. HL and colleagues are based in the London School of Hygiene and Tropical Medicine, one of the institutions that spawned AllTrials – somewhere with close links to Sense about Science.

You’d never guess from this document that the HPV vaccine was adopted in most countries after intense corporate lobbying. Instead, we are told:

According to experts in rumor psychology, rumors help people make sense of the world and offer an initial explanation for anxiety-provoking information and events. The longer situations of uncertainty and anxiety persist, the easier it becomes for rumors to spread and the more difficult they become to counteract.

Governments need to get in there, we are told, and be the first to provide information; they need to tell people we feel your pain; when people raise concerns they need to be encouraged to “talk to your doctor”, (who of course has been briefed by our side only). Governments are told they need to avoid a vacuum that might be filled by “people who don’t have the public’s best interest at heart”. They need to be on board with Project Fear.

HPV or not HPV that is the question

In Europe, especially in Denmark, there has been work in parallel to the MedWatcher Japan efforts, undertaken by Peter Gotzsche and Tom Jefferson who have filed a complaint with the European Ombudsman centered on maladministration by the European Medicines Agency of the safety data for HPV aimed at getting access to the data. See HERE. Preliminary work on this material had shown real cause for concern – see Jefferson.

In response to the Wall Street Journal’s article above, Peter Gotzsche said:

Tom and a PHD student I employed two months ago are working with CRFs from the EMA on the HPV vaccines. To say that “most reported cases were likely psychosomatic” is an insult to these girls and their families. There are good data that make is pretty likely that most suffer from an autoimmune disease with antibodies against nerve tissue, but whether caused by the vaccine, a virus or something else needs to be found out.

We had a meeting about HPV vaccines on 24 Nov in Copenhagen. One of the presenters showed a slide that in Denmark, provided 100% of 12 year old girls get vaccinated, and that the vaccine is 70% effective, and protects against dying from cancer (which we don’t know but just think), then in the next 30 years, 10 will die if not vaccinated and 7 if vaccinated. Thus, even in the best of scenarios, the effect of the vaccine is likely to be very very small”.

What Gotzsche hasn’t said here is that company marketing of these vaccines has been full of rumors and scaremongering, portraying the vaccine as the last defense against a nasty and aggressive cancer, a defense that is close to completely successful and comes without problems.

In fact Pap Smears manage the problems very successfully, just as hand washing is our best defense against many other infections and both defenses come without a risk of neuropsychiatric adverse events. But we hear nothing about these approaches.

It’s not impossible that some of the Japanese cases are hysterical. The bigger problem we all have is that in the wake of the revelations about Tamiflu and Study 329 it is impossible to accept the bona fides of companies whose health depends on ensuring we get their treatments rather than rely on something else that is safer and costs almost nothing.

There is a certain sense in which the forces that fueled Brexit are fueling a Vaccinexit. If this happens the powers that be will have no one to blame but themselves. Peter Gotzsche and Tom Jefferson knew nothing about MedWatcher Japan before the post last week. The more people like this find each other, the more difficult it will be for the Heidi Larson’s of this world to manage the debate.

When the going gets tough, get a woman

hpv1

64 women to sue in 3 Japanese courts over health woes from cervical cancer vaccines

A group of lawyers for 64 women who are suffering health problems from cervical cancer vaccines said Tuesday the victims will file damages lawsuits against the government and two drug makers that produced the vaccines through four district courts on July 27.

Of the 64 women, 28 will lodge their suit with the Tokyo District Court, six with the Nagoya District Court, 16 with the Osaka District Court and 14 with the Fukuoka District Court, according to the lawyers.

Initially, the victims, mainly teenagers, will demand ¥15 million in damages each, for a total of ¥960 million, and increase the amount later depending on their symptoms. The victims’ health problems include pain all over the body.

The average age of the 28 planning to file their suit with the Tokyo court is 18. They received the vaccination when they were between 11 and 16 years old.

Noting that the cervical cancer vaccines have caused nerve disorders and other problems due to the excessive immune reactions they caused, the lawyers claimed that the government’s approval of the ineffective vaccines was illegal. The drug makers bear product liability, they added.

Masumi Minaguchi, one of the lawyers, said, “We aim to clarify the responsibilities of the government and the drug makers through the lawsuits so that the victims can live without anxiety:’

Cervical cancer vaccines were included in routine vaccination programs in April 2013. But the government stopped its recommendations for the use of the vaccines in June the same year after receiving reports on complaints of health damage.

