clinical trials

Profits Over People: Medication Risk and Drug Company Misconduct

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If you haven’t read Chandler Marrs’ article on the safety of medications, take a moment to do so and understand that no medication is, as Marrs puts it, “perfectly safe.” I’m here to reaffirm this harsh pill to swallow (pun intended) through the telling of my own experience and the showcasing of research that reveals just how much sway Big Pharma has over the safety of medications.

I was 20 years old when I decided to take my doctor’s advice and go on hormonal birth control to help regulate my periods. I remember my mother, a registered nurse who worked in a local hospital, voicing her concerns about the oral contraceptive. At the time, she was seeing quite a few girls my age come in with clotting complications related to the pill.

Thinking I knew what was best for me, I ignored her advice to stay off of the medication. I was comforted in knowing that almost every single one of my close friends was taking some form of birth control, and they were fine. I’d be fine too.

I couldn’t have been more wrong.

Two months later, I was in the emergency room with a bilateral pulmonary embolism or multiple blood clots in my lungs. What I originally thought was a relatively safe medication turned out to be a life-threatening decision. Suddenly gone forever was my notion that any medications I was prescribed would be taken without risk.

After six months on blood thinners to dissolve the clots, I went back to living my life normally, both clot and birth control-free.

Fast forward four years, and I’m reading news stories discussing the thousands of lawsuits that have been filed against the makers of Xarelto, the same blood thinner I was prescribed to help me recover from my embolism. Although I suffered no complications from the medication, I was clearly one of the lucky ones this time. The anticoagulant, which is still on the market today, has no known antidote to reverse its blood-thinning effects, and it has caused so many severe internal bleeding incidents and deaths that legal action has been taken.

Prior to doing any research, my emergency room experience would have made me cast aside the lawsuits as frivolous. There’s a risk with any medication; I can’t deny that I knew the risks before I opted to take birth control. But, didn’t they also know the risks before agreeing to take the blood thinner just like I did?

Drug Company Misconduct

After digging deeper, I realized there was a bigger issue at hand. Drug companies wield an incredible amount of influence within the healthcare sphere that can lead to the approval of medications that should never find their way into patients’ hands in the first place. A major showcase of this influence is seen in Big Pharma’s ability to fund clinical trials.

These clinical trials must be conducted before a drug is approved for market, and funding has typically come from government sources like the National Institutes of Health. But in recent years, more and more industry-funded clinical trials are taking place, meaning that drug companies can sponsor their own medications studies. Critics of this funding allowance point to the fact that the potential for financial gain can lead to a conflict of interests. Companies that have a vested interest in a drug’s approval because it brings a boost in profits could favor positive outcomes while ignoring any negative results.

In the case of Xarelto’s industry-funded clinical trial, it was discovered that Johnson & Johnson withheld information from the FDA that would have highlighted the blood thinner’s inferiority to its comparison warfarin. During the study, 14,000 patients were given an overdose of the traditional anticoagulant due to the use of a faulty blood-testing device, decidedly skewing the results. The design of the company-sponsored trial also limited the distribution of Xarelto to once-a-day dosing that weakened the medication’s effects on participants. With less severe side effects being observed because of the smaller dose, Xarelto’s clinical trial looked favorable for the new experimental drug.

We see a similar story of clinical trial misconduct being told with another blood-thinning medication, Pradaxa. Pradaxa was put through an industry-funded study whose poor trial design led to FDA approval. Critics point out that there was probable cause for bias since it failed to be a double-blind study. Its trial participants were also made up of a demographic of people who were less likely to be prescribed the medication once it hit the market.

The FDA went on to approve the anticoagulant despite the lack of an antidote, but its decision was based on the fact that Pradaxa “wasn’t inferior” to traditional warfarin. This labeling could bring the drug to market, but it wouldn’t be able to give manufacturer Boehringer Ingelheim a leg up in its promotion of the medication. Therefore, the drug company requested that Pradaxa be labeled as “superior” to warfarin in its ability to reduce strokes so that it could make this claim in its marketing materials. The FDA granted the company’s request, decidedly ignoring its original concerns with the blood thinner.

Pradaxa hit the market without an antidote just like Xarelto, and I bet you can guess what happened next. Thousands of patients taking the medication suffered severe internal bleeding complications and even succumbed to the side effects. Like Johnson & Johnson, Boehringer Ingelheim faced a shocking number of Pradaxa lawsuits and created a $650 million settlement fund in 2014 to satisfy the claims.

Profits Over People

We cannot deny that every medication presented to us comes with some sort of risk to our overall health and well-being. I suffered the risks of birth control but miraculously avoided the complications associated with Xarelto. Costs and benefits are just a fact of the pharmaceutical industry.

But, the issue lies in the influence of Big Pharma. If drug companies, who are so clearly focused on boosting their profit margins, can impact clinical trials in such a way that it costs patients more than it benefits them, where do we draw the line?

It will take massive changes in the drug approval process and overall state of healthcare before we can start to see patient lives being placed above profits. But, what we can do is stay informed and educated on the prescriptions we’re taking. There is a lot going on behind the scenes before a medication makes its way into that little orange pill bottle, and it’s up to us as consumers to do our research, look into the possible complications, and voice any and all concerns with our doctors.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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This article was first published in January 2018. 

Reframing Maternal Health: How Do We Know What We Think We Know?

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I had the great pleasure of speaking to the Washington Alliance for Responsible Midwifery (WARM) recently about re-framing the concepts around maternal health and understanding the biases in medical research. One of the great questions that has been occupying my time lately is understanding how the frameworks for understanding medical concepts emerge. Shorthand: how do we know what we think we know? Below is an annotated and somewhat edited (for publication) version of the talk I gave. Enjoy.

What is Health?

When we think about health and illness, we all think we know what they are. We can see, touch, and measure health and illness in some very discrete and obvious ways. For example, in Western culture thin is good, fat is not good. If one is skinny, one must be healthy whereas if one overweight, one must be unhealthy.

