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What does a new drug cost? Part II: The productivity problem

A few weeks ago I reviewed Ben Goldacre’s new book, Bad Pharma, an examination of the pharmaceutical industry, and more broadly, of the way new drugs are discovered, developed and brought to market. As I have noted before, despite the very different health systems that exist around the world, we all rely on private, for-profit, pharmaceutical companies to supply drug products and also to bring newer, better therapies to market. It’s great when there are lots of new drugs appearing, and they’re affordable for consumers and health systems. But that doesn’t seem to be the case. Pipelines seem to be drying up, and the cost of new drugs is climbing. Manufacturers refer to the costs of drug development when explaining high drug prices: New drugs are expensive, we’re told, because developing drugs is a risky, costly, time consuming endeavor. The high prices for new treatments are the price of innovative new treatments, both now and in the future. Research and development (R&D) costs are used to argue against strategies that could reduce company profitability (and presumably, future R&D), be it hospitals refusing to pay high drug costs, or changing patent laws that will determine when a generic drug will be marketed.

The overall costs of R&D are not the focus in Goldacre’s book, receiving only a short mention in the afterword, where he refers to the estimate of £500 million to bring a drug to market as “mythical and overstated.” He’s not alone in his skepticism. There’s a fair number of papers and analyses that have attempted to come up with a “true” estimate, and some authors argue the industry does not describe the true costs accurately or transparently enough to allow for objective evaluations. Some develop models independently, based on publicly available data. All models, however, must incorporate a range of assumptions that can influence the output. Over a year ago I reviewed at a study by Light and Warburton, entitled Demythologizing the high costs of pharmaceutical research, which estimated R&D costs at a tiny $43.4 million per drug – not £500 million, or the $1 billion you may see quoted.  Their estimates, however, were based on a sequence of highly implausible assumptions, meaning the “average” drug development costs are almost certainly higher in the real world. But how much higher isn’t clear. There have been at least eleven different studies published that estimate costs. Methods used range from direct data collection to aggregate industry estimates. Given the higher costs of new drugs, having an understanding of the drivers of development costs can help us understand just how efficiently this industry is performing. There are good reasons to be critical of the pharmaceutical industry. Are R&D costs one of them?

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Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

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Bad Pharma: A Manifesto to Fix the Pharmaceutical Industry

“There is no medicine without medicines” write Ben Goldacre in his new book Bad Pharma. To Goldacre, an author, journalist and physician, this cause is personal. The title, a reference to both his first book, Bad Science, as well as the pharmaceutical industry’s nickname Big Pharma, is a bit of a misnomer. While the focus is pharmaceutical companies and their actions, there are a number of enablers in the health care system – medical journals, regulators, and even medical professionals, all of whom have put the industry’s needs ahead of good medicine. According to Goldacre, the damage is pervasive and deep, right to the roots of modern medicine. These problems know no borders, and affect us all. Despite the different health care systems that exist worldwide, we all depend on for-profit pharmaceutical companies to develop and market new medicines. These companies collectively wield enormous clout, due in part to the remarkable success of medicines over the past several decades. The global pharmaceutical market will probably top $1 trillion (yes, 12 zeros) this year. And Goldacre argues the industry is not only compromised, it is broken. And over 400 pages, he defends the following paragraph:

Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don’t like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug’s true effects. Regulators see most of the trial data, but only from early on in a drug’s life, and even then they don’t give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion. In their forty years of practice after leaving medical school, doctors hear about what works ad hoc, from sales reps, colleagues and journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are, too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it’s not in anyone’s financial interest to conduct any trials at all. These are ongoing problems, and although people have claimed to fix many of them, for the most party they have failed; so all of these programs persist, but worse than ever, because now people can pretend that everything is fine after all.

We all have our own biases, and I should disclose mine. I’m a pharmacist who has seen HIV go from a death sentence to a chronic disease, thanks to newly developed drugs. I’ve watched cancers like leukemias be effectively cured, thanks to medication. And I’m amazed that surgeries like double-lung transplants, impossible in the past, are now a reality, thanks in part to drug treatments. Yet I’ve also spent more than a decade reviewing the efficacy and safety of prescriptions drugs. Regrettably few are truly innovative. Many are approved with lingering questions about long-term safety and effectiveness. The value some offer can be questionable. I’ve also seen tremendous harms caused by drugs – from individual patients who have suffered horrible adverse drug reactions to population-level disasters like the Vioxx (COX-2) debacle. And I haven’t ignored the countless fines levied on pharmaceutical companies for bad, and sometimes even criminal, behavior. With its repeated capacity for self-sabotage, the pharmaceutical industry is its own worst enemy. My colleagues who work in the pharmaceutical industry agree. They’re smart, honest people that genuinely want to help get good treatments to patients. They’re embarrassed by what they see. So while I have no doubts about the astonishing track record of innovative new drugs that have transformed medicine, I also have no illusions that drug companies always behave in ways that support science-based medicine. And I think there is the potential for the industry to do much better. So how do we get this? (more…)