Meanwhile, the Japan Pediatric Society and 16 other institutions in April recommended active use of the vaccines, saying it is clear they are effective in preventing cervical cancer.

mm2

The organization behind this action is MedWatcher Japan, who have been one of the most effective organizations in the world at holding Pharma to account. Two of their key players Masumi Minaguchi and Hiro Bepu are seen here. Masumi Minaguchi is the lawyer taking this case.

In this case MedWatcher have capitalized on the fact the HPV Vaccine is given primarily to girls and women who are old enough to be able to complain when things go wrong afterwards.

The science behind the MedWatcher case is presented in their refutation of the Global Advisory Committee on Vaccine Safety position which can be accessed HERE.

The HPV vaccines look like being a problem for vaccine advocates in that they puncture the claim that vaccines are safe and the only risks stem from not giving them.

Earlier this year Merck admitted their Shingles vaccine could cause eye damage. Again the difference is that the people suffering the harm are old enough to make their voices heard.

The response from vaccine advocates in the case of HPV vaccines has been to push for giving these vaccines in infancy.

Vaccines are a conundrum. They can clearly be effective and most of us would want to avail of most of them. But where elsewhere in medicine, it is legitimate to be against over-medicalization, being against over-vaccination puts anyone who advocates it beyond the pale.

Why?

Go Figure: Where Does All the Pain Come From?

opioid_wordcloud16679096_m

Editorial Note: This anonymous comment featured toward the end of the Murder or Accident post. It seemed worth transforming into a post in its own right. In the week of the US vote, a key question facing voters is where does all the pain come from.

A colleague and I gave a talk to family docs this year and we discussed the opioid epidemic, including the 1% risk of addiction myth in Letters to the Editor at NEJM. One Key Opinion Leader (KOL) is now acknowledging that he may have overstated the safety of opioids but maintains that they still have a role in chronic pain, see Dr Russell Portenoy here: http://www.wsj.com/articles/SB10001424127887324478304578173342657044604

He strikes a controversial chord with others involved in treating the outcomes of chronic pain killer addictions, like Dr A. Kolodny, see here: http://www.medpagetoday.com/painmanagement/painmanagement/47855

Other KOLs like Dr Jane Ballantyne, have made 180 degree turns regarding opioid use in chronic pain, this article is well worth the read: http://www.nytimes.com/2012/04/09/health/opioid-painkiller-prescriptions-pose-danger-without-oversight.html?_r=0

Challenging myths that have so much resources poured into them to maintain is very difficult. We were all taught that pain was the “fifth vital sign” by the American Pain Society (around the same time OxyContin approval occurred). You can see the sordid history, including how patient satisfaction scores may have a role in this epidemic, here: http://www.kevinmd.com/blog/2016/04/the-opioid-epidemic-its-time-to-place-blame-where-it-belongs.html

The US Docs probably had some scare put into them by the successful legal case brought against a doctor (Dr Chin) in 1998 who was charged for not treating pain adequately. Incidentally, this was the same time as the heavy marketing machine was revving up for Purdue. http://articles.latimes.com/2001/jun/15/news/mn-10726

The appalling story about Purdue/Abbott’s role in this public health disaster is outlined nicely here:

https://www.statnews.com/2016/09/22/abbott-oxycontin-crusade/

There has been very vocal opposition from pain advocacy groups and physicians when British Columbia adopted the March 2016 CDC pain guidelines that discuss opioids and state they are not effective and should not be used for chronic pain and that doses should not exceed 50 mg equivalents of morphine.

Pain BC is encouraging patients who have been affected by these new regulations to complain to the College! https://www.painbc.ca/news/howdothesenewopioidguidelinesaffectyou. Nothing strikes fear into physicians quite like a good old College complaint!

