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

Pharmaceutical Rape: Doctors still know best

caravan

Editorial Note: This is part 4 of Laurie Oakley’s series on Pharmaceutical Rape.

Many who experience life-altering, adverse outcomes after taking their medicines as prescribed do not receive acknowledgment of what they have experienced, let alone the medical care they need. Medical systems do not recognize many treatment related outcomes and patients are therefore denied knowledgeable, compassionate treatment for the iatrogenic illnesses they experience after following doctors orders. While health practitioners can generally make a good living within healthcare systems, thousands of patients end up on disability after adverse pharmaceutical outcomes. Without the support of a doctor to verify one’s condition, there are others who, tragically, end up on the streets.

Pharmaceutical privilege

The privilege of one who benefits within a system that uses pharmaceutical products to improve one’s own life and well-being while denying or remaining oblivious to harms suffered by others within same system.

Pharmaceutical oppression

Deriving benefit from and/or being complicit with healthcare systems while refusing to consider or acknowledge pharmaceutical harms suffered by others; routinely ignoring, denying, and/or explaining away harms reported by others.

Medical fragility

In regard to pharmaceutical rape, this is an emotionally reactive, often arrogant stance that is taken when an individual (medical professional or otherwise) is exposed to suggestions of widespread iatrogenic drug induced harms. It is defensiveness on the part of the individual who often exhibits behaviors that include automatic skepticism, extreme unease, an unwillingness to listen, impatience, condescension, anger and argumentativeness.

Persons who demonstrate this fragility are unable to consider or acknowledge a medical reality that challenges a status quo that benefits them. They automatically discount information or ideas that make them uncomfortable and often attack those who are making claims. This stance is rooted in deeply ingrained ideas about the power of science and the prestige of the medical profession, as well as in the “goodness” of modern medicine. For many, one’s very identity as a doctor or as a patient depends upon viewing the systems in which one gives or receives care as safe places of care. Reflecting on or seriously considering the many ways people are harmed by pharmaceutical products is intolerable, as one believes these kinds of things “just don’t happen” in modern medicine.

Medical professionals who think in this way dissociate themselves from the idea of systemic, iatrogenic harms, and instead think of the injuries they do recognize as solitary incidents resulting from the “bad” behavior of others (whether the patient, drug industry or other medical professional). Doctors tend to be high achievers with a perfectionist bent. While attaining the high degree of competency required to practice medicine, many also acquire a deep sense of earned superiority. Any challenge to this core identity, or to the systems in which one is enmeshed, is intolerable.

Story: doctors in denial

I never set out to become a medical heretic. That job was ascribed to me by certain pharmaceuticals that are said to work wonders for the majority of the human race, but not for me: miracle drugs like the SSRI anti-depressants and the ever safe benzodiazepines. So when I described to doctors all that had happened to me while on these medications, most stared at me as if I’d just grown a second head. My report, it seemed, was over-the-top.

One doctor congratulated me for kicking my “benzo habit” even though I had told her I’d taken only a small dose as prescribed by my doctor. When I tried to explain how tolerance withdrawal symptoms had been repeatedly misdiagnosed as somatization, and for that I had been given more psychiatric drugs over a period of several years while my physical and mental health deteriorated, she may as well have plugged her ears and shouted, la la la la la! Instead, she said, “uh huh,” before opening my chart and recording my history with benzodiazepines in the illicit drug use category.

After she left the agency, I started seeing a different doctor who listened to my stories in utter amazement. My experience was unlike anything he had ever heard in his many years of prescribing psychotropic medications. When I suggested that my ongoing, chronic insomnia might be a residual effect from having been prescribed a benzodiazepine for eight full years, he responded by saying there was no way of knowing for sure, and at one point even asked, if the benzodiazepine had helped me to sleep, why didn’t I just keep taking it?

Time for a new doctor.

I jumped from the frying pan into the fire. This new psychiatrist had a penchant for sighing and rarely looked at me. He mostly just shuffled papers and wrote things down. He wasn’t interested in knowing what my experiences with medications had been, my complex history, or anything else about me. He was interested in prescribing a certain medication for my insomnia which he pushed even after I had educated myself about side-effects and informed him I didn’t want to risk it. I did finally end up trying the medicine, which I didn’t like and didn’t continue. Then his impatience with me turned into disgust as he no doubt thought my fear of taking medications was irrational. He went on to tell me that millions of dollars and years of study went into the research and development of the drugs he prescribed and he was confident that they were safe.

—Rxisk. January 13, 2015

Pharmaceutical rape apology

An umbrella term for arguments suggesting that serious pharmaceutical violation does not exist or that it is not a widespread cause for concern. “Apology” in this context means defense or justification, like in Christian apologetics, not as a statement expressing regret.

Pharmaceutical rape apologists frequently view patients and doctors who recognize serious adverse events as misguided persons who are anti-science, conspiracy theorists, anti-vaccinationists, or some other type of deviant. Pharmaceutical rape apologists disbelieve pharmaceutical harms because evidence of harm is not forthcoming in the scientific literature. They deny any adverse outcome that does not conform with harms already commonly noted within the medical establishment, and dismiss reports of adverse effects when they have witnessed the drug in question work well for others.

Pharmaceutical violations are dramatically under-recognized. There is an enormous amount of misunderstanding and stigma associated with people who claim to have been harmed. Physician skepticism and outright denial prevents victims from having their claims validated, let alone officially reported to regulatory agencies. Instead of gaining support from a doctor to make sense of what has occurred, adverse effects are often trivialized or misdiagnosed as separate conditions (usually needing additional treatments).

Allegations of false reporting of injury often occur (within the realm of childhood vaccine administration, for instance). The medical establishment maintains that most pharmaceuticals, with rare exception, are safe and effective when taken as prescribed. There is very little room left for discussion of even the known risks of harm. Serious adverse events are said to be “rare,” yet when they occur, victims and/or their families often find it difficult if not impossible to convince medical authorities that the event is related to medication.

Pharmaceutical rape myths

  • The FDA protects the public.
  • Drug safety is assured through hard science.
  • Doctors have access to clinical trial data and are aware of all known risks.
  • Serious adverse events are extremely rare.
  • Development of drug dependence or addiction is unrelated to accepted prescribing protocols.
  • Adverse events are always recognized by doctors and a connection to the drug is normally made.
  • Harmful drugs are always recalled.
  • “Safe” drugs are always safe.
  • Pharmaceutical injury occurs only as a result of medication error or malpractice.
  • All vaccines are completely safe and effective.
  • A good relationship with one’s doctor protects one from a pharmaceutical injury.
  • Individuals who make claims about pharmaceutical harms are against all medications and do not value the contribution of pharmaceuticals to society.
  • Those who warn about pharmaceutical products are anti-science, refusing to listen to reason or to think rationally.

Secondary victimization

Secondary victimization is the re-traumatization of the pharmaceutically injured through negative social responses from medical, mental health and/or legal professionals, as well as from others (sometimes including one’s own family). This is a nearly universal experience for those who have been harmed and may be especially insidious for those who are diagnosed with mental illness, chemical dependency, as well as the vaccine injured (and their families). Behaviors associated with secondary victimization include:

  • Societal as well as individual denial of pharmaceutical harms. The tendency to remain oblivious in the face of evidence of harm.
  • The trivialization of pharmaceutical violation. A response to harm denying that real damage was done.
  • Skepticism and distrust of those who report harms instead of recognizing the harm potential of the treatment.
  • The misdiagnosis and false labeling of individuals who have experienced adverse effects from their medicine.
  • Reducing the patient to an “unusual anecdote.” Accepting evidence from controlled clinical trials only, to the exclusion of what the patient says about effects of a drug treatment.
  • Failure to report a patient’s adverse events.
  • Victim blaming: when the victim of a crime or any wrongful act is held entirely or partially responsible for that harm. It is your fault you were hurt because you did x, y, z. If you hadn’t done x, y, z, you would not have been harmed. You went to the doctor, you asked for medication, you consented to the treatment, you kept going back to the doctor, you didn’t do your homework, you should have known better, you should have listened to your body, I knew better and I didn’t do those things.
  • or, what you experience is your own illness: caused your poor diet, your lifestyle, your lack of exercise, your use of alcohol or other drugs, your age, your family genetics, etc. Claims are easily neutralized or discredited because health is subjective and adverse effects are easily attributed to other causes.
  • or, you are at fault because you are a drug addict, (even though the addiction came about through or was aided by what is considered legitimate prescribing).

Pharmaceutical violence typically leaves the individual with an array of new problems that were not present when the treatment in question was first initiated. Many hurtfully deny or disbelieve the iatrogenic nature of the person’s condition, and additional physical and/or mental effects caused by treatments often bring about additional stigmatization. The alienation suffered as a result of these acts is deeply felt:

“I am a wreck after 8 years on Effexor, but of course once on the drugs your credibility is gone, so who listens to a person with a psychiatric “label” even though the label is false? Not only victims, we are totally ignored, while the psychiatrists somehow get put on a [false] pedestal. Challenge them at your own risk of getting a “label.” No other doctors on earth have this sort of irrational power; just because they judge someone as this or that, often in a 10 minute appointment. I would like to know of just one person who ever went to a psychiatrist and didn’t get [labeled].”

—Commenter, DavidHealy.org. May 14, 2015

Post traumatic stress reactions and pharmaceutical violation

Unlike sexual rape, pharmaceutical violations almost always occur over a more prolonged period of time. Where a sexual assault survivor may experience a post traumatic stress reaction in the months and/or years following the event, pharmaceutical victims oftentimes experience these physical and psychological symptoms as adverse-effects while taking psychotrophic medications. Prolonged discontinuation syndromes upon stopping some medications are common and may overlap with a post-traumatic stress reaction from taking psychotropics. The trauma experienced from pharmaceutical violation can include disruptions to normal physical, mental, emotional, cognitive, and interpersonal behavior. Whether from a discontinuation syndrome or from the medications themselves (which are often reinstated to avoid this withdrawal-like condition), pharmaceutical survivors end up suffering, often for many years, with symptoms identical to PTSD.

Effects associated with both sexual rape and pharmaceutical violation include but are not limited to:

  • Diminished alertness
  • Numbness
  • Dulled sensory, affective and memory functions
  • Disorganized thought content
  • Vomiting
  • Nausea
  • Paralyzing anxiety
  • Pronounced internal tremor
  • Hysteria, confusion and crying
  • Bewilderment
  • Acute sensitivity to the reaction of other people
  • Profound inner turmoil
  • Poor health in general
  • Sense of helplessness
  • Hypervigilance
  • Inability to maintain previously close relationships
  • Experiencing a general response of nervousness known as the “startle response”
  • Persistent fear and or depression at much higher rates than the general population
  • Mood swings from relatively happy to depression or anger
  • Extreme anger and hostility
  • Sleep disturbances such as vivid dreams and recurring nightmares
  • Insomnia, wakefulness, night terrors
  • Flashbacks
  • Dissociation
  • Panic attacks
  • Reliance on coping mechanisms, some of which may be beneficial (e.g., philosophy and family support), and others that may ultimately be counterproductive (e.g., self-harm, drug or alcohol abuse)
  • Sense of personal security or safety is damaged
  • Feel hesitant to enter new relationships
  • Unable to re-establish normal sexual function
  • Discontinue previously active involvements, social groups
  • Acute somatoform disorders (physical symptoms with no identifiable cause)
  • Physiological reactions such as tension headaches, fatigue, general feelings of soreness or localized pain in areas of the body
  • Dissociation and trying to get back to life before the assault
  • Fears and phobias
  • Nightmares, night terrors
  • Violent fantasies of revenge may arise
  • A fear of being in crowds
  • A fear of being left alone anywhere
  • A fear of going out at all, agoraphobia
  • Paranoia
  • Suicide

Oliver’s story

Prior to taking Seroxat (Paxil), I had symptoms of tiredness and nausea. My general practitioner (GP) diagnosed me with anxiety and prescribed an anti-psychotic drug. Within 3 days I couldn’t eat or sleep due to severe agitation. I was vomiting, pacing the floors, and crying uncontrollably. My GP diagnosed this as an anxious state and started me on Seroxat. (During this time it was discovered that I was badly anemic and needed a hysterectomy due to severe blood loss. This was more than likely the cause of the original tiredness and nausea). Even though I had informed my GP of heavy bleeding, etc., it seemed easier for him to give my symptoms a label of anxiety and start me on a roller coaster of dangerous psychiatric drugs .

