Deciding on Drugs
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SUSAN DENTZER: In the space of just three days last week, two widely used drugs were withdrawn from the U.S. market following reports of dangerous and even deadly side effects. The first announcement came last Tuesday, when the drug company Parke Davis/Warner Lambert said it was withdrawing the drug Rezulin at the request of the federal Food and Drug Administration. The drug was approved for sale in 1997 as a treatment for so-called type-2 diabetes. Formerly known as adult-onset diabetes, the disease afflicts nearly 16 million Americans.
Rezulin was considered a breakthrough drug because it made diabetics’ bodies more sensitive to the hormone insulin; that enabled them to use the hormone effectively in the all important process of metabolism. Demand for prescriptions grew quickly, and an estimated 2 million people eventually used the drug. But just eight months after Rezulin was approved for sale, the FDA began receiving occasional reports of liver damage apparently caused by the drug; also reported were some sporadic deaths. A handful of critics, including at least one within the FDA, wanted the agency to withdraw Rezulin from the market immediately.
But the FDA declined after others, including the manufacturer, argued that vast numbers of people were using the drug successfully. As a result, they said, the benefits to millions outweighed the risks to a relative few. Pressure to withdraw the drug began to mount again last summer, after the FDA approved two new diabetes drugs that seemed safer and as effective as Rezulin. So last week the FDA asked Parke Davis to withdraw the drug and the company agreed. In total, the agency concluded, Rezulin had possibly or probably contributed to 90 cases of liver failure, leaving 63 dead, 20 patients alive but with serious liver damage, and seven who survived only after undergoing liver transplants.
The second withdrawal came on Friday, when the manufacturer of the anti-heartburn drug, Propulsid, announced that it, too, was removing its drug from the market. Approved in 1993, Propulsid attacks the condition known as gastro-esophageal reflux. That’s when a faulty valve at the entrance to the stomach allows the stomach’s contents to flow back up into the esophagus. That leads, in turn, to the symptom known as heartburn. Propulsid works by speeding the emptying of the stomach so there’s less to flow back. Tens of millions of Americans have taken the drug.
But just a year after its release, Propulsid was also linked to growing reports of abnormal heart rhythms in users of the drug, many of whom had more serious conditions than heartburn. Eventually the drug was implicated in 80 deaths. Last week, as the FDA contemplated proposals to ban the drug or sharply restrict its use, the manufacturer, Janssen Pharmaceuticals, announced it would take the drug off the market next July, after patients and doctors had time to switch to other medications.
GWEN IFILL: Joining us now are Raymond Woolsley, president of the American Society for Clinical Pharmacology and Therapeutics. He’s also a professor of pharmacology at Georgetown University; and Thomas Moore, a health policy analyst at George Washington University Medical Center. He is author of the book Prescription for Disaster: The Hidden Dangers in Your Medicine Cabinet. Mr. Moore, only a few years ago, the FDA was accused of moving much too slowly in approving drugs. Now it’s accused in some quarters of moving too quickly. Which is it?
THOMAS MOORE, George Washington University: I think it’s not simply fast or slow. It is what are the risks of the drugs that are being withdrawn. In the case of Rezulin in particular, it seemed that this drug from its early testing really had unacceptable risks and it just took us several years to get the drug off the market.
GWEN IFILL: But obviously there are far more people — there are people who swear by Rezulin, who said it really helped them, far many more of them than people who had adverse effects.
THOMAS MOORE: Well, that’s true but the problem here is we have safer alternatives. There were 11 other drugs for adult onset diabetes that were available that didn’t have these risks and weren’t as dangerous. And so why should we expose people to the possibility that the drug will destroy their liver when we have safer alternatives available?
GWEN IFILL: Dr. Woolsley, is it possible that drugs like Rezulin and Propulsid should never even have been on the market in the first place?
RAYMOND WOOLSLEY, Georgetown University: No, Gwen. I think the data were compelling and supported approval of these drugs. I think Tom is correct that there were alternatives available but there was a serious concern about the safety of those drugs. A lot of studies have shown that they may actually increase mortality. And there was a major push in the medical and drug development to find replacements for those drugs. I would quickly add though that it was known when the drug Rezulin went on the market that it could cause liver damage. The fear was that it could be a major problem and it turned out that it was a major problem.
Unfortunately, I don’t think the mistake was made in putting it on the market. I think the mistake has been that the FDA has not been given adequate resources that it’s asked for to monitor new drugs once they go on the market to get that data that they really need. They delayed taking this drug off the market or encouraging it to be taken off because they were concerned that the two replacements may be just as bad or perhaps even worse. And that’s because we don’t have mechanisms in the community to allow us to compare the relative effectiveness of drugs. It’s very clear, as you reported, that this drug had a major problem. We didn’t know the magnitude of it. That’s the big problem.
GWEN IFILL: And is the major problem, Mr. Moore, perhaps, is the major problem that people aren’t administering these drugs correctly or is the major problem that they’re being approved too quickly?
THOMAS MOORE: Well, in the case of Rezulin, I think I have a slightly different view of this than Ray Woolsley does. A year ago I sat in a meeting in which David Graham, the senior drug safety officer for the FDA, gave a presentation that showed this drug was much more dangerous than any other drug we had on the market. It was an excellent kind of safety analysis. But the FDA didn’t pay attention to him. Instead, they believed the company that argued the drug wasn’t so dangerous. It turned out that David Graham and the FDA’s experts were right and the company was wrong.
GWEN IFILL: Let’s take a step back, Dr. Woolsley. Is this a question of when you’re balancing risk and benefit and human lives are involved, how do you begin to do that?
