MAMIE JOHNSON: I'm a very angry woman that this medicine have destroyed my health.
ANNOUNCER: Each year, toxic side effects from prescription medicines injure tens of thousands of Americans, and sometimes it becomes big news.
NEWSCASTER: Tonight, one of the most popular drugs taken for allergies-
NEWSCASTER: -is being pulled off the shelves in the U.S.-
ANNOUNCER: Since 1997, over a dozen drugs had to be taken off the market because of severe side effects.
NEWSCASTER: -off the market-
NEWSCASTER: -pulled from the market-
ANNOUNCER: FDA administrators say these problems could not have been prevented.
PAUL SELIGMAN, MD, MPH, Dir, Office of Drug Safety, FDA: At the time a drug is approved, we don't have all the information that we would like to have.
NEWSCASTER: -off the market-
NEWSCASTER: -off the market-
ANNOUNCER: But is there pressure on the FDA staff to allow dangerous drugs on the market?
MICHAEL ELASHOFF, PhD, Former FDA Drug Reviewer: I was told very explicitly, "Don't write in your review that you're recommending against approval."
ANNOUNCER: Tonight, FRONTLINE investigates the integrity of our drug safety system.
NARRATOR: Outside Washington, D.C., sit the main offices of the U.S. Food and Drug Administration, the guardian of drug safety in America. Here, every day, some 100 reports arrive indicating that somebody somewhere has experienced a serious side effect with a drug.
Back in 2000, an unusual number of reports started coming in about people like Angus McLean, a retired naval intelligence expert. While raking leaves one weekend, Angus suddenly felt intense muscle pain all over his body, a severe reaction to a new "statin" drug he was taking to lower his cholesterol.
ANGUS McLEAN: I was just sore, like you'd worked out too much. As this progressed over just a couple of days, it didn't respond to limbering up or my wife trying to give me a little rubdown. In fact, it accelerated.
NARRATOR: When his symptoms became severe, his wife rushed him to the hospital, where he was diagnosed with a life-threatening muscle-wasting condition called rhabdomyolysis. It's a rare side effect that can cause a person to lose vast numbers of muscle cells, which then have to be eliminated from the body.
Angus required emergency kidney dialysis. For an entire week, he hovered on the edge of death, drifting in and out of consciousness.
ANGUS McLEAN: When you're afraid to go to sleep because you think, "Man, if I go to sleep and don't fight hard, then it's going to be over"- you don't know how many times that creeps into your mind, but once is enough.
NARRATOR: The drug that caused Angus's problem, Baycol, had recently been approved by the FDA.
RAYMOND WOOSELY, MD, VP, U of Arizona Health Sciences Ctr.: I think Americans need to recognize that every time they put a pill in their mouth, especially a new pill that they've never taken before, it's an experiment.
NARRATOR: Dr. Raymond Woosely runs a national center to study the side effects of drugs at the University of Arizona College of Medicine. He worries that most people don't understand how much about new drugs is unknown.
Dr. RAYMOND WOOSELY: When a drug goes on the market, only about 3,000 patients have ever been given that drug. We will never know all the toxicity that can occur, especially the 1 in 10,000 or the 1 in 20,000 that could be seriously harmed. Our detection of that will only happen after the drug is on the market and exposed to huge numbers of patients.
NARRATOR: Precisely because of such uncertainties, there's a special division at the FDA to monitor drugs after they go on the market.
FDA STAFFER: I'm calling from the FDA Office of Drug Safety. I'm calling in regard to a report that you had sent into us earlier this year where the patient went into renal failure. And I wanted to get-
NARRATOR: The Safety Office at the FDA is staffed by about 50 pharmacists, doctors and epidemiologists, plus support staff. They find out about what's going on in the outside world through Medwatch reports.
Director of the division, Paul Seligman.
PAUL SELIGMAN, MD, VP, U of Arizona Health Sciences Ctr.: We receive approximately 1,000 reports every day at the FDA.
NARRATOR: Medwatch reports typically start out when a doctor or nurse notices a problem after a patient gets a drug. But there's no legal obligation to report such problems.
Dr. PAUL SELIGMAN: In the United States, the initiator of the report does so on a voluntary basis. But it's critical that we get these reports. There's no other way that the FDA has for understanding what's going on with a medicinem once it's been marketed, without the voluntary reporting by astute clinicians and health care providers.
NARRATOR: Doctors rarely contact the FDA directly. They usually send the reports to drug companies, which then are obligated tell the agency about any adverse events.
Dr. PAUL SELIGMAN: If an adverse event is serious - which means it could cause death, it resulted in hospitalization or was potentially life-threatening, or prolonged hospitalization - the manufacturer has a legal responsibility to report that case to the FDA within 15 days of receipt.
NARRATOR: Medwatch reports often don't contain enough details to determine if the suspected drug really caused the problem. So then the staff here has to contact the doctors who made the report. With nearly 300,000 Medwatch reports coming in every year and over 3,000 drugs on the market to monitor, some critics say the job is just too overwhelming for the small staff here.
Dr. RAYMOND WOOSELY: The number of people hired at the agency to protect, to analyze data on drug safety is criminal.
NARRATOR: Dr. Woosely was a top candidate to head up the FDA last year and believes safety should be a much higher priority at the agency.
Dr. RAYMOND WOOSELY: The teams that are needed to do drug safety are infinitely more than what they've got right now. We don't have a safety system in this country.
NARRATOR: Dozens of new drugs come onto the market each year, continually adding to the FDA's burden. Some are completely new, while other are variations on existing products, like the many statin drugs, which are hugely popular for lowering cholesterol.