I remained on Seroxat for 6 years as every follow up I was just given more prescriptions. I decided to take myself off the drugs during my 6 years of use with disastrous consequences. I became obsessed with trying to hang myself and couldn’t function due to multiple horrendous symptoms, both mental and physical. Needless to say, I admitted myself to hospital as I had no idea what was happening to me. [I] felt better after Seroxat was reinstated.

I then decided to wean off again with instructions from my GP to taper for 9 months using alternate days[…]That was September 2004. I am now 8 years drug free and still living with damage incurred from taking Seroxat. The first 3 years of quitting were hell. Symptoms included anxiety, panic attacks, paranoia, agoraphobia, hives, itching, tingling, agitation, aggression, suicidal thoughts, homicidal thoughts, weak muscles, vision coordination issues, cognitive problems, dizziness, nausea, headaches, manic behaviour, racing thoughts, gastric upset, balance problems, burning sensations, heartbeat irregularities, palpitations, night sweats, insomnia, and total feelings of despair.

Eight years later to date I still have all these symptoms randomly. They come and they go, and although not as intense as the first years, it still gets pretty scary at times. Is this anything like prior to taking the drugs? No. I felt tired and nauseous. Was it worth taking this drug? No. The side effects of insomnia, muscle pain, blurred vision, weight gain, and feeling null and void of everything was worth nothing. Zero. Zilch. Will I ever recover? Who knows? GP’s offer no validation or support. Will anyone be accountable for the damage I have? No. Everything is denied.

—Rxisk.org. August 29, 2012

Pharmaceutical Rape: The Good Patient

Useless_Science

This is part 3 of Laurie Oakley’s series on Pharmaceutical Rape.

In our society

We learn a social script in which a “good patient” obeys the orders of doctors as authority figures. The ideal patient is a passive patient, subordinate to the physician. We are expected to relate to doctors as experts whose judgment we should trust when being prescribed medication. Because of drug industry influence, this everyday scenario invites pharmaceutical violation. Thus a pharmaceutical rape culture exists that fosters widespread harms to individuals. In those instances where a patient ends up recognizing that something has gone wrong, he or she will often place full blame on the doctor without recognizing that entire systems of individuals are ultimately responsible for the damage, with participants in those systems remaining far removed from the consequences of their actions. Only rarely does a victim of this kind of offense see the inside of a courtroom. Lawyers who represent the giant pharmaceutical companies will then scrutinize a victim’s traits and behaviors in an attempt to prove personal factors such as poor health habits or an individual’s own underlying illness are responsible for the condition.

Between 1999 and 2004, the heavily marketed pain reliever, Vioxx (rofecoxib), caused an estimated 88,000 heart attacks and strokes, with an estimated 38,000 deaths. After the drug was withdrawn from the market in 2004, lawsuits by patients and their families against the drug manufacturer, Merck, were beginning to pile up. One of the plaintiffs was the wife of Jamie Gregg:

“Jamie Gregg, a 32-year-old construction worker from Katy, Tex., and father of three boys, had just reported for a job at Houston’s Hobby Airport when he collapsed, apparently from a heart attack.

“He was rushed to the hospital, where a medical team saved his life. But his brain had been deprived of oxygen for so long that Mr. Gregg is now in a nursing home in Lufkin, Tex., fed through a tube, unable to move more than his head or to utter more than a few syllables[…]

“Mr. Gregg, who had undergone a series of back surgeries, had been taking a high dosage of Vioxx, 50 milligrams a day, for four years to treat back pain. So the day after Mrs. Gregg heard that Vioxx was being withdrawn from the market, she walked into the offices of Goforth Lewis Sanford, a law firm in Houston. That firm, along with W. Mark Lanier, a prominent Houston plain-tiffs’ lawyer, are now preparing a lawsuit against Merck.

“‘[Vioxx] has got to be the reason,’ she said[…]

 “But the plaintiffs’ lawyers face a big obstacle in convincing juries that a person’s heart attack or stroke was caused by Vioxx, because many people suffer such attacks for many reasons[…]

“Thomas B. Moore, a Los Angeles lawyer who represents pharmaceutical companies in such matters, although not Merck in this case, predicted that even the estimate by Dr. Graham of the F.D.A. that the drug caused more than 27,000 deaths and heart attacks would not help plaintiffs win cases. “‘The problem is that David Graham can’t name one of them,” Mr. Moore said. “He can’t name one of those 27,000.'”

—The New York Times. November 14, 2004

It is no remedy for pharmaceutical companies to pay out large settlements in instances where survivors are able to prove injuries were caused by medications that were prescribed with undisclosed risks. Since the problem lies in a culture that trusts in doctors who prescribe medicines to fix health problems while patients remain largely passive and dependent, one solution is to look at pharmaceutical injuries, in part, as a product of this authoritarian/passive relationship and to begin by addressing it at a personal as well as cultural level.

Social conditioning through direct to consumer advertising firmly establishes this pharmaceutical rape culture. When individuals are daily encouraged to “talk to your doctor,” the implicit message is that the starting point for good health is regular visits to a doctor who will prescribe medications to be taken regularly. Accustomed to turning to pharmaceuticals for what ails us, we have all but forgotten that all medicines are poisons which pose risks of harm, even when instances are rare.

The mother of three-year-old, Brianna Maya, was advised by a pediatrician to give her daughter the over-the-counter medicine, Children’s Motrin (Ibuprofen), for a fever and cough. The girl developed a rash but since her mother was not aware that this was a side-effect, she continued giving her daughter the medicine. As ABC News reported:

“Over the next few days, a fine rash on her body and mild redness around her eyes morphed into something insidious: a rare, painful and potentially fatal skin reaction that burned and blistered her body inside and out, blinded her in one eye and left her fighting for her life in a burn unit 1,000 miles from home.

“‘It was like something you see in a science fiction movie,’ said her mother, Alicia E. Maya Donaldson, 34, an assistant professor of social work at the University of Tennessee at Martin, as she recalled how her daughter looked at the time[…]”

“Brianna, now 13, has spent the last decade living the painful aftermath of SJS/Tens: She has undergone repeated eye surgeries and suffered recurrent eye and lung infections. Last summer, she developed seizures stemming from oxygen-deprivation during the worst of her illness. One of the ironies is that doctors have had difficulty controlling her seizures because anti-seizure drugs can trigger Stevens-Johnson syndrome. Because of vaginal scar-ring, “she will never be able to have normal sexual relations or bear children,” her mother said[…]”

Dr. Bernard Cohen, director of pediatric dermatology at Johns Hopkins Medical Institutions in Baltimore, reminds us:

“All drugs have risks, whether they’re topical, oral or intravenous, The patient takes some risk, the nurse-practitioner or physician prescribing it takes some risk. Sometimes pharmaceutical companies are at fault.” In the case of Stevens-Johnson syndrome, “this is one where everybody should take some responsibility for it.”

—ABC News, June 3, 2011

The drug manufacturer in Brianna Maya’s case was ordered to pay her family $10 million for her injuries because the label on over-the-counter Children’s Motrin had not warned of this rare but life-threatening condition. Stevens-Johnson syndrome had been a known risk, fully acknowledged by the drug company; the prescription version of Children’s Motrin had always carried a warning. Yet when the risks are this rare, safety information is brushed aside.

The cultural tendency to focus only on a drug’s benefits has been set in place by pharmaceutical companies and reinforced by the medical establishment; this denial of potential risks prevents patients from being able to make an informed choice. While many of us benefit from “safe” medications, children like Brianna (and her family) pay the horrendous consequences alone.

Pharmaceutical rape culture

A pharmaceutical rape culture is a culture in which iatrogenic harms are pervasive and normalized due to societal attitudes about medicine and health care. It is a complex set of beliefs that tolerates the commercialization of healthcare and supports everyday harms in medical and mental health care settings. It is a society where harm is only acknowledged as rare, yet is accepted as necessary, and inevitable. In a pharmaceutical rape culture, doctors and patients unknowingly trust what are oftentimes pseudo-scientific facts put forth by drug makers about drug safety. Both doctors and patients end up disbelieving the reality of the adverse events they see, and instead believe alternate explanations for such events. A pharmaceutical rape culture condones widespread medical harms that are rooted in reckless practices within the industry-government-medical trade alliance because multiple societal systems are involved in producing, reproducing, and disseminating “information” about pharmaceutical products. This “information” sat-urates the public and reinforces that alliance.

A veteran’s story

Jeremy Brooking was a U.S. Marine who, after surviving a sniper attack in Iraq, was sent to Camp Lejeune, NC, to recover. It was then, he says, that the real battle began. News correspondent, Bob Segall of Indianapolis, reported in April of 2014:

“The battle Brooking is talking about is an addiction to pain killers. Military doctors prescribed him 22 different medications – many of them powerful narcotics like Oxycontin and Hydrocodone – to numb his chest pain. A VA hospital gave Brooking 43 pills a day. That’s nearly 1,300 pills a month. More than 15,000 pills a year. A 1-month supply of medication filled a plastic grocery bag.

“‘I lost three years of my life where I barely remember anything,’ he said. ‘I’d sleep 23 out of 24 hours of the day because of those pills. It destroyed our family. It really destroyed me.’”

His wife, Tia, who witnessed him turning into a different person, decided to consult with medical staff at the VA to inquire about alternative treatment options.

“The doctor said ‘Your husband is never going to get better. This is how he’s always going to be.’ And I said ‘What can I do?’ And he said ‘I can write you any prescription you want. Tell me what you want, and I’ll write it.’ He said ‘I’m in the business of writing prescriptions.’ I remember him saying that, and I said ‘I don’t want prescriptions. I want him to get better,” she recalls, shaking her head. “It was horrible. Sometimes […] when I got home, I thought he was going to be dead.”

Jeremy Brookings did eventually break free from his addiction to narcotics after he gave up on the VA’s pain program and found a doctor willing to try other options. But thousands of returning veterans have lost the quality of their lives, while many others have died, as a result of the prescribing practices at the VA.

Dr. Pamela Gray, a VA Medical Center doctor in Hampton, Va., from 2008 to 2010, advocated for alternatives to the routine practice of prescribing narcotics but was told to stop by VA Administrators:

“I was told by the department chair of internal medicine to think twice about not prescribing these narcotics,” the doctor said. “I was ordered to write these drugs or be fired. I was ordered, as a physician with 25 years of experience, by a non-physician to do something that was medically incorrect. That is an intolerable position.”

Gray recalled a severe shortage of qualified pain specialists within the VA yet the idea of creating pain management programs was rejected by supervisors. Treatments other than the prescribing of narcotics were not a cost effective option for the VA so doctors continued to over-prescribe.

WTHR 13 Indiana’s News Leader. April, 2013

Medical/pharmaceutical objectification/commodification

An attitude about patients that places primary value on what treatments or procedures can be employed for reimbursement or compensation. Reducing the patient to a commodity with value being limited to financial usefulness.

Many in our communities, from the most vulnerable children to military veterans, end up experiencing serious medical consequences and unacknowledged suffering after trusting a doctor’s advice. This is a literal type of rape that is downplayed by medical practitioners, regulators, and the entire healthcare systems that are charged with our care.

Pharmaceutical Rape: Cast of Characters

Remedios Varo

Ed Note: This is part two in Laurie Oakley’s Pharmaceutical Rape series.

WHEN IT COMES to pharmaceutical rape, it is no simple task to determine just who the “rapists” are (or to determine the safety or lack of safety of the treatments that they promote), but we are certain that the behavior exists, and that decisions are being made with no regard for the lives that are damaged and/or ended by the reckless promotion of pharmaceutical products. This type of industry behavior, and the behavior of all who are in collusion with it, makes it clear that the untold suffering of millions is not too great a price to be paid for the satisfaction these individuals get from their advancing prestige and monetary gain.

