Bad Pharma: A Manifesto to Fix the Pharmaceutical Industry

22Nov12


“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?

Goldacre, a medical doctor by training who is still in active practice, has been writing a column on science and evidence for The Guardian for almost a decade. He hasn’t pulled any punches, calling out bad reporting, taking on media personalities who spout pseudoscience, and even even getting sued for libel by a vitamin purveyor. (Goldacre won.) He compiled many of these themes into his first book Bad Science, one of the best resources for non-scientists interested in learning the practical application of the scientific method. From homeopathy to media nutritionists, Goldacre effectively demystifies scientific inquiry and exposes the tricks that can be used to spin and obfuscate the facts. The pharmaceutical industry makes an appearance in the book as well, which Goldacre uses to point out how it can also manipulate good science, using the same tactics (though perhaps with more sophistication) than alternative medicine purveyors. In his discussion of the industry, he foreshadows the thesis of Bad Pharma:

Whatever our political leanings, everyone is basically a socialist when it comes to healthcare: we all feel nervous about profit taking any role in the caring professions, but that feeling has nowhere to go. Big pharma is evil: I would agree with that premise. But because people don’t understand exactly how big pharma is evil, their anger and indignation get diverted away from valid criticisms—its role in distorting data, for example, or withholding life-saving AIDS drugs from the developing world—and channelled into infantile fantasies. ‘Big pharma is evil,’ goes the line of reasoning, ‘therefore homeopathy works and the MMR vaccine causes autism.’ This is probably not helpful.

Goldacre’s comment captures the trepidation I had before reading the book. Constructive criticism of the pharmaceutical industry is surprisingly difficult to find. Many critics have a clear bias. Big Pharma is evil…and…that’s where it ends. There’s no acknowledgment of the value medicine offers, or the recognition that industry can do better. Big pharma’s failings are a blunt instrument that drive home an unsophisticated, and demonstrably incorrect, point: Medicine itself is bad. Some critics seem to have given up entirely on improving the system: It’s hopelessly rigged and even corrupt, they argue. Lest you think this is solely the domain of CAM providers or advocates like Joe Mercola or Mike Adams, it’s not hard to find academics, and sometimes even medical doctors, whose pharmaceutical industry criticisms are not driven by a desire for better science, but rather reflect a rejection of it. In short, they become cranks.

Reassuringly, Goldacre doesn’t get into black helicopter, medical-industrial complex, conspiracy theories with crank objections to industry. He’s a practicing physician who acknowledges the benefits of drugs but laments a system which has even compromised his own treatment decisions. One of his early anecdotes describes how the publication bias of trials for reboxitine, an antidepressant, gave a skewed perspective of the evidence:

I did everything a doctor is supposed to do. I read all the papers, I critically appraised, them, I understood them, I discussed them with the patient, and we made a decision together, based on the evidence. In the published data, reboxitine was a safe and effective drug. In reality, it was no better than a sugar pill, and worse, it does more harm than good. As a doctor I did something which, on the balance of all the evidence, harmed my patient, simply because unflattering data was left unpublished.

Goldacre’s passion and palpable outrage at the fact this has occurred, and continues to occur, are written with a call to action: The situation can can be fixed. And there’s a larger cause – we can all benefit:

However rich you are, if you are sick you can’t innovate new medicines overnight, because that takes time, and more money than even you have. And you can’t know the true effects of the medicines we have today because nobody does, if they’ve not been properly tested, and if some results go missing in action.

Certainly, compared to Bad Science, this is a much longer, much more detailed read. Goldacre recognizes the need for meticulous accuracy but also strove to make the book readable and understandable to the lay reader. It is a tough balance, but I think it largely succeeds. There are only six chapters, of which the first chapter, on missing data, and the final chapter, on marketing, take up almost two thirds of the book. Each chapter provides some illustrative anecdotes, summarizes the overall evidence base, and then proposes a number of possible solutions – some for individuals, and some calling for system-level change. An afterword sums up his detailed prescription. I’ll take the chapters in the same order.