America spends some $12 billion a year on statins, so there's a strong incentive to enter this competition with new products. And health insurers are always looking for cheaper alternatives.
Which brings us back to the story of Angus McClean. For more than a year, he had taken the industry leader, Lipitor, which effectively controlled his cholesterol and didn't cause him any problems. But then the U.S. Navy switched him over to a new statin drug, Baycol, which was dramatically cheaper.
Around the time Angus made the switch, Baycol was just capturing a significant share of the U.S. market. It had been a tough battle because the originally approved dose didn't lower cholesterol as much or as fast as many other statins.
KIP PETROFF, Attorney, Petroff & Associates: The FDA originally approved it at .2 milligrams, and .3 became an accepted use. But the problem was, to really compete in the marketplace, they had to be a much higher dosage than that.
NARRATOR: Kip Petroff represents Angus McLean and many others who have sued Bayer, the manufacturer of Baycol. He and other lawyers have uncovered detailed information about how the Baycol problem got out of hand. Two years after approving Baycol, the FDA OK'd a higher dose, .4. Sales started to rise. But soon Bayer began getting a troubling number of reports that patients were developing that muscle-wasting condition, rhabdomyolysis.
Since many had also taken a second cholesterol drug, Gemfibrozil, in December 1999, Bayer sent out a letter warning physicians not to use the two drugs in combination. But almost half had taken Baycol alone. So the company continued its investigation.
KIP PETROFF: When Bayer realized that they were getting increased numbers of reports, what they wanted to do was try to compare it to the other statins, to see if the other statins had just as high an incidence.
NARRATOR: To do that, the company asked the FDA for copies of all Medwatch reports associated with Baycol and its competitors. While Bayer was waiting for the information, a company memo shows there was growing concern among some doctors that Bayer wasn't being honest about what was going on.
"Board member thinks Bayer is not forthcoming," "Dr. Palmer thinks Bayer is hiding something," "Boston-area cardiologists seem to be concerned about Baycol."
After some rhabdomyolysis patients died, another company memo shows that Bayer was worried about the news getting out. A company safety officer addressed this memo in a deposition.
KIP PETROFF: Was there some effort being made at Bayer to try to keep information regarding these deaths related to Baycol quiet?
ROGER CELESK, Sr. Clinical Safety Officer, Bayer: No.
KIP PETROFF: Doesn't this, that ends with, "So much for keeping this quiet"- doesn't that imply to you that somebody, at least, wanted to keep this quiet?
ROGER CELESK: I don't know what the context was. I can't get into the mind of the writer.
KIP PETROFF: Well, the context is right here. There's widespread concern, people are hearing of things, and "so much for keeping this quiet."
NARRATOR: In the spring of 2000, Bayer received and analyzed the Medwatch reports it had requested from the FDA. Company officials compared Baycol with the industry leader, Lipitor, and got discouraging results. For every 100,000 prescriptions given without other cholesterol drugs, Baycol had 20 times more reports of rhabdomyolysis than Lipitor, also known by its chemical name Atorvastatin.
The situation was discussed at a July 2000 teleconference, where extensive notes were taken by Bayer safety officer Raj Sharma.
RAJESHWAR SHARMA, Bayer Drug Safety Officer: My note says, "Clearly, substantial increase than Atorvastatin reporting rate. Very strong signal."
ATTORNEY: Very strong signal.
RAJESHWAR SHARMA: That's correct.
ATTORNEY: And you underlined that.
RAJESHWAR SHARMA: Yes.
KIP PETROFF: A signal is meant to alert you to act. And there were people at that time, in the middle of 2000, who, according to their own memos- "We would do something now," is what some of these people were saying.
If I had been at that meeting in July of 2000 and asked you, "Dr. Sharma, can you tell me if you think this drug is safe," you would have said, "I don't know"-
KIP PETROFF: -in July of 2000, wouldn't you.
RAJESHWAR SHARMA: At that time, we did not have the complete data to say whether it is safe or not safe.
KIP PETROFF, Attorney, Petroff & Associates: And what the drug company chose to do was study it further and continue marketing the drug as aggressively as possible. And that's where they crossed the line, in terms of drug safety.
NARRATOR: At the head office of the FDA's drug division, FRONTLINE asked deputy director Steven Galson if anybody at the FDA knew about the Lipitor-Baycol comparison.
STEVEN GALSON, MD, Dpty Dir, FDA's Drug Division: We weren't aware, at that point, of the difference between Baycol and the other similar classes of drug. Our expectation is, when a company becomes aware of a specific problem with their drug, they come to us.
NARRATOR: With the FDA in the dark about Bayer's Medwatch report analysis, in the summer of 2000, the agency approved sales of Baycol .8, an even higher dose that Bayer needed to compete effectively against Lipitor.
David Archer was one of many patients put on the new Baycol .8 dosage. He also was switched over from Lipitor, and his wife, Lucy, remembers that her husband was in excellent health until he began taking Baycol.
LUCY ARCHER: David was always very active. He would chop trees. He would do a lot of things. But then, as he was taking the Baycol, I noticed, as we walked, especially, he would complain about his toes. Then he would complain about the calf, his legs, and then his muscles, his back. Finally, it got so that he just couldn't seem to bend over to put his socks on and shoes. And no way had I ever thought that this Baycol was doing this. He took it October, November. And December, he was gone. He should have never, never died.
NARRATOR: Lucy Archer's husband died more than five months after Bayer had strong indications their drug might be less safe than Lipitor.
Bayer declined FRONTLINE's request for an interview to explain why the company continued selling Baycol despite the safety concerns.