Posted in: Book & movie reviews

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It’s time for true transparency of clinical trials data

What makes a health professional science-based? We advocate for evaluations of treatments, and treatment decisions, based on the best research methods. We compile evidence based on fair trials that minimize the risks of bias. And, importantly, we consider this evidence in the context of the plausibility of the treatment. The fact is, it’s actually not that hard to get a positive result in a trial, especially when it’s sloppily done or biased.  And there are many ways to design a trial to demonstrate positive results in some subgroup, as Kimball Atwood pointed out earlier this week. And even when a trial is well done, there remains the risk of error simply due to chance alone. So to sort out true treatment effects, from fake effects, two key steps are helpful in reviewing the evidence.

1. Take prior probability into account when assessing data. While a detailed explanation of Bayes Theorem could take several posts, consider prior probability this way: Any test has flaws and limitations. Tests give probabilities based on the test method itself, not on what is being tested. Consequently, in order to evaluate the probability of “x” given a test result, we must incorporate the pre-test probability of “x”. Bayesian analysis uses any existing data, plus the data collected in the test, to give a prediction that factors in prior probabilities. It’s part of the reason why most published research findings are false.

2. Use systematic reviews to evaluate all the evidence. The best way to answer a specific clinical question is to collect all the potentially relevant information in a structured way, consider its quality, analyze it according to predetermined criteria, and then draw conclusions. A systematic review reduces the risk of cherry picking and author bias, compared to non-systematic data-collection or general literature reviews of evidence. A well-conducted systematic review will give us an answer based on the totality of evidence available, and is the best possible answer for a given question.

These two steps are critically important, and so have been discussed repeatedly by the contributors to this blog. What is obvious, but perhaps not as well understood, is how our reviews can still be significantly flawed, despite best efforts. In order for our evaluation to accurately consider prior probability, and to be systematic, we need all the evidence. Unfortunately, that’s not always possible if clinical trials remains unpublished or are otherwise inaccessible. There is good evidence to show that negative studies are less likely to be published than positive studies. Sometimes called the “file drawer” effect, it’s not solely the fault of investigators, as journals seeking positive results may decline to publish negative studies. But unless these studies are found, systematic reviews are more likely to miss negative data, which means there’s the risk of bias in favor of an intervention. How bad is the problem? We really have no complete way to know, for any particular clinical question, just how much is missing or buried. This is a problem that has confounded researchers and authors of systematic reviews for decades. (more…)

Posted in: Clinical Trials, Politics and Regulation

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Weak drug regulation and patient tragedies: We’ve seen this story before

Plenty of new drugs, but few that are truly innovative. Growing costs from their use. Physicians deemed “Dupes of Big Pharma” for their interactions with the pharmaceutical industry. A call to produce better information on which drugs work best. Finally, shoddy drug manufacturing is injuring and even killing patients. These stories could be lifted from today’s headlines — but they’re actually from 1962. Problems with the behavior of the pharmaceutical manufacturing industry, and our relationship with it, are not new. Nor are they restricted to one country. Every developed country’s health-care system is different, but one feature is near-universal: none have a public pharmaceutical industry. Ever nation relies on for-profit, private companies to supply its population with drug products.

Blog posts here can get pretty wonkish about health policy, as many of the substantial challenges to science-based medicine have their roots in regulation — whether it’s DSHEA which implemented a regulatory double-standard for supplements, or the state-by-state legislative alchemy that Jann Bellamy has documented, which transforms magical thinking and pseudoscientific practices into registered and regulated health practitioners. Federal food and drug regulations have also come under some scrutiny (and praise). The FDA’s under fire again; this time over its responsibility to oversee pharmaceutical manufacturing. But in this case, it’s not Big Pharma that’s the villan — it’s pharmacies. (more…)

Posted in: Pharmaceuticals, Politics and Regulation

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Don’t call CAM “cost-effective” unless it’s actually effective

Your health insurance plan probably covers anti-inflammatory drugs. But does it cover acupuncture treatments? Should it? Which health services deliver good value for money? Lest you think the debate is limited to the United States (which is an outlier when it comes to health spending), even countries with publicly-run healthcare systems are scrutinizing spending. Devoting dollars to one area (say, hospitals) is effectively a decision not to spend on something else, (perhaps public health programs). All systems, be they public or private, allocate funds in ways to spend money in the most efficient way possible. Thoughtful decisions require a consideration of both benefits and costs.

