by Marcia Angell
Random House Trade, 2004
Review by Nassir Ghaemi, M.D., M.A., M.P.H. on Feb 5th 2006
Marcia Angell, a physician and former editor of the New England Journal of Medicine, says that we are the victim of a pharmaceutical-governmental-academic complex whose bottom line is money and power, rather than the public health. This is quite an indictment. But, contrary to some reviews of her book in medical journals, while her tone is rhetorical, I found it hard to disagree with many of her major claims. However, I do have some concerns about the validity of some of her facts, and, in her anger at her own profession, I think she fails to appreciate the important role of individual ethics, as opposed to law and public policy, in medicine.
Her basic argument is that there are three myths about the pharmaceutical industry -- that it produces innovative new drugs, that it is essential to the American free enterprise system, and that its high prices reflect research costs.
Innovation and the pharmaceutical industry: The history of psychopharmacology
Her weakest argument involves innovation. She states that most of the innovative work that leads to new classes of agents happens in universities and the National Institute of Health (NIH), not in the basic laboratories of drug companies. She provides a few cases that follow her pattern, but she ignores many others that do not. If she had written a scientific paper, instead of a book, this would have been considered a highly selective review of the literature, where one proves any points one wants to prove by only choosing data that support them; that kind of study surely would not have passed muster in her tenure as editor of the New England Journal of Medicine.
An objective reading of the history of psychopharmacology, for instance, clearly demonstrates the essential role of the pharmaceutical industry in the discovery and development of antidepressants and antipsychotics -- agents that, most would agree, have helped many people (despite the fact that they might also be inappropriately used in some people). The relevant facts have been well described by historians of psychiatry Edward Shorter (A History of Psychiatry, 1997, John Wiley and Sons) and David Healy (The Antidepressant Era, 1999, Harvard University Press), both of whom are also highly critical of the pharmaceutical industry on many other topics.
Take the first antipsychotic, chlorpromazine, which more or less emptied the mental hospitals and rendered obsolete other more harmful treatments (like insulin shock, electroshock, and frontal lobotomy):
The whole class of phenothiazine antipsychotics were developed by the Rhone-Poulenc drug company in France in the 1930s, mainly due to an interest at the time in the potential medical benefits of antihistamines. Paul Charpentier, a phenothiazine specialist at the drug company, had synthesized what would later be called chlorpromazine. Meanwhile, a surgeon, Henri Laborit, had noted that some of the Rhone antihistamines, when given to potentiate anesthesia, made patients very calm and indifferent. Laborit then convinced some skeptical psychiatric colleagues to give it to patients, who improved, and the drug took off. As Shorter puts it, "The ultimate force behind the discovery and adoption of new drugs such as chlorpromazine was not academic scientists or clinicians...but the drug companies. Although Rhone-Poulenc had not identified chlorpromazine as an antipsychotic, it was company scientists who had systematically designed the compound and tested it on animals. The drug's discovery owed nothing to serendipity." (Shorter, p. 250)
Now take the first antidepressant, imipramine:
"In 1950, the J. R. Geigy pharmaceutical firm in Basel asked staff physicians to the Munsterlingen asylum in Switzerland to see if an antihistamine that Geigy had developed might serve as a sleeping pill....[Staff psychiatrist Roland] Kuhn asked Geigy -- or Geigy asked Kuhn, according to some accounts -- if the hospital might try another drug in the antihistamine series, one with a chemical side chain exactly identical to chlorpromazine's....The staff tried it on patients with schizophrenia. It made many of them worse, converting quiet chronic patients into agitated whirlwinds of energy. Kuhn consulted with Geigy scientists on what the drug could possibly be doing to procure such bizarre effects, and sometime in 1955 the decision was made to give it to depressed patients. The response was 'absolutely incredible, so exciting', electrifying both to hospital staff and the Geigy scientists who had been following all this with bated breath. Kuhn and the Geigy people had obviously discovered a drug that could relieve depression." (Shorter, pp. 259-260)