ROGER CELESK, Sr. Clinical Safety Officer, Bayer: And in no case is a reporting rate from spontaneous data-
NARRATOR: But company safety officials have had to answer questions in legal proceedings, where they have attacked the findings of their own Medwatch analysis. The problem, they said, is that this data depends on voluntary cooperation. Side effects for some drugs can get reported more often than for others. And only 1 to 10 percent of all side effects ever get reported.
Dr. STEVEN GALSON: The system is imperfect, and without being able to require people to make those reports - and we don't have the authority to do that - it's hard to increase it beyond that.
NARRATOR: While sales of Baycol continued, Bayer conducted a new story that didn't use Medwatch data. After almost a year had gone by, the FDA began noticing increased problems with the higher Baycol dose and asked the company for its information.
Dr. STEVEN GALSON: They came to us with this study, which tended to minimize the problems with the drug. We didn't agree with them on this analysis, and this is why the action occurred.
NEWSCASTER: The cholesterol-lowering drug Baycol is being pulled off the market-
NEWSCASTER: It's been linked to 31 deaths in the U.S. from muscle destruction.
NARRATOR: Under pressure from the FDA, Bayer voluntarily took Baycol off the market in August, 2001, two years after first getting reports there might be problems with the drug. Although the company hasn't acknowledged any wrongdoing, Bayer paid an undisclosed amount to settle a lawsuit brought by the widow of David Archer. Bayer also settled a lawsuit with Angus McClean, who now spends many hours each week trying to rebuild his muscle strength.
ANGUS MCLEAN: I didn't choose this, nor did I do anything that is overtly the cause on this. So I'm angry about it happening. But now that it's happened, what can I do about rectifying it?
NARRATOR: Although Bayer has won a few jury trials in cases where it was unclear that Baycol caused the damage, the company has settled more than 1,200 lawsuits and paid over $430 million to victims.
Beyond the harm done to individuals, though, the Baycol story reveals how dependent the FDA is on information supplied by drug companies.
LEO LUTWAK, MD, Former FDA Drug Reviewer: The FDA is wholly dependent on trust, on trusting that the company is providing all the truth, all the time, that the company is not hiding information, the company is not covering up information, the company is not changing information.
NARRATOR: Dr. Leo Lutwak, a retired FDA drug reviewer, says reliance on companies was central to the biggest disaster in the agency's history, the Fen/Phen tragedy, in which two FDA-approved weight loss drugs injured tens of thousands of Americans. Lutwak struggled within the agency to keep those drugs out of consumers' hands.
Dr. LEO LUTWAK: I felt it was an open-and-shut case. This was a dangerous group of drugs with very little, if any, benefit, and that they should immediately be removed from the market, removed from use, discontinued, disappeared. When that didn't happen, I became disturbed. I became concerned about the system. I became concerned about the drug company's role in this. And I was particularly concerned with the potential effect on the thousands and millions of people who would be using the drug.
NARRATOR: Mamie Johnson, from Houston, Texas, was just the sort of person Lutwak worried about when he considered the dangers of those diet drugs.
MAMIE JOHNSON: I was really ready to lose some weight. That was the main reason I got on the Fen/Phen because I thought it was a safe drug.
NARRATOR: Mamie started taking Fen/Phen in 1995. A year later, she developed pulmonary hypertension, a constriction of blood vessels inside the lungs that dramatically reduces their ability to absorb oxygen.
MAMIE JOHNSON: It's a terrible feeling. You feel like you're passing out because you're not getting any oxygen.
Oh, wait a minute. I got- I have to rest a little bit.
And then you start aching in your chest and your arms, and then your fingers and things become numb- oh, Lordy! And right now, still, after me getting my wind back, there's still a pain up in here.
Curtis, you need to turn that oxygen up all the way.
NARRATOR: The only cure is a lung transplant, but Mamie's overall condition made her ineligible.
MAMIE JOHNSON: It's a very serious disease. And you know yourself, without your lungs, you can't live. There's no future. You know, death is soon.
NARRATOR: The Fen/Phen Mamie and others took wasn't actually a single drug. It was a combination of fenfluramine - sold under the name Pondimin in the U.S. - and Phentermine. Thus the name Fen/Phen. Both were diet drugs, but only Pondimin caused pulmonary hypertension, which was thought to be an extremely rare side effect.
In the early '90s, the maker of Pondimin, Wyeth, and a partner company asked the FDA to approve an updated version called Redux, already on the market in Europe. Because it was so similar to Pondimin, Lutwak, in his review of Redux, investigated how much of a pulmonary hypertension risk it would pose.
Dr. LEO LUTWAK: When I started looking at the actual reports, it didn't seem that rare. And I was told by the company that, no, this just doesn't occur in enough individuals make it worth being concerned about.
NARRATOR: The question was soon clarified by Chicago cardiologist Stuart Rich and colleagues, who were finishing a three-year European study on pulmonary hypertension and diet drugs. Their results showed the risk for Redux was real, and increased the longer you took it.
STUART RICH, MD, Cardiologist, Rush Heart Institute: What was particularly shocking to me was that on the heels of reporting that this drug caused a fatal, incurable disease in Europe, that the company was planning to put it on the American marketplace. When I had heard this, I'd said, "Well, you can try, but it's never going to get in this country." The FDA would never permit a drug that had little benefit, terrible risk on the American marketplace. The FDA is your watchdog that looks out for your safety.
NARRATOR: FDA reviewer Lutwak also believed the agency would not approve the drug.