Weight is a key parameter by which we all shorthand our assessment of health and illness. Indeed, weight, along with other visible qualities, like pallor and disposition, and some less immediately visible but easily measurable qualities like blood pressure, glucose, and other standard labs are key indicators that define health versus illness.

More often than not, however, our definitions of health and disease have been guided by external forces and systems of thought that are inherently biased, even though they claim the objectivity of science and evidence. These biases not only impact our views on health and illness, but in many ways, define what questions are acceptable to ask about health and disease.

Perinatal Mental Illness: An Entrenched Framework for Maternal Health and Illness

In my own research on perinatal mental illness, the prevailing wisdom was and still remains focused on questions that frame the discussion incorrectly. What I mean by that is the original ideas that initiated our notions of what causes postpartum mental illness – the change in progesterone and the estrogens – have become entrenched. Indeed, the ideas that the symptoms are a standard clinical depression or somehow a more serious degree of baby blues and tearfulness are well established.

When you think about pregnancy and postpartum, there are huge hormone changes, progesterone and estriol and estradiol being the most obvious, so it was reasonable to begin looking there. The problem is that, more than not, these hormones were never measured and when they were measured in association with depressive symptoms there were only weak correlations, if any correlations at all. After a while, one would think researchers would begin looking elsewhere, other hormones, other symptoms, but they didn’t. They just dug in deeper. The framework for perinatal mental health issues had already be set and to deviate was difficult at best, impossible for many.

I came to this conversation as a lowly graduate student. I thought, let’s look at other hormones and other symptoms, not just depression, and see what happens.

Lo and behold, other hormones were involved, as were other symptoms. But again, the framework was established and so the idea of expanding definitions of perinatal mental health, especially by someone who wasn’t a named researcher, was not a positive one.

The research was rejected over and over again and the politics of the maintaining the framework and only incrementally changing it were made quite clear to me, repeatedly. So much so that those controlling the dialogue were willing to dismiss where the data pointed to in order to frame the conversation as conventionally accepted – that progesterone and estrogens caused varying degrees of depression postpartum. Even though this made no sense logically; if this were the case, all women would be suffering and they were not. There was no supporting data, but it didn’t matter because as one reviewer commented about my research – ‘that is not the direction the hormone research is going’. So much for unbiased science.

This experience, added to my already disquieted disposition, led me to always dig deeper and look at the frameworks through which the research or ideas were being proposed. These are more philosophical questions, and yes, I have a degree in philosophy so I am naturally inclined towards these – but I think it is important to question how you know what you know and how others know what they know; those rules of knowledge determine, in large part, what can be known in a public sense, and will lead to tremendous insight in your practice – especially when what is accepted as standard clinical practice – doesn’t quite mesh with the patients in front of you. Dig and figure out what the framework was that developed those particular guidelines. Was it valid, was it commiserate with modern patients and current health issues or was it something that was skewed to begin with and has become increasingly more skewed – but we’re holding on to the practice anyway because it has become just the way we do things.

It’s a big topic – one where women and childbirth should play central roles but historically, we have been left out of the conversation.

Historical Frameworks for Maternal Health

To give you some context about how the frameworks impact clinical practice, let us consider the evolution of modern medicine. Historically, medicine has asserted the primacy of the physician’s ability to ‘see’ and thus, identify illness, over the subjectivity of the patient’s perspective about his or her health. So much so, that patients need not even speak unless spoken too and may only aid the physician to the extent they can answer those questions that the physician is interested in.

To say this has been a paternalistic approach is an understatement. Within this model of the physician as ‘seer’ and interpreter of signs and symptoms there is no room for the patient and his or her interpretation of the illness – especially her interpretation.

Despite its flaws, however, in many ways, this was a net positive for medical science. It allowed medicine to progress, for diseases to be systematically recorded and discussed – amongst other physicians of course – but still a critical step forward in medicine. Most importantly, this framework allowed medical science to begin developing treatments to specific diseases.

On the most basic level, one cannot manage a condition unless one can measure it, and to measure it, we have to be able to identify it and distinguish it from other diseases. And herein, lays much of problem with general women’s health and maternal health: what to measure, how to measure and what those measurements meant were largely decided by men who had no lived experience of ‘women’s health’ save perhaps, an observed experience with mothers, wives, sisters – which for all intents and purposes because of the political and cultural norms – women were separate.

So, the framework for women’s health, and most especially, maternal health was fundamentally flawed and inherently biased – from the onset. No matter that midwives had been delivering babies for generations and had built a wealth of knowledge – their influence, and power was usurped by physicians and that knowledge was summarily rejected. In its place practices and technologies that, in many cases, did not benefit women. Indeed, from the early 20th century onward, obstetrics considered childbirth a pathogenic condition requiring medical intervention.

Since within this model the patient had no role in either diagnostics or treatment consideration, but lay simply in front of the physician for him to ‘see’ and interpret the signs and symptoms of disease, the definitions of women’s health and disease and most especially maternal health – were obviously skewed. How could they not be, looking from the outside in – framing the questions from a distance?

Consider that not only were the very questions asked about women’s health defined by men, but the research subsequently, if it included women at all, was guided by the false presumptions that women were simply men with uteri.

And I should note, that women were summarily excluded from research until the late 1990s – so everything we know about medications prior to the 90s was based upon research with men, generally, young, healthy men at that.

It was believed and still held by many, that except for reproductive processes, men and women were fundamentally the same. Once we isolate those specific functions, there is no need to address women’s health any differently than men’s health. Or is there?

Is a Woman Simply a Man with a Uterus?

As women, I think we would all argue in favor of assessing women’s health differently than men’s health.

From a physiological and biochemical standpoint, male and female bodies are quite distinct, far beyond differences in reproductive capacity. In fact, these differences are exactly because of reproductive capacity and more specifically, the hormones that mediate those abilities.

If men and women are different – and of course they are – how do we know that what we know about women’s health is in fact accurate when most of women’s health research was defined by men? Do we really know anything, beyond the most basic assessments about women’s health?

