Articles

Posts Tagged Pharmaceutical Industry

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?

(more…)

Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

Leave a Comment (20) →

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

Leave a Comment (27) →

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

Leave a Comment (18) →

All Medicines Are Poison!

That’s the title of a new book  by Melvin H. Kirschner, M.D. When I first saw the title, I expected a polemic against conventional medicine. The first line of the Preface reassured me: “Everything we do has a risk-benefit ratio.” Dr. Kirschner took the title from his first pharmacology lecture in medical school. The professor said “I am here to teach you how to poison people.” After a pause, he added, “without killing them, of course.” 

He meant that any medicine that has effects has side effects, that the poison is in the dose, and that we must weigh the benefits of any treatment against the risks. Dr. Kirschner has no beef with scientific medicine. He does have a lot of other beefs, mainly with the health insurance industry, the pharmaceutical industry, and alternative medicine. (more…)

Posted in: Book & movie reviews, Pharmaceuticals

Leave a Comment (7) →

A Not-So-Split Decision

For those who battle tirelessly against the never ending onslaught of anti-vaccine propaganda, misinformation, and fear, there was great news the other day from Merck. The pharmaceutical company, and maker of the MMR vaccine against measles, mumps, and rubella, has decided not to resume production of the individual, or “split”, components of the vaccine. A Merck representative made the announcement during a meeting of the CDC Advisory Committee on Immunization Practices (ACIP) on Tuesday. During previous ACIP meetings, science experts on that committee presented compelling arguments against  continued, large scale production of the monovalent components of the MMR vaccine, which were echoed by scientists in Merck’s vaccine division. In a moment, I’ll discuss the arguments against the split vaccine, and why this is so important a decision. First, some background on the issue of splitting the MMR.
(more…)

Posted in: Science and Medicine, Vaccines

Leave a Comment (36) →

Book Review: Triumph Of The Heart, The Story Of Statins

Triumph of the Heart, as its name does not suggest, is about science. The book’s author, Jie Jack Li, is a medicinal chemist who meticulously reviews the history relevant to the discovery of lipid-lowering drugs. He spares no details, even recounting the amusing quarrels and quirks of the scientists engaged in the “apocryphal showdowns” leading to the manufacture of cholesterol in a laboratory.

The personalities of the various scientists and Nobel laureates described in the book are highly entertaining. From beating one another with umbrellas, to insisting on wearing blue clothing only, to egos so large and unappealing as to empty an entire academic center of all its promising young recruits, one has the distinct impression that brilliance does not go hand-in-hand with grace.

That being said, each of these scientists did seem to share a common approach to research: carefully testing hypotheses, repeating peer study results to confirm them, and patiently exploring complex biochemical pathways over periods of decades. The physicians, physicists, and chemists showed an incredible ability to doggedly pursue answers to specific questions – understanding that the results might influence human health. But even more importantly, they were each willing to invest their careers in analysis that may never lead to anything more than a dead end. In fact, the book is full of examples of great ideas, developed over decades, that did not lead to a marketable drug. In some cases the research was halted due to lack of efficacy, in others political forces or personal whims influenced the course.
(more…)

Posted in: Book & movie reviews, Pharmaceuticals

Leave a Comment (20) →

Wyeth Vs. Levine: Joe Six Pack Trumps The FDA

The New York Times has called today’s US Supreme Court ruling in the Wyeth vs. Levine suit the “most important business case in years.” I have been following this case for many months, astonished that a medical malpractice suit had gotten all the way to the Supreme Court. But even more shocking is the fact that the court actually ruled that lay juries may evaluate the accuracy of FDA-approved drug labels written for healthcare professionals.

In other words, after a team of FDA regulators decide on the very best language to describe potential risks of a drug -  Joe Six Pack can overrule their expertise and hold the drug company liable for any deficit (as he interprets it) in label language, awarding millions to anyone who experiences harm, no matter how well disclosed that risk is.

I reached out to Wyeth’s attorney, Bert Rein, for comment. Here are the highlights from the interview (a podcast is available here)…

Dr. Val: The New York Times is calling Wyeth vs. Levine the most important business case in years. Can you summarize what just happened?

Rein: The court determined that Wyeth’s liability for Ms. Levine’s injury was not preempted by the FDA-approved drug label warnings. They were not convinced that the FDA had declined to strengthen the warning language on the label prior to Ms. Levine’s injury, though Wyeth had in fact requested a label change. In addition, the court held that the FDA’s regulatory regime was insufficient to preempt Ms. Levine from suing Wyeth, because the FDA doesn’t have a regulational requirement for all label updates to undergo federal approval. The court therefore ruled that the suit was well founded and that the state of Vermont should decide whether or not Wyeth’s conduct was appropriate.

(more…)

Posted in: Pharmaceuticals, Politics and Regulation

Leave a Comment (18) →