Dr. LEO LUTWAK: According to what I read and the way I interpreted the Food and Drug Administration's role, we're supposed to evaluate drugs for their safety and efficacy. And when the safety is questionable, it requires an awful lot of efficacy to be warranted.
Dr. STUART RICH: If you look at the efficacy studies, you found out that it's efficacy was minimal, at best- 3 percent weight loss after one year. If you weighed 300 pounds, I could say, "End of a year, I'll get you down to 291, with a risk of dying of pulmonary hypertension."
NARRATOR: With controversy surrounding Redux, the FDA called an advisory committee meeting to get the views of outside experts. Lutwak presented data showing that the average weight loss was unimpressive.
Dr. LEO LUTWAK: The use of the drug provided approximately a 3-kilogram greater weight loss than the placebo alone.
NARRATOR: Rich was there, too, warning about the dangers of long-term use.
NARRATOR: The drug companies that were seeking to sell Redux also got a turn to speak. They presented data showing that some patients lost a lot of weight and argued that for society as a whole, obesity was more harmful than any side effects. Eventually, the 11 committee members had to come up with a recommendation, which the FDA could either accept or ignore.
[www.pbs.org: More on the drug approval process]
Dr. STUART RICH: The committee voted unsafe, so they voted thumbs down for safety. But they were leaning towards yes for efficacy. But if you're not safe, you're not going to get approved. That meeting was suddenly and unusually halted by Jim Bilstead, who was the director of the division.
NARRATOR: He was the FDA official overseeing the meeting, and late in the day, after several of the committee members had already left, he posed an extra question: Were the benefits of Redux sufficient to make the risks acceptable?
Dr. LEO LUTWAK: It was a rather unusual move, but some of the higher-level managers, administrators at the FDA announced that a second advisory committee meeting would be held to review this in a few months.
Dr. STUART RICH, Cardiologist, Rush Heart Institute: It was at the other meeting, where none of the consultants were invited to come back and testify, that that was approved, 6 to 5 in favor.
NARRATOR: Before that second meeting, Lutwak had agreed to support the approval of Redux, so long as there were restrictions that severely limited the number of people who might get the drug. But some of those restrictions were never adopted.
Dr. LEO LUTWAK: I was very disturbed. And then we talked about it internally, within the division at the FDA. And there is one tool that's left, and that's the labeling. And so we would see if we could get the company to put these warnings in what's called a "black box."
NARRATOR: About 10 percent of all drugs have "black box" warnings, and these always appear at the beginning of the information sheets that come with drugs. Such warnings are never good for sales, and Wyeth documents show the company wanted to do everything possible to avoid a black box on the Redux label.
A top Wyeth executive explained the company's view in a deposition.
JOSEPH MAHADY, Pres., Wyeth Pharmaceuticals, NA: We have many responsibilities, as a company. We have responsibilities to patients. We have responsibilities to those in the company, to those who support the research of the company, to shareholders, that we accept and produce appropriate black-box, as appropriate, labeling. And there are many reasons. And to sacrifice a company's sales just for the purpose of accepting an approval with the black box is not a responsible action.
NARRATOR: When the FDA sided with Wyeth, people at the company were jubilant. Leo Lutwak was devastated.
Dr. LEO LUTWAK: I thought it was wrong that the company was allowed to have a second chance at the advisory committee. I thought there were wrong decisions made. I expressed that. I started feeling enough heat to make me recognize that my opinions were not only not respected, but they would be disregarded and pushed out of the picture.
NARRATOR: So Redux entered the market, joining the related drug. Pondimin. Now it was up to the FDA's Medwatch system to monitor any serious side effects of both drugs.
The agency would soon be put to a severe test. The story begins in Fargo, North Dakota, at a small regional medical center.
KAREN BERGER, Echocardiogram Tech, MeritCare: Hi, Marlee. My name is Karen. I'm going to do your ultrasound here this afternoon.
NARRATOR: Ever since 1994, when millions of Americans began taking Pondimin as part of the Fen/Phen craze, young women were showing up here with strange heart problems.
KAREN BERGER: Most of the patients that we saw came to us because they had a new murmur. There was an extra sound in their heart that the physician hadn't heard before.
NARRATOR: Each time a new patient came in, echocardiograms were ordered to get a better look at their hearts. Over the course of two years, Karen Berger and fellow technicians saw 10 young patients with heart valve problems. With every heartbeat, blood was rushing around their valves in the wrong direction.
KAREN BERGER: I just was struck by the unusualness. It was just very curious. We commonly see that in the elderly. The valve will get stiff and not open or close properly. But these patients were very young, and it just didn't fit.
NARRATOR: Karen's curiosity led her to ask the very first patient if she was taking any medications. Marlee Siewert answered "Fen/Phen."
MARLEE SIEWERT: I was taking Fen/Phen because I was morbidly obese. I was well over 100 pounds overweight. And this looked like the solution, according to my doctor. There was some media, oh, probably about six months after I started with it on how fabulous this product was, and it was touted as the miracle drug.
TELEVISION COMMERCIAL: What about a pill that tells your brain you're not hungry?
MARLEE SIEWERT: And I had to agree because I was having the results that they said you were going to have.
TELEVISION COMMERCIAL: And I had lost 31 pounds. Take it off. Lose the weight with Fen/Phen or Redux-
MARLEE SIEWERT: I was on Fen/Phen for 15 months, and the first 12 months, it was the miracle drug. I was losing weight. I felt great. I was doing everything exactly the way they said it should happen. And then my miracle turned into my nightmare.
NARRATOR: After hearing other similar stories, Karen and fellow technicians told the hospital cardiologists they believed Fen/Phen was causing valve problems. Cardiologist Jack Crary was skeptical.