Although the evidence of harm is abundantly clearly (lack of efficacy in chronic pain, massive overdose deaths, lives in ruin, 80% of heroin users report starting drug use with physician prescriptions), both people and doctors choose to ignore this and some doctors fear College investigators. Sounds a lot like Dr Chin all over again…

Big Pharma’s influence in Canada continues. See here for Purdue’s lobbying of the Federal Government: http://canadians.org/blog/who-behind-canadas-opioid-epidemic. A coalition of chronic pain and addiction specialists signed a letter earlier this year, requesting that Federal Health Minister Philpott consider making oxycodone only available as a tamper resistant formulation (of which Purdue holds the patent). Sixty percent of the signatories have ties to industry. http://www.theglobeandmail.com/news/national/ottawa-urged-to-reconsider-tamper-resistant-oxycodone/article29813367/?utm_source=twitter.com&utm_medium=Referrer:+Social+Network+/+Media&utm_campaign=Shared+Web+Article+Links

Dr David Juurlink may have said it best in the Globe and Mail piece referenced above:

“It’s time we stopped listening to pain specialists. Their messages, which were wrong, got us into this mess in the first place,” “Many of these physicians are deeply in the pockets of the companies that make opioids and that stand to profit immensely from the sale of these new products.”

Ontario released a new “Strategy to Prevent Opioid Addiction and Overdose” on October 12, 2016. This milquetoast framework to our public health crisis makes several vague recommendations, one of which is to make more substitution therapy available, specifically access to buprenorphine/naloxone (Suboxone). The document fails to provide suggestions for how to carry this out nor does it make mention of the potential public health risks. Studies have shown that Suboxone is ten times more likely to be diverted than methadone (i.e. not taken by the intended person and diverted to illicit market). We may want to ask Finland for some advice (buprenorphine, has been at the top of drugs misused in that country): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154701/

The provision of methadone (the other substitution treatment available) in the province received well-deserved criticism from the “Methadone Treatment and Services Advisory Committee”. http://health.gov.on.ca/en/public/programs/drugs/ons/docs/methadone_advisory_committee_report.pdf. Page 11 details some of the most egregious concerns:

 Lack of access to comprehensive care in stand-alone fee for service clinics: Many of these clinics provide little more than urine drug screening and methadone prescribing and dispensing, leaving patients without access to primary care, mental health and addiction screening, brief intervention or counselling, and management of acute and chronic illnesses. Variation in the quality of clinical services: Some clinics require frequent attendance for urine drug screening and a brief office visit regardless of the state of recovery demonstrated by the patient. This is wasteful and can be harmful to patients’ recovery as attendance can be inconvenient and at times very challenging, particularly for those in rural and geographically isolated areas.”

Profit driven care has clearly moved the patient far way from being in the centre.
Some are sounding the clarion call of “another epidemic” happening where over 50,000 patients in Ontario are now on methadone https://substanceabusepolicy.biomedcentral.com/articles/10.1186/s13011-016-0055-4

Perhaps the most astonishing elephant in the room is “why are so many people in pain?” As a society we must look at the root drivers of this epidemic and that must also focus on prevention. We need to do some serious soul searching as a nation, as a community of peoples. We will need to address poverty, hopelessness, dislocation, safe housing, disintegration of community, lack of meaningful employment, adverse childhood experiences, resiliency, etc. if we have any hope of bringing this epidemic under control.

Comment

The links above are chilling. The video clip of Russell Pourtenoy is beyond belief.

It raises the question as to whether there is a growing amount of pain in the world as this US election suggests. The alternative is that doctors been adding to whatever pain and anxiety there is and to other dis-ease. While opioids and other pain-killers can give wonderful relief when given short term, as can benzodiazepines for anxiety, there is good evidence that given chronically opioids and benzos increase the amount of pain and anxiety we have – by altering physiological thresholds in the wrong direction.

Old style doctors, professionals, knew this. New style technocrats – we have the technology to fix your pain and anxiety – don’t know it.

It was and is an important part of caring for you to know the limits to what we can offer. But we now live in a world where choices like opioids are put on plate in front of you and your doctor and you are invited to choose. The right choice will supposedly deliver the jackpot – this is what marketing promises.

But somehow wisdom is never on the list of options – it can’t be – it’s not evidence based. It would be irrational to let you choose something that is not evidence based – like less medication or vaccines. That’s not a free choice.

Study 329 Trick, Treat or Treximet

treximet-wsj

The plan this morning was to continue coverage of the Opioid Epidemic but perhaps because it is Halloween a link to a Wall Street Journal story on how Drug Makers Turn Cheap Generics into Expensive Pills arrived by email. It was difficult to resist. Here’s why.