I would argue that what we know or rather what we think we know, pretend to know, especially in western medicine, may not be accurate. The questions were framed incorrectly – from the perspective that women’s reproductive capacities, organs and hormones had no impact on the rest of her health. We could probably make the same argument for men, as their reproductive organs and hormones were dissociated from the rest of their health too – but because men controlled the research, defined the research, and importantly, had personal insight regarding their own physiological functioning, health knowledge is likely more accurate than what has been conveyed about women.

Shifting Frameworks Means Changing Definitions of Maternal Health

This isn’t just about differences in human physiology. If we dig into the framework by which we understand health, if we dig into the systems at play, we can see trends in how, as that power structure, as the lens, the framework for understanding health and disease shifts, so to do the definitions of health and disease and so too does the range of acceptable and unacceptable questions to ask.

If we look at recent decades with advent of HMOs and other payer contracts, along with the growth of hospitals, we see ever changing health and disease models. The model with physician as the central and all powerful seer and knower has shifted quite significantly by financial interests producing a factory like approach to healthcare.

With any factory, efficiency and cost cutting are key indicators of success. Instituting those efficiencies, however, largely removes the physician’s authority by shifting the primacy of his views towards the more efficient and less authoritative matching of symptoms to medications and billing codes. Cookbook medicine.

If symptoms reported by a patient don’t fit the ascribed to criteria, for all intents and purposes, the illness does not exist.

The physician, in many ways and recent decades, has become no more than a well-educated, technician answering not to his or her patients, but to the factory bosses – the insurers, the hospitals, and the regulators – the bean counters.

The physician is no longer central to medical science and clinical care. He/she is in many ways an administrator of care – a provider, not a healer, not even a scientists or medical researcher, save except to proffer funding from pharma or device companies.

Physicians have no power, no say in patient care, except to the extent that they can dot the i’s and cross the t’s according to billing codes. If their gut, or more importantly, if the data tell them that a particular treatment is dangerous, or conversely, is needed, but it doesn’t fall within the ascribed treatment plan, the physician has little recourse but to comply or risk losing his/her livelihood and, in more extreme cases, his/her reputation.

We see the barrage of reputation ending slanders hurled at physicians and researchers who dare to speak up and say that perhaps pesticide laden foods are not as safe as chemical companies make them out to be or that perhaps vaccines or other medications are neither as safe nor as effective as pharma and governmental institutions funded by pharma suggest. When physicians speak up, they risk their careers and reputation.

And while, you might be thinking there might be some positives to this shift, it is no longer such a paternalistic system where the physician has total power, in reality, this shift in healthcare towards efficiency still leaves women’s health high and dry and pushes the patient’s experience of his/her illness even further from the ‘knowledge base’ of western medicine.

Who Determines What We Know about Health and Disease? The Folly of Evidence Based in Women’s Health

So, back to this idea of frameworks, if neither the physician nor the patient is central to our definitions of health and disease, who is?  Who determines what we know about health and disease?

In recent decades, clinical practice guidelines have emerged from what are called evidence-based claims. Evidence-based clinical guidelines sound like a perfectly acceptable and reasonable approach to medical science. Research should be done on clinical decisions and outcomes, the data paint a picture of the safety and efficacy of a particular treatment or approach.

Evidence-based is certainly far better than consensus based – which means the ‘experts’ agree that this approach or that approach is optimum – something that has been the norm in women’s health care for generations.

Indeed, most medications were (and are still) never tested on women, pregnant or otherwise, so clinical practice guidelines that involve medication use are developed by ‘consensus’ and what many doctors like to call ‘clinical intuition’.

But since the long-term effects of these intuitive decisions are rarely seen by the clinician whose intuition guided the initial decision, and rarely shared with others, the notion of consensus based medical decision-making becomes sketchy at best, dangerous at worst; unless, you are lucky enough to have a highly skilled and thoughtful practitioner who is able to discern and act upon the best interests of his patients, even if it means going outside the parameters of what the rest of the profession says is appropriate. Most of us are not that lucky and as women we are faced with a medical science that doesn’t quite fit our experience of health and disease.

Of Weight and Health: The Obesity Paradox

If we go back to the shorthand measure of weight as a marker of health – how many of us tell ourselves if we just lose 10lbs we’ll be healthy. Every one of us, at some point or another has fallen into the weight = health trap. While it is true on extreme ends of the weight continuum that weight is related to disease, everywhere else and for everyone else, weight has little to do with ‘healthiness’.  Weight loss has been noted to reduce blood pressure and type 2 diabetes, but the relationship is not as straightforward as it seems. Being of normal weight does not necessarily equal low blood pressure or increase your longevity. Weight is not correlated positively with mortality – death by heart attack or stroke. In fact, the relationship between weight and surviving a life-threatening disease is almost always inverse – the heavier you are, the better the chance for survival. Those fat stores come in handy when we are deathly ill.

Wait, what did I just say that?  We should all go get fat and live longer – well, not really. Rather, I think we should look beyond weight as measure of health and to more appropriate measures like fitness, quality of life and the nutrient density of the diet. If you are eating well, active and feeling good, without any need for medication, then you are healthy.

Back to our evidence based approach – How can it be that the evidence behind what are gold standards of clinical practice be incorrect?

That is a big question that involves a little more background.

We all want our physicians to make healthcare decisions based upon the best available evidence and we can all think of ways that evidence is better than consensus, but each of these methods have their flaws.

Defining the Gold Standards in Clinical Care

When we look at the gold standards in clinical practice, those that align with evidence-based care, we have ask ourselves, from where did that evidence emerge, what were the variables, populations, and other factors studied and how were the outcomes determined.

How we define a good outcome versus a bad outcome determines how we design a particular study and what we results we will show.

Recall my example of the postpartum depression discussion – if we only ever measure progesterone and the estrogens (or don’t measure the hormones at all, simply assume those changes are at root of mood and psychiatric changes) and if we only measure depressive symptoms – then we have narrowed the framework such that we will only find associations or as the case may be – a lack of associations. And if there are no associations in the data – well then the disease must be made up and not real – all in the patient’s head.