My hunch is that Angell did not study the history of psychopharmacology very carefully. And my hunch is that similar histories exist behind many of the new drugs in cardiovascular disease, epilepsy, and other medical fields. Clearly, although academics had a role, the pharmaceutical industry was key to the development of these revolutionary drugs in psychiatry. Shorter concludes:
"For the most part, the new psychopharmacology was driven by the drug industry and not by the academy....the private sector made a fundamental contribution to neuroscience. The drug industry funded research into such matters as chlorpromazine's action on the brain....In fact, one could call psychopharmacology the creation of the drug industry, rather than the academy or clinicians." (Shorter, p. 265)
It should be kept in mind that in the 1930s through the 1960s, the vast majority of psychiatrists, both clinicians in practice and academic leaders, were enthralled with the religion of psychoanalysis and had absolutely no interest in studying or using drugs. The pharmaceutical industry discovered that certain drugs seemed to have psychiatric benefits, and they had to drag the profession of psychiatry, somewhat involuntarily, into studying and using those drugs. If left to pure academia, with no ties to the pharmaceutical industry, as Angell would have it, we might still be practicing daily psychoanalysis for years on end to "treat" most mental conditions.
Angell is denying innovation to make the point that most drugs are in fact "me-too" drugs -- similar copies of truly innovative agents. Yet the reality is that the two are not contradictory: the pharmaceutical industry is innovative, and, at the same time, most agents are me-too drugs. Yet even with me-too drugs, Angell oversimplifies matters, implying that all me-too drugs are basically the same. Angell argues, citing data from FDA definitions, that only 17 of 78 drugs approved in 2002 were innovative. Her view is that the rest are superfluous and could be more or less removed from medical care with little loss in the public's health. Let's test this claim with the serotonin reuptake inhibitors (SRIs): the first SRI in the US, Prozac, was followed by a number of others (Zoloft, Paxil, Luvox, Celexa, Lexapro). Clinicians and patients know, and there are some clinical trials that demonstrate, that sometimes one of these agents works, while others do not. Although the drugs share one mechanism (serotonin reuptake), they differ on their potency of effect on that mechanism (Celexa is much more potent in serotonin reuptake than Prozac) and in other mechanisms (Zoloft has dopamine effects, Paxil has norepinephrine effects) and other relevant drug features (drug interactions, side effects). So although the drugs belong to the same class, they are not exactly the same. While the me-too critique is relevant, it is more complex than she makes it.
The other myths
Angell is more effective in her critiques of the other two myths.
The claim that any government intervention on the pharmaceutical industry, such as price regulations, would be a major blow to the American free enterprise system is an easy claim to refute. It is quite clear that the pharmaceutical industry is already highly regulated, based on the patent laws it enjoys, its ability to negotiate prices with insurance companies and the government rather than leave them to direct consumer decisions, and strict laws regarding the ability to make efficacy and safety claims about drugs. This is a very regulated industry already, Angell claims; it is just poorly regulated.
The third myth that high prices reflect research costs is also relatively easily rebutted by showing the numbers of how much is spent on marketing, as opposed to research, as well as emphasizing the marketing orientation of much of what is called research.
Most of the book involves providing details that are relevant to her attacks on these myths. For instance, while discussing the heavy lobbying and influence of the pharmaceutical industry in Washington and state governments, Angell notes that the current ambassador to Sweden was the former CEO of Bristol Meyers Squibb, that the former director of George W. Bush's White House budget office was a senior vice president from Eli Lilly, that former president George H. W. Bush sat on the board of directors of Eli Lilly, that the secretary of defense, Donald Rumsfeld, was the CEO of Searle, and that the pharmaceutical industry has more lobbyists (675, 20 of whom are former congressmen) and spends more money (about $80 million yearly) than any other lobby in DC (with 80% going to Republicans). These kinds of facts are useful to know, as are her claims that the pharmaceutical industry has much higher profit margins than other industries (banking comes in second), and that some pharmaceutical CEOs make about $40-70 million yearly in salary (with the same amount also added in stock options).