One of the consistent positions put forward by contributors to this blog is that all health interventions should be evaluated based on the same evidence standard. From this perspective, there is no distinct basket of products and services which are labelled “alternative”, “complementary” or more recently “integrative”. There are only treatments and interventions which have been evaluated to be effective, and those that have not. The idea that these two categories should both be considered valid approaches is a testament to promoters of complementary and alternative medicine (CAM), who, unable to meet the scientific standard, have argued (largely successfully) for different standards and special consideration — be it product regulation (e.g., supplements) or practitioner regulation.

Yet promoters of CAM seek the imprimatur of legitimacy conferred by the tools of science. And in an environment of economic restraint in health spending, they further recognize that showing economic value of CAM is important. Consequently they use the tools of economics to argue a perspective, rather than answer a question. And that’s the case with a recent paper I noticed was being touted by alternative medicine practitioners. Entitled, Are complementary therapies and integrative care cost-effective? A systematic review of economic evaluations, it attempts to summarize economic evaluations conducted on CAM treatments. Why a systematic review? One of the more effective tools for evaluating health outcomes, a systematic review seeks to analyze all published (and unpublished) information on a focused question, using a standardized, transparent approach to evidence analysis. When done well, systematic reviews can sift through thousands of clinical trials to answer focused questions in ways that are less biased than cherry-picking individual studies. The Cochrane Review’s systematic reviews form one of the more respected sources of objective information (with some caveats) on the efficacy of different health interventions. So there’s been interest in applying the techniques of systematic reviews to questions of economics, where both costs and effects must be measured. Economic evaluations at their core seek to measure the “bang for the buck” of different health interventions. The most accurate economic analyses are built into prospective clinical trials. These studies collect real-world costs and patient consequences, and then allow an accurate evaluation of value-for-money. These types of analyses are rare, however. Most economic evaluations involve modelling (a little to a lot) where health effects and related costs are estimated, to arrive at a calculation of value. Then there’s a discussion of whether that value calculation is “cost-effective”. It’s little wonder that many health professionals look suspiciously at economic analyses: the models are complicated and involve so many variables with subjective inputs that it can be difficult to sort out what the real effects are. Not surprisingly, most economic analyses suggest treatments are cost-effective. Before diving into the study, let’s consider the approach:

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Posted in: Acupuncture, Chiropractic, Energy Medicine, Herbs & Supplements, Homeopathy, Naturopathy, Science and Medicine

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Iron supplements for fatigue

How are you feeling today? Tired? Is it your active lifestyle wearing you down? Or is it a sign of something more serious? Complaints about fatigue seem ubiquitous. Perhaps it’s a product of a culture with little downtime. Yet from a medical perspective, fatigue can’t be dismissed with a simple instruction to “get more sleep”. When approached in the pharmacy, I take the perspective that anyone actively seeking advice on treatment probably needs a medical assessment. That’s not something I can offer, but I try to impress upon patients the importance of finding the cause, rather than reaching for any quick fix that may be for sale. (5-hour Energy, anyone?) And I can use the opportunity to discuss the appropriate role of supplements for treating fatigue. (more…)

Posted in: Herbs & Supplements, Science and Medicine

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Magnesium: The cure to all disease?

Having spent many evenings and weekends working in a retail pharmacy with a thriving vitamin and supplement aisle, I’m no longer surprised at the purchasing habits of consumers. The setting gave me not only the opportunity to learn about the latest supplement fads, but also to speak with consumers that place great faith in these products. A recent paper suggests 25% of CAM users account for 75% of all expenditures on CAM. And that’s consistent with what I saw in the pharmacy. Some consumers spend hundreds per month on supplements, so the belief that these products are beneficial must be very strong. So I like to ask about reasons for use. Many attribute their current health status to supplements, and usually tell me that their supplements are for preventing disease, optimizing health, or “boosting” the immune system. And while I’m encouraged to see these consumers take an active interest in maximizing their own health, I’m often puzzled by the decision-making that’s occurring. In some cases, beliefs about health, medicine, or the effectiveness of their supplements are misguided, or flat-out wrong. They’re getting expensive urine and positive feelings, but there’s little evidence to suggest the supplementing is having any objective benefits. More surprisingly, some consumers take products for which there is no medical indication at all – it’s intended as “primary prevention” of a medical condition they believe they can avoid through supplement use. Afraid of macular degeneration? Take lutein. Or worried about Alzheimer’s? Grab some ginkgo biloba. No matter your anxiety, there’s a supplement marketed for your. One supplement with enduring popularity is magnesium.  It cures cancer. And depression. Throw away your inhalers, because it cures asthma too. Read enough online, and you’ll conclude that magnesium is quite possibly the prevention and the cure to all disease. (more…)

Posted in: Herbs & Supplements

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Rejecting cancer treatment: What are the consequences?

