The producer of FRONTLINE's "Dangerous Prescription" offers two stories, not included in the documentary, about how pharmaceutical companies have been known to handle bad news.
Nov. 13, 2003
Whenever you make a television documentary, inevitably you shoot more material than can possibly fit into a one-hour program. That certainly happened to us in making "Dangerous Prescription." After we had researched our program and begun filming a broad story about drugs that had recently come off the market, current and former Food and Drug Administration employees began coming forward, little by little, to give us a powerful critique of what was going on inside the agency. Our story gradually began to evolve, and rather than making a documentary about drug safety in general, we ended up shifting our focus to the FDA.
But drug safety isn't just in the hands of the FDA. Americans -- and the Food and Drug Administration itself -- rely on pharmaceutical companies to be honest about what works and what doesn't. The ways in which pharmaceutical companies can "spin" bad news about their products, or influence the distribution of that news, in order to control damage and impede important information from reaching consumers and doctors, are revealed in two cases that didn't make it into the program.
What Bad News?
The first of these stories is about patients getting "less effective drugs" when better choices are available. If your doctor prescribes a less effective drug, you're not being helped as much as you could be helped. And when you think about it, that means you are being harmed.
About 50 million Americans have hypertension (commonly known as high blood pressure) -- and an estimated 30 million need some sort of medical treatment to bring their problem under control. Patients who fail to lower their blood pressure face increased risk of heart attacks, strokes and diabetes -- so the treatment of hypertension has become one of the largest markets for drugs in America and everywhere else in the developed world.
By some estimates, there are as many as 180 different prescription medications used in the United States to treat hypertension. Almost every major drug company has at least one product for lowering blood pressure, and doctors are generally happy to have these choices. But having so many choices does create a problem. Some drugs are bound to be more effective than others -- so doctors urgently want to know what's best.
Unfortunately, pharmaceutical companies rarely conduct clinical trials that fairly and objectively compare other companies' drugs against their own. And the FDA doesn't conduct such trials either, because the agency is not in the business of doing medical research -- only reviewing the results submitted by pharmaceutical companies.
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With Americans spending $16 billion a year on blood pressure medicines, and no objective information to show which ones were most effective at reducing the problems caused by high blood pressure, about 10 years ago the National Heart Lung and Blood Institute (a division of the National Institutes of Health) started a long-term clinical trial that would honestly and fairly compare the effectiveness of the leading types of blood pressure medicines. The study, called ALLHAT (short for Anti-Hypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) enrolled over 42,000 Americans, lasted for some eight years, and cost over $140 million.
It was the kind of study that only a government agency could organize -- comparing four major classes of competing hypertension drugs, each of which lowers blood pressure in its own unique way. The drugs included: a diuretic (one of the oldest and cheapest treatments for hypertension, and widely available as a generic drug); Lisinopril (one of the popular, widely prescribed "ACE inhibitors," a class of drugs that includes Capoten, Vasotec Lotensin, Monopril, Univasc, Aceon, Accupril, Altace, Mavic); Norvasc (a "calcium channel blocker" made by Pfizer and the country's largest selling treatment for hypertension according to a Pfizer annual report); and Cardura (an "alpha blocker").
According to ALLHAT's principal investigator, Dr. Curt Furberg, "since the early 1990s, ACE inhibitors and calcium channel blockers had captured maybe a third or maybe 40 percent of the market" for treating high blood pressure, cutting into the prescriptions for older drugs that had a long track record of effectiveness and that were much cheaper. "And there wasn't good evidence that the newer drugs were better, or even as good," says Furberg, "so this study was undertaken to help us figure that out."
About six years into the study, its organizers halted treatment with one of the drugs, Cardura, because an early data analysis showed that patients on Cardura were 25 percent more likely to develop cardiovascular disease than patients on diuretics, and twice as likely to develop heart failure. It wasn't that Cardura was bad, but for most people it was clear that diuretics were significantly better.
The study continued with the three remaining drugs until the summer of 2002, and then in December of last year the results were announced at a packed press conference in Washington. The news was dramatic.
While all the drugs helped lower patients' blood pressure to about the same degree, according to the ALLHAT results patients on Norvasc -- an expensive and highly-advertised product -- were 38 percent more likely to develop heart failure than patients on the cheap, tried-and-true diuretics. And patients on Lisinopril (also more expensive than diuretics, and just coming off patent) were 15 percent more likely to develop strokes, 19 percent more likely to develop heart failure, and 11 percent more like to have angina than patients on diuretics. So, as a first-line treatment, the cheapest, oldest and least-promoted drug was significantly better at preventing the serious problems that can arise from having high blood pressure.
"ALLHAT demonstrated that, in the past, we didn't spend our drug dollars wisely," says Furberg. "We put too much money into drugs that are now shown to be inferior. And we need to learn more from that. And I think it's important for society to step in and not just leave it to drug companies to promote their drugs."
In Furberg's opinion, the fact that millions of people took -- and are still taking -- less effective drugs means that tens of thousands of Americans have been developing health problems that could have been prevented by a more effective drug.