JACK CRARY, MD, Cardiologist, MeritCare: We shared their concern, but we just couldn't substantiate it. When we looked at the echoes, clearly there were valvular abnormalities. The patients were on Fen/Phen, along with other medications. And to go from one to the other, at least no one in the department was convinced that the connection was real.
NARRATOR: Crary remained unconvinced for many months, until a patient of his own became a victim. One day she was fine, then, soon after taking Fen/Phen, she had severe valve damage. In his head, he calculated that if so many people were getting harmed in a small city like Fargo, then huge numbers must be getting hurt nationwide.
Crary knew the FDA was completely unaware of the possible heart valve problems, and he also knew he might have to pay a high price if he reported them.
Dr. JACK CRARY: There was going to be potential major litigation, if this was real. I mean, I was very happy with my life. I didn't really want to rock the boat. But I couldn't just walk away from that and just say, "Well," you know, "let somebody else sort this out." I just don't think that I would have been able to face another patient.
NARRATOR: In January, 1997, Crary decided to take action. Seeking the credibility of a prestigious academic medical center, he contacted the Mayo Clinic in nearby Minnesota and told them about Fargo's 11 cases. As it turned out, Mayo had two similar cases of its own, and one patient needed valve replacement surgery.
After some back-and-forth discussions, in late February, a doctor from Mayo called the Pondimin and Redux manufacturer, Wyeth, to inform the company about the heart valve cases. Within a few weeks, Wyeth officials went out to Fargo and Mayo to investigate further and concluded there might be a connection between their drug and the heart valve problem.
It had been over two years since the problem was first noticed in Fargo. And now, in mid-April, 1997, Medwatch reports were finally on their way to the FDA. But there wasn't any red flag to alert the agency that a serious new side effect had been discovered. Wyeth simply met its legal obligation to inform the FDA through the Medwatch system.
By mid-May, Crary was puzzled why the FDA hadn't taken any action yet.
Dr. JACK CRARY: I was frustrated enough that I had called the FDA, and the person I talked to at the FDA knew nothing about it.
NARRATOR: Despite Crary's urgent call, the FDA treated his reports in a routine manner until a call came in from Mayo six weeks later, saying they and Crary were holding a press conference.
MAYO PHYSICIAN: Today, my colleagues and I from the Mayo Clinic, in conjunction with Dr. Crary from MeritCare in Fargo, North Dakota-
NARRATOR: It was early July, 1997, and this is how the world found out about the heart valve problems caused by the drugs known as Fen/Phen. Only now did the FDA swing into high gear, and within a few weeks, Pondimin and Redux were off the market.
NEWSCASTER: In the United States, two highly popular diet drugs are being pulled from the market-
NEWSCASTER: One is fenfluramine, sold under-
NARRATOR: Just before the withdrawal, the FDA discovered that from 1992 to 1996, Wyeth had actually sent in almost two dozen Medwatch reports from Europe, which were headlined "pulmonary hypertension" or "renal failure," but that contained clear references to heart valve problems.
LEO LUTWAK, MD, Former FDA Drug Reviewer: The company had this information. The company had the information that people had heart valve disease. And that was reported to the FDA in a way that was very difficult to pick it out.
NARRATOR: Without Wyeth red-flagging the heart valve problems, the FDA didn't catch their significance. But it would be the company's failure to warn the public about these problems that would give lawyers their smoking gun.
1st ATTORNEY: So who knows where the FDA box is? It's a whole box of FDA documents.
2nd ATTORNEY: I've got that in my office.
NARRATOR: Over 200,000 Americans have sued or are planning sue Wyeth for damages. These are all videotapes of echocardiograms just at Kip Petroff's firm. To date, the cases have cost Wyeth nearly $13 billion. And in the end, it could cost the company much more.
KIP PETROFF, Attorney, Petroff & Associates: This is probably unprecedented, in terms of anything that's been seen, other than perhaps asbestos.
NARRATOR: It's too late for monetary settlements in the case of Mamie Johnson. Three months after we filmed her at her 65th birthday, she died from lung problems.
As for Marlee Siewert, some day soon she'll probably need surgery, with all its risks, to replace her leaky heart valve.
MARLEE SIEWERT: I am mad, angry and frustrated for the fact that they took a good part of my life away. They may have taken a good section of my life away just by using this drug. And I do understand they're in the business to make money, but I'm in the business to live.
NARRATOR: Wyeth declined FRONTLINE's invitation to be interviewed for this program, but in a written response to some of our questions, they said the company issued appropriate warnings about Pondimin and Redux in letters sent to doctors and in the "general cautions" part of their labels.
We asked the FDA's deputy director Galson what the agency learned from Fen/Phen.
Dr. STEVEN GALSON: Our system isn't perfect. It sometimes can detect things after other parts of the medical care system is able to detect it. In this case, what happened is some very astute physicians were lucky enough out in Minnesota to see a series of similar cases, where they saw heart valvular abnormalities and they put the link together. Again, looking at our data after the initial case reports that came in from the Mayo Clinic, we could see the signal. I think that the lesson is that there's a lot of room for us to go, in terms of making improvements with the system.
NARRATOR: Some critics say the agency needs to learn more from disasters like Fen/Phen.
RAYMOND WOOSELY, MD, VP, U of Arizona Health Sciences Ctr.: We need for the pharmaceutical industry something analogous to the National Transportation Safety Board, so that when a plane goes down, they go in and analyze what happened. And they may find that the plane was the problem and the manufacturer, or they may find that the regulations were inadequate. But they're independent. When a drug comes off the market, we have no analysis to say, "Should it have ever have gone on the market? Was it a mistake at the agency, or was it a mistake at the industry? Or was it something that was totally unpreventable?"
