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I recently had the pleasure of seeing a new patient. This gentleman is a truck driver and relies on bilateral vision for his profession. He had seen another retinal specialist four months previously and was correctly diagnosed with an occlusion of a venous branch in one eye and vision loss from related swelling. Although a moderate occlusion like this would have had an excellent chance of responding to available therapies, he was told that there was no treatment, and that he should wait until a study of an obscenely expensive new medicine was available. He was not told of the options nor was he told that the doctor would be paid handsomely for enrolling him in this study. He became disenchanted and came to our office for a second opinion. One month after treating him, his vision is improved enough to renew his CDL and resume driving.
Is that what we’ve come to? Withholding treatment purely to make patients our pawns to make more money? As in all professions, there always have been and always will be doctors who are primarily financially motivated. This used to be the exception. The physician as patient advocate used to be the clear norm. More and more doctors now consider this to be naïve and sentimental.
After all, this is the new millennium. Technology is king, and why shouldn’t doctors share in the windfall? Doctors see surreal incomes among executives in the business world, just as their own compensation is scheduled to decrease dramatically while the cost and risks of practicing soar. This is especially true in the pharmaceutical industry, the darling of Wall Street and the very industry most accessible to physician involvement. It is natural and tempting to ask, ‘Why not me?” After all, if physicians drive health care, why not be paid by the industry that fuels so much of it? If doctors diagnose and treat illness, why not get paid to implement the plans of an industry that works to “define” new illnesses and new “needs” for its products. If doctors do research and if industry is rapidly taking over control of what is studied and how it is studied, why not become a paid mercenary in this process? If industry is so eager and financially capable of funding healthcare, and all physicians have to do is accept the argument that industry’s intentions are good, well, why not just give in? It’s convenient and rewarding and, hey, you can’t fight it anyway, right?
The problem with giving in is that with each step, the patient becomes more of a commodity and a pawn instead of the focus of our service. Giving in betrays that which defines the character of the physician. We simply cannot do that and continue to be a healer, teacher, advocate, and care giver to our patients.
Giving in to profitable complicity with the pharmaceutical industry, or any other industry for that matter, betrays the fundamental ethical difference between the practice of medicine and the practice of business. This is not to suggest that one is right and the other wrong, only that they have different ethical constructs that are fundamentally different. The business ethic accepts that the businessman or woman will act so as to promote his or her business. The business person is expected to be honest but not so altruistic as to prevent making a profit. The relationship with the client is an adversarial negotiation in which a product or service is provided for the highest price that the market will bear, and the consumer’s admonition is to beware lest the price and/or quality of the transaction not be ideal.
The physician’s ethic is entirely different. His or her relationship with the patient is not adversarial, but one of advocacy wherein the physician is expected to serve the patient’s best interests at all times. The defining role of the physician is to be an advocate, to be wary on behalf of the patient and not to be that of which the patient must beware. The physician is to work to make the patient healthy and less reliant on therapy, not more so as is the goal of any pharmaceutical marketing department. There is the expectation that the patient will not be taken advantage of physically or financially or be subjugated to the interests of the physician or any industry agent.
The pharmaceutical industry is a hybrid. It is a business entity and can be expected to behave like one. Unlike other industries though, it trafficks in the health of its consumers, and therefore has a responsibility to the public trust. This industry used to be faithful to that trust, but now increasingly only pays lip service to it. On the whole, the industry has run amok and pragmatically betrays its responsibility to the public when it is financially expedient to do so. Such a charge may seem extreme, but there are countless examples of drug companies justifying outrageous pricing or marketing and research practices as being consistent with their “responsibility to shareholders”.
Although physicians have a right to make a comfortable living, they are obligated to refuse profiteering and even racketeering at the patient’s expense. The medical profession, like all professions, has some members whose primary goal is personal profit. The majority have higher goals, but many have none-the-less followed an insidious slide into the hands of corporate and especially pharmaceutical interests. Like many “slides”, it starts innocently enough. A T-shirt at the Academy booth for listening to the pitch. Later, maybe the company sponsors a dinner for you and your referrals, some nice CME, and of course you pick a topic that flatters the sponsor, or at least doesn’t criticize them. Later they ask you to give a talk with an honorarium and travel expenses, and again the talk appropriately expresses your gratitude. Then maybe a trip to be on the advisory board, and finally the big time: you are asked to be on the “research team”, but of course they own and control the analysis and presentation of the data. You don’t like that, but what the heck. It’s great for the practice, and “everyone is doing it anyway”. It all seems okay, you guess. The only trouble is,
It’s not.