The article features Treximet, a combination of sumatriptan and naproxen, used for migraine. These two drugs are ancient. They come from the last millenium and should cost almost nothing. But Treximet is retailing at $750 for 9 pills. The two drugs as separate ingredients can be bought separately for next to nothing.

This hike in price is heading toward the 5000% hike in price Martin Shkrelli hit the headlines for when he jacked up the price of Daraprim a year ago. This was noted at the start of a series of posts on Pharmaceutical Rape by Laurie Oakley.

Pernication

Behind Treximet lies trials comparing the combination to sumatriptan alone and to naproxyn alone and to placebo showing some benefit it seems – if these trials can be believed. The trials were run by GlaxoSmithKline, for whom sumatriptan had been a flagship drug for decades, and Pozen Inc. Once concluded, in 2014 GSK transferred the rights to Pernix.

This smelt fishy to RxISK’s super-sleuth Johanna Ryan. What’s going on here? In related posts she also fingered the weight loss med Qsymia as egregious and both as indicators of something new this way coming and Qsymia features in the WSJ article also along with Duexis for pain, as price gougers extraordinaire. The new development seems to find new painkillers and new weight loss meds fertile ground. Regulators seem all too happy to license ever more dangerous variations or combinations of older drugs in these groups already on the market and causing serious problems.

This willingness has offered an opening for financial speculators to make a killing speculating on the likely profits these drugs could yield and getting out of the game before much happens. Pernix may be primarily an umbrella for some smart speculation of this sort. It certainly doesn’t look like a pharmaceutical company or anything to do with the actual delivery of healthcare.

Martin Shkrelli has since made it clear he’s been taking Efexor, and it made him feel so good, “invincible”, that he figured people will be more than willing to pay pretty well any price for these wonders of modern science.

Begs the question as to what the regulators in FDA are taking.

It’s more complex with Andrew Witty. You’d have to think GSK didn’t run the trials of Treximet just to hand it over to Pernix, no strings attached. What is the business model here. Is it Rape or is it Pernication? What drug do I have to be taking to make it work?

Mi Grain and Your Grain

When trying to get Study 329 published, we ran up against Liz Loder in the BMJ. She seemed completely resistant, stating on many occasions that we were biased – had conflicting interests. The article only got published after a conflict of interest duel. We wrote to the editor, Fiona Godlee, laying out Dr Loder’s possible conflicts. BMJ have never offered a satisfactory response to this letter.

The main conflict lay in Dr Loder’s husband working for a law firm, Ropes and Gray, who have worked on most of GSK’s recent difficulties including in relation to Study 329.

But in addition we pointed out that:

Dr Loder has made public statements favourable to GSK products, including: ‘For all of these reasons my mantra is that “You haven’t failed sumatriptan until you have failed to respond to a full dose of injectable sumatriptan given early in an attack!” There is also evidence that combining a triptan with an anti-inflammatory drug might improve the likelihood it will be effective’.

(http://live.washingtonpost.com/how-serious-are-migraines.html)

This article was published just before GSK’s Treximet (combination triptan and antiinflammatory) came on to the market – years after Dr Loder was supposed to have renounced all links to companies and their marketing.

bn-qn450_cdrug_m_20161030123816

Trick or Treat or Treximet?

Go Figure: Murder or Accident?

Harold Shipman

Harold Shipman was a doctor in Britain, who was arrested for murder in 1998. He turned out to be a true Angel of Death, the most prolific known serial killer, who killed it is thought between two and three hundred of his patients by prescribing opioids in large doses.

After his trial and conviction and jailing, he committed suicide in jail with no-one any the wiser as to why he had behaved the way he did.

His killing spree led to a change in medicine’s regulatory apparatus, ostensibly to ensure this couldn’t happen again. Boxes were put in place, and mandatory courses on a range of issues from consent to continuing education. All of this takes time away from seeing people. But if Shipman’s case held any lesson it is that he was assiduous at ticking the boxes that registration bodies like the General Medical Council in Britain put in place. The system probably makes a future Shipman more rather than less likely.

Short of doctors who have been struck off for proven cases of negligent care or abuse of patients, we might all on average be safer with doctors the regulator is having problems with, who for the most part are more keen on seeing patients than spending time ticking boxes, rather than with the doctors who are in good standing with the regulator. But what can the system do? We, the public, won’t let it do nothing.