[www.pbs.org: Read Woosely's interview]
NARRATOR: But is the FDA ready for such scrutiny? In the aftermath of Fen/Phen, Leo Lutwak says he was actually punished for having opposed the drugs.
Dr. LEO LUTWAK: I didn't expect the Congressional Medal of Honor for this. I didn't even expect a $50 bonus for it. But it would have been nice if somebody had said, "Hey, you did a good job." And the opposite happened. I found myself trivialized within the FDA, and I was reassigned to areas that I found very dull, unrewarding.
NARRATOR: Lutwak retired from the FDA a few months after FRONTLINE interviewed him, and he is now consulting for plaintiff's lawyers.
Back in the 1930s, when the FDA was originally set up, scientists there were encouraged to be skeptical about the claims made by companies. But critics say a major pro-industry shift occurred at the FDA, particularly after this 1988 rally in front of headquarters.
Demonstrators complained it was taking too long to approve new AIDS drugs. In response, Congress passed the Prescription Drug Users Fee Act, or PDUFA, a law that requires companies to pay up to a $500,000 fee with each new drug application, to help the FDA hire more reviewers and get drugs onto market quicker. Today, over half the FDA's drug reviewers are paid with industry money, and the approval time for many drugs has gone from over two years to less than six months.
That's all good news, according to drug industry spokesman John Kelly.
JOHN KELLY, MD, PhD, Drug industry spokesman, PhRMA: The pharmaceutical industry has been pleased with PDUFA and has been very supportive because what it has done is to improve the efficiency of the review process. It's in the pharmaceutical industry's interest and in the public's interest to have that review process as thorough and effective as it can be.
[www.pbs.org: More on industry lobbying efforts]
SIDNEY WOLFE, MD, Health Research Group, Public Citizen: The culture at the FDA has become "Please the industry, avoid conflict, look upon our role as getting out as many drugs as possible."
NARRATOR: Sidney Wolf of Public Citizen's Health Research Group in Washington believes industry funding has created an FDA that's reluctant to challenge company claims about safety and effectiveness.
[www.pbs.org: How independent is the FDA?]
Dr. SIDNEY WOLFE: This system has created a very unhealthy relationship between the industry and the FDA, where the FDA says, "We have to be nice to these people because they are paying our bills."
NARRATOR: Michael Elashoff thinks this new relationship partly explains what happened to him at the FDA three years ago, when he opposed the approval of a new anti-flu drug called Relenza.
WOMAN: [sound of doorbell] Who is it?
MAN AT DOOR: It's me, influenza- you know, the flu? Coming in!
MICHAEL ELASHOFF, PhD, Former FDA Drug Reviewer: Simply stated, Relenza just didn't work in the United States clinical trials. It really had no effect at all on the symptoms of influenza. It had no effect on influenza complications.
ANNOUNCER: Introducing Relenza, a new prescription medicine to help you start feeling better sooner.
MICHAEL ELASHOFF: It maybe knocked half a day or less off the duration, and even that wasn't established statistically. So it was pretty much no different from placebo, as far as efficacy.
ANNOUNCER: Those with chronic lung disease or asthma may experience wheezing-
NARRATOR: What also bothered Elashoff was a life-threatening side effect that caused some users to have trouble breathing.
TELEVISION COMMERCIAL: Relenza is an antiviral medicine that's inhaled. You should be shown how to use the inhaler.
MICHAEL ELASHOFF: One of the concerns during the review was that Relenza had the potential to cause bronchospasm, or constriction of the airway, and it was observed in several patients in the clinical trials.
NARRATOR: To sort things out, the FDA called an advisory committee meeting. Elashoff told the panel of 17 experts that Relenza had little benefit and real risk.
MICHAEL ELASHOFF: Ultimately, they decided that it was not worth approving, and voted 13 to 4 to reject the drug. The next day after the advisory committee, several people in FDA management told me that they blamed me for the drug getting turned down at the advisory committee, that I wouldn't be allowed to present at the advisory committee meetings in the future for any other drugs.
NARRATOR: Elashoff still had to write up a formal review of Relenza, and here he says he got reined in again.
MICHAEL ELASHOFF: I was told very explicitly, "Don't write in your review that you're recommending against approval. Write that the data is unclear, you could go either way." So it was- it was quite explicit.
NARRATOR: Where Elashoff wrote that patients would be exposed to risks while deriving no benefit from the drug, supervisors weakened his report to say that safety data should be "considered" in making risk-benefit decisions.
In the end, the FDA approved Relenza after the manufacturer, Glaxo, sent the agency a strong letter complaining that Elashoff was judging their drug by stricter standards than what had been agreed upon before the review began.
Nine months later, the FDA forced Glaxo to put a new warning on the Relenza label saying that deaths and injuries can occur from bronchospasm, the very thing that worried Elashoff. By then, Elashoff had left the agency after working there five years. He says his experience wasn't an isolated example of an FDA scientist being asked to brush aside bad news about a drug.
MICHAEL ELASHOFF: In nearly all the cases I was familiar with, both that I worked on and other people in my division worked on, there would be a pressure to approve those drugs or soften the language in the review, soften the language in the labels, so that they could have a more easy justification for why they were approving. So I would say it was very common.
NARRATOR: FRONTLINE asked the FDA's Steven Galson about Elashoff's charge.