The lack of questioning of one’s own biases, of the lens through which the research was designed or the parameters of what fits within that framework necessarily limits the understanding, making it easy to blame the patient. But if we step outside the framework, and listen to the patient’s experience, believe the patient experience and let it guide us, then we can break through the limitations of any particular framework and move science and healthcare forward. It sounds simple, and it is, but only if you recognize your biases and the biases of others and begin questioning, how you know what you know. And if that is not on solid ground, re-frame the questions.

Lies, Damned Lies and Statistics

You’ve all heard the phrase ‘lies, damned lies and statistics’   – it comes from the notion that research design, and particularly, the statistics can be swayed, intentionally or unintentionally, to prove or disprove anything. In medical science, this is especially true. Pick any medication for any disease and ask yourself how we determine whether it is effective or not?

First to mind, ‘it reduces symptoms’

Sounds reasonable – but dig deeper – which symptoms? All of the symptoms? Some of the symptoms?

And then if we dig even deeper…

Who decides which symptoms are important or even which symptoms are associated with a particular disease process? Over recent history, these decisions have been controlled by the pharmaceutical companies, insurance companies and hospital administrators – each with a specific bias and vested interest. The pharmaceutical companies want to sell products, the insurers and hospitals want to reduce costs and make more money. These should be counterbalancing agendas, but unfortunately they are not. The pharmaceutical companies have brilliantly controlled this conversation, defining not only the disease, but also, by controlling the research and defining the symptoms and prescribing guidelines. (I should note they also create new symptoms and disease processes to re-market old drugs to new populationsantidepressants for menopauseantidepressants for low sex drive in women, for example. The symptoms for both of these conditions are made worse by the very drugs being prescribed.)

If institutions or organizations with a vested interest are allowed to define the disease and the research by which a therapy is considered successful, how do we judge the validity of evidence-based guidelines?

Are the assumptions about the disease and the symptoms correct? Do these symptoms apply to all individuals with the disease or only those of certain age group? How about to women versus men?

Treatment Outcomes Determine Product Success or Failure

Take for example the case of statins, like Lipitor or Crestor, some of the most highly prescribed drugs on the market designed to lower cholesterol – because cholesterol was observed to be associated with heart disease in older men, particularly those who have had a heart attack previously.

Reducing cholesterol in this particular patient population might be beneficial to improved longevity (although, that has been questioned vigorously). However, does the rest of population benefit from cholesterol lowering drugs? It depends upon what outcomes are chosen in the research. If we, look at decreased mortality and morbidity as an outcome, then the answer to the question is no, statins are not good for the entire population with high cholesterol. A healthy diet and other lifestyle changes would be better.

Indeed, in women in particular, these drugs are dangerous because they increase Type 2 diabetes, increase vitamin B12 and CoQ10 deficiencies, among other nutrients (which initiates a host of devastating side effects), and most importantly, statins may increase the risk for heart attack and death in women.

So the drug promoted as one that prevents heart disease, may worsen it in women. Not really a tradeoff I would take.

This is problematic if one’s job is to maximize product sales. What do you do?

Let’s change the outcomes to the very simple, lowering of cholesterol. No need to worry about extraneous details like morbidity and mortality, keep it simple stupid.

Also, no need to compare the health of women versus men. Indeed, outcome differences between women men and women are rarely conducted, since statins decrease cholesterol in both women and men. Outcome achieved, evidence base defined, built and promoted.

A couple of points here…

He who defines the research design, controls the results. Across history, patients, especially women, have had no impact on these variables.

First it was the physicians, mostly male, and more recently, the product manufacturers have controlled the very definitions of health and disease, which in turn, determine treatments. To say evidence-based medicine is skewed is an understatement.

Now what?

While I’d argue that we have to re-frame the entire conversation about women’s health and include more voices in that conversation, voices that may not have been heard previously. I would also argue that we are never going remove biases from research and decisions about health and disease, but we can understand them and maybe even use them more effectively.

Revisiting the Foundations of Maternal Health – Enter Obstetrics

In maternal health, consider the Friedman curve and the failure to progress, though certainly not a product based bias as discussed previously, the Friedman curve, created in the 50s by a male physician at the height of hospitalized birth, where hospitals had a vested interest in understanding the progression of labor and its relationship not only to physician efforts, but time and outcome. For generations, this one study has guided OBs in their decisions to expedite labor – and as much research has found – has led the unheralded increase in cesarean delivery. Why?

One could argue that the study was flawed – it was – but most research is flawed in some way or another. I think the important thing is to understand the biases, how the question, and therefore, the answer were framed, and as importantly, who made the decisions about what was important in the framing of question?

Begin with the study population, was it skewed? Yes, it was.

For the Friedman study, more than half of the women had forceps used on them during the delivery (55%) and Pitocin was used to induce or augment labor in 13.8% of women. “Twilight sleep” was common at the time, and so 23% of the women were lightly sedated, 42% were moderately sedated, and 31% were deeply sedated (sometimes “excessively” sedated) with Demerol and scopolamine. In total 96% of the women were sedated with drugs. What might these drugs do to the progression of labor – stall it perhaps?

Digging deeper, consider the framework within which this study was conducted. Hospital births in the 1950s were predominantly drugged, sterile (or presumed sterile). Efficiency and scientific prowess were on the rise. Time was of the essence and there was very strong impetus to gauge decisions based upon the most advanced medical science – drugs, interventions – and an equally strong pull not to allow women to progress more naturally – because then science would not have intervened.

How did this one study become the guiding factor in obstetrical care? Why did we think that this particular study group was representative of the entire population of birthing women? The obvious answer was that women had no voice in this conversation or in the birth itself. It was medical science and intervention from a place of ‘all-knowingness.’

There was never any question that these results could be skewed, until recently. It was accepted, and perhaps the only reason questions have arisen, I suspect, is because of the links between the medical management of birth and the increasing rates of cesareans and maternal and infant mortality in the US over recent decades. Would this study have become so entrenched if the patients – the women – had a voice in the conversations about childbirth or the outcome was not so closely tied to hospital efficiencies? We’ll never know, but one could postulate that under different circumstances the study might have been framed differently and netted different results entirely.