The Violators (knowingly) – Corporate and governmental decision makers involved in the processes of production, approval, and marketing of said products; academic researchers involved in the study of said products while receiving industry funding; those psychiatrists, medical doctors or other professionals receiving financial compensation for lending their names to ghostwritten articles and other misleading materials about said products. (Key opinion leaders).

In the case of pharmaceutical rape, the “DNA” or proof that links industry behavior to individual injury is often found in a company’s internal documents. For example, e-mails and memos from the makers of the blood thinner, Pradaxa (dabigatran), showed they had both knowledge of Pradaxa’s dangers and financial incentive to let the drug onto the market without issuing any warning:

“Employees of Boehringer Ingelheim, the German drug maker, continued to express concern over whether sales of their blood thinner, Pradaxa, could be harmed if the public learned that some patients might need regular testing for safety reasons, according to new documents unsealed by a federal judge in Illinois on Thursday.

“The documents, which include a series of internal emails and memos, add to a trove of court records that were made public last week by Chief Judge David R. Herndon, of the United States District Court in East St. Louis, who is overseeing thousands of lawsuits filed by patients and their families, who say that Boehringer Ingelheim failed to properly warn them about the risks of taking Pradaxa.

“Since its approval in 2010, the drug, which can cause fatal bleeding, has brought in more than $2 billion in sales in the United States, according to the research firm IMS Health. It has been prescribed to 850,000 patients, but has also been linked to more than 1,000 deaths.”

—The New York Times. Feb. 7, 2014

The Accomplices (unwitting, assumed unknowingly) – Shareholders, government officials, the psychiatric establishment, persons in academic institutions, medical journals, medical and mental health care systems, front groups, pharmacists, other prescribers, and the media. In practice, doctors act as accomplices; because many are unaware of the extent to which the drug industry permeates medical education and culture, they are also victims.

Gwen Olsen, author of Confessions of an Rx Drug Pusher, worked as a pharmaceutical drug rep until she figured out that people were being harmed by her participation in this system:

“I was being encouraged to minimize side effects when I talked to doctors. I started to realize that these patients were literally being tortured by the drugs. There is no such thing as a safe drug. I was so disillusioned, as well as angry, when I found out how much deception, how much misinformation was taking place and how I’d been used in that game. I literally was the one on the frontlines. I was harming people unintentionally, but I was responsible. I carry a burden for that now.”

—Global Research. March 26, 2015.

When Bruce Levine, a clinical psychologist, recognized that he was a cog the system  alongside doctors who prescribed medications in ways that were harmful to children, he began speaking out against it:

“[I] wanted to distance myself from [the mental health profession]. In the 1990s, I used to say, half-seriously, that when kids found out what had been done to them – including shrinks’ pathologizing and drugging their reasonable rebellion –- these kids, when they grew up, would go after mental health professionals, and I was hoping that by speaking out that they would spare me. I was only half-joking.”

—Daily Kos. March 4, 2014

Psychiatrist, Mark Ragins, had prescribed the psychotropic medication, Zyprexa, trusting that it was safe. Later he would learn that it caused diabetes in many patients:

“For me the last straw with drug companies was when I found out that they knew about diabetes and Zyprexa all along and intentionally hid it from doctors, leading us to put people at risk without knowing it. That felt like a terrible betrayal to me. (though, of course, not in the same league as what the people who got diabetes or even died went through)[…]

Although I’m sure that I’ve helped many people with medications, the drug companies are extraordinarily dangerous partners[…]”

—Psychology Today. October 10, 2010

The Victims – Persons who experience unexpected physical, emotional, mental, and/or psychological adverse effects (immediately or from longer-term use) as a result of being prescribed products where insufficient or misleading information has been given. (Also victims are doctors who have been led to prescribe said products without giving full safety information, whether because of drug industry influence or by following accepted prescribing protocols within medical and mental healthcare systems).

A Post-SSRI Sexual Dysfunction (PSSD) Story

I first took citalopram (Celexa) in November 2007, at the age of 22. I had quite bad obsessive compulsive disorder (OCD) and because there was a long wait to try cognitive behavioral therapy, I was persuaded to try citalopram to treat my OCD.

Initially it made me feel a bit sick, but the most noticeable thing was it completely abolished my sex drive. I simply stopped thinking about, desiring, or fantasizing about sex in any way. When I had an orgasm, it was nearly pleasure-less, and my penis felt anesthetized.

I only took the drug for 4 weeks, but when I stopped taking it my libido didn’t return to anywhere like it was before. After 2 months I became concerned, and asked my GP. He said my low libido and citalopram could not be connected in any way, as I had stopped taking the drug, and my low libido was likely down to low mood/anxiety. I wasn’t convinced as I know how low mood or stress can affect my libido, and it is nowhere near as severe, and returns quite quickly when I relax, or my mood lifts. I wasn’t too concerned though, and assumed it would just take a few more months to return to normal.

I was then persuaded to take fluvoxamine (Luvox) for at least 3 months, as this is the time it is supposed to take before improving OCD symptoms. I started taking this drug in July 2008, and took it for about 5 months. I stopped after seeing no improvement in my OCD symptoms. I felt fluvoxamine had no effect on my sexual functioning whatsoever, and ironically it is the SSRI that has been reported to cause the least sexual problems, although some people are affected.

I was persuaded again to try citalopram for a longer period of time, and I agreed as I was ignorant to the potential of SSRI’s to cause long lasting sexual dysfunction. In December 2008, I took it for about 3 weeks. This time I noticed an even further decrease in libido, and two days after taking it, I developed severe premature ejaculation. I had never experienced premature ejaculation up to this point in my life. After 3 weeks I developed a severe headache, which my GP thought was connected to citalopram, so this is why I stopped taking it.

After a few months of being off all SSRI’s, my libido was still non-existent; I still had pleasure-less orgasms, my penis still felt anesthetized, and I had severe premature ejaculation. I started to become more concerned. Puberty had started for me at thirteen, so I have had many years to get to know how my libido works, and how it is affected by my mood or stress levels etc. The sexual dysfunction I experienced since taking citalopram was much more severe, was consistent every day, whatever mood I am in, and started directly upon taking citalopram.

Low mood, stress or OCD had never caused pleasure-less orgasms, severe premature ejaculation, or for my penis to feel anesthetized. All of these symptoms have been known to be caused by SSRIs, including citalopram. So I went to my GP hoping he would see that citalopram was the most likely cause. I explained the situation to him, and he told me there was no way citalopram could have caused my on-going sexual problems, as the drug was not in my system anymore.

He said “you will get better when you decide to get better.”

Frustrated, I went to another doctor, this time with literature from credible scientists who had expressed concern that SSRI’s could cause persisting sexual dysfunction, even after cessation of their use. She briefly looked at them, suggested my OCD could be the cause of my problems, and said I should never mention this problem to a doctor again. She also told me that as I had a history of mental health problems, it is unlikely that I would be taken seriously.

So I met with the psychiatrist who initially prescribed the citalopram. I sent him some literature I had found on the internet regarding post SSRI sexual dysfunction, as that was what I was now sure I was suffering from. He refused to read the literature, and also stated he felt my sexual problems were down to low mood or OCD. Eventually I insisted on him reading the literature. He then told me that although PSSD might exist, he couldn’t say whether or not I was suffering from it.

I have been to many doctors in the following years, explained to them why I was convinced I was suffering PSSD, and they have all attributed my sexual problems to low mood/ anxiety. My problems have been attributed to almost everything, apart from citalopram.

The only exception was a GP, ex psychiatrist, who told me he had no doubt citalopram was the cause of my on-going sexual dysfunction, and that he had a number of ex patients who had a similar experience to me; ongoing sexual dysfunction long after stopping an SSRI, that he had no doubt was caused by an SSRI. He then told me he couldn’t predict if or when I would recover, but that if I did recover, it would take years.

The effect of living with PSSD is devastating. It has destroyed two relationships. Relationships with women end up being like an asexual friendship, with sex being like a pleasure-less boring chore, with no emotional connection or lust whatsoever. If I don’t make a full recovery I don’t think I will ever be able to have a “normal” sexual relationship in the future.

This obviously has serious implications for my future. In the years after developing PSSD, I have suffered from a severe depression, as I have been left in a horrible limbo state which has gone on year after year. This is directly linked to PSSD and has resulted in self-harm, a suicide attempt, and I have often contemplated taking my own life.

I feel alienated from my peers, as I can’t relate to them – I can’t get excited about girls with them and relationships, etc. I don’t like listening to music as much anymore, as nearly all music is about love, sex, and romance in one way or another, and I don’t like to be reminded about what I am missing out on. The same applies to certain films and T.V programs.

It is difficult to talk about this problem. When I have talked to people about it I have regretted it. People don’t understand, or don’t believe you. I have been laughed at even by doctors. People have suggested I might just be gay. In my social circle, only my parents and one close friend knows. The subject is taboo. This must be why this problem hasn’t received much publicity. You are shamed into not talking about it.

I have now lived with PSSD for almost 7 years. The severe premature ejaculation has resolved, but it took 15 months to do so. The pleasure-less orgasms, penile anesthesia and non-existent sex drive remain. I live with a barely suppressed rage about what has happened to me, and especially about how I have been treated by the medical profession.

Since I first took citalopram I have felt like an old man, in a young person’s body. I don’t even feel like a proper human being anymore, I would describe PSSD as a protracted mental torture. I hope that one day I will recover, and be able to put this behind me, and that the medical profession will eventually treat this serious condition with the respect it deserves.

—RxISK. July 15, 2014

As with sexual rape, the victims of pharmaceutical violation are everywhere, walking among us unrecognized. Many may not even connect what they experience to their medications. This is a violation involving physical, emotional, mental, social, and spiritual damage at the hands of those holding power over medicines, who deny any wrongdoing and remain free to do the same to others.

Pharmaceutical Rape is not a Metaphor

Ed Note: This is the first of a 5 part series on Pharmaceutical Rape by Laurie Oakley. We are looking for images to illustrate the series and would welcome any cartoons or other images that are germane to themes below. The first image here is Martin Shkreli, the man who raised the price of Daraprim by 5000% recently on the back of claims that profit was necessary for research activities.

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PHARMACEUTICAL RAPE is a relatively new phenomenon. It is a culturally invisible harm outside the domains of public, medical, and political discourse. However this type of violation is commonplace and stories of these harms are especially visible on internet forums. This new definition is meant to challenge the current, widely accepted societal assumptions about pharmaceutical harms, their prevalence, causes and consequences. It provides an alternative framework for defining and interpreting serious adverse events that are rooted in corporate pharmaceutical behavior. Through this definition it is hoped that pharmaceutical violence will begin to be publicly recognized as the serious public health problem.

Pharmaceutical rape stems from the collective decisions of powerful individuals within an industry-government-medical trade alliance. It is an offense that results in an invasive violation of bodily autonomy for the victim. A pharmaceutical product is introduced into one’s body that causes harm — something one did not consent to — something that one had a legal right to more information about so that a different choice could have been made. Most often, it involves trusting and having that trust violated.

Joanne’s story

In April 2011, I was prescribed Cipro (ciprofloxacin) for an uncomplicated, routine urinary tract infection. After only 6 days of 250mg twice daily, I was suddenly hit with a host of symptoms. Within two hours I went from being a healthy, 49-year-old to someone mutilated from head to toe, fighting for my life. My life has changed irreversibly. I have medical documentation of partial paralysis, head to toe tendon damage, hearing loss, heart murmur, kidney and liver damage, erythema multiforme, extreme food allergies.