Missing Data
Goldacre starts with missing data, the basis of his thesis and one of the most fundamental problems in medicine today. As I noted in a recent post on on clinical trials transparency, missing data compromises our evaluation of the evidence base, prevents science-based care, wastes resources, and ultimately, does a disservice to patients. If trials are conducted that don’t support efficacy claims, yet are never published, the evidence base becomes biased in favor of treatments and interventions. Goldacre summed up the issue concisely in a recent interview in The Economist:

If I were to run a study, and then just remove half of my data points so that my results looked much better, well, you would laugh in my face. It would be obvious to anyone that it was research misconduct. You might even call it fraud. And yet we tolerate the results of entire clinical trials—a huge proportion of them—being withheld from doctors and patients. In medicine, we rely on summaries of evidence, we collate the results from many different trials. So withholding the results of whole trials is exactly the same insult to the data as fraudulently deleting data points from within individual studies.

There is ample evidence that the evidence base we are currently using in medicine is distorted exactly as Goldacre describes. However, the extent to which this has harmed our treatment evaluations is probably impossible to discern. Goldacre points out that this isn’t just pharma’s fault – research ethics boards, universities, regulators, and medical journals have all failed to follow-through on new standards for data transparency and access. Goldacre calls these “fake fixes”, such as the requirement from the world’s top medical journals to ensure that all published trials are registered before they commence – but the requirement isn’t subsequently enforced. These fake fixes extend to regulators who offer lip service on transparency, and even block access to the evidence they have used to determine if a drug should be approved for sale. Instead there is a “yes” or “no” decision, with little public sharing of the evaluation process and information considered. Goldacre makes an important point about regulatory decisions versus those made by health care professionals:

Contrary to what some regulators seem to think, a drugs is not either ‘good’ and therefore on the market or ‘bad’ and off it. A regulator makes a decision about whether it’s in the interests of the population as a whole that the drug should be available for use, at all ever – even if only is some very obscure circumstance, infrequently and cautiously. The bar is set pretty low, as we shall see, and lots of drugs that are on the market (in fact, the overwhelming majority) are hardly ever used.

A doctor needs to use the same information as that available to the regulator in order to make a very different decision: is this the right drug for the patient in front of me right now? The simple fact that a drug is approved for prescription doesn’t mean it’s particularly good, or the best. In fact, there are complex decisions to be made in each clinical situation about which drug is best.

Goldacre concludes the chapter with an extended list of fixes, outlining ways to strengthen the checks and balances to ensure that the results of all human trials are made publicly available. Some are major policy issues, others are much more simple to implement. Would they improve transparency? Undoubtedly. Are these new issues? No. But the culture of complacency that exists in the health care system about this issue has so far been remarkably resistant to meaningful change.

Where do new drugs come from?

The second chapter looks at the drug development process, and covers a huge subject in a handful of pages. Consequently the complexity and risk of drug development is simplified, which is unfortunate, as it’s important to keep in mind that we have collectively decided that much of this risk must be carried by these for-profit companies. A later mention of drug development costs is also abbreviated, which again minimizes the financial consequences of development. (See my old post on this issue for a detailed discussion of drug development costs.)

One of the most interesting sections is a discussion on just who is participating in clinical trials. Until the 1980′s, many trials in the United States were being performed on prisoners. Today, it’s increasing likely that the crucial trials supporting the approval of a drug are being conducted overseas, where it’s apparently much easier, and less expensive, to run a trial. The challenges with ensuring effective ethical standards and clinical trials oversight should be obvious. Some of the problems with poor countries accessing these drugs are discussed, and Goldacre explores the ethical issues with studying drugs in patients who will never be able to afford the treatments.

Bad regulators
The overall purpose of clinical trials, from a manufacturer’s perspective, is to collect information to support a drug’s regulatory approval. If you’re a frequent reader of this blog you’ll know that there is no shortage of criticism of regulators for the work they do in evaluating new drugs. One of the biggest is the challenge of obtaining expert opinion on new drugs from individuals who may have significant conflicts of interest. This is a common problem, where those with the most experience using a drug, are often in direct conflicts of interest, most frequently because of compensation for participation in clinical trials. The conflicts that can exist between regulators and the industry it regulates are real, and probably managed less transparently than we would like.