Opioid

While Shipman’s killing spree with opiods was unfolding, North America was sinking into a prescribed opioid epidemic that now accounts for 100 deaths per day, over 30,000 per year, over half a million since the epidemic began, perhaps the single greatest cause of death in America today.

The way in to the epidemic was laid during the 1980s with the marketing of Oxycontin by Purdue Pharma, supported by Abbott, and later Janssen pushing Fentanyl. There was an astute marketing of an idea – that people with real pain do not become addicted to opioids – a myth equivalent to the myth of lowered serotonin in depression. This was allied to new standards of care for pain management which hinged on RCTs, all of which demonstrated that opioids were effective – again exactly the same dynamic exploited by companies marketing SSRIs. The result was mass prescription of opioids by doctors, many whom felt trapped between clinical wisdom and the risk of being sued. But clinical wisdom never makes it into guidelines or standards of care, and since standards of care emerged in the 1980s managers sack doctors who don’t stick to the guidelines – or refer them to their registration body.

Prescription-only status is another part of the regulatory apparatus. It was introduced in America in 1914 in response to escalating concerns about one of the first opioids – heroin.

Purdue’s marketing of Oxycontin exploited this deftly. Companies and doctors were in the clear provided all prescriptions were for physical conditions causing pain. Patients and doctors on cue, to a background tune being piped by Purdue and Janssen, engaged in a dance about the management of pain. There were no problems for doctors prescribing for pain but if they had been prescribing the same drugs for addiction they would have been struck off.

Faced with the horrific consequences of this dance, FDA intervened in extraordinary fashion two years ago. In 2014, a century after the introduction of prescription-only status, FDA made a potent opioid, naloxone, available over the counter in US States who were willing to endorse this option. Given intravenously or nasally, naloxone can save lives by reversing the effects of an overdose by other opioids.

To murder is human. To mass murder needs a regulatory apparatus. We have no problem viewing Shipman as a murderer. But what about Purdue or Janssen? And what about the role of regulators from FDA to the GMC?

Go Figure: Study 329

3067308799_2_3_doaxbgue

Editorial Note: This post merges the Go Figure sequence of posts from several weeks ago with the 329 series.

In the wake of the French Revolution of 1968, the government was still tottering when on February 4 1970, sixteen miners died with twelve others maimed in an explosion at a mine in Lens in France. The mine owners pitched the event as an accident. It didn’t help their case that Northern France had a history mine disasters, including the worst ever in Europe in 1906 at almost exactly the same spot, when over a thousand men lost their life. This is the reason we have insurance, the owners said. This is what the law of 1898 was all about.

The miners called on the Left-Wing philosopher Jean-Paul Sartre to prosecute their case. Sartre claimed there were no accidents, the owners knew there would be a certain number of deaths each year and factored this into their costs. There had been five the year before in a nearby mine. While injured workers thought of their job as risky and that when injured they had just been unlucky, they were wrong. It was murder, Sartre said.

quote-i-say-a-murder-is-abstract-you-pull-the-trigger-and-after-that-you-do-not-understand-anything-that-jean-paul-sartre-162916

Calling these deaths murder made the disaster an event. If it was murder, the owners should go on trial. Capitalists in general should go on trial. Perhaps even the government. This was a pivotal moment for the Left. Despite the lack of trust of many in France in their government, society didn’t follow Sartre down this route. Perhaps because the French State made a display of solidarity. The Left lost its grip to a New Left and others who were looking for a Third Way.

coup-de-grisou-du-6-de-fouquieres-2-1

A century earlier faced with a predictable number of deaths from anesthesia each year, American surgeons in the first place, because anesthesia was developed there, faced questions about the ethics of doing evil in order to do good. If the patient died from the anesthetic, were they murderers?

We somehow collectively decided that no they weren’t. No-one sees us as duped for doing so, even though roughly one per thousand anesthetic events today lead to death. There are likely more deaths from anesthesia than from mining disasters each year. There are certainly more deaths per person year exposure.

1445110601947

The death of the comedian, Joan Rivers, some years ago under light anesthesia for an endoscopy, rather than plastic surgery, threw a light on this issue. Deaths under anesthesia have been happening for one hundred and seventy years but every so often a death or other happening becomes an Event. In this case, nothing happened.