I was initially told that these symptoms, especially appearing collectively, was “rare.” While this did little to help me, at least I thought I was just unlucky. Imagine my horror when I found that, even using conservative numbers, hundreds of people are poisoned from fluoroquinolones each year with the same devastating result I endure. Not only are there countless scores of facebook, YouTube, and blogs on the internet from people with crippling stories almost exactly like mine, there are many people I have met within just my local area that are suffering in this same way. There is ample documentation to show that the FDA knows that these effects appear syndromically. The FDA knows the devastation caused by fluoroquinolones. Yet, the FDA allows these “medications” to be used in a flippantly casual manner by unknowing doctors with only a black box warning of possible tendon damage. Possible tendon damage implies a bad case of tennis elbow or, at worst, a rupture of the Achilles tendon. Nothing can explain my terror at suddenly having every tendon in my body as fragile as wet tissue paper. Nothing can explain the heartache of having to be fed like a baby by my eight-year-old child or being unable to use the bathroom without the assistance of others. Although I have made improvements in the last seven months, my chance of complete recovery, based upon expert information, is almost non-existent.

MedWatch, as it currently stands, does not work as an accurate reporting system. It requires doctors to report on their own errors. If physicians recognized the error, it is doubtful they would have made it in the first place. My PCP is a conscientious physician but just did not have enough information on the effects of fluoroquinolones. He reported to MedWatch that I was “recovered” only about 10 weeks out from the onset of my initial symptoms because I was no longer using a wheelchair full-time. He simply could not believe that the plethora of symptoms I suddenly had could be caused by a drug. I have to agree that it is completely unbelievable that anything so dangerous would be out on the market.

The subsequent specialists I now see: cardiologist, nephrologist, endocrinologist, immunologist, orthopedist, GI specialist, neurologist, physical therapist, etc., feel they cannot report my symptoms to MedWatch because I was not under their care at the time of the poisoning and, so, cannot confirm the cause and effect.

There is no established first-aid protocol for those poisoned by fluoroquinolones. We called the Poison Control Center. They confirmed that the effects I was experiencing were caused by Cipro but when we asked what to do they said, “Well, if you rupture, go to the emergency room.” This was not helpful. My doctor also prescribed NSAIDS. Not only should physicians be informed that NSAIDS and steroids are contraindicated, there should be an intervention that includes the immediate administration of antacids or something to bind the remaining fluoroquinolone in an attempt to reduce damage.

—RxISK. September 7, 2012

The driving causes of pharmaceutical rape are drug industry influence in the medical setting and the commodification of healthcare. Because this type of violence does occur, it constitutes a social problem that must become an accepted fact to be addressed within wider society.

The word rape

Pharmaceutical rape is not a metaphor for sexual rape*. It is a life-altering violation with parallels to child sexual abuse and rape. This writing borrows from a wide range of activism literature including feminist definitions of child sexual abuse and rape. It should serve to raise awareness for both issues.

For some, the use of the word rape in this context is offensive. I have been told that it trivializes “real” rape and retraumatizes survivors. Speaking only for myself as a survivor, I don’t agree.

If you are not comfortable with this usage and yet think these definitions apply, feel free to use whatever words work for you. If you decide to use the word, please note that there is a radical type of social justice warrior who may challenge (i.e. bully) you on this.

“I have decided to stick with Love.
Hate is too great a burden to bear.”

—Martin Luther King Jr.

I would suggest taking the high road:

  1. Don’t be like them. This type of activist seeks not to understand but to dominate. They often “call out” others whom they choose to be offended by before considering who the person is or where they might be coming from. One thing you will never see this type of social justice warrior do is ask a question. Asking for clarification might lead to a better understanding and that would ruin all the fun.
  1. Be like them. This type of activist demands to be heard. When the subject is a particular form of oppression that you haven’t experienced, it’s your job to shut up and listen. While I don’t advocate being unkind, I believe these activists are onto something. When the subject is your pharmaceutical reality and one of them starts getting nasty (perhaps demanding you not use the word rape), tolerate none of their nonsense. Call them out for derailing your thread and keep the focus on pharmaceutical rape.

[*As a survivor of multiple traumas, including child sexual abuse/rape, I have found it essential to discover and use precise words to both name and make sense of my experiences. My choice to use the word rape to describe pharmaceutical violation comes not from a misunderstanding of the gravity of sexual assault, but from my understanding of it as an abuse of power that takes one by surprise, leaving confusion and destruction in its wake. It is my hope that this new definition can be approached with an open mind and that survivors of all abuses, regardless of what type, will extend the use of full vocabulary to fellow survivors.]

Other Definitions You Might Want To Know:

Word/Tone Police – One popular Urban Dictionary definition reads: tone police are people who focus on (and critique) how something is said, ignoring whether or not it is true. They will discard a true statement simply because they don’t like how it is presented. People who word/tone police take issue with the speech of others instead of hearing the message. They do not respect a person’s right to choose their own words and tone when expressing outrage for injustice they have experienced.

Dog Pile – Also from Urban Dictionary: a disagreement on an internet message board wherein one person says something [that is unpopular] and a large number of people comment in response to tell the person how wrong and/or horrible they are, and continue to disparage the original commenter beyond any reasonable time limit. People who contribute to a dog pile are usually reacting and therefore not listening. Their only concern is shutting up the person who triggered their reaction.

These kinds of behaviors have been used against the term pharmaceutical rape by people who either subscribe to a social justice dogma that prevents them from thinking critically, or who do not yet understand the seriousness of the current pharmaceutical reality. Fortunately or unfortunately, there are few things that exemplify a pharmaceutical rape culture more clearly, as well as our need to address it, than the knee-jerk reactions of these individuals.

Other things pharmaceutical rape is not:

Involuntary Treatment – Also referred to as forced drugging, this is: medical treatment undertaken without a person’s consent. In almost all cases, involuntary treatment refers to psychiatric treatment administered despite an individual’s objections. While forced drugging is considered a serious violation in its own right and often involves the use of pharmaceutical products that can cause life-altering harms, involuntary treatment in and of itself is not what is meant by this definition of pharmaceutical rape.

Recognized Side-Effects – A side-effect is described as: a secondary, typically undesirable effect of a drug or medical treatment. Recognized side-effects are acknowledged drug reactions that are included on medication warning labels. Some harms are going to occur even when risks are disclosed and precautions are taken. Pharmaceutical assault involves drug risks and reactions that patients have not been sufficently warned about. Many of these risks have gone intentionally unacknowledged, whether through bias in scientific research or failure to conduct follow-up studies, as well as failure to take anecdotal evidence seriously.

Medication Error – A medication error is described as: any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems including: prescribing, order communication, product labeling, packaging and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use. Medication errors happen when things go wrong. Pharmaceutical violence results from intentional and systemic modes of operation within the drug industry and healthcare systems, as well as within academic, regulatory, and governmental institutions.

Medical Malpractice – The definition of medical malpractice is: any act or omission by a physician during treatment of a patient that deviates from accepted norms of practice in the medical community and causes an injury to the patient. While medical malpractice is considered professional negligence, or conduct that falls short of accepted medical standards, pharmaceutical violations always occur within the common, accepted standards of medical practice.

Tenets of Pharmaceutical Rape:

Full, informed consent is paramount. If any information for a pharmaceutical product is withheld, omitted, faulty, or misleading, full, informed consent is not possible. The lack of awareness of the full range of hazards about a drug should never obscure a basic acceptance that all drugs are poisons. Where adverse events are occurring and yet fail to become the subject of further attention or scientific study, this is pharmaceutical rape.

No pharmaceutical (including vaccines) is completely safe for everyone in all circumstances. Many have more dangers than are acknowledged. In the current climate, it is difficult if not impossible to judge whether or not full information for a product is being made available. Whenever a pharmaceutical treatment is offered, available alternatives must also be discussed.

Without judicious prescribing and adequate information, any patient can become a pharmaceutical rape victim. There are as many types of pharmaceutical violation as there are pharmaceutical products for which information has been withheld, omitted, or is faulty and/or misleading.

The Root of Pharmaceutical Rape:

The production and promotion of commercial products that have undisclosed/unacknowledged adverse outcomes for which complete scientific data has been withheld and/or kept unavailable for independent analysis. It is the continued promotion/prescribing of products irregardless of potential/unknown harms for which no follow-up studies are initiated or undertaken to confirm or rule out risks. It is the caviler prescribing of medications while ignoring or downplaying known risks.

In 2014, writing for Daily Kos, Lynn Vogel noted the lack of any meaningful response by medical authorities to the polypharmaceutically induced death of four-year-old Rebecca Riley:

“Psychiatrist Dr. Kayoko Kifuji of Tufts-New England Medical Center had prescribed 4-year old Rebecca Riley psychotropic drugs for more than a year prior to the child’s drug-induced death in December 2006.

“CBS News reported that Dr. Kifuji had authorized a prescription regimen of ten medications per day for her patient’s symptoms.

“Rebecca Riley’s death prompted national attention because her parents were charged and convicted of murder. Dr. Kayoko Kifuji continues to practice medicine.

“There has been no meaningful introspection on the part of the medical community regarding these polypharmaceutical practices and the FDA has not intervened. Enter ADHD on the computer and one will find numerous practitioners promising quick diagnosis and treatment.

“At the time of the 60 Minutes Rebecca Riley broadcast, one million children were receiving psychotropic drugs, today the figure is 6 million according to The New York Times. The number of deaths and impairments caused by these commonly-prescribed childhood drug cocktails are not dutifully tracked.

“Some of the medications attributed to Rebecca’s death were Depakote /750 mg, Seroquel /200 mg, and Clonidine /.35 mg. PhRMA members have repositioned these epileptic, depression, and hypertension control substances to treat ADHD and Bipolar disorders. These recycled drugs are not approved by the FDA for use in children under the age of six.”

Daily Kos. Apr 29, 2014.

To simply consider the concept, pharmaceutical rape, (and the fact that it goes so widely unnoticed, not to mention unprosecuted), is to take instruction in the power relationship between the multi-billion-dollar pharmaceutical corporations and the individuals for whom their products are targeted.

Pharmaceutical rape involves the reckless behavior of industry decision makers (and those who collude with them) that results in bodily damage to individual persons. It results from aggressive corporate decisions as well as drug company dominance in governments, regulatory agencies, academic institutions, medical journals, the psychiatric establishment, medical and mental health care systems, front groups, and the media. Because pharmaceutical rape can be so physically and psychologically destructive to its individual victims, it is a type of violence as opposed to being merely an effect of fraud for financial reward.

In 2006, Rebecca Riley’s death brought widespread attention to the the emerging practice of the prescribing of powerful antipsychotics to toddlers who were being newly diagnosed with mental illness. These and other drugs that were being used off-label had never been tested in children. A report in the The Boston Globe, illustrated how “key opinion leaders” are rewarded by the pharmaceutical establishment to make this happen:

“Psychiatrists used to regard bipolar disorder as a disease that begins in young adulthood, but now some diagnose it in children scarcely out of diapers, treating them with powerful antipsychotic medications based on [Joseph] Biederman’s work.

“‘We need to treat these children. They are in a desperate state,’ Biederman said in an interview, producing a video clip of a tearful mother describing the way her preschool daughter assaulted her before the child began treatment for bipolar disorder. The chief of pediatric psychopharmacology at Mass. General, he compares his work to scientific breakthroughs of the past such as the first vaccinations against disease[…]

“Part of the criticism of Biederman speaks to a deeper issue in psychiatry: the extensive financial ties between the drug industry and researchers. Biederman has received research funding from 15 drug companies and serves as a paid speaker or adviser to seven of them, including Eli Lilly & Co. and Janssen Pharmaceuticals, which make the multi billion-dollar antipsychotic drugs Zyprexa and Risperdal, respectively. Though not much money was earmarked for bipolar research, critics say the resources help him advance his aggressive drug treatment philosophy.”

The Boston Globe. June 17, 2007.

While Joseph Biederman may have faced some criticism after the pharmaceutical rape of Rebecca Riley, this kind of prescribing only escalated. Four years later, Forbes Magazine would report how the pharmaceutical industry responded to her death:

“It is not illegal for a doctor to prescribe a drug off-label, that is, for a non-FDA-approved use, but a drug marketer cannot lawfully encourage a doctor to do so. The profits in psychoactive drugs, however, make it tempting to flout the law. In the past four years, AstraZeneca, Pfizer, Eli Lilly, Bristol-Meyers Squibb, and Forest Labs have all settled federal charges of marketing psychoactive drugs off-label, at a cost running into hundreds of millions.”