One of the points I’ve tried to emphasize through my contributions to Science-Based Medicine is that every treatment decision requires an evaluation of risks and benefits. No treatment is without some sort of risk. And a decision to decline treatment has its own risks. One of the challenges that I confront regularly as a pharmacist is helping patients understand a medication’s expected long-term benefits against the risks and side effects of treatment. This dialogue is most challenging with symptomless conditions like high blood pressure, where patients face the prospect of immediate side effects against the potential for long-term benefit. One’s willingness to accept side effects is influenced, in part, by and understanding of, and belief in, the overall goals of therapy. Side effects from blood-pressure medications can be unpleasant. But weighed against the reduced risk of catastrophic events like strokes, drug therapy may be more acceptable. Willingness to accept these tradeoffs varies dramatically by disease, and are strongly influenced by patient-specific factors. In general, the more serious the illness, the greater the willingness to accept the risks of treatment.

As I’ve described before, consumers may have completely different risk perspectives when it comes to drug therapies and (so-called) complementary and alternative medicine (CAM). For some, there is a clear delineation between the two: drugs are artificial, harsh, and dangerous. Supplements, herbs and anything deemed “alternative”, however, are natural, safe, and effective. When we talk about drugs, we use scientific terms – discussing the probability of effectiveness or harm, and describing both. With CAM, no tentativeness or balance may be used. Specific treatment claims may not be backed up by any supporting evidence at all. On several occasions patients with serious medical conditions have told me that they are refusing all drug treatments, describing them as ineffective or too toxic. Many are attracted to the the simple promises of CAM, instead. Now I’m not arguing that drug treatment is always necessary for ever illness. For some conditions where lifestyle changes can obviate the need for drug treatments, declining treatment this may be a reasonable approach – it’s a kick in the pants to improve one’s lifestyle. Saying “no” may also be reasonable where the benefits from treatment are expected to be modest, yet the adverse effects from treatments are substantial. These scenarios are not uncommon in the palliative care setting. But in some circumstances, there’s a clear medical requirement for drug treatment – yet treatment is declined. This approach is particularly frustrating in situations where patients face very serious illnesses that are potentially curable.  This week is the World Cancer Congress in Montreal and on Monday there were calls for patients to beware of fake cancer cures, ranging from laetrile, to coffee enemas, to juicing, and mistletoe. What are the consequences of using alternative treatments, instead of science-based care, for cancer? There are several studies and a recent publication that can help answer that question. (more…)

Posted in: Cancer, Herbs & Supplements

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Cinnamon for diabetes? The consequences of “natural alternatives”

A customer strolled up to the counter one night when I was working in a retail pharmacy:

“My doctor says I have prediabetes. I don’t want to take any drugs. Do you have something natural I can use to cut my blood sugar?”

I looked at him in the eye, and pointed at his sizeable midsection. “Sir, if you’re at risk for diabetes, and you don’t want to take medication, the single best thing you can do for yourself is lose some weight.”

He grinned and asked, “Great – what supplement can I take to help me?”

This type of discussion occurs all the time. A patient has been assessed by their physician, and informed that they have a medical problem of some sort. The patient, reluctant to accept the physician’s evaluation, heads to the pharmacy for a second opinion. In some cases, the patient may question the physician’s advice: “All my physician wants to do is prescribe drugs.” Yet there’s a disconnect when it comes to strategies for management. More often than not, non-drug approaches are rejected out-of-hand (probably because the sample I speak with have already made the decision to buy something). And in those that are leery of medical management, there’s often a willingness to consider anything that’s available without a prescription – particularly if it’s perceived as “natural.” Natural products are gentle, safe, and effective, while medicine is thought of as unnatural, harsh, and potentially dangerous. This is the naturalistic fallacy, nothing more. Purveyors of supplements leverage the naturalistic fallacy into the marketing strategy of choice for almost all supplements and “alternative” medicines.  And it leads to bad health care decisions. (more…)

Posted in: Herbs & Supplements

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Book Reviews: “The Cure for Everything” and “Which comes first, cardio or weights?”

Do you have any skeptical blind spots? I’ve had a skeptical perspective for a long time (my teenage cynicism wasn’t just a phase) but the framework for my thinking has developed over years. Professionally, the blind spot that the pharmacy profession has towards supplements and alternatives to medicine was only clear after I spent some time working in a pharmacy with thriving homeopathy sales. In looking for some credible evidence to guide my recommendations, I discovered there was quite literally nothing to homeopathy. Once I discovered blogs like Respectful Insolence, the critical thinking process, and scientific skepticism, took off. (more…)

Posted in: Book & movie reviews, Naturopathy

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