“With plastic surgery, the general anesthetic is like a black-velvety sleep, and that’s what death is – without waking up to someone clapping and going, ‘Joan, wake up, it’s all over and you’re looking pretty’.

What is less forgivable perhaps is that anesthetists have a blind spot for the difficulties that may emerge days or weeks later linked to their procedures and agents.

String of Pills

Where do the adolescents or young adults or any of us who commit suicide or homicide triggered by an SSRI taken, or given, on the back of studies like 329 fit? What do we call this?

British papers over the weekend were full of a trial involving a footballer and an inebriated woman where he was convicted of rape in the first instance, with the sentence later quashed in controversial fashion. American and world media were filled with stories of Donald Trump and the question of consent. In the light of Study 329, is the consent people or their families have given to take a medication like paroxetine any more valid than a consent that after the event an inebriated woman is claimed to have given?

Like the mining accident in Lens, the Evans rape trials, the Trump candidacy, the republication of Study 329 is an event, possibly a pivotal moment. Details outlining trends in the rate at which articles are ghostwritten, or patients enter hospital because of treatment induced injuries are features of the contemporary landscape but every so often these features come together to make an Event and Events make history. They create a before and after – even if not necessarily right there and then.

Study 329 Taper Phase

money-bag

Editorial Note: It was tempting not to run a post today for fear it might get lost in the wash of the Clinton-Trump debate. But today is the fourteenth anniversary of the day FDA issued an approvable letter for Paxil for children, as well as the fifty-fourth anniversary of the 1962 FDA Act that created the playing field on which Study 329 happened. It’s also World Mental Health Day. Freud might have been amused.

Study 329 recruited its last patient in 1997. The data was analyzed in 1998. Faced with the results, the plan was to pick out the good bits and publish them. This meant never publishing the Continuation Phase – the 24 week extension to the Acute Phase of Study 329. The good bits of the Acute Phase became the Keller et al 2001 paper – possibly now the most famous clinical trial publication of all time.

The Continuation Phase was published for the first time by Le Noury and colleagues in September 2016 – eighteen years later. It is available HERE along with reviews from JAACAP – not the journal in which it was published.

Among the most interesting findings are those from the Taper Phase. Publishing the Acute Phase only meant that the Taper Phase vanished. Whatever way the data are cut, whether in terms of all severe adverse events, or behavioral adverse events or suicidal adverse events the picture remains the same – the taper phase of this trial was the riskiest period for those on active treatment. This will come as no surprise to many who have learnt the hard way after the event. Others like Bruce Springsteen do not yet seem to have put two and two together – see Born to Withdraw.

withdrawal-image

Or

taper

The years 1997 and 1998 may be as important as the data. The Moneybags image above, an internal SmithKline Beecham image from 1997, brings out how the issue was viewed within the company. SmithKline were at the time under intense pressure from Lilly and Prozac, with Lilly running adverts for Prozac like the one below.

Prozac withdrawal

The material accompanying adverts like this specifically targeted Paxil – Seroxat, the drug that was Prozac’s most direct competition. This is an unusual thing for a pharmaceutical company to do. They have to be on solid ground. It was also deeply cynical in that Prozac also causes dependence and withdrawal but with the right study its long half life can appear to make this problem disappear.

SmithKline’s response was maybe even more cynical. For women worried about getting pregnant and possible risks to their unborn baby, the short half life of paroxetine and being able to get off it quickly was a blessing. If you were on Prozac, the implicit message was you were “fucked”.

Extraordinarily in the face of this – twenty years ago – most doctors and regulators affected not to notice anything. Were they being adults trying to ignore children squabbling in the back of the car, or were they like terrified kids in Jurassic Park trying not to draw the attention of the Tyrannosaurs sniffing the air around them?

Most doctors still affect surprise at the idea SSRIs might come with withdrawal problems. Regulators since 2002 know very clearly about the problems but have decided to leave any communication of these issues in company hands.

It needs an anthem from someone like Bruce Springsteen to find the millions of people whom “Progress” has left washed up on a shore they never wanted to be on. An anthem to put the island on which they have been Shipwrecked on the map.

Study 329 Continuation Phase

continuation-efficacy

Editorial: We interrupt the Go Figure series of posts to return for two posts to Study 329. We will then return to Go Figure.

All the fuss about Study 329 centers on its 8 week acute phase. But this study had a 24 week Continuation Phase that has never been published. Until Now.