Forbes. June 30, 2011

Little Red Stethoscope

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To be read in conjunction with Little Red Riding Hood.

Once a newly qualified doctor, wearing her red stethoscope, set out to treat an older woman, bringing medicines and the milk of human kindness. As the doctor was walking through the hospital, the medical director came up to her and asked where she was going.

“To Mrs Clinton’s bedside”, she replied.

“Which path are you taking, the path of clinical experience or the path of the guidelines?” “The path of the guidelines”.

So the medical director took the path of clinical experience and arrived first at the bedside. Mrs Clinton was dead. She had been taking warfarin and a device the hospital had been supplied for free as part of a Xarelto clinical trial had malfunctioned and she had had a stroke.

The medical director drained her blood and poured it into a bottle, sliced her flesh onto a platter, and stored it in the fridge. Then he called an inquiry. Little Red Stethoscope was summoned.

“Knock, knock.”

“Come in, my dear”.

“Hello, I’ve brought with me the medicines and milk I was bringing to Mrs Clinton as you asked.”

“Have something yourself, my dear. The lunch on the table in front of you is free”.

Little Red ate what she was offered. As she did, an app on her phone said: “Slut to eat the flesh and drink the blood of Mrs Clinton!”

“Then the medical director said, “While waiting for a report on Mrs Clinton’s death, you will have to be suspended”.

“Where shall I put my white coat?”

“Throw it in the sluice room; you won’t need it any more”.

“For each item ‑ pager, ophthalmoscope, radiation badge ‑ Little Red asked the same question; and each time the medical director answered, “Throw it in the sluice room; you won’t need it anymore.”

When she was finished Little Red said to the medical director, “Oh!  How hairy you are!”

“Yes its the testosterone – power does this to you, my dear.”

“Oh!  What big shoulders you have !”

“All the better to carry my laptop, my dear”.

“Oh!  What manicured hands and nails you have ?”

“Its for writing reports better, my dear !”

“Oh!  What big teeth you have !”

“Its for eating you better, my dear.”

And he sank his teeth into her with a report that made her solely responsible for Mrs Clinton’s death.

RR3

Little Red Riding Hood and Little Red Stethoscope are both cautionary tales about risks and their management. When I began training, no-one ever heard the words Risk Management even though medicine was obviously about managing risks.

Several decades later, Risk Management was everywhere with most nurses and doctors spending their time managing any risks there might be to the organization that employs them.

When I began training medical directors were in the business of guiding junior doctors down the path of clinical experience as they recognized that the best way to manage risks was to have the best possible people in place. Whatever about surgical procedures, the idea that risks could be managed by ticking boxes was famously met with a response – we’re not running a Chinese take-away here.

Medical directors now are more concerned about the brand value of the organization they work for and their own brand within it than they are for any patients or staff.

When I began training everyone bought their own stethoscope and they were all grey. Then somewhere toward the end of training red stethoscopes appeared. They initially came as gifts from drug companies. Where could the problem come from having a red stethoscope? Surely the more stethoscopes around the place, whatever their color, the better.

Some day a Coby and Mina Grimm may update the Red Stethoscope story – giving it an alternate ending, in which someone, could be Little Red herself, strangles the medical director with a red stethoscope. As long as no-one offers an “interpretation” that this feature reveals that the true meaning of the story lies in a latent lust for power, the essential meaning will not have been perverted.

Little Red Riding Hood

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This is the first of a two part piece. Little Red Stethoscope follows. More on the current post can be found in Images of Trauma.

A grimm tale

The development of psychoanalysis depended heavily on Freud’s approach to the interpretation of dreams and myths. Key to these interpretations were his claims about the symbolic nature of certain elements of dreams, myths or conversations. Interpreting the symbol revealed what the dreamer, myth-maker or patient really meant.

Following Freud a number of prominent psychoanalysts analyzed various fairy tales and claimed to offer their timeless and true meaning. Chief among these analysts were Bruno Bettleheim and Erich Fromm.

At the centerpiece of most of these interpretive efforts was Little Red Riding Hood.

In recent years Angela Carter’s short story made into a marvelous movie by Neil Jordan, The Company of Wolves, hinged on this true meaning revealed by the analysts.

Briefly, the Red Riding Hood indicates a young girl on the verge of puberty. The Bottle she carries in her basket symbolizes her virginity. Her mother’s Warning not to stray from the path is an injunction against sexual intercourse. Visiting her grandmother is an Oedipal abolition of her mother. The Wolf represents her Id and her Father. The saving huntsman is her rational ego.

A grimmer tale

The analytic claim that interpreting this fairy story in these terms reveals the correct and timeless significance of the story offers a wonderful and beautiful tale in its own right. But it’s a fiction. These interpretations cannot be correct. They are based on a fundamental inaccuracy, which is that the text used for these interpretations comes from Jacob and Wilhelm Grimm, which is a corruption of the version that came down through the oral traditions of French peasants.

The origi­nal version is as follows:

RR2

Once a little girl was told by her mother to bring some bread and milk to her grandmother. As the girl was walking through the forest, a wolf came up to her and asked where she was going.

To grandmother’s house“, she replied.

Which path are you taking, the path of the pins or the path of the needles?”

The path of the needles“.

So the wolf took the path of the pins and arrived first at the house. He killed grandmother, poured her blood into a bottle and sliced her flesh onto a platter. Then he got into her night­ clothes and waited in bed.

“Knock, knock.”

“Come in, my dear”.

“Hello, grandmother. I’ve brought you some bread and milk.”

“Have something yourself, my dear. There is meat and wine in the pantry”.

So the little girl ate what was offered. As she did, a little cat said:

“Slut to eat the flesh and drink the blood or your grandmother !”

Then the wolf said,

“Undress and get into bed with me”.

Where shall I put my apron ?”

Throw it on the fire; you won’t need it any more“.

For each garment ‑ bodice, skirt, petticoat and stockings ‑ the girl asked the same question; and each time the wolf answered,

“Throw it on the fire; you won’t need it anymore.”

When the girl got into bed, she said,

“Oh, grandmother !  How hairy you are!”

Its to keep me warmer, my dear.”

Oh, grandmother !  What big shoulders you have !”

Its for better carrying firewood, my dear“.

Oh grandmother !  What long nails you have ?

Its for scratching myself better, my dear !

Oh grandmother !  What big teeth you have !

Its for eating you better, my dear.

And he ate her.

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There are no red hoods, bottles, admonitions to stay on the narrow path or saving hunters in the original. The interpretation of elements of a story in terms of its symbolic qualities may be justified but if this is to be undertaken it would seem necessary to establish beforehand the correct version of the story to be interpreted – or you can make up what you want.

Antidepressants & The Undead

9d041d40-e872-0132-c046-0a13eebe068d Several of us involved in RxISK.org monitor other groups setting up to offer information on medicines. Some of these, like eHealthMe, offer useful information sometimes with innovations we wish we had thought of first. The general sales pitch is under the umbrella of Personalized Medicine.

As ever pharmaceutical companies are in there early. The Brintellix website, as noted in We Should Talk about Brintellix, is a masterclass is how to appear patient centered, and patient friendly. How to move with the times and make the new way of doing things yours – “Give us your stories of the impact of treatment on you… segues sweetly into:

“Keep, ancient pharma, your storied pomp!” cries she
With silent lips. “Give me your tired, your poor,
Your huddled masses yearning to breathe free,
The wretched refuse of your teeming shore.
Send these, the homeless, tempest-tost to me,
I lift my lamp beside the golden door!”

It is likely that many will view the concern expressed on websites like the Brintellix one as genuine. People have to be let make their own minds’ up; the sites come clearly badged for what they are.

AllTrials is a much greater conundrum. Friend or Foe? Liberation Movement or Trojan Horse?

Iodine

Start Io

Into this mix, a little over a year ago, stepped Iodine.com. San Francisco based, it proclaimed itself as totally independent of the pharmaceutical industry with an awesome panel of pharmacists and MD-PhD candidates. It aimed at offering people-powered information on medication to guide you in your choices.

Billed by Time as the Yelp of medicine, and by the New York Times as addressing a notable information gap in healthcare, it seemed like the kind of thing to keep an eye on – with perhaps the kind of mixed feelings that Buffy clearly had with the arrival of Faith. Always good to have another Vampire Slayer but where exactly is she coming from?

Several weeks ago Iodine launched Start – a new way to tell if your antidepressant is working for you. You would interact with it and it would guide you without – it promised – giving any of your data to the pharmaceutical industry. It offered reports to help you work out if your medication was helping or not. Sounded a bit too close to RxISK for comfort.

Its testimonials say its empowering and that being able to track your personal journey to wellness makes a big difference.

Some of us downloaded it. The technoranti (tech-ignorant) among us couldn’t get it to work, which is where the real story lies. Others could get Start to start.

If you’re tech savvy (technoscenti) you’ve got time left over to be mischievous. So one of us began Brintellix with the intention of becoming suicidal on it to see what Start would do. Despite a clearly deteriorating mental state, Start stuck to a line that it was best to continue with the medication as that’s what works – and works even better in anyone who is seriously ill. The prompts to fill reports come in relentlessly and no matter how suicidal the report the response was invariably a cheery message that salvation through pharmaceuticals is just around the corner – even if your doctor does have to switch you to something else.

Start screenshots and testimonials are attached here.

Vampire manual

daybyday

The responses for something like this have to be generic – in other words its vampire meets human body rather than vampire meets you. If the vampire ever becomes concerned about you, its the vampire equivalent of salt losing its bite – as Angel found out when he fell in love with Buffy.

Being generic the responses have a certain timeless and universal quality. They keep going for the same spot – the jugular. The Start responses map eerily onto the responses in a medication guide for Prozac produced by Lilly in the mid-1990s – long before Apps were born. A different millennium. But close to word for word the same – no matter how bad you are feeling keep taking the meds.

Calling it Night by Night would have been too much of a give away. The Day by Day brochure is here. It’s difficult to see this information – billed as helpful – as anything other than more poisonous than the medication.

No smell?

But as I said the real story lies with the technorant. You might not be able to get something to work but its almost impossible not to be able to download it. If you live in the US, Iodine will install Start on your phone for you if you call them.

But if you can’t then get it to work, it doesn’t go away. It continues to message you for months even though you haven’t filled up the rating scales necessary for your report. You could be swinging from the chandelier or in your grave but the beeps will still come – as long as there is life in your phone.

For centuries, maybe millennia, people have worried about evil spirits and vampires because of unsettling features like the fact that nails and hair keep growing after death. The possibility of possession seemed real enough to make it look like a good idea to dispose of a corpse quickly.

Who knows what the peasants of Eastern Europe – or an Irishman like Bram Stoker – would have conjured out of Start?

Buffy

Sorry Buffy getting beeped when the Apocalypse comes is so last millennium. The beeps from the Undead go on beyond the Apocalypse – beyond even the Twilight of the Undead.

Whatever about a mirror image or a pulse, a clue for any technoscenti tracking down the new vampires is that they have no smell.

Motivation Is Worth More Than Expertise?

Objectivity

Editorial: I was asked to MHRA (Britain’s FDA) to give a 20 minute presentation on Spontaneous Reporting Systems to a group looking at a birth defect related issue. This is close to what was said – minor items like the HRT trials got lost in delivery. The Slides numbered in the text are attached Here.

Are we anecdotes?

On this first slide (1) you can see a recent article from Vice, which along with other new media outlets often offers better reporting on a range of issues from the Islamic Caliphate to healthcare than traditional media. This article on Pfizer’s varenicline – Champix in the UK and Chantix in the US – runs to 10 pages with great illustrations.

The piece outlines the case of Chris Kunkel who went on Champix to stop smoking. He found that it killed the craving for nicotine very effectively. But after being on the drug for a few weeks an urge to kill himself came over him just like the urge to go and get a sandwich from the fridge. He took a huge number of pills but survived because his wife came home early and found him. He had no prior history of mental illness, no reason to think he was going to commit suicide. His case. as outlined, was convincing.