Maternal Hypertension

Another, more recent example of how the framing of the question determines the conclusions of the research, involves how we view high blood pressure in pregnant women. Hypertension during pregnancy is dangerous for the mom – but what do we do? Treat it with non-tested anti-hypertensives, for which we know nothing about the potential side effects to the fetus short or long term ? Do we change diet? Do we simply monitor and hope for the best? What do we do? We don’t know. There is limited research on the topic, including on commonly used interventions.

With such limited research, I had high hopes for recent study, Less-Tight versus Tight Control of Hypertension in Pregnancy.  It was a huge and well-funded study with a wonderful opportunity to determine the risks/benefits of anti-hypertensive therapy, but by all accounts, and in my opinion, it failed because the questions it asked were framed incorrectly. (Or were they? For pharmaceutical companies, the study was success. More on that in a moment).

That is, rather assessing the safety and efficacy of anti-hypertensive medications used during pregnancy (remember safety data for medication use during pregnancy is severely lacking), this study investigated a very narrowly defined and essentially meaningless question. The study asked whether controlling maternal blood pressure strictly within a pre-defined and arbitrary range of blood pressure parameters provided better or worse maternal or fetal outcomes compared to a more flexible approach that allowed broader range of accepted blood pressure metrics.

It did not analyze maternal or infant complications relative to particular medications to determine whether some medications were safer than others. It did not look at dose-response curves relative to those medications and outcomes or sufficiently address the role of pre-existing conditions relative to medications and outcomes. All it did, was ask whether or not managing maternal blood pressure more or less tightly with medications (that were not assessed in any meaningful way) was beneficial or harmful to maternal or infant outcomes. Since both groups of women were on various medications, varying doses and had a host of pre-existing conditions, the results showed that both groups had complications. It did not tell us which medications were safer, what doses of these medications were more dangerous or anything useful for clinical care. It just told us that anti-hypertensive medications during pregnancy, reduce blood pressure (we knew that) and cause complications (we knew that too). My review of the study.

Now, because of way the study was framed and especially how the conclusion was framed – that both tight control and loose control of maternal blood pressure show equal numbers of complications – the message will, and already has, become – blood pressure medications during pregnancy are safe.

The study found no such thing. In fact, the study found nothing really, but because of how it was framed it now becomes shorthand evidence of drug safety during pregnancy. Only those who read the full study with a questioning mind will know that this is not accurate. Most of the population, including physicians, will see only the shorthand PR surrounding the study and assume drug safety.

Conclusion

In conclusion – I want you to go back to practices and think about how you know what you know and if something doesn’t quite mesh – dig deeper – look at the framework from within which that guideline came to be. Look at the original research and decide for yourself.

I think it is time for women, midwives to have a much stronger voice in maternal health care, but to do that, we have to speak up and speak out and not accept the ‘gold standards of care’ just because they are the gold standards. While it is true, sometimes those standards will align well with maternal healthcare, other times, I think you’ll find that because of how the questions were framed, the solutions were skewed and do not match the reality of maternal health and disease.

Thank you.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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Originally published March 31, 2015.

Women in Clinical Trials

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Do Hormones Matter with Clinical Trials Research?

I am repeatedly struck by the avoidable ignorance that surrounds this industry. Women’s hormones are considered a fringe science by many, despite the fact that hormones modulate all bodily functions and impact all aspects of pharmacokinetic and pharmacodymanic response, the key variables evaluated in clinical trials research. Repeatedly, we face the assumption that hormones make no difference to women’s health – quite ironic since simultaneously hormones are blamed for everything from migraines to mental health.

And then there is the long held notion that we don’t need any more data in women’s health – quite striking considering only 30% of Ob/Gyn clinical practice guidelines are based on data. Just the other day, a well-positioned female physician, one of the fewer than 4% female healthcare executives, argued that while what we doing was interesting,  it was unnecessary because the 1993 Gender Guidelines ‘mandated’ women be included in clinical trials.

Perhaps some history is in order. Until 1993, women of ‘childbearing potential’ were prohibited from participating in clinical trials research. This means that all of the drugs developed before 1993 (most are still being used today) were not tested on women; any potential dosing differences, sex- specific side-effects could not be found until after the drug reached the market and even then it was and is difficult to ascertain because sex-specific analytics were not, and are still not, routinely performed. This makes proving sex-based adverse events all but impossible.

In 1993, thanks in large part to efforts of the first large group of women to enter the US Congress (women in Congress matter); the FDA removed its prohibition against women with childbearing potential participating in clinical trials. The regulations, however, were not established until 1998 and what was implemented, though an improvement over the earlier prohibition of women in clinical trials was less specific than the original guidelines and resulted in less than satisfactory results. When those regulations are evaluated alongside industry trends over the last decade, it becomes abundantly clear why women suffer disproportionately from adverse events compared to men and why everyone in the healthcare industry should be concerned.

From Proposed Guidelines to Regulation

The 1993 guidelines recognized that women might process and react to drugs differently than men (indeed they do and this has been shown repeatedly) and therefore, it was recommended that pharmacokinetic studies be done to evaluate the difference in drug absorption, distribution, metabolism and excretion. It was further recommended that menstrual status, hormonal supplementation (oral contraceptives, HRT and the like) be evaluated.

The FDA was quite clear in its ability to mandate these changes – there was none.  Indeed, all that was possible was suggestion.

The agency recognizes that this change in FDA policy will not, by itself, cause drug companies or IRBs to alter restrictions they might impose on the participation of women of childbearing potential. We do not at this time perceive a regulatory basis for requiring routinely that women of childbearing potential be included in particular trials, such as phase 1 studies. However, careful delineation of drug effects by gender is expected by the agency and the FDA is determined to remove the unnecessary federal impediment to the inclusion of women at the earliest stages of drug development.  The agency is confident that the ethical, social, medical, legal and political forces will allow greater participation of women at the earliest phases of drug development.