We might have Marty Keller to thank for this Continuation Phase. His big deal was the long term treatment of depression. He made his name on the back of claims that depression was more chronic than people thought, and that treatment might have to carry on much longer than had been thought. Or perhaps industry made his name for him as this was such an appealing idea for them. He rapidly became one of the go-to key opinion leaders for antidepressants, along with Charlie Nemeroff in the US and Stuart Montgomery in Europe.

Rhode Island, and Brown University, must have looked Providential to Pharma in the early 1990s. Peter Kramer of Listening to Prozac fame was there too, also advocating pretty well permanent treatment for people who might be somewhat less than entirely chipper 100% of the time. Well would you take off a pair of spectacles if your sight was crisper wearing them? Why treat a drug any differently? We need to get over these Calvinist hang-ups about feeling better on medication, maybe even feeling better than well.

The continuation phase

The Acute Phase of Study 329 ran for 8 weeks – slightly longer than usual because the worry even before it began was that it was going to be difficult to show that treatment worked. But then after that the children could enter a further 24 week continuation phase. The idea was to see how ongoing treatment shaped up. The continuation phase was never published. Never even talked about.

To coincide with the Autumn Equinox, the International Journal of Risk and Safety in Medicine has published Study 329: The Continuation Phase.

The full text is available on Study 329.org, along with the reviews from the Journal of the American Association for Child and Adolescent Psychiatry (JAACAP). Click HERE.

JAACAP is not IJRSM – what’s up?

The original Keller paper was published in JAACAP. The former editor Mina Dulcan and the current editor Andres Martin and the American Association for Child and Adolescent Psychiatry were lobbied heavily over the years by Leemon McHenry and Jon Jureidini, trying to get them to do the decent thing and retract the paper. In vain.

So it seemed like a good idea to send Study 329 The Continuation Phase to JAACAP first. We were pretty certain they would refuse it. But they needed to be given the opportunity to dig a deeper hole. And they did. The reviews are published on Study 329.org.

JAACAP

The primary theme of the reviews is there is too much data here, tell us what it means. Interpret it for us, and then we can tell you whether we agree with you or not. The paper may in fact have too many tables and figures but the key message behind Study 329 is that there is no authoritative interpretation. A lot hinges on almost arbitrary categorizations of the data. You the reader need to be able to play around with the data; you may well spot things others have missed. When it comes to adverse event data in particular there is no expertise. Things need to be picked over.

Off a cliff

There are some things about the Continuation Phase that are almost too shady to pick over too much, and we did not spend time on them. At the end of the Acute phase, for instance, there was an option for patients to continue into the next phase. It’s easy to understand why people doing poorly in the trial might have opted to drop out at that point. Some people doing well can also have been expected to drop out. What is harder to explain is why most of those doing well who dropped out were on placebo. A mixture of reasons were offered such as non-availability of trial medication but two thirds of those dropping out while doing well were taking placebo. This does not seem random. From GSK’s point of view having a large number of people doing well on placebo enter the continuation phase would not have been ideal.

The findings

Despite the placebo dropouts, there are more data to pick over in this study that for any other study. The data are not flattering for paroxetine – Paxil / Seroxat.

relapse

The relapse rate on paroxetine was higher than for imipramine or placebo. This relapse rate makes paroxetine a Gateway drug. People taking it end up worse off and their difficulties are interpreted as further evidence of illness, and in the real world this is likely to lead to additional diagnoses and additional treatments.

As the Efficacy data above shows, there is no evidence that patients given paroxetine show any benefits compared to placebo over the longer run – even when the deck is stacked against placebo by eliminating many of those who are taking it and doing well.

The suicide data also continued to be a problem into the Continuation phase as the graph below shows.

suicidality

The word AG1TA here stands for agitation.

But there was another even more interesting finding in this paper which will feature in next weeks post. If you download the paper you will likely spot it. Surprisingly in the light of the finding, or unsurprisingly given the finding, the reviewers paid no heed it.

To be continued…

Go Figure: A Geek Tragedy

ddt1

In 1939, in the laboratories of Geigy pharmaceuticals, Paul Mueller discovered that DichloroDiphenylTrichlorethane DDT killed insects more effectively that anything else then available.