The article makes it clear that there have been thousands of other spontaneous reports like this that appear to make a strong case. But the article also makes clear there are a large number of Randomized Controlled Trials (RCTs) that have been meta-analysed by Pfizer which show no signal of an increased rate of suicidal or homicidal events on Champix. When these studies are analysed by experts independent of Pfizer, they too have found no evidence of a linkage.

This leaves independent experts saying that they as scientists have no option but to go with what the scientific literature shows. That the Chris Kunkel and other cases are simply anecdotes. It’s just as though someone gave an MMR vaccine to one of their children who later develops autism and claimed that the vaccine must have caused the problem. This is anecdotal.

Lightbulb moments

These are anecdotes is not a reasonable characterization of many of the reports of what happened on Champix and it is not the case with drug induced injuries in general.

The strongest evidence we have as to whether a drug causes a problem does not come from RCTs or any other controlled study but rather from good clinical accounts which include the elements of challenge, dechallenge and rechallenge.

This is the ‘Christmas tree light bulb’ test (2). When Christmas trees had real light bulbs rather than diodes, invariably when they were taken down after being stored for a year the lights didn’t work. The trick was to unscrew each bulb in turn until you unscrewed one and the bulbs came on. You could screw that back in again and the bulbs would go off again. So you removed it and threw it away and the lights worked fine. This is absolutely conclusive evidence that this was the dud bulb. Similar evidence is the strongest we have that a drug can cause a problem. It doesn’t tell us how often the drug causes the problem but nothing gives us this information.

The trouble is challenge – dechallenge – rechallenge cannot be undertaken easily in the cases of drugs given during pregnancy. It is against that background that companies claim that RCTs offer the only gold standard. That all other kinds of observational studies are flawed.

RCTs: The gold standard way to hide adverse events

Some of you may be aware of the Restoring Study 329 article that appeared in the BMJ 3 months ago. It is now among the articles with the highest impact of any article in the last 25,000 that the BMJ has published (3).

This illustration (4) taken from the article shows you at the bottom under the heading Keller et al what the original publication reported in terms of the suicidal events that happened in this trial of paroxetine given to adolescents.

In the box above it labelled SKB, SKB some years later conceded that there were more suicidal events than had appeared in the published article. In the box above that labelled FDA you see FDA stating that in fact they were of the opinion that there were more such events than GSK had now reported to them.

Finally in the box at the top labelled RIAT you see that in our publication we were of the view that there were yet more events than the ones FDA had found and in fact we think there are even more than what we’ve reported here.

This may hint at one reason why when experts analyse the Champix clinical trials they don’t find an increased risk. They are analysing the published literature for the most part and the published literature doesn’t necessarily show all that happened. The Study Reports companies increasingly post on websites do not offer the full data either.

On this next slide labelled Box 2 (5) you see some of the many ways we found that data can be hidden in controlled trials.

  • The company may use an idiosyncratic coding system. In the case of Study 329 they coded the suicidal events as emotional lability.
  • There can be a failure to transcribe the raw data into the forms then used to analyse what happened – 15% of the events went missing in this way.
  • There are various different ways to group the events that may hide the problem from an outsider who is unaware of the issues and not especially motivated to look more closely.
  • In the trials of many drugs from statins to antidepressants, it is common that concomitant drugs will be given to both the active treatment and the placebo groups and this dilutes any apparent signal from the active treatment.
  • There is usually no effort to analyse the events that happen during the taper phase of a trial – often the most dangerous phase.

Even if done by angels

But even if the trials were done by angels, so there was no hiding, no miscoding, nothing untoward, RCTs can still hide adverse events. In the case of the Champix studies it may be that plunging people into nicotine withdrawal is a dangerous thing to do and that compared with that Champix treatment comes up as being somewhat better even if Champix itself can cause people to become suicidal.

Is this bizarre possibility possible? Yes it is. You see here the proceedings of a symposium held in Cambridge in 1959 a year after imipramine the first antidepressant was launched. On the next two slides you see delegates to the meeting talking about the fact that imipramine which treated the kinds of patients that would otherwise have been referred for ECT, severely depressed patients, could in the opinion of these clinicians also cause people to become agitated and suicidal and that the problem cleared up once the drug was removed. I can show you more quotes than the ones you see here but there was no argument from anyone at the meeting against the notion that this wonderfully helpful drug could also cause people to become suicidal (6, 7, 8).

That sets up the scenario you see in this next slide which is that if imipramine is an effective treatment for severe depression in the way that the SSRIs for example aren’t, then it will reduce the rates of suicidal events that happen in this trial compared to placebo even though it’s a drug that can cause people to have a suicidal event (9). If you were to put imipramine into the kind of trials that the SSRIs were put into, that is trials of patients with mild depression, you get the same result as you get with the SSRIs – namely that on the active treatment there is an increased rate of suicidal events compared to placebo (10).

This kind of problem happens every time an illness and a drug can cause a superficially similar thing. It means that controlled trials are not a good way to discover whether a drug is causing a problem or not (11).

I could show you a range of other tricks that companies can do with controlled trials. There are several ways to use the problem a drug causes to hide the problem that the drug might be causing.

The basic message on this Fishing slide is that if you don’t know what the problem is to begin with, RCTs won’t help you. RCTs are principally useful when you know what you are doing in the first instance and they are used to demonstrate that you know what you are doing (12).

Even then they may come up with the wrong answer but as in the case of the HRT studies where they suggested that it might not be a good idea for everybody in the entire universe to be taking HRT, even if the answer is wrong it puts the onus back where it should be which is on large and powerful corporations who have a lot of resources to pinpoint the populations where the benefit is likely to exceed the risk if they want to continue to make money out of vulnerable people.

Observational studies

So if controlled trials don’t sort the issue out for us as to whether a drug causes a problem, what are the other options? There are a variety of case controlled studies, cohort studies and nested cohort studies.

In the case of SSRIs and autistic spectrum disorder (ASD) there are 5 such studies as you see here (13). When you analyse these you find that there is an almost two fold increase in the risk of a mother having a baby with ASD when she has been on an SSRI compared to when she has not been on an SSRI.

The standard company response to data like you see here is that in a few of the studies the confidence intervals touch the 1.0 line and their view is that because they do that there’s no increase in risk in these studies and because we have a mixture of studies some of which show an increase in risk and others which show no increase in risk, therefore in fact there is no problem.

On the next slide you see 17 studies which have looked at what could be termed developmental delay (14). I’ll just quickly draw your attention to the Malm et al study 7 lines down.

Broadly speaking when you sum all of these studies, you get a result which shows that there is a close to a doubling of the rate of developmental delay in children born to women taking SSRIs during pregnancy.

On the next slide you see a very provocative image of holocaust denialism (15). Texts like this ask you to note that General Eisenhower wrote a 600 page book about events from June 1944 through to the end of the War and didn’t once mention concentration camps. Do you think that if what people claim was really happening that he wouldn’t have mentioned it?

The issue here is not to impute motives of Holocaust Denialism to companies but to show you how a problem can be structured so that that is the de facto outcome you get.

Faced with a problem like ASD companies convene panels of experts within the company – the epidemiology group, the animal testing group, the pharmacological group, the pharmacovigilance group, the risk management group and others – all of whom will be given a portion of the problem to look at from their point of view. All groups are asked is there incontrovertible evidence from your point of view of a problem. All will answer no there isn’t. This is a system where it’s almost impossible for a problem to register.

The person coordinating this will often be a person who knows nothing about any of these areas. Their job is to coordinate. When faced with for instance evidence of the developmental delay studies this coordinator if asked whether it would be appropriate to include studies of developmental delay with the ASD studies would say “Well, we didn’t do that”.

Why not? “My brief was to only look at studies that had ASD specified in the article.

Do you not think that developmental delay is much the same thing? “I don’t know. I know nothing about these things, we simply stuck to articles that had ASD in their body”.

This is standard company approach and may explain what researchers find when they go into company archives and seem to be faced with overwhelming evidence that the company knew there was a problem but denied all knowledge.

A structure of this kind is put in place in the name of Objectivity. In practice it makes it impossible for the company to see the bigger picture.

In public when a company is faced with the data from the previous slides for ASD or any problem. They say (16):

  • The ASD rate in these studies doesn’t exceed the background rate in the wider population
  • There is no evidence that ASD (leaving out neuro-developmental delay (NDD) or that NDD is leaving out ASD) is caused by SSRIs.
  • There is no evidence that ASD is caused by Prozac, or by Paxil – Seroxat or by Zoloft and if not caused by any individual SSRI cannot be caused by SSRIs.
  • The risks are not statistically significant and therefore do not exist.
  • They will claim that depression causes ASD, just like it causes birth defects and suicide and dependence and ingrown toenails.
  • They will claim only RCTs give conclusive answers. This unthinking mantra allows companies to get away with a lot.

Registries & objectivity

In terms of adverse events, there is one more option – pregnancy registries. These are a specific birth defect option and arguably the best option. FDA and some companies have put limited registries in place (17). These have been piecemeal and voluntary. To really look at what is going on we need to exploit the possibilities of Big Data. Every woman who gets antenatal care has the details of the pregnancy and every drug she is taking recorded as is, including over the counter medication. If such material were made available in e-form, including data on the children followed out to five or ten years, we would be better able to pinpoint issues than we are now.

Who should analyse the data? A lot depends on your vision of what is needed.

Regulators and companies have been the traditional people to interrogate post marketing data but their brief has never been exploratory (18). The SSRIs have now been on the market 25 years and the data linking them to Developmental Delay is just emerging – when we could have had warnings of this possibility 20 years ago.

For instance, take the Malm et al study that I mentioned earlier. This was a large epidemiological study by a good group of researchers who as a footnote at the end of their article noted a 10 fold increase in Foetal Alcohol Spectrum Disorder (FASD) in children born to women taking SSRIs during pregnancy. They clearly had no idea what to make of this (19).

This incidental finding is exactly the kind of thing that needs someone other than an epidemiologist to spot possible connections. SSRIs can cause compulsive alcoholism, so the Malm finding is not surprising to some of us – including to pharmaceutical companies who are running trials of S2 and S3 blockers as a treatment for alcoholism because they are persuaded the link is solid.

It clearly was a surprise to Malm and would be to most epidemiologists or regulators. Spotting connections like this needs a convergence of different skill sets – exactly the opposite model to the one companies and regulators have in place. For any event that is new, almost by definition, motivation counts for more than expertise as expertise is expertise in what has happened that will often block perceptions of something new that breaks the mold. There is no more motivated group of people in this universe than mothers or mothers to be.

At the heart of the proposal that women should be the main interrogators of pregnancy registry data lies the question of objectivity (20). Objectivity doesn’t come from mechanical exercises like RCTs or case controlled studies. It comes from having the best data you can get and having people with a range of biases look at that data to see if a consensus emerges. The range of “biases” can help a group see why what may appear to be a link really isn’t one and how things that might seem to make no sense initially actually do make sense. It’s when people with different starting points agree that we get objectivity. It comes from just the opposite approach to the one Companies and Regulators take – in the name of objectivity.

It is nineteenth century paternalism to think that women will be scared by some oddity tumbling out of such a database and that they will act rashly as a result. Women as a group spend more time risk managing than men and will look for consensus and operate on the basis of that consensus. Telling women that they shouldn’t have access to this data is rather like telling them that they shouldn’t have control of their own bodies, that men or the state are going to decide for them. This might be the case in the Caliphate but here in London?

The Ghost of Research Future

Califf FDA nomination Portola

Editorial Note: This post is by Johanna Ryan. As with all posts by Jo, it unearths angles on current stories that everyone else seems to have missed.

A column here last month followed the legacy of Study 329 into the present. By taking apart one 2015 study of Vraylar, a new antipsychotic, I tried to show that clinical research in 2015 is even more ghost-written, and more tightly controlled by industry, than that infamous 1990’s study. I had planned to follow up with a look at what the official authors and contract researchers involved in that Vraylar study were up to now.

Then Robert Califf was nominated to head the U.S. Food and Drug Administration, and I recognized the real Ghost of Research Future. He was right there on Capitol Hill in a white coat and a winning smile, holding forth to politicians and the media at his Senate confirmation hearing.