The book's main weakness
Perhaps the main weakness of the book is that Angell's sources are mostly newspapers (such as the New York Times and the Boston Globe) and consumer advocacy groups (mainly Common Cause and Families USA). One sees little evidence of any original research or scholarship; she has taken what was available in the media and constructed an argument from it. But an argument is only as good as its logic and its content. I follow her logic, but I worry about some of the content. The innovation and me-too drug examples suggest that she has not delved into this material sufficiently. She is taking for granted that the reporters on whom she relies got accurate and complete stories; Angell trusts them implicitly. Given recent scandals at even the most respected newspapers (like the New York Times), one wonders whether this is the best policy.
Further, she makes some errors of fact that raise concern about some of the details in the book: for instance, she gets the dates and order of the introduction of serotonin antidepressants wrong on page 112 (and then contradicts her wrong dates there with other wrong dates on page 190). One would expect better fact-checking. At least a historian of psychiatry (and a psychiatrist) like Healy actually interviewed many of the protagonists of the history he describes; others have obtained new documents from the government through the Freedom of Information Act. Angell does not, as best as I can tell, interview a single person for her book.
A proposal for reform
After her critique, Angell offers a program of reform that is not particularly revolutionary. She does not claim that we should do away with the pharmaceutical industry entirely, as some fed up doctors and patients seem to want. She does not paint them as entirely evil, and emphasizes that many decent people work for the industry. She also makes the important point that we all rely on drugs for our health; thus it is in everyone's best interest to improve this system, rather than simply to demonize or destroy it.
Thus, she wants to restructure our regulations so that we promote what the industry does well (mainly distributing and packaging drugs, as well as some marketing) and end what it does poorly or wastefully (inflating prices, excessive marketing, me-too drug production, involvement in medical education). Overall, most of her suggested changes seem reasonable to me, especially the suggestions to require proof of benefit compared to older medications in clinical trials (thus providing more clinically relevant data on the relative efficacy of drugs) as well as the idea (long promoted by others as well, like E. Fuller Torrey of the Stanley Foundation) that the government, through the NIH, needs to be much more involved in clinical drug research, as opposed to leaving it to the pharmaceutical industry, as it has.
The academic-pharmaceutical link
Her harshest criticisms are reserved for her medical colleagues. As an academic clinical researcher, like most of my colleagues, I have received and continue to receive pharmaceutical funding for research and for medical education. I am fully aware of the many problems that result from that interaction between the industry and academia; and, while I agree with much of her critique, and with many of her reform ideas as they relate to the government-pharmaceutical link, I think she does not adequately assess the complexity of what needs to happen next in the academic-pharmaceutical link.
For instance, she claims that any academic who has any financial tie to a company is biased (she even suggests at the end of her book that patients should ask their doctors whether they have such ties, and if so, they should change their doctors; with this advice, most patients would have to change their doctors). The problem here is that while the broad claim is likely true -- the current system has led to a great deal of bias among academic doctors in research and education -- I would suggest that the narrow claim is untrue -- it is not the case that every single doctor who has such financial ties is always biased. Here is an example from my experience: I have been invited to give a lecture at a major annual meeting of psychiatrists in which I critiqued a drug made by the sponsor of that symposium; I was then not invited again by that company. The next year, I was invited to give a lecture at the same meeting by a competitor of that drug, and I gave the same critique. Where is the direction of bias? The listener cannot know whether I am critical of the drug because of who is sponsoring the lecture, or whether I am asked to lecture by a company because they know I am critical of the drug. If every utterance is judged based on financial ties, then we will never be able to know if anything said by an academic is based on his or her best assessment of the truth, or based on financial bias. The problem is that the opposite does not occur: one is not paid to criticize a drug, because one is not paid to say what one believes by companies who stand to suffer from such views. This complexity is rarely appreciated by those not involved in this complicated academic-pharmaceutical web. It is not a justification of the current system, but an indication that the simple solution of judging bias by financial ties is, at least sometimes, incorrect.