Dr. STEVEN GALSON: We're certainly not proud to hear that there's anybody that has opinions like that, but we just don't think it's average or even reflective of what most people think. We wouldn't condone anyone being asked to change their review. I think the idea of forcing someone to change something that they've written or something that they've analyzed is highly unusual.
MICHAEL ELASHOFF: That's a joke! I mean, it happens all the time. I guess the only reason it doesn't happen as frequently as it might otherwise is people start censoring themselves, that they say, "OK after the first time I've noted a problem and it's been glossed over, well, you know, why bother the second time?"
[www.pbs.org: Read Elashoff's interview]
NARRATOR: An investigation by Sidney Wolfe's Heath Research Group revealed that charges like Elashoff's are common at the FDA.
Dr. SIDNEY WOLFE: In the context of the large number of drugs that had to come off the market in the late '90s, we did a study of physicians at the FDA who are in the drug approval division and found that, between them, they had identified 27 drugs that they thought were too dangerous to come on the market. But those drugs were approved over their objection.
NARRATOR: In late 2000, soon after the Health Research Group study was published, the FDA completed its own survey about morale at the agency. FRONTLINE obtained the results of this internal study. Among those who responded, a number said their reports were edited and they had been asked to change negative opinions about pharmaceuticals. One third said they feared being stigmatized if they recommended that a drug not be approved. And a third also said that they were uncomfortable expressing differing scientific opinions.
Dr. STEVEN GALSON: I don't think it's characteristic of how our scientists feel. For one, this is a 3-year-old survey. For two, it was not done as scientifically as some of the more recent surveys that we've seen in the last few years. The people that work here are challenged, they're gratified, and by and large, they enjoy what they're doing.
NARRATOR: Whether or not there are morale problems at the FDA, administrators insist, safety is not being compromised.
PAUL SELIGMAN, MD, VP, U of Arizona Health Sciences Ctr.: For the consumer, they need to understand that the FDA's mission is to ensure that drugs are safe and effective before they are approved for marketing and that the vast majority of medications meet that very high standard prior to their approval. We have in this country, and I think throughout the world, achieved extraordinary benefits from the use of pharmacologic agents. We, as a society, are living longer, and that, in large measure, is due to the high quality of the medicines that we, as a nation, receive.
NARRATOR: To demonstrate how seriously safety questions are taken at the FDA, administrators invited us to film a staff meeting about a drug that recently went on the market.
1st FDA STAFFER: Now that the drug is available and it's being used by larger numbers of people, in fact, there are rare but severe cases of liver toxicity.
NARRATOR: The meeting was held just for our cameras, and the name of the drug was kept secret. But the staff members took positions they had argued at a real meeting a little earlier.
1st FDA STAFFER: None of the drugs that are available to treat this disease really provide a perfect remedy.
2nd FDA STAFFER: But this drug has a safety problem. And to the best of our knowledge, we don't think that that problem exists with similar drugs of this class.
NARRATOR: The question was, What action should the FDA take in light of the drug's association with liver damage?
2nd FDA STAFFER: The safety problem is real. And at the very least, we should inform clinicians that this is what we see and this is what they expect because this is lifetime therapy we're talking about.
1st FDA STAFFER: Right. Well, there are different kinds of remedies that we can imagine to apply, such as try to reduce the usage, but not necessarily removing the drug from the market.
NARRATOR: The leader of the meeting, who used to work in the approval part of the FDA, proposed letting the company kept its drug on the market, provided it conducted more studies.
3rd FDA STAFFER: My concern will be, I think, the time of the action. I certainly wouldn't want to wait for five years and hear much more reports of this kind of severity.
1st FDA STAFFER: Do you favor that we should give strong consideration to asking the company to consider withdrawing this drug?
3rd FDA STAFFER: This is what I would suggest, yes.
1st FDA STAFFER: And your reasoning is that there are potentially other alternatives?
3rd FDA STAFFER: Yes.
1st FDA STAFFER: I frankly don't agree with you. And the reason I don't agree with you is that I agree that there is a bad outcome in a very small percentage of users, but from the clinician's perspective, there is some merit to saying that clinicians should have some freedom of action in dealing with patients and choosing-
NARRATOR: Over the next few months, the arguments that took place here became a contentious issue inside the FDA, as reports of liver damage continued to arrive. The safety staff wrote up a 37-page document detailing all the cases, including nine deaths. And then in March, 2003, a public advisory committee meeting was called to review the safety of the product. Here we learned the drug's identity. It was a medication to treat rheumatoid arthritis called Arava.
The scientists who had argued at the internal meeting that the drug should be taken off the market were here, along with a senior epidemiologist and physician, David Graham, who's been with the FDA for two decades and who helped write that 37-page report.
For months, FRONTLINE had requested an interview with Graham, but FDA administrators would not let us talk to him on camera.
The first thing committee members found out was that they weren't going to hear from the authors of the safety report, a message delivered by Dr. Sidney Wolfe, who had petitioned the FDA to stop sales of Arava.
Dr. SIDNEY WOLFE: Despite this 37-page evaluation, which concluded the drug should be withdrawn from the market, none of the authors of this review were allowed to present their work to the advisory committee and to be questioned by you, in terms of what you agree with, what you disagree with.
NARRATOR: Making the FDA's presentation was a scientist not from the safety division but from the division that originally approved the drug.
LAWRENCE GOLDKIND, MD, FDA: There was extensive confounding-
NARRATOR: He downplayed the significance of the Medwatch reports.
Dr. LAWRENCE GOLDKIND: -other likely causes for liver toxicity in the majority of those cases.
NARRATOR: Then he pointed to other databases where there were no cases, concluding his one-hour presentation saying the liver problem must be very rare.