Another criticism Goldacre raises is the problem with accepting surrogate markers as endpoints in trials. Manufacturers want their drugs approved as quickly as possible (the patent clock is ticking) so often ask to measure what are called “surrogate” indicators, which are proxies for “hard” indicators which are the outcomes we are really interested in. For example, blood pressure, or cholesterol measures may be the endpoint measured in a clinical trial, rather than a more meaningful indicator like heart attack, stroke, or death. Measuring surrogates is easy. Measuring hard outcomes is time consuming and could mean the need to study hundreds more patients. When surrogates are demonstrably accurate predictors of hard outcomes, we’re in a good place – it’s fair to use a short, smaller trial. But assuming a surrogate predicts a hard outcome can lead to bad decisions. The classic example is the CAST trial, which tested a group of heart drugs for their ability to control abnormal heart rhythms – the surrogate. But the trial also measured hard outcomes. And the trial answered the question – the surrogate improved, but the treatments were killing, not helping patients.
Goldacre gets into the problem with so-called “me-to’s” which are variations of a competitor’s drug product. For example, there are several different but similar “statin” drugs on the market, as there are a group of similar drugs for blood pressure called “ACE inhibitors”. The typical pharma criticism is to berate industry for lacking innovation and playing it safe. But this is a view shaped by an ignorance of the pharmaceutical development process. First, these drugs are often all in development at the same time. Once a potential pathway or drug target has been identified, it’s a race to design drugs, complete the trials and be first on the market. And until the trials are done, and the drugs are approved, it’s anyone’s guess which is going to be the “new” drug and which will be the “me-too”. So we may have a dozen or more similar drugs on the market. That’s a consequence of a competitive marketplace. I share Goldacre’s mixed feelings about me-too’s. This kind of variety is useful to patients who may prefer one over another. Yet it’s also true that the pharmaceutical industry really doesn’t compete on price, nor does it regularly conduct head-to-head trials comparing drug A versus drug B. So we end up with markets where there’s little clear information on which drug is best, and worst of all, no price competition, which would at least reduce the costs of treatment. Goldacre points out the pressing need for comparative effectiveness research, studies which compare treatments and help us determine which is superior.
One of the most important roles of a regulator is the requirement to monitor its safety after approving it for sale. Given a drug is usually tested in small numbers of patients who are carefully selected and closely monitored, there can be a number of surprises once a drug is unleashed on a market. I covered a lot of this ground in a prior post on adverse event reporting. Goldacre spends time describing how regulators worldwide do a generally poor job of both collecting safety information, but also sharing it with health professionals and the public. Some of the recommendations he has to improve regulation includes:

  • requiring companies to compare new drugs against the current “standard of care” rather than placebo
  • raising the evidence bar to demand trials that answer more relevant questions useful for patients and physicians
  • dramatically increasing the transparency of drug evaluation process, so that the evidence supporting decisions can be evaluated
  • improving the way we share information on the risks and benefits of drugs

All of these solutions are achievable. Transparency and data access are obvious. There is little cost and tremendous upside. Changing the standards for clinical trials would have a much more profound effect on drug development, possibly delaying new drugs for years. Goldacre argues this is justified – we’re not losing out if there’s no evidence to demonstrate that the new treatment is better than the current standard. It’s an important policy issue which merits discussion.

Trials
Two chapters are devoted to the structure of clinical trials – how they’re often flawed, and how biases can work their way into the evidence. Patients may be carefully selected for a study and they may be largely unrepresentative of the real population that ultimately take the drug. So new medication that appears to offer a substantial benefit may offer little improvement when it’s used in the real world. Unfortunately, this happens all the time. Or trials may not even answer relevant questions we might have: Studies may be too short (surrogate markers again) or they compare a drug to something inappropriate (placebo, perhaps, instead of the current best treatment). The chapters are essentially a quick-and-dirty critical appraisal guide, and Goldacre gives example after example of the spin that can occur. One of the interesting projects that Goldacre describes is his work in promoting real-world evaluations of effectiveness, which have the potential to tell us which drug works best in a representative population. Clearly he’s excited by the possibility of these pragmatic studies to answer questions that have (so far) been unattainable.