So, the FDA was confident that ethical and social pressures would convince pharmaceutical companies to do the right thing. How well has that gone? The guidelines also indicated that it was not necessary to include women in phase 1 or 2 trials because there was no evidence to suggest sex differences in drug effectiveness:

Because documented demographic differences in pharmacodynamics appear to be relatively uncommon, it is not necessary to carry out separate pharmacodynamic – effectiveness studies in each gender routinely.

To summarize, data were never collected in the first place to suggest sex-differences might exist (remember before 1993, women were prohibited from participating in clinical research) and because there were no data to suggest a sex-differences, there was no need for additional data – makes perfect sense to me.

Fortunately, the National Institute of Health (NIH), the federal funding agency for health-related research, took the reins with a clear mandate – no funding unless the study included women in clinical research.  The NIH Revitalization Act of 1993, followed by updates and regulations in 1994, 2000 and 2011, mandated that all NIH funded clinical trials have sample sizes adequate to support ‘valid analysis’ of gender and racial subgroup effects. Unfortunately, however, NIH-sponsored clinical trials represent only 20% of all clinical trials. The remaining 80% are sponsored by pharma and fall under the FDA’s guidelines. And even though, by all accounts the NIH has done substantially better than the FDA, a recent report by the National Heart, Lung and Blood Institute (NHLBI) – a sub agency of the NIH, found that in clinical trials between 1997 and 2006 where the outcome of the study was stroke, myocardial infarction or death found that women represented only 27% of trial participants and only 13-19 of the studies included sex-based analyses.

Back to the FDA Regulations

In 1998 and 2000, the FDA officially instituted the Guidance for Industry, requiring all new investigation drug (IND) and new drug application (NDA) submissions include data on trial participation, efficacy and safety, be presented by age, race and sex. A report in 2001 by the General Office of Accounting (GAO) (no further GAO reports could be found on this topic) evaluated the success and failures of the gender guidelines. It wasn’t pretty:

The 1998 regulation has the force of law, but it is less specific than the 1993 guidance. The regulation required that safety and efficacy data already collected be presented separately for men and women in new drug application summary documents. It does not include criteria for determining the number of women to be included in clinical studies, nor does it require any analysis of the data presented. The 1998 regulation also requires the tabulation of the number of study participants by sex in investigational new drug annual reports. The regulation enacted in 2000 allows FDA to halt research programs for drugs for life-threatening conditions if otherwise eligible men or women are excluded from participation in studies based solely on their reproductive potential, but it does not require inclusion of any particular number of men or women.

How well did the FDA do in meeting and enforcing the guidelines? According to the GAO:

  • NDA and IND summary documents and annual reports often failed to meet the data presentation requirements
  • 30% the new drug application summary documents submitted to FDA by drug sponsors did not fulfill the requirements for the presentation of available safety and efficacy outcome data by sex
  • 39% of IND annual reports did not include demographic information
  • The FDA has the authority to suspend proposed research for life-threatening conditions if men or women are excluded, but has not yet done so

As a result of the non-enforcement, the GAO found that although the number of women in clinical trials now averaged 52%, most were enrolled in later stages of the trial. Women represented only 22% of early phase clinical trials. This is where most of the safety and dosing considerations are determined.

Finally, and perhaps the most troubling aspect of this report was that, the FDA had no procedures in place to evaluate, manage or enforce the regulations. As a result, they had no way of knowing whether women were included in the trials in sufficient numbers or whether the medications or devices gaining approval had gender-specific safety issues.

What does this mean?

For all drugs and devices approved before the 1998-2000 regulations and likely many years after, the safety and efficacy data were lacking for women. Despite the 52% female participation number that is bandied about as proof positive that women are represented sufficiently in clinical trials, that number reflects later phase trials, after safety and efficacy parameters are established. In the early phase trials, the number of female participants remains at a paltry 22%. Today, when large women-only (Women’s Health Initiative and Women’s Health Study) research are removed from the tabulations, the mean proportion of women included in all clinical trials hovers around 27%.

Most recently, the Institute of Medicine (IOM) Committee of Women’s Health Research reports a continued lack of

taking into account of sex and gender differences in the design and analysis of studies, lack of reporting on sex and gender differences, has hindered identification of potentially important sex differences and slowed the practice in women’s health research and its translation into clinical practice.

And although the IOM reports that the most progress has been made in cardiovascular research, the NHLBI and Cochrane Reports suggest otherwise. The NHLBI found female participation hovering around 27% in certain cardiovascular trials and Cochrane Reports found that out of 258 clinical trials, only 196 included women and only 33% of those reported sex or gender analytics.

Cardiovascular disease is the most common cause of death in American women and in recently recalled medications for heart disease there were disproportionately higher fatalities and serious adverse events in women than in men.

With high risk cardiac devices, a recent review of FDA pre-market approved devices from 2000 – 2007 (78) found significant gender bias in sampling and data reporting and significant lack of sex-specific safety data.

  • FDA summaries did not report gender data in 28% of studies examined
  • For studies reporting gender distribution, 67% of the participants were men

So, the suggestion that additional data in women’s healthcare are not needed is unquestionably false and dangerously ill-informed. The notion that hormones, which regulate every aspect of pharmacokinetics and pharmacodynamics are an irrelevant and a fringe science, is ignorant bordering in negligent. It is time for women to stand up and demand inclusion and analytics by sex for all drugs and devices.

Postscript: NIH Update 2014

Since this article was first published in February 2013, the NIH has made inroads towards more thorough assessment of the role of sex in basic, pre-clinical research. Recognizing the almost total reliance on male animals and cells in preclinical research obscures key sex differences that should guide clinical studies, the NIH instituted new guidelines in October 2014

…that require applicants [for NIH grant funding] to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions. 

It remains to be seen how rigorously these new guidelines will be enforced and whether they will impact health research in any discernible way.