Readers who have come this far will get the sense that I struggle with what we should do next in academic medicine. In our current system, clinical research remains predominantly funded by the pharmaceutical industry. As a clinical researcher, to refuse such research funds would be to give up on research altogether, since universities will not pay for such research time, and federal grants are limited (and usually given to those who first establish a track record with pharmaceutical research). Further, medical education remains mostly funded by the pharmaceutical industry, again mainly because universities do not want to provide the funds needed to legitimately compensate speakers for the time they take away from their work and private lives to travel and prepare conferences or lectures. Angell dismisses these concerns, but it is relevant that much medical education would not happen unless people are paid for their time and effort to provide that education. So, for now, we are faced with temporary steps toward progress: medical education is being more and more done in a setting where the pharmaceutical grants are not tied to the choice of speaker and topic, which is left instead to the inviting university. Research grants, though still pharmaceutically funded, can be conducted on important scientific questions designed by the academic researchers (not by the industry) with all data analysis and writing conducted by the researchers. Academics can avoid "promotional" dinner lectures, and focus on the continuing medical education (CME) programs that are designed to minimize bias and direct pharmaceutical influence. Of course any of these measures can be avoided or abused. Hence the need to reform our current system, as Angell rightly argues, yet I think she underappreciates the role of the ethics of medical practice -- the importance of the individual ethics of each physician -- since an individual physician could seek to proceed ethically with approaches such as those just described.
Medicine is a profession that can be easily abused; doctors have special knowledge; ultimately patients need to put some trust in their doctors; their doctors need to be worthy of that trust. I am surprised how frequently some doctors (usually in private practice and completely uninvolved in research or teaching) are critical of the ethics of other doctors who have any connection to the pharmaceutical industry; clearly many doctors with such ties have unethically abused them, but many of those same private practitioners have abused the medical system in the past, by overcharging patients and insurance companies and by fee-padding, which led to the reaction of the managed care industry. There are no paragons of good or evil in this picture, rather human beings with foibles who are sometimes excessively seduced by mammon. Some physicians can be quite ethical within the current system, even when having ties to the pharmaceutical industry; others will be unethical even in Angell's ideal reformed system.
Every doctor knows that William Osler, the founder of modern medicine, was right when he said that medicine is a calling, not a business; yet it is relevant that he needed to emphasize this axiom because many doctors practice medicine like a business (if in doubt, one episode of "Dr 90210" should suffice to make the point). Osler even warned about the dangers of pharmaceutical industry around 1900, when it was in its infancy. A great deal of effort needs to be put into keeping medicine focused on the calling of healing persons, rather than simply being run as a business. Yet pharmaceutical industries are clearly businesses, hospitals are businesses, universities are run like businesses, and at least one of our two parties thinks the role of the government is mainly to encourage business. Health is a value in its own right, though, one that trumps Adam Smith. So we should push ahead on two fronts. Politically, we should push for reforms, not only of the pharmaceutical industry but also of the managed care insurance industry, that place public health above all other factors -- whether share prices, or innovation, or capitalism, or patent law, or economics; and professionally, we as physicians need to set a higher standard about how to function within this system while remaining personally committed to the Oslerian ethic of medicine as a calling.
© 2006 Nassir Ghaemi
Nassir Ghaemi, M.D., M.A., M.P.H., Associate Professor, Department of Psychiatry and Behavioral Sciences; Director, Bipolar Disorders Program, Emory University School of Medicine. Dr. Ghaemi is author of The Concepts of Psychiatry: A Pluralistic Approach to the Mind and Mental Illness, Johns Hopkins University Press, 2003.