Marketing
The last chapter is devoted to marketing in all its guises. Goldacre describes it as a “chaotic and biased” system, which is a fair description. Regrettably most countries rely on pharmaceutical companies to disseminate information on their own products – and they are hardly unbiased sources of information. One of the challenges we have in the way drugs are prescribed and distributed is that we have a set of misaligned incentives that create market failure. These incentives are easily manipulated through marketing. Consider the following:

  • The patient wants the best treatment, and generally trusts the physican’s decision-making. Their opinions may have been influenced by direct-to-consumer advertising. In some cases, they may believe they are ill because of advertising. Costs of treatment may or may not be a concern, depending on insurance coverage.
  • The physician prescribes the drug. The decision making process for physicians is not always rational, or evidence-based. They may have been exposed to biased sources of information about a drug’s merits. The cost of the drug may not be known – and the physician may not care.
  • The pharmacist has verify the safety and appropriateness of the drug, but well after the treatment decision has already been made. The question of “who pays” has to be sorted out. There is usually little opportunity to help guide drug selection. The pharmacist may also be a target of direct marketing from pharmaceutical companies.
  • The insurer (private, government, or otherwise) will often know little about the individual patient circumstances. They generally want the same thing as the patient – the most appropriate therapy – but know the cost of each treatment and will have a preference for using more cost-effective treatments first.

Take for example, the now infamous case of the COX-2 drugs (Vioxx and Celebrex) when they were launched. Here were drugs that seemed to offer marginal but promising benefits (fewer gastrointestinal bleeds) in selective patients based on short trials. However, they were significantly more expensive that other anti-inflammatory drugs. Yet massive marketing created both patient demand and physician prescribing, accelerated by manufacturer-sponsored “continuing education” programs, and unbelievably, even fake journals created to give the impression of academic credibility. And insurers, who might have preferred less expensive anti-inflammatory drugs, had to make decisions about whether to restrict funding, or pay a tremendous premium for the potential minor benefits of these new treatments. These drugs went on to be blockbusters – but with tragic consequences.

It’s the overall issue of misaligned incentives that I would have liked to see explored further in Goldacre’s book. The United States is 45% of the global pharmaceutical market, followed by Japan (9%), Germany (5%) and the United Kingdom, at 4%. For-profit companies will act to maximize their revenue in the biggest market. It’s arguable that the United States has the least cost-efficient health care system in the world. As long as that system continues to allocate health resources in inefficient ways (e.g., paying for drugs that don’t offer meaningful new benefits), can we really expect pharmaceutical companies to change on their own? Regulation is important, but incentives drive behavior, and we should reward companies who bring the truly innovative therapies to market.

Again, Goldacre writes a number of prescriptions for improvement. They range from the simple (“Don’t see drug reps”) to bigger policy issues about how we can improve the continued professional development of physicians. All merit consideration. And there’s no question, that if implemented, they would dramatically improve the way we use medications.

Closing thoughts
This is a book with important messages for patients, pharmacists, physicians, governments, and the pharmaceutical industry. It may anger, and even infuriate you. It should. Yet Goldacre sketches out a path for reform – one in which transparency is the rule, not the exception, and one in which the pharmaceutical industry can engage with the health care system in ways that will help it do what we all want it to do – bring innovative new medications to market that improve the health and welfare of patients. This change, however, will only come when we demand better – better from pharmaceutical companies, better from regulators, and better from our fellow health professionals. Ultimately, we’ll have the industry we deserve – if we’re not willing to demand better, we’re never going to see any improvements. This book is your call to action.

Bad Pharma hasn’t been published in North America yet. But I’m told some have had success with their Kindle using Amazon.co.uk.

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