Postscript: Update 2019

From a recent 10 year follow-up study assessing sex-inclusive research practices of journal articles published within nine of the biological disciplines, including pharmacology, researchers found some improvement in most of the disciplines, except pharmacology. Compared to 2009, where only 29% of the studies reviewed included male and female subjects, in 2019, 49% included both. In contrast however, pharmacology trended downward with only 29% of articles reporting the use of both sexes in 2019 compared to 33% in 2009.  Nevertheless, even though more women were included in more research studies across the disciplines reviewed, few researchers thought it was important to analyze sex based differences. Indeed, of the 49% of journal articles that included both sexes in 2019, only 42% analyzed data by sex, compared to 50% in 2009. Ironically, in pharmacology although the total number of women decreased in studies during this time period, analyses of sex based differences was more frequent increasing from 19% in 2009 to 48% in 2019.

Overall, it appears that we have yet to make much progress.

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This article was first published in 2013. 

Out of Balance: The Unbridled Power of the Pharmaceutical Industry

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A staggeringly large number of people are hurt or killed by pharmaceuticals each year. Medical mistakes and pharmaceutical induced injuries are the 4th most common cause of death in American hospitals (1).

Casualties reveal that the medical system is broken, and it is broken in ways that are systemic, complex and difficult to fix.

Every large system that works well has a foundation of checks and balances that keeps power from being too concentrated. Unchecked power corrupts – it has been shown to be true millions of times throughout history. The need for checks and balances on the power of pharmaceutical companies is just as great as the need for checks and balances on the power of any given branch of the government. There are organizations, individuals and institutions, that should be checking and balancing the power of pharmaceutical companies, and keeping them from maiming and killing thousands of people each year; but those organizations and institutions are failing. They are not keeping the pharmaceutical industry in check, and thus, the problems with the pharmaceutical industry are systemic.

Here is a list of institutions and groups of people who are supposed to be protecting the public from the pharmaceutical companies, but who are not:

The FDA does not Regulate the Pharmaceutical Industry

It’s self-evident that the FDA is failing. Deaths from pharmaceuticals don’t get to the point where thousands of people needlessly die each year while using drugs as prescribed when a regulatory agency is doing its job. “Every week, about 53,000 excess hospitalizations and about 2400 excess deaths occur in the United States among people taking properly prescribed drugs to be healthier. One in every five drugs approved ends up causing serious harm, while one in ten provide substantial benefit compared to existing, established drugs(2).” This sorry state of affairs doesn’t happen with a regulatory agency that is working properly to protect the people.

Most people assume that the FDA tests drugs for safety. They don’t. The FDA reviews tests performed by the pharmaceutical companies, the same company that developed the drug and stands to profit from the drug(3). It’s a system that is rife with conflicts of interest and perverse incentives that allow dangerous and/or ineffective drugs onto the market.

The FDA is approving drugs that are linked to cancer in clinical trials (new diabetes drugs, Farxiga and Invocana showed high incidence of bladder cancer in clinical trials (4). CANCER. When it is discovered after drugs are released onto the market that they are cancer-causing, the FDA doesn’t remove them from the market or insist that pharmaceutical companies try again to make a better formula that DOESN’T CAUSE CANCER, they simply make the warning label longer – as is the case with TNF inhibitors like Humira and Enbrel (5,6).

Those at the FDA are apparently incapable of making connections between drugs and chronic diseases. When the FDA added the risk of permanent peripheral neuropathy to the 43 page warning label for fluoroquinolone antibiotics, they noted that the mechanism for action that caused the peripheral neuropathy was mitochondrial dysfunction. There are hundreds of studies that link mitochondrial dysfunction to every chronic disease of modernity (Alzheimer’s disease, Parkinson’s, autoimmune diseases, chronic fatigue syndrome / M.E., fibromyalgia, etc.), but rather than restrict the use of dangerous mitochondria damaging drugs like fluoroquinolones, they just increased the length of the label, and people keep getting sick from these drugs (7).

The FDA is not looking out for the people. The notion that they are actually protecting people from dangerous drugs is laughable.

The Courts Rule in Favor of the Pharmaceutical Industry

If you’re hurt by a drug, you can sue, right? After all, the United States is the most litigious country in the world. People sue for all sorts of things all the time, surely those who are legitimately hurt by pharmaceuticals have legal recourse, right? And the legal system must be keeping pharmaceutical companies from hurting people, right?

It’s not that easy.

If the “side-effect” of a drug that you suffer from is listed on the warning label for the drug, you can’t sue the drug companies for failure to warn. So, for example, if you develop a severe psychiatric illness like bipolar disorder or severe depression after taking Chantix, an anti-smoking drug, you can’t sue the manufacturer of the drug, even if your declined mental health ruins your life, because the warning label for Chantix says that serious psychiatric ill-effects have followed treatment with Chantix (8).

If the side-effect that you suffer from isn’t listed on the warning label for that drug, you’re not much better off than you are if it is. If it’s not listed on the warning label, the connection between the drug and the disease is not established and proving that the drug caused the adverse reaction is close to impossible.

Additionally, those who take generic drugs have no legal recourse against the manufacturers of the drugs, thanks to the U.S. Supreme Court. On June 24, 2013, the U.S. Supreme Court ruled that generic drug manufacturers could not be held liable for the effects of the pharmaceuticals that they manufacture. A New York Times piece pointed out that, “The decision is a significant victory for the generic drug industry, but further narrows the recourse for people who are injured by such drugs” (9). People who have been hurt by a drug manufactured by a generic drug company have no recourse now – no chance for justice – regardless of how horribly they are harmed by a drug. Lawyers aren’t even taking cases of people hurt by generic drugs.

The justice system is doing a horrible job at providing justice for those who have been hurt by pharmaceuticals. In not getting justice for the people who have been hurt by pharmaceuticals, they are giving the pharmaceutical industry no incentive to stop hurting people.

Media Ties to the Pharmaceutical Industry Hamper Objectivity

If you read a newspaper, news based magazine, or watch television news, you will be bombarded with advertisements for pharmaceuticals. A quick review of a few issues of Time, U.S. News and World Report and Reader’s Digest revealed that 15% of the advertisements in those “news” magazines were for pharmaceuticals. Television news programs are even worse with constant bombardment of advertisements for antidepressants, erectile dysfunction drugs, etc.  How can we expect the news media to cover the dangers of drugs and the malfeasance of the pharmaceutical industry when advertisements from the pharmaceutical industry provide a significant portion of the revenue for those media sources?