Two facts about Robert Califf are beyond question. He is an expert on clinical trials, who is already seen as a leading architect of the future of medical research. And as the New York Times put it, he has “deeper ties to the pharmaceutical industry than any FDA commissioner in recent memory”. A lot of senior figures in medicine support Califf in spite of his ties to Pharma. The guy is just so bright, and understands the nuts and bolts of drug research so well! Surely a person like this is more useful than some outsider who offers only a squeaky-clean resume, they argue.

Other researchers and healthcare activists are not so sure. They point to clinical trials run by Califf and his Duke colleagues for Xarelto, a new anti-clotting drug, that were flagged by FDA reviewers as being biased in Xarelto’s favor. The studies were funded by Johnson & Johnson, and the concerns were serious enough that two senior reviewers voted against Xarelto’s approval. Former FDA cardiovascular analyst Thomas Marciniak called Califf “one of the architects” of a broken clinical trial system run by drug companies, a feat for which he should be “held accountable, not appointed to run the FDA.”

Most of the senators at his confirmation hearing shared a rare bipartisan enthusiasm for Califf, but a few had their doubts. Vermont’s independent senator Bernie Sanders, currently running for president as a Democrat, wants the FDA to take on prescription drug price-gouging. He doubts Califf is the man for the job. Senator Elizabeth Warren thinks the FDA must insure new blockbuster drugs like Xarelto are actually effective and safe. She has asked Califf for a look at the terms of his contracts with the drug companies that funded his research.

The Duke Clinical Research Institute

The Duke Clinical Research Institute (DCRI) will likely be Senator Warren’s first stop. Califf cofounded the DCRI and was its first director. Since then he’s helped launch a dizzying array of Institutes, think tanks and public-private partnerships: the Clinical Trials Transformation Initiative, the Clinical Research Forum, the Duke Translational Medicine Institute, which he headed just prior to joining the FDA, and more. But the DCRI is his signature achievement, his baby, so to speak. And if Duke University was the mother and Califf the midwife, the father was Research Triangle Park, the Silicon Valley of corporate medical R&D just down the road from Duke.

Back in the 1990’s, the problem posed by Study 329 was medical school researchers letting their work be funded and co-opted by industry. By 2015, things were worse. It was common to see these same researchers signing on to clinical trials designed and controlled by industry from the start, with minimal input from their universities. The Vraylar studies were an example of med school faculty lending their prestige and credibility to work that was actually done in dozens of commercial Contract Research Organizations (CROs) far from the campus, and written up by medical communications agencies hired by the drugmakers.

Robert Califf’s DCRI is a new hybrid: a CRO built right into the university, but whose mission is to solve whatever research questions matter to its paying customers, like any other CRO. DCRI describes itself as:

“… the only one of its kind that can offer all the services of a commercial contract research organization (CRO) with the academic credibility and expertise of an academic research institute. From planning to execution to publishing results, the DCRI excels at every facet required for a speedy, effective research project. Our unique operational model ensures that all aspects of a project account for both our dedication to patients and the business needs of our sponsors.”

Some of this research is done at Duke. Most, however, takes place at outside research sites recruited and managed by the trial experts at DCRI. In cardiology, DCRI touts its ability to run global commercial megatrials in dozens of countries.

DCRI also provides “strategic communications”: everything from crafting effective journal articles and conference presentations, to designing CME programs that make sure prescribing doctors absorb the key results of the sponsors’ research. It connects companies with “thought leaders” who “are uniquely positioned to understand the operational, financial, and regulatory implications of numerous project designs, to the great benefit of our clients.” It even offers clinical-research classes delivered directly to corporations through DCRI Learn: “Let DCRI customize an experienced-based learning program for your employees. Proposals are confidential and programs individualized.”

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Faculty Connection, LLC

It’s hard to imagine an industry-sponsored project Duke faculty members could sign up for that would not “fit within the mission of the university”. Yet in 2005 “Faculty Connection, LLC” was formed to help professors do just that, with Robert Califf on its board of directors. FC negotiates contracts (and aims to limit confidentiality clauses to “five years or less”), takes care of required conflict-of-interest reports, and “shields consultants from personal liability” through its LLC structure, as this 2011 video explains. In return it charges a 25% overhead fee which it says is often paid by industry; if not, it takes 20% of the faculty member’s earnings.

Most of Califf’s personal consulting fees for work with industry appear to have come through FC. If so, the “nonprofit” to which he famously donated his fees would usually have been DCRI itself, through its fellowship programs for promising young Duke researchers.

The Xarelto story: Safe and effective compared to what?

“Bias in choosing the question is a much bigger problem than lying about the data.”
Robert Califf, February 12, 2013

Xarelto is one of several new anti-coagulant drugs approved in recent years to prevent strokes and other clot-related complications, especially in people with heart-rhythm disorders such as atrial fibrillation. All aim to replace a much older, cheaper and more well-known drug called warfarin.

Anti-coagulation or “blood thinning” is a trick that needs to be done just right. It must work well enough to prevent formation of clots that can lead to strokes or heart attacks. But if it works too well, even minor internal bleeding can become life-threatening. That’s why warfarin requires careful dosing, limiting certain foods and alcohol, and periodic tests to make sure your blood level is in a therapeutic range. It’s also why people with milder cardiac conditions are often advised to take aspirin instead, which is less effective but simpler to use.

What drugs like Xarelto and Pradaxa promised was anti-clotting action as good as or better than warfarin, but in a convenient once-daily dose with no need for monitoring. That was Dr. Califf’s message when he presented the ROCKET-AF trial to the American Heart Association in 2011. Even then, he faced pointed questions about conduct of the trial, especially in the non-US trial centers. Warfarin doses for subjects in the control group were so poorly controlled that their blood levels were often outside therapeutic range. That set them up for a higher risk of strokes – and also made Xarelto look better than it was.

Cardiology expert Steven Nissan considered it a “fatal flaw” – and added that those more cynical than he might think the trial committee had planned it that way. The FDA reviewers agreed, pointing out that warfarin treatment in the ROCKET-AF trial was worse than either the Pradaxa trials or older studies. Patients in the U.S. who had access to good quality warfarin treatment might actually be in more danger, not less, on Xarelto.

ROCKET-AF had been billed by Califf and Duke as more convincing because it was a “real-world” trial, in which warfarin doses would be left to clinicians’ judgment rather than subject to a strict protocol. This could also lead to trouble if local trial sites had an incentive for sloppy use of warfarin, or trial designers had an incentive to choose second-rate clinicians. Xarelto would be “safe and effective” – but compared to what? Bias in choosing the question would have the same effect as rigging.

The reviewers’ next worry was a problem Xarelto shared with Pradaxa: the convenience of once-daily dosing with no blood tests, which just might be too loose to guarantee safety. Prior to the trial, the FDA had recommended that Xarelto be tested in a twice daily dose, due to its short half-life, but the ROCKET-AF group used the once-daily dose anyway – just like the trials of competitor Pradaxa. Critics charged that the makers of both drugs had sacrificed safety for the marketing value of “convenience” as an incentive to put more patients on the expensive new products.

There were two more potential safety problems: Stopping Xarelto had led to 22 strokes in 30 days, compared to just six in the control group – even though the Xarelto group were transitioned onto warfarin. It seemed quite possible that stopping Xarelto put patients in a “prothrombic state”. This could leave them in a dangerous bind if they needed to stop Xarelto, in order to have surgery for example.

Finally, unlike warfarin, whose effects can be reversed by vitamin K or plasma, there was no antidote for drugs like Xarelto and Pradaxa. In an emergency, patients could bleed uncontrollably and doctors might be unable to stop it.

The Portola story: Who needs an antidote?

To your family doctor, the lack of an antidote might sound scary – as it did to the FDA reviewers. However, developers of Xarelto insisted there was no cause for concern. A 2014 paper co-authored by Robert Califf pointed out that “all-cause death after bleeding was similar in the rivaroxaban arm compared to warfarin” in their study. It also noted that “although physicians may express a desire for specific ‘reversal agents’, these interventions are not used in the vast majority of bleed events,” and the reversal agents for warfarin were “sub-optimal” anyway. Reading that, physicians might think their worries were overblown after all.

So they might have been surprised to hear that DCRI was already working on an antidote to both Xarelto and Eliquis, made by a company called Portola Pharmaceuticals – with Robert Califf on the board of directors. In 2014 Portola announced that FDA had granted Fast-Track status to its antidote, andexanet-alfa, opening the way for faster approval with less evidence. Fast Track is reserved for drugs that address a life-threatening condition for which no approved treatments exist – and uncontrolled bleeding in Xarelto or Eliquis users qualified.

It wasn’t until January 26, 2015, when Califf joined the FDA as interim deputy commissioner, that he announced he would be retiring from Portola’s board and selling his shares. Fortunately this was after Portola’s January 9 announcement of the success of its Phase III trials, which sent its stock price soaring. (Califf also sold off a “significant” investment in N30 Pharma, a startup developing drugs for cystic fibrosis.) Duke scientists continue to work with Portola on another anticoagulant called betrixaban, and with Perosphere Pharma on PER977, an antidote to edoxaban which may reverse other anticoagulants as well. (Meanwhile, Boehringer-Ingelheim gained fast-tracked FDA approval for Praxbind, an antidote for the “life-threatening” effects of its own drug, Pradaxa. A single Praxbind injection will cost somewhere in excess of $3,000 wholesale.)

Regado

Regado exuberance

This wasn’t Califf’s only foray into anticoagulants and antidotes, or the business end of drug development. In March 2014 a similar fanfare greeted the announcement of fast-track status for Regado Bioscience’s anti-clotting drug and antidote combination, dubbed REG1 and REG2, for use in stenting and other cardiac procedures. A small number of serious allergic reactions in the Phase 2 trial three years earlier were not enough to slow the progress of Regado’s potentially life-saving therapy. Regado was known as a Duke spinoff, and Robert Califf had served on its its scientific advisory board since 2009, joined by DCRI colleagues Thomas Povsic and Robert Harrington.

A few months later, however, those allergic reactions were judged serious enough to shut down Regado’s Phase III study. By early 2015 the company had ceased to exist. Both Povsic and Harrington joined former Regado CEO David Mazza at Caladrius Biosciences, whose cell-based treatment for ischemic cardiac damage may well come up for approval during Califf’s tenure. Portola’s and Perosphere’s antidotes are sure to do so, and perhaps Portola’s betrixaban as well.

An obligation to report?

Seeking Alpha Regado

Names like Portola, Regado, Caladrius and Perosphere have seldom come up in discussions of Califf or DCRI. These companies don’t turn up in a search of the Sunshine Act database, which only tracks payments on behalf of drugs that are already FDA-approved. Often these days it’s established Pharma giants that will market the drugs and deal with any problems they cause, while the startups that handled the clinical trials may fade from view.

It’s unlikely the Senate would consider a seat on a pharma board to be a black mark for Califf, and certainly there is no shame in working on a drug like REG-1 that didn’t pan out. However, the results of such “failed” trials are just as important as successful ones, and sometimes more so. In recent years Califf has spoken and written extensively on the need for transparency, data sharing and the importance of trial registries like ClinicalTrials.gov. He’s also been asked to serve on both government and private task forces to fix a troubled clinical trial system.

So it’s worth asking: What about the trials for Regado’s REG-1 and REG-2? The initial good news about the drugs was discussed in several journal articles, but no results were ever posted on ClinicalTrials.gov. The results on the 3232 subjects in the terminated trial were never posted, and the registry says only that the trial is on “clinical hold.” The outcome was reported at a March 2015 cardiology conference, but not in any articles to date. A similar shortage of results seems to plague Portola, as well as DCRI studies of an Alzheimer’s drug and its work with Perosphere.

The brave new world of faster trials

The stakes could not be higher. In the coming year the US Senate will complete work on a total overhaul of the drug approval process, known as the “21st Century Cures Act.” Faster trials, lighter regulation and a bigger role for industry, all Califf watchwords, are central to the bill. The FDA has also approved two expensive new biologic drugs to manage cholesterol (PCSK-9 inhibitors), whose safety and real-world impact on health need to be closely watched. Califf served as advisor to the makers of both.