It leads insidiously to full complicity with the marketing efforts of industry at the cost of the patient’s well-being. This complicity comes at many levels. The most self-evident is through the promotion of new, patented (and therefore more expensive) “me-too” drugs of dubious value, through direct-to-consumer marketing and the provision of samples to cajole doctors to use these agents. Another more egregious example of complicity is industry manipulation of the research process wherein they have an inappropriate influence on what to study, how to study it, and how to integrate the research process with the marketing plan.
Stories from the trenches-
In the world of retinal medicine, the ultimate me-too drug is Lucentis, an agent so outrageously priced that if it was used just for new cases of Macular Degeneration according to the company’s protocol, it would each year cost more than twice the entire 4.7 billion dollar Medicare budget for all or eye care. I will use the Lucentis debacle as an example of how the ethical practice of medicine has been compromised.
Complicity over what to study-
Genentech developed a true wonder drug with Avastin. It was originally approved and marketed to treat colon cancer and has now been expanded to other cancers in doses of 500 to 1500 mg. IV every two weeks. The pricing was set such that a cancer patient could be expected to pay around $50,000.00 per year. The drug is actually a bivalent antibody that blocks abnormal blood vessel growth and would be expected to work very well for abnormal vessel growth in and under the retina. Normally, if a drug might show potential elsewhere it would be tested, but Avastin was not. It had already been priced at about $5.00 per milligram for cancer therapy, and inexplicably it was kept out of sight. Instead of testing it, it was claimed to be too large to penetrate the retina, creating a plausible reason to split a molecule that already worked, rename the active fragment and give it a new name and price of $2000.00 per half milligram! Retina doctors hired to do the company sponsored research were pleased to go along. Even developing Lucentis required an incredible break in logic, which is beyond the scope of this essay, but which is detailed below.
Complicity over how to study new drugs (and what to report or not report)-
This example comes from the development of Photodynamic Therapy (PDT) using Visudyne, a drug that ushered in the era of exorbitantly expensive retinal therapies with marginal efficacy. Histologically, PDT does some very bad things to the retina that can explain why vision doesn’t improve more often and in fact why PDT often causes significant visual harm. Although the ability to detect this existed at the time, original studies did not focus on histologic effects. In fact, histologic study with OCT was not only ignored, post-treatment study data was not even collected for three months after the treatments. Subsequent work shows that PDT with Visudyne causes immediate, nonselective devastation to the neovascular membrane and surrounding tissue. The original lesion is actually widened by the treatment, and eventual aggressive neovascular recurrence may occur. The original studies were performed by researchers who, in many cases, were paid with company stock options. Without the suppression of this data, and the redefinition of “visual success” to include 3 lines of vision loss, it might have been more difficult to even get this drug approved and marketed.
Complicity over how to treat patients-
Back to Lucentis, the ultimate me-too drug. In spite of all attempts to obscure it, Avastin was independently found to be safe and phenomenally effective. In most surveys, 70 to 80% of retina surgeons in this country and nearly all in other countries use Avastin in preference to Lucentis. Even so, almost a billion dollars is spent annually on Lucentis for what can be accomplished with less than a million dollars worth of Avastin. So what are the incentives to use Lucentis? Fear, misinformation, and money. The company has spared no effort to promote Lucentis over its own parent compound, from inception to the present. They offer free Lucentis to any Avastin study willing to switch, but will offer no free Avastin for any purpose. They have used their paid speakers bureau to spread scare tactics about using Avastin off-label, while they simultaneously support off-label studies and use of Lucentis. (Keep in mind that any use of Lucentis less than every 4 weeks is “off label”.) Beyond that, there is a built-in $100.00 per dose inducement to use Lucentis over Avastin because CMS will pay 106% of wholesale price, which is over 100.00 for Lucentis at $2000.00 per dose and virtually nothing for Avastin at $10-30.00 per dose. This means that for every 40 patients a doctor commits to Lucentis every 4 weeks, he or she makes an extra $50,000.00 per year. Recently, Genentech offered a program that would pay doctors up to $40,000.00 per quarter if they showed an increased use of Lucentis and if they agreed to deny having any knowledge of the program to outsiders! They called this a “rebate” program, although the recipients were doctors who were already profiting from using Lucentis, rather than payers and patients, who continue to get milked.
Redefining Character in Medicine-
That is a lot of money. In spite of that, most doctors continue to use Avastin. Why? Because it is the right thing for the patient, and most doctors are still committed to doing the right thing for their patients. The Lucentis story is repeated countless times in this current era of industry controlled medicine. Still the question remains: what defines the physician’s ethical imperative? What defines the physician’s character? Is the doctor’s primary responsibility like the businessman’s, to maximize profits for him or herself, or is it to be an advocate, even an activist, for patients regardless of the prospect of greater personal gain?