"If you eliminated all the ACE inhibitors and calcium antagonists [calcium channel blockers] for the first-line treatment of hypertension," says Furberg, and if patients were put on diuretics, "we would avert maybe 60,000 events per year -- 60,000 heart failures or strokes. These are devastating complications. So, if you want to know what has happened over the past five years, we'll you can multiply by five. So we're talking about a large number of people who unnecessarily have suffered these events because we didn't have the knowledge we have today."
Furberg does note that many patients need to combine two or more different drugs to adequately lower their blood pressure -- so there's an important role for less effective drugs. And some patients don't tolerate diuretics so they need other options. But for the vast majority of people who have just been diagnosed with high blood pressure, according to ALLHAT, diuretics were the best as a first-line treatment -- and also the cheapest.
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Given the ALLHAT data about calcium channel blockers and ACE inhibitors, the question was, how to get doctors to change their prescribing habits? For that to happen, first they would have to get the news.
But as Furberg soon discovered, the maker of one of the less effective but highly popular hypertension drugs wasn't going to let its market share slip away without a fight.
On the same day that the NIH scientists announced their results to the nation, Pfizer, the manufacturer of Norvasc, started a quiet campaign to counter the study results. First, the company issued a press release highlighting all of the study findings that were positive for Norvasc -- but leaving out the findings that were negative. (The release did mention that patients should first be started on diuretics, but it didn't mention that starting patients on Norvasc would lead to more heart failure.)
Then the company sent to television stations a videotaped interview with Dr. Michael Berelowitz, vice president of Pfizer's Metabolic and Cardiovascular Group, who declared that the ALLHAT study was an affirmation for Norvasc. "This study confirms what I think we have felt all along," Dr. Berelowitz says on the tape. "And that is that Norvasc is a safe, effective, well-tolerated agent for lowering blood pressure. … Accepting that diuretics are safe and effective and decreased cardiovascular disease, ALLHAT looked to see how the new agents -- calcium channel blockers like Norvasc, and an ACE inhibitor -- compared to the diuretic. And these agents were equally effective."
Read a letter from Berelowitz responding to FRONTLINE's request for an interview.
Compare Dr. Berelowitz's statement in the video to a statement made by the NIH research team that conducted the study. "Each of the newer drugs had significantly higher rates of one or more forms of cardiovascular disease," the ALLHAT team said. They went on: "Because of their superiority in preventing one or more forms of cardiovascular disease and their lower cost … diuretics should be the drugs of choice for the initial treatment of hypertension in most patients requiring drug therapy."
In the eyes of Curt Furberg, who had spent almost 10 years organizing and supervising the ALLHAT study, Pfizer was not telling the whole story. "I have problems with any drug company pushing an inferior product," says Furberg. "I don't think that's in the best interest of the patients. This is a difficult issue that somehow I have to deal with, society has to deal with: how we handle the situation where we have good knowledge that there is a difference between drugs and whether we should allow both of them to be out there competing, or whether we should put some restriction on the inferior drugs."
It's not hard to imagine why Pfizer might have responded to the ALLHAT study the way it did. Norvasc is a very profitable drug. According to the company's summer 2002 quarterly report, "Sales of Norvasc, the world's largest-selling medicine for hypertension and angina and the fourth-largest selling pharmaceutical of any kind grew 8% … to $931 million in the first quarter, compared to the same period in 2001."
In light of Pfizer's campaign to put its own positive spin on the ALLHAT study, Furberg decided to hit the road and start a "counter campaign" -- to make sure that doctors and patients got the entire story about ALLHAT. That meant getting himself booked on radio talk shows and traveling to medical conferences to set the record straight on the study.
Unfortunately, Furberg says, he has to play the same public-relations game the pharmaceutical companies play, or his message is going to get lost in the company's PR campaign. He has to go to the media, visit the offices of influential doctors -- and get them to look at the data. "One of our biggest problems, to tell you the truth," he says, "is that diuretics don't have any champions. They're all generic drugs nowadays and drug companies don't make much profit on them. By and large, companies are only going to promote what earns them profits. And sometimes that's not good for your health and safety."
A Doctor Feels the Heat
In our documentary segment about the Fen Phen disaster, we met Dr. Stuart Rich, a respected cardiologist and pulmonologist from the Rush Heart Institute in Chicago. During the mid-1990s, Rich played a central role in conducting the International Primary Pulmonary Hypertension study -- a large study of European men and women who were taking diet drugs, including Pondimin, which was on the market in the United states, and a closely-related "sister drug," Redux, which was not yet on the American market.
One of the main goals of the study was to evaluate the connection between these drugs and pulmonary hypertension, a devastating side effect that reduces the lung's ability to absorb oxygen, leading to constant shortness of breath and ultimately death. While a few cases had been reported around the world, drug manufacturers had long claimed that Pondimin and Redux only rarely caused pulmonary hypertension. Furthermore, they said, the benefit of losing weight was far more significant than the risk of developing the side effect.
In their three-year study, Dr. Rich and his colleagues found that Pondimin and Redux posed a "significant risk of dying from pulmonary hypertension," according to Rich. "And the risk went up the longer you took the drugs." Those results, and the fact that on average most people only lost a small amount of weight when they took these medicines, made Rich an opponent of FDA approval for Redux -- particularly for long-term use.