I don’t believe that the media can be objective toward those who ensure their livelihood. Don’t bite the hand that feeds you, as they say – and the mainstream media is well-fed by the pharmaceutical industry.

Doctors and the Pharmaceutical Industry

Doctors generally know too little about the drugs that they prescribe. Most are not pharmacologists and they count on the FDA to tell them whether or not a drug is safe to use.

In some ways, I feel sorry for doctors. They don’t intend to hurt people with pharmaceuticals – they mean to help people with pharmaceuticals. There are good drugs that do what they’re supposed to do and even save lives. But the entire medical profession seems to have lost critical thinking skills when it comes to evaluating the appropriate use of powerful drugs. Drugs can do harm, and many pharmaceuticals do more harm than good. Admitting that will not mean that any physician has to have his or her prescription pads taken away.

There is an appropriate time and place for every type of health therapy – nutritional, herbal, pharmaceutical, etc. – but the dependence of physicians on the exclusive use of pharmaceuticals has made them so entrenched in the system, and so dependent on the pharmaceutical industry, that the questioning of the appropriateness of drug therapies is rarely done. Doctors aren’t keeping the pharmaceutical companies in check by questioning them and refusing to tolerate the inordinate number of harmful drugs going through their office because doctors cannot operate without those dangerous drugs. It’s a sad state of affairs.

Some push-back on the pharmaceutical industry by doctors is entirely appropriate. They should push back on the pharmaceutical industry – for their patients and for their conscience.

Pharmacists and the Pharmaceutical Industry

Pharmacists understand the mechanisms of drug actions. They are trained in pharmacology. They are the gate-keepers for dispensing drugs to the public. I cannot, for the life of me, figure out why there isn’t more uproar among them about harmful drugs.

Scientists and the Pharmaceutical Industry

Everything that I know about biochemistry, cellular biology, how drugs interact with cells, etc. is from journal articles written by scientists. I thank them very much for their work. It is with science that the fraud and crimes against humanity perpetrated by the pharmaceutical industry will be revealed.

Unfortunately, the pharmaceutical and agricultural biochemical corporations have a strangle-hold on much of the work being done by scientists. Objectivity and scientific principles are lost as health research is corrupted by corporate funding at multiple levels. Selection bias has been demonstrated repeatedly, showing that negative results in drug research are not published. Scientists are put in a difficult position as their status and livelihood depend on publishing (publish or perish) so, they must only publish positive findings. Moreover, much of their work and their institution’s research funding comes from the pharmaceutical companies, either directly with drug development or testing grants or indirectly via the NIH inasmuch as the NIH won’t fund adverse events research but only that which has the possibility of a drug discovery. Researchers who dare to question the safety of a particular drug are often disciplined by their institutions for fear that the institutions will lose the millions of dollars drug companies funneled to them, and then if the researcher does speak out, the personal campaigns against them by the drug companies will end their research career. It’s a very untenable position for anyone with a brain and a conscience.

Even though I understand that research scientists are in a difficult position, I get frustrated with the lack of screaming and grand-standing that I don’t see from the scientific community. Scientists have the tools to see the damaging effects of pharmaceuticals. They have the intelligence to connect the dots. They have the credibility to make a difference in people’s lives. They have the ability to save lives. But most aren’t screaming about the harm caused by drugs, partly for the reasons listed above, and partly because they seem to be stuck in an outdated mode of caution and gentlemanliness. They know that they can say that a drug is associated with a higher incidence of cancer, but they are reluctant to say that the drug CAUSED the cancer. They can say that a drug had hugely harmful effects on the cells of rats, but they are reluctant to make any recommendations about human use of those drugs based on those studies of rats – even though the rats are effectively canaries in the coalmine and screaming about hurt rats may prevent future hurt humans. I understand this caution and the rules of science. But it would be really nice if more scientists were using their credibility and intelligence to push back against the pharmaceutical industry.

The People Must Resist Pharmaceutical Industry Marketing

Without the FDA, the media, the justice system, doctors, pharmacists or scientists standing up to the pharmaceutical companies and putting a check on their (currently unmitigated) power, patients are left to fend for themselves. Unfortunately, most patients don’t have the time or capability of doing the necessary research to determine the safety of any given drug. Patients depend on the system to have checks and balances to keep them safe, but those systems that are supposed to be providing checks and balances are failing.

I don’t think that the pharmaceutical companies are evil entities that are conspiring to decrease the world’s population. But I do think that they are profit motivated businesses with obligations to enrich their shareholders, and that their obligations to enrich their shareholders are in direct conflict with any mission of making the people that they sell drugs to healthy. There is an inherent conflict of interest born from the fact that sick, especially chronically ill, people are the best customers of pharmaceutical companies. A poisoned, sick, population is in nobody’s interest except those who leach money from the ill.

Systematic corrections are needed to fix the problem of an obscene numbers of casualties from the pharmaceutical industry.

Stopping the pharmaceutical companies from hurting people is the right thing to do.  I hope that the FDA, the media, the justice system, doctors, pharmacists and scientists start doing so.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

Sources:

  1. Journal of American Medicine, “Incidence of Adverse Drug Reactions in Hospitalized Patients
  2. Harvard University Edmond J. Safra Center For Ethics, “Risky Drugs: Why the FDA Cannot be Trusted
  3. FDA Drug Development and Approval Process
  4. Huffington Post Healthy Living, “Farxiga, Just Approved by FDA, Uses New Approach to Treat Diabetes
  5. Medscape Medical News, “FDA Safety Changes: Humira
  6. FDA Warning Label: Humira
  7. Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology, Pharmacovigilance Review, April 17, 2013, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure
  8. Chantix Warning Label
  9. New York Times, “In 5-4 Ruling, Justices Say Generic Makers Are Not Liable for Design of Drugs

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