Clearly, the ethical practice of medicine demands the latter. This is not to say that medical care must be free, but it does mean that the doctor must:
At a recent local society dinner in our town, the speaker, a local retina guy, announced that he had no financial ties to any of his material, and then proceeded to give an infomercial for numerous company-sponsored “studies”/marketing ventures, each with financial relationships and some with the promise of consulting and speakers fees . When I pressed him on the point, he explained that he was “just an employee” of his practice, and therefore he had no disclosure obligation. The speaker’s partner suggested that I should keep quiet because “everyone (including me??) is doing it anyway”. That got me thinking again about the various conflicts of interest that have become so commonplace in the retina world today. I posted an essay about such ethical issues last year and received voluminous and unanimously encouraging feedback including a nice note from one of the patriarchs of the ASRS who decried “the pathetic slide of our profession into the hands of the drug companies”.
It has been a slide. Like many “slides”, it starts innocently enough. A T-shirt at the Academy booth for listening to the pitch. Later, maybe the company sponsors a dinner for you and your referrals, some nice CME, and of course you pick a topic that flatters the sponsor, or at least doesn’t criticize them. Later they ask you to give a talk with an honorarium and travel expenses, and again the talk appropriately expresses your gratitude. Then maybe a trip to be on the advisory board, and finally the big time: you are asked to be on the “research team”, but of course they own and control the analysis and presentation of the data. You don’t like that, but what the heck. It’s great for the practice, and “everyone is doing it anyway”. It all seems okay, you guess. The only trouble is,
It’s not.
It’s often so hard to see where that line is and whether or when you’ve crossed it. Indeed, there is much discussion about “the line”, but most seem to agree that there is one and our profession has slipped well across it. The Lucentis/Avastin drama provides an excellent case study. I had a long conversation a few months ago with an associate professor of a major eye institute and his Genentech “handler”. We discussed many of the ethical facets of the Lucentis/Avastin debate, and as they were both expressing their personal belief that the two drugs were equivalent, the doctor explained to me that, in any case, he was “only a scientist” and as such had no obligation to address “the business ethics”. That was a real eye opener for me. He seemed oblivious to his glaring conflict of interest and only too willing to absolve himself of its very existence.
As I have been involved in the national discussion regarding the Avastin/Lucentis controversy, I have had conversations with various bioethics leaders on the role of the drug companies in affecting the independence of medical practice and research. This is not particular to the retina world. Here is how it often works (as summarized from “On the Take”, by Jerome P. Kassirer, MD):
A company has a new product for which they need Phase III or Phase IV data. They recruit willing doctors to whom they pay up to several thousands of dollars just for signing up a patient and then more for collecting the data. The data BELONGS, by contract, to the company. The company takes the data, ghostwriters write what favors the company and they often conceal whatever data doesn’t suit them. They then attach some or all of the names of the hired docs to the ghostwritten paper and have it published. Since the study is designed to favor the drug, and since negative data is often suppressed, it is often not true science but rather more of a marketing project that looks scientific. It’s a win-win. The company gets their product out, marketed in a way that looks like legitimate peer-reviewed development, and the docs get money and a little prestige as well. After that, the docs may get more money to be on the speaker’s bureau to promote the product. Since there are innumerable combinations of products out there now, there is virtually no limit to how many marketing projects can be made into such “research”. The crux here is that docs are paid a sufficient premium that there is an inducement to go along with the company on care decisions and data management that could compete with patient welfare. Since over the last decade or more the government has stepped back from funding clinical research outside of the NIH, companies are only too willing to pick up the mantle and fit “research” into their marketing plans. As physician reimbursements have come under increasing pressure, it has become tempting to replace perceived lost patient care revenue with drug company revenue. And why not? “Everyone else is doing it anyway.”
Don’t take it from me. Consider the books “The Truth about the Drug Companies”, by Marcia Angell, MD, and “On the Take”, by Jerome P. Kassirer, MD, both former Editors in Chief of NEJM. The first considers the manipulation of the drug development and marketing process by the drug companies and the second deals with physician complicity in this process. Both books should be required reading for anyone who seeks to be informed about the conflicts of interest in clinical care, research, and medical education.
The ophthalmology and retinal specialties were not deeply explored in these books, but our issues are very much on the battleground that they discuss. It is virtually impossible to find a meeting where speakers’ are not compromised by financial conflicts of interest. Many colleagues have written to me in the past year that it is hardly worth even going to meetings anymore since so much of what we hear is nothing more than advertisement for the speakers’ various sponsors. It would be easier if the speakers just wore NASCAR style jackets emblazoned with their sponsors’ logos. The drug companies’ influence is pervasive even beyond overt sponsorship. I was recently to give a talk on some of these ethical issues, but five minutes before speaking I was asked to change my topic because one of the companies had just given a large sponsorship check for the meeting.