Dr. LAWRENCE GOLDKIND: Cases did not occur in these large databases, so we can't really quantitate what the rate would be.
NARRATOR: While Graham and the other safety staff members watched in silence, the pharmaceutical company, with its army of scientists surrounded by stock market analysts, got to make a one-hour presentation, too.
WILLIAM HOLDEN, PhD, Aventis Pharmaceuticals: The first study we did was a retrospective cohort study using Aetna claims data-
NARRATOR: The company pointed to databases where they could compare the rate of liver problems associated with Arava, also known as leflunomide, to other rheumatoid arthritis drugs.
WILLIAM HOLDEN: What we are claiming, based on the analyses presented here, is that leflunomide is just as safe.
NARRATOR: Towards the end of the meeting, a special consultant to the committee expressed concern that the FDA was ignoring its Medwatch reports.
LEONARD B. SEEFF, MD, FDA Consultant: While the database that I heard was so compelling, and all of this seems so wonderful that there is really nothing to show acute liver failure, these were sent to me. I mean, I didn't make them up. They were sent to me, and they were actually listed as either "serious liver disease" or "liver failure." And going through them, I was unable to be absolutely certain that there was not.
NARRATOR: As the discussion continued, suddenly, one of the committee members surprised everyone at the meeting.
ALLAN GIBOFSKY, MD, JD, FDA Consultant: The suggestion that the proceedings here are somehow tainted by the absence of individuals who wrote a report, and the absence of our opportunity to have a colloquy with officers of the agency who may have differing viewpoints, is a concern.
NARRATOR: With just a little time left - it was almost 5:00 P.M., and the meeting was supposed to be over - the discussion was opened up to anybody who wanted to speak.
MEETING CHAIRMAN: If there is somebody who would like to comment, address Dr. Gibofsky's comment, I think we would be open to that.
NARRATOR: Dr. Graham, who had been told by his bosses that he could not speak here, decided not to volunteer.
In the end, the committee recommended keeping Arava on the market, despite the safety concerns raised by the Medwatch reports.
After the meeting, we caught up with David Graham in the hallway. Now he decided to speak to us without the FDA's permission.
DAVID GRAHAM, MD, FDA Epidemiologist: We had a different perspective, and we really weren't given an opportunity to present our side of the story. And the people who did present, the reviewing division and the company, you know, they didn't see a problem and they presented. We found a problem, and we weren't permitted to present.
INTERVIEWER: You were invited to go up and speak. I mean, why didn't you get up and speak when you were invited?
Dr. DAVID GRAHAM: Dr. Goldkind had about an hour to present his analyses, the company had another hour to present theirs, and they were basically each presenting the same thing. I didn't think that much would be accomplished in a 30-second sound bite. This was a very hostile process. And let's just leave it at that.
NARRATOR: Critics suggest what went on at this meeting, and what's been happening inside the agency for many years, has a simple explanation.
LEO LUTWAK, MD, Former FDA Drug Reviewer: He who pays the piper calls the tune. I think that a regulatory agency should be independent of the industry it's regulating.
NARRATOR: Top administrators at the FDA insist that industry money isn't a problem.
STEVEN GALSON, MD, Dpty Dir, FDA's Drug Division: We don't really feel pressure to please the industry. We feel quite independent. In among the scientists, we have a large number of mechanisms for assuring high quality of the reports that we do do to make decisions about new drugs. So we just reject that we're actually influenced by that.
NARRATOR: In fact, thanks to recent congressional legislation, the FDA's approval division will get more industry money than ever this year. And for the first time, the Office of Drug Safety will also get industry money to increase its staff for monitoring drugs after they go on the market.
JOHN KELLY, MD, PhD, Drug industry spokesman, PhRMA: The Congress has repeatedly looked at how it wants to fund the FDA. And so once, twice, and again last year, the Congress decided the best way to fund the FDA was to look to the pharmaceutical industry to provide a portion of the funds to help support review. That's the decision of the Congress.
WRITTEN, PRODUCED AND DIRECTED BY
FOUNDATION GRANT MANAGER
WEBSITE MANAGING EDITOR
A FRONTLINE Co-production with Resolute Films, Inc.
FRONTLINE is a production of WGBH Boston, which is solely responsible for its content.
ANNOUNCER: This report continues on our Web site, where you'll find additional reporting by the producer on drug safety issues beyond the FDA, a summary of the dozen drugs pulled off the market since 1997, more on the politics of drug safety, including an interview with veteran reporter Philip Hilts, author of a new book on the FDA's history, plus FRONTLINE's extended interviews with FDA officials, scientists, critics and more. And watch the full program again on line, then join the discussion at pbs.org.
Next time on FRONTLINE: He was a lost soul.
-He believed violence was the only effective tool.
ANNOUNCER: On a political mission.
-He wanted to bring about a new world order.
NEWSCASTER: President Kennedy's been cut down by an assassin's bullets.
NARRATOR: Did Lee Harvey Oswald act alone, or was he part of a vast conspiracy? Forty years later, review the evidence and decide for yourself next time on FRONTLINE.
To order FRONTLINE Dangerous Prescription on videocassette or DVD, call PBS Home Video at 1-800-PLAY-PBS. [$29.98 plus s&h]
Support for FRONTLINE is provided by U.S. News & World Report.
Trust. For over 70 years, a commitment to playing it straight, getting it right. U.S. News & World Report. Trust matters.
With additional funding from the Corporation for Public Broadcasting.
FRONTLINE is made possible by contributions to your PBS station from viewers like you. Thank you.
posted november 25, 2003