While Rich was appalled by the drug company's determination to put its drug on the American market, he was even more upset when the FDA acquiesced and approved the drug in the summer of 1996. "My reaction was despair," he told us. "Why despair? My specialty is I treat patients with pulmonary hypertension. These are the sickest cardiovascular patients that exist. They're young people. They're tragic stories. We have some treatments … but it's a death sentence. And it's a slow death, drowning, months to years."
Rich's only comfort was knowing that the European study would soon be published in The New England Journal of Medicine -- one of the most prestigious medical journals in the world. The drug company may have pushed this controversial product onto the market, thought Rich, and the FDA may have gone along with the idea, but doctors would soon read the study's findings about Redux when the Journal came out. Then, he hoped, doctors would stop prescribing the drug so often.
But getting out a clear message to consumers and the medical community about the risks posed by these diet drugs proved to be more difficult than Rich imagined.
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The day before his article officially came out, Rich got a phone call from a newspaper reporter who had received an advance copy of the Journal and wanted Rich's reaction to an accompanying editorial -ã which Rich hadn't seen yet. (As was the custom at The New England Journal of Medicine, the magazine's editors had invited two prominent scientists to write an editorial about the European study to put it into perspective and help doctors determine whether and when the risk of using the diet drugs would be justified by the benefits.) Much to Dr. Rich's dismay, the editorial claimed that the benefits of using Pondimin and Redux far outweighed any risks and compared the risk of taking the diet drugs to taking penicillin for an infection. In effect, the editorial advised the medical community not to pay too much attention to Rich's study, and not to stop prescribing the drugs.
When Rich heard who the authors of the editorial were -- Dr. JoAnn Manson and Dr. Gerald Faich -- he realized immediately that both had financial ties to the drug companies that were making and/or selling Redux. And both had done work with those companies specifically in connection with Redux. "This was one of the greatest scandals that ever hit The New England Journal of Medicine," says Rich.
To guard against such potential conflicts of interest, it had been the Journal's policy to always ask editorial writers whether they had any "ongoing financial associations" with the company producing the product. In this case, the two scientists who authored the diet drug study editorial had told the magazine's editors -- in writing -- that they had "no financial interest or equity in any pharmaceutical company producing anti-obesity agents."
As word of the editorial controversy spread, the Journal's editors asked the two scientists to explain their written statement that they didn't have any financial interest in the company. In their defense, both authors downplayed their financial connections to the companies, and pointed out that the Journal had defined "ongoing financial associations" as "equity interest, regular consultancies, or major research support" and that their associations were neither "regular" nor "ongoing" but more occasional and not relevant to their editorial.
Despite the authors' explanations, a few weeks after publishing the pulmonary hypertension study the Journal's editors, Dr. Marcia Angell and Dr. Jerome Kassirer, ran a new editorial acknowledging that the authors may have misinterpreted the Journal's definition of "financial associations," but the editors also cast doubt on the credibility of any editorial written by someone with the kinds of financial ties that the authors had. (You can read the original Journal article [free registration required to read the full text] on the study and the accompanying editorial on the New England Journal's Web site. And you can also read the editors' follow-up editorial.)
But by that time, the damage may have been done. Thanks to the editorial that had run with the study article, many doctors around the world may well have dismissed the study's results and decided not to worry about prescribing Pondimin and Redux.
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The Journal affair wasn't the only development that interfered with getting the story out about the European diet drug study, says Rich. The drug manufacturer, he says, tried to stop him from talking to the general public.
The news that popular diet drugs carried significant risks prompted NBC's Today show to invite Rich to appear on their morning program to talk about the study. Host Bryant Gumbel asked him to tell the country about the study and put it in perspective. "What I said," Rich recalls, "was nothing that was not mentioned in the paper: that the drug carried a very high risk of developing this fatal disease, that it should not be prescribed lightly."
A couple of hours after the live broadcast, Rich returned to his office where, he says, he received a phone call from a senior executive at Wyeth Pharmaceuticals.
"He told me he saw my interview on the Today show and warned me that it was very dangerous for me to talk to the press about that, that if I had any issues regarding their product that I wanted to publish in a scientific journal, so be it. But if I spoke to the media about their drug, bad things would happen. 'Bad things would happen' was the exact phrase he used. ... And I never talked to the press again. Because I didn't know what they had in mind. ... They are a very big, a very powerful company."
Rich has told his story under oath in several legal depositions as part of lawsuits brought by Fen Phen victims against the company.
For his part, the senior Wyeth executive has testified under oath in at least one deposition and denied having ever threatened Rich.
We will never know whose version of the facts is correct -- because none of the parties can prove one way or the other that they are being truthful. One thing is certain, however. Dr. Rich didn't speak to the popular press about Redux and Pondimin for many years after that appearance on the Today show -- and until now, he never told anybody in the media the details about that phone call.
Andrew Liebman is a Boston-based documentary filmmaker and the founder of Resolute Films. He has been producing programs for FRONTLINE since the early 1980s and also works extensively for DISCOVERY Channel.