RAYMOND WOOLSLEY: Well, you’d like to do that with data. And that’s been the problem. The FDA makes risk-benefit analyses all through the life of the drug, and when the drug is being developed, we have very good data on its relative safety and the risk-benefit within limits of the number of people that have been exposed. But once it goes on the market, that’s when we don’t have the adequate data to make those risk-benefit assessments. And they have to use very crude tools. The voluntary reporting system that they have had to rely upon is a good system. It picks up a signal and it will tell you very correctly if there is a problem with the drug, but it doesn’t tell you how big the problem is.
GWEN IFILL: But it sounds like you’re using the general population as guinea pigs in this process.
RAYMOND WOOLSLEY: That’s something the general population should alwaysm — the public needs to understand that these are chemicals. They’re being put on the market as prescription drugs because they are complex. They have known toxicities and they have unknown toxicities. And until a drug is used in hundreds of thousands of people, we will really never know whether it’s another Rezulin or another Propulsid. And that is something the public has to understand: That the FDA cannot protect them against those kinds of rare events.
GWEN IFILL: Buyer beware, Mr. Moore?
THOMAS MOORE: Well, I would just like to enlarge on an important point that he was making. The numbers we showed about deaths on the show in the lead-in, those were spontaneous, voluntary reports. Our post-market surveillance system is so weak today that we think that anywhere depending on the drug and the condition, anywhere between only 1 in 10 and 1 in 100 and in some cases for smaller adverse effects, 1 in 10,000 ever get reported to the FDA. So take every number you’ve heard on this show and multiply it by at least 10. That means that, for example, for Propulsid or for Rezulin thousands of people, thousands, not a dozen, not a hundred, but thousands suffered serious injuries. We don’t know how many thousands because we don’t have a good enough system.
GWEN IFILL: Well, let’s talk about Propulsid for a moment. Five times they changed the label so that doctors and patients could try to administer that better. But that still didn’t work and they still had to pull it off — the heart burn drug — they still had to pull it off the market. Was it worth the risk that we now saw to leave it on the market for something like heartburn that people can basically live with, as opposed to a heart medicine or a diabetic medicine, Doctor?
THOMAS MOORE: I believe that with five safer alternatives, this drug at best should have been restricted to only very serious cases while other drugs had been tried first. It shouldn’t have been the best seller with literally billion-dollar sales a year because in some people it caused cardiac arrest. No matter what your doctor did, in some people you couldn’t stop them from being killed.
GWEN IFILL: Dr. Woolsley.
RAYMOND WOOLSLEY: Well, I think that’s true. You would never accept this type of toxicity from a drug for heartburn but the FDA’S advisors and practicing physicians were telling them that it’s a very effective drug in people who failed to respond to other drugs and the pediatric community especially, premature babies often were given this drug. So they were being told that there is a need for the drug above and beyond the treatment of heartburn and that was, I think, a large basis for them to leave it on the market as long as they did. I think — I’ll go back and say Tom and I would agree on one thing. That is, that we need to find these problems much more quickly. We need to respond to them more quickly to save more lives. We need for Congress to give the FDA the resources that it’s asked for and needs to get these data more quickly — to save lives from these drugs with known side effects.
GWEN IFILL: As a patient and not an expert here, I assume when I hear know the FDA has approved a drug that it is safe. Is that not true?
THOMAS MOORE: No drug is safe. What the FDA has done has been to require very extensive testing, usually now in thousands of patients, to have its independent experts review that testing, and if the system is working right– and I don’t think it has been– to make a judgment that that drug has benefits that outweigh its risks. And we understand what those risks are. And my criticism of the FDA in recent time is there have been too many judgments that were wrong. Since 1997 there have been nine drugs withdrawn for safety reasons. And it’s hard to find another 4-year period in which there are more than two or three.
GWEN IFILL: So what’s your suggestion about how to fix this problem?
RAYMOND WOOLSLEY: Well, Gwen, I think Congress had a chance in 1997 and did make a major step forward in fixing this — and that is to invest in the community, to have academic medical centers working as centers for education and research on therapeutics — to actually be in the community, monitoring the way medicines are used, looking at the people, the patients that are actually receiving these drugs and giving the FDA feedback on their relative safety. Unfortunately, there are only four of these centers now created. And we need many more of those. We need for the community to be more educated on the appropriate use of medications, and we need for physicians to be given balance in the information they receive about medications. These centers could make a difference. I know that John Isenberg who is the head of Agency for Health Care Research on Quality is eager to increase these if, again, Congress will give them the budget to do so.
GWEN IFILL: Is it possible, Mr. Moore, that we just have to get used to the idea of acceptable risk?
THOMAS MOORE: Absolutely not. These drugs cause thousands of serious injuries when, in most cases, safer alternatives are readily available. The reason why we have a safety system is to eliminate preventable serious injuries and deaths. The safety wasn’t system wasn’t working and so we experienced thousands of them. And we need better policies to correct those. Now, Dr. Woolsley named a very good start. We do need to better work to get better information to patients and physicians about what drugs do and don’t do. But we also need a much stronger post-market surveillance system at the FDA And we need a new attitude. Something has gone wrong when the industry, when the FDA seems to be paying more attention to industry than to its own experts. And that needs to be addressed. That was the story of Rezulin.
GWEN IFILL: Final word, Dr. Woolsley. How does the FDA fix this, if it’s the FDA’s problem?
RAYMOND WOOLSLEY: Well it’s not an FDA problem entirely. I think it’s a public health problem. It’s a need for the community to recognize that these medications are dangerous. They can harm some people. There is a relative risk involved in every foreign chemical you put in your body. We need to invest — we need for Congress to give the FDA The resources that they need to make sure that we respond to the safety needs of these drugs.
GWEN IFILL: Ray Woolsley, Thomas Moore, thank you both very much.