Robert Domenjoz, the later creator of imipramine, had the job of evaluating it. He did the testing on lice that was to make DDT one of the best-selling pharmaceuticals in the world. He asked the Salvation Army to bring him two of the paupers who slept there and he bought their shirts – for their lice. He put the lice in small boxes which could be sealed with a sieve so that the lice could breathe. He attached the boxes to his arms so that they could live off his blood. Over weeks, they multiplied. When he had enough, they started testing DDT on them. It worked a treat.

Lice carried typhus, which killed more people in wars since Napoleon than the actual wars had killed. Domenjoz headed straight to the Swiss army who started using it and then presented the results at the American embassy in Bern. When the Americans invaded Italy soon after, the troops were all sprayed with DDT and pretty soon everyone who was liberated from the Germans was liberated from lice also.

After the war was over

ddt2

After the War it became common to spray the public in cinema queues and at football games across Europe and America for instance as the photo shows. Mueller won the Nobel Prize in 1948. Domenjoz might have thought at the time he should have shared it.

As almost every ghostwritten article about all of the drugs in current use now says, DDT was very clearly safe and effective.

The use of DDT spread. The images most of us have now is of planes dusting crops with plumes trailing behind them.

Then in the early 1960s the wheels came off the bandwagon. By the time Rachel Carson’s Silent Spring was published, DDT was on the road to oblivion, with most of us thankful we had been saved from oblivion. DDT it became clear accumulated in the food chain, with small doses in some insects and crops, ending up as larger doses in the predators living on them,and larger and lethal doses in the birds, fish and other mammals living on them, or in their eggs or milk. And larger doses in us.

We had learnt that the acute effects of a drug given in a particular way might be dramatically different to the effect that came with chronic exposures or from unexpected routes of administration.

Wasn’t this what we learnt?

Geek tragedy

Controlled trials (RCTs) are all about establishing the acute effects of a drug given in a standardized way by drug companies who hope the verdict will be their chemical is safe and effective so that they can head out and put it in the drinking water (metaphorically). People will end up on these chemicals chronically and they will be mixed with lots of other chemicals in ways never imagined when the drug was first tested.

The result is biphosphonate drugs marketed to reduce the risk of fractures which increase the risk of serious fractures. Antidepressants marketed to reduce suicide risk, alcoholism, substance misuse, marriage breakdown etc which increase the risk of all these things, as well as causing Autistic Spectrum Disorder and birth defects. Statins marketed to reduce risks linked to diabetes which increase rates of diabetes, and to reduce the cognitive problems stemming from strokes but causing cognitive problems in their own right. RCTs miss all of these things – and when they don’t miss them as in the case of the antidepressants and suicide the data is fudged, sometimes fraudulently.

Far from recognizing the role of RCTs in producing a new Silent Sprint, RCT enthusiasts are spreading the word that we need more of them. No-one should be on a treatment who isn’t in an RCT. This is the script for a Geek Tragedy.

RCTs do more than miss the long term injuries a drug might do us. They get used to build standards of care to which doctors are obliged to adhere. Anyone who figures it might not be wise to add a sixth drug into the mix a person is on, or that thinks that maybe adolescent crises are not something that need medicating, will find themselves up against these standards of care facing managers who ask Who are you to go against the Standard of Care? Sorry we have to let you go.

Part of the tragedy is that we would in fact save vast amounts of money by giving the pharmaceutical companies 10 times the inflated prices they currently receive for drugs as part of a bargain where their marketing ensures that only 10% of those currently taking lipid-lowering drugs, antidepressants, biphosphonate and other drugs end up on them – and perhaps slightly higher proportions for hypoglycemic drugs, antihypertensives and antibiotics. The savings would come from shutting down osteoporosis screening services. From the savings on not having to treat treatment induced disabilities. From Elective patients (patients on cancer chemotherapy) not having their bed blocked by an antidepressant induced suicide attempt or biphosphonate triggered fracture of the femur, or a hypoglycemic episode (the biggest cause of brain damage) triggered by the use of extra hypogylcemic drugs being used to lower blood sugars elevated by the use of Statins that current standards of care mandate in diabetes.

Most of us thankfully won’t get tangled up in these elements of the tragedy – the final scenes where as in King Lear the corpses are strewn around the stage. For most of us the ending will more like the ending of a play by Samuel Beckett – The Algorithm will See You Now.