The fight for open data access, in the wake of Study 329 and countless other scandals from Vioxx to Avandia, may be even more important. Here again, the news is strange. Bristol-Myers Squibb has announced its own “transparency” initiative in which an Independent Review Committee will oversee sharing of clinical trial data with selected researchers. The “independent” committee will be set up by the DCRI, and consist entirely of Duke faculty.

It’s all part of a Strategic Partnership between BMS and Duke which was publicly celebrated at this 2014 event featuring Califf. The brochure has all the feel of a wedding announcement. Should any doctor, even one as wise as Robert Califf, be asked to monitor and report on his own spouse?

Study 329: Big Risk

Light bulb hit by hammer

Editorial Note: This is the Fourth Crusoe Report.

“Death waits for these things like a cement floor waits for a dropping light bulb”

Big pharma

Study 329 seems to fit the classic picture. It has Big Pharma ghostwriting articles, hiding data, corrupting the scientific process and leaving a trail of death, disability and grieving relatives in its wake.

Pharma began in the middle years of the nineteenth century when advances in the chemical and biological sciences underpinned the development of analgesics and antipyretics and later antibiotics. Within medicine, these were the first drugs that reliably worked. Within business, they led to developments in patenting and trade-marking, big profits and the emergence of an industrial-scientific complex.

The Second World War put a premium on pharmaceuticals. The development of Atabrine for malaria and Penicillin for everything else helped win the War – a lesson not lost on Governments. Pharma had become a strategic industry.

Government investment led to a cornucopia of new treatments in the 1950s and 1960s that transformed medicine. Lives were saved that would have otherwise been lost, research flourished, and the specter of premature death began to lift

Previously drugs had been developed in the pharmaceutical divisions of chemical companies. These divisions were now hived off as independent companies (Little Pharma) and these new companies rapidly became the most profitable on the planet.

In the late 1960s and early 1970s, Little Pharma called in management consultants in a bid to keep the goose laying the golden eggs. These outfits advocated outsourcing clinical trials to Clinical Research Organizations (CROs) and medical writing to Ghost Writing Agencies. They also advocated having businessmen and marketers as CEOs of the company rather than chemists or scientists or medics. They insisted on five year development plans that put a premium on the selling and reselling of popular diseases where even less effective products could be made into blockbusters rather than developing medicines for conditions that had no treatments. If the company was in the business of making profits, this switch in focus was a no brainer.

This advice created the very model of a modern major pharmaceutical – out of which came Big Pharma and Study 329.

But is this the whole story?

Big risk

The nineteenth century also gave rise to another profitable industry – the linsurance industry which is now a broader risk management industry.

The collection of data by the first life insurance companies in the eighteenth century led in the nineteenth century to the creation of public health and the idea of preventive medicine. (This will come as an extraordinary claim to many, but the underpinnings of this can be seen in books like The Creation of Psychopharmacology).

The interests of the insurance industry to manage risks laid the basis for epidemiology and an interest in numbers in health. It led to calls to eradicate filth even before the germ theory had established what it might be about filth that caused problems. Today the preventive impulse in public health medicine leads to calls to eliminate poverty – which brings medicine into politics and politics into medicine.

The first public health physicians in the early nineteenth century were called Hygienists or Sanatarians. In addition to campaigning against filth, and the adulteration of food, and for temperance, the Hygienists in Germany and Britain advocated strongly for pensions as a public health measure which in turn furthered the growth of the insurance industry. And ultimately healthcare today worldwide is (or will be with the latest Trade Treaties) delivered through insurance schemes of one sort or the other.

In the second half of the nineteenth century, therefore, the growth of the economy and of the modern world got a huge boost from both the emerging biomedical and epidemiological sciences and their linked industries.

We celebrate the gains that medicine made in the 1950s that stemmed from the discovery and production of new drugs. We miss the transformation of medicine that data from yearly insurance check-ups produced in the 1960s. These data created the notion of risk factors such as hypertension, raised cholesterol levels and raised blood sugar. From a risk management point of view the data put a premium on treating risk factors – giving drugs to people the vast majority of whom had nothing wrong with them. This was not a Pharma plot – or not solely a Pharma plot. The story has been told in Jeremy Greene’s Prescribing by Numbers.

And just as the dynamics of modern corporations transformed pharmaceutical companies from companies at the forefront of an effort to discover drugs that treat the disorders that need treating for which we have no treatments into companies that focus on the production of drugs that make a profit, so also these dynamics changed the insurance industry. It changed from an industry that viewed the environment as risky and aimed to ensure our safety from these threats and to provide our families with a safety net in the event of our death, into an industry that located risks within us and wanted to protect itself from us. Big Risk will refuse to cover anyone who is in fact risky.

The marriage of pharma and risk

The pharmaceutical and insurance industries were initially not perfect bedfellows. The insurance industry was hostile to individual doctors doing whatever they liked such as using the latest drug. But most doctors believed that medicine cannot be practiced by numbers – that the duty of the doctor is to the patient in front of her rather than to the population.

But still the early interplay between science and business within the health domain and between preventive medicine and biomedicine worked to the advantage of all. New drugs liberated us from the specters of disease. Insurance highlighted things we could do to safeguard ourselves, our families and communities.

But the situation became more ambiguous as the twentieth century went on. With the virtual elimination of mortality linked to bacterial infections some of the greatest hazards to health came from pollution linked to other new industries such as the lead and tobacco industries. Tackling the health problems that stem from industries that are important to the economy and jobs cannot expect to mobilize the same degree of community or political support, as fighting Tuberculosis or Ebola can.

In addition, the links industry developed with science in the nineteenth century left it well placed, and financially more able than academia, to mount epidemiological studies in the twentieth century. This awareness of the benefits of research along with greater resources to sponsor studies was deployed to great effect for instance in the defense of tobacco smoking and lead where industry demonstrated it had learnt to exploit the radical doubt that drives science.

There is also the tricky balance of working out where politics ends and medicine begins. There were vicious disputes in the nineteenth century between biomedicine and public health over filth. Mainstream medicine didn’t see it as its job to clear up filth. Public health insisted it was. Mainstream medicine discovered germs and embraced the elimination of germs as a legitimate medical contribution. Many in public health held out against the germ theory.

Is eliminating poverty (the modern equivalent of filth) a medical task? Or should medicine make its contribution by recognizing that many poor (a.k.a. non-white) children live in slums that still have lead in their paint and that lead poisoning knocks several points off a child’s IQ and is associated with criminality and that the medical contribution is to flag this up and find ways to eliminate lead poisoning in the face of determined efforts by a powerful industry to block them – leaving poverty to politicians?

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The shipwreck of the singular

Whatever balance you opt for in the above disputes, today, as has ever been the case, when you take a problem to a doctor for help, both you and she expect to be able to draw on the best evidence to solve your problems.

In 1990 at the start of the Big Pharma era, you and your doctor lived in a world where medical issues were found in journals, textbooks and a small number of popular books. Today there is likely to be a health story on the front page of the newspaper, with an entire section inside devoted to health. The amount of health related material on the Web is second only to pornography and even pornography is grist to the medical grind.

The political has become personal in an extraordinary fashion.

Unlike any time in medicine hitherto, when you go to a doctor today you will have to take your place in a queue of people, many of whom have been summoned to a consultation by a clinic screening for a wide range of things none of which bother the people who have been summoned. They will come to the clinic unaware of any problem but will leave with diagnoses and on medication. The doctors call them in not out of concern for them but because the doctors have targets to meet in order to get reimbursed – targets set by Big Risk.

Big Pharma play on this pitch but it’s Big Risk that draws the lines and sets up the goalposts.

When you do get in to see the doctor, you’ll find someone who adheres to Guidelines. She will do so in good faith, figuring this the way to bring the best evidence to bear on your case. She will not recognize she is being guided to see problems in certain ways and to deliver on patent treatments. She will not be treating you according to the Guideline for Treating You. If there were such a Guideline, the first point would be pay little if any heed to Guidelines for treating diabetes, or hypertension or depression or the menopause. (See The Macbeth Test).

If the problem is a mental health one, both you and your doctor are likely to be aware of conversations denigrating biological reductionism claiming that it risks dehumanizing clinical encounters. In practice however biology contributes almost nothing to clinical encounters about nervous problems.

These encounters are being dehumanized but the problem lies with an informational reductionism linked to the use of rating scales and operational criteria.

Within the mental health domain, a great deal of public discourse claims the medical model is inappropriate, diagnosis unhelpful, and the word “patient” to be abjured along with an increasingly long string of politically correct replacements. But in practice patients seek diagnoses, and the appeal of the language of chemical imbalances lay in the fact it was destigmatizing. The allure of biomedicine lies in its promise of treatments that work.

But for the first time in a century, today’s first line treatments are likely to be less effective than yesterdays.

In all of medicine, one of the greatest sources of morbidity and mortality – perhaps the greatest – now stems from the treatments patients have been put on, the multiplication of hazards by polypharmacy and the denial of the possibility of risks by corporations whose own health depends on the continuing consumption of the greatest possible number of medications by the greatest possible number of patients from the earliest possible age.

In most of the medical and lay media, Big Pharma is the only whipping boy for these evils. But is it?

Epidemiological methods are used to deny these treatment related risks. RCTs come from Big Risk not Big Pharma. When they were introduced first they were a way to contain the pharmaceutical industry. Pharma lobbied vigorously against them. They began as a Risk Management Tool but have become the gold-standard way to hide risks – as Study 329 shows so dramatically.

Economically you might have thought it was in Big Risk’s interests to map out the epidemiology of treatment induced morbidity – the problems treatments cause. But it doesn’t do this. Big Risk’s traditional methods of prevention – Guidelines and RCTs – don’t work for treatment induced problems. And why solve a problem that generates more turnover?

Meanwhile so uncertain has Big Risk made access to care – so shredded has the safety net become – that any suggestions that consuming fewer drugs might be healthier are drowned out for most people by concerns about access to medicines. The ACLU for instance will not take up the issue of whether treatment induced violence might have led to inappropriate incarceration for fear it might complicate their efforts to ensure that prisoners have access to healthcare.

Just as a balance in drug development has tipped so that it no longer serves medical treatment, so also a balance within prevention has been perverted.

Big Risk should make it impossible for Big Pharma to take separate patents on drugs as similar as two drops of water by refusing to reimburse the second drop of water. It should make it impossible to ghost write over 90% of the literature for on-patent drugs and to sequester the data from clinical trials, in contravention of the fundamental norm of empirical science – but it doesn’t do any of these things.

Big Risk underpins a comprehensive failure to diagnose and treat in the face of morbidity and mortality on an epidemic scale. Before blaming Capitalism, the problem is the market isn’t working. It’s Big Risk that should make the market work and they aren’t. What we are looking at is the behavior of Corporations. This behavior is shaped by Rules and at the moment the Rules are not working for us.

Medicine is no longer what it was. Your doctor needs to relearn the skills of listening to, seeing and touching you. She will have to engage with a biology that recognizes the brain as a social organ rather than with the biobabble that stems from Pharma marketing. She will have to ignore an epidemiology that figures you can design authoritative RCTs without understanding the biology being investigated (most RCTs).

Both Big Pharma and Big Risk justify the status quo by saying they don’t want to impinge on the sanctity of the doctor patient relationship. So she will have to be able to take the dynamics of industrial power into account and Industry will have to figure she is made of the Right Stuff – unless we can find a way to rescue her from the pot in which she is now stewing.

Until such treatment becomes possible, we are all shipwrecked. We are all Crusoe.

Death waits

BR1

“This generation thinks that nothing faithful, vulnerable, fragile can be durable or have any true power. Death waits for these things as a cement floor waits for a dropping light bulb. The brittle shell of glass loses its tiny vacuum. This is how we teach metaphysics on each other”.

The quote is from Saul Bellow’s Herzog. In Bellow’s imagery, the vacuum in the dropping light bulb contains our hopes, our aspirations, our fears. Big Pharma and Big Risk were once our allies in keeping our hopes alive – in keeping our children alive and well. They are now a threat. And of the two – Big Risk is the bigger threat.