Call me sentimental, but I still admire research that is done to gain unbiased knowledge, and I miss the time when our academics and “opinion leaders” never needed to explain (or euphemize) their financial interests at meetings and in papers. The financial conflicts that Dr. Kassirer talks about in his book are rampant in the retinal world.
There is a very good reason for this growth of corporate sponsorship of physicians. Over the last five or more years, there has been increasing downward pressure on physician reimbursement. Simultaneously, since the precedent of obscenely priced retinal pharmaceuticals was ushered in with Visudyne, drug costs have been eating into the Part B revenue pie. This has come to a head with Lucentis. Few dispute that Lucentis and Avastin work very nearly identically, and many suspect a primarily financial motivation for Lucentis’ development. Nonetheless, by the company’s own estimates quoted in the recent Wall Street Journal article, Lucentis should take close to 1 billion dollars from the Medicare Part B budget for eye care in 2007. This is about 20% of that budget right here and now, and it creates a virtual certainty that physician reimbursement and patient benefits will suffer accordingly. One option for physicians is simply to sell out, jump on the bandwagon, and replace lost patient care revenue with Big Pharm payoffs. These are available in the form of payment for corporate controlled research, marketing, speaking engagements, and the like. There is even a $100.00 per dose inducement to use Lucentis over Avastin, since CMS pays 106% of AWP, which is about $100.00 more for Lucentis than Avastin. And why not just give in? “Everyone is doing it anyway”.
And what about the patients? Well, they’re on their own, aren’t they?
What about research? Real research still happens; it’s just obscured by ever increasing volumes of corporate research that is too often designed to serve marketing interests at the expense of scientific interests. Even if good research is done by those who accept compensation from drug companies, that financial conflict makes it impossible and impractical to discern which data is biased and which isn’t. Even the good, nonbiased data is tainted by the possibility of undetected bias. Before all these financial intrusions, we didn’t have this problem. Furthermore, research that doesn’t support marketing interests is often spurned. Take the head to head CATT study. This is being done without any corporate help because Genentech publicly admits that it will support no research on Avastin because “it is not in their best financial interest” (personal communication with a Genentech executive who will remain unnamed). So much for bringing a vision of (true) science to the science of vision. Maybe Genentech should change its motto to “Bringing the Science of Marketing to the Marketing of Science”.
What of our societies and our academic “leaders” and “opinion shapers”? It would be nice to think that biased research happens only in the less regimented world of private practice, but it doesn’t. Many, though certainly not all, of our academicians and “leaders” are hugely affected by financial conflicts of interest. It is no longer possible to go to a website or even a journal that is not affected by the infamous “unrestricted grant” from one or more corporations. In this context, “unrestricted” too often means, “spend this grant on what you want, but if you ever want another one, don’t displease us”. This has made it difficult for doctors who want to practice good medicine with reliable information. There is still a significant quorum of our peers who want nothing more than this, to practice good, evidence-based medicine in the best interests of their patients. How do we find unbiased information and teachers? Who can we trust? How can we connect with government in a sincere attempt to provide good and cost effective care? How can we advocate for patients and keep our health system solvent?
We must find answers to these questions in the decade to come. In spite of the apparently impregnable fortress of “Big Pharma”, I hope that we can decide that patients are more important than shareholders or various individuals’ consulting deals. I think we need to speak up and act out. I have heard many, many insightful and deeply ethical thoughts from many colleagues since I first joined this discussion a year ago. I think we need to make a stand and let the chips fall where they may. Truth tends to eventually bubble to the surface against all odds. New therapeutic development is vital, but unbridled marketing hubris has gotten out of control. “Opinions” that are crafted and purchased to serve corporate interests often just don’t make sense for the public welfare. We need new opinions that serve the interests of patients and society, and if that means we need new “opinion leaders” who are willing to serve an ethic of truth over financial expedience, well that wouldn’t be so bad.
In the spirit of providing a forum for discussion of these issues, several physicians have created a website and a grass roots organization called Physicians for Clinical Responsibility. This is meant for physicians who have decided not to enter into financial interests that might conflict with patient interests. This essay and several earlier ones as well as news articles and links to Dr. Kassirer’s and Dr. Angell’s books are on the www.clinicalresponsibility.org website. I invite you to take a look, sign up to be a member of Physicians for Clinical Responsibility and even leave a comment or cosign any of the pieces on the site. If you agree with the content, say so. If you disagree or have other input, say so. The independent literature there speaks for itself. The members’ essays are not intended to be dogmatic and certainly are not intended to be inaccurately critical. If there are inaccuracies, please post corrections. The intent is simply to catalog opinions in a dedicated clearinghouse, stimulate input, and create a forum for concerned members of the medical profession.
“Bringing the Science of Marketing